A Phase 1 interventional study of PF-02341066 and Rifampin in Non-Small Cell Lung Cancer ALK-positive, Non-Small Cell Lung Cancer c-Met Dependent and Non-Small Cell Lung Cancer ROS Marker Positive, sponsored by Pfizer. Completed at 29 sites in 4 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2023-02-08.
Sponsored by Pfizer · Phase 1, Interventional, and Treatment
PF-02341066 may work in cancer by blocking the cell growth, migration and invasion of tumor cells. PF-02341066 is a new class of drugs called c-Met/Hepatocyte growth factor receptor tyrosine kinase inhibitors. This compound is also an inhibitor of the anaplastic lymphoma kinase (called ALK) tyrosine kinase and ROS receptor tyrosine kinases. This research study is the first time PF-02341066 will be given to people. PF-02341066 is taken by mouth daily.
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Drug: PF-02341066 · Drug: Rifampin · Drug: Itraconazole
Escalating doses of PF-02341066 will be administered orally on a continuous dosing schedule. Doses to be evaluated will range from 50 mg to 2000 mg/day administered either once or twice a day. A treatment cycle is considered to be 28 days (or 21 days depending on the cohort).
600 mg QD administered from Cycle 1, Day 16 to Cycle 2, Day 1 (14 days of dosing) in combination with PF-02341066.
Multiple Dose Design: 200 mg QD administered from Cycle 1, Day 1 to Cycle 1, Day 16 (16 days) in combination with PF-02341066.
Dose-Escalation Cohort: Maximum Tolerated Dose (MTD) of Crizotinib
MTD: Dose level at which at most 1 of 6 participants experienced DLT within and including 28 days of treatment (during Cycle 1 \[1 cycle=28 days\]) with next higher dose having at least 2/3 or 2/6 participants experiencing a DLT. DLT was defined as any of following: Hematologic toxicities- 1) prolonged grade 4 neutropenia for \>7 days. 2) Febrile neutropenia: grade 4 neutropenia with fever greater than (\>) 38.5 degree Celsius, both sustained over a 24 hour period (3) neutropenic infection: greater than or equal to (\>=) Grade 3 neutropenia with Grade \>=3 infection. (4) Grade \>=3 thrombocytopenia with bleeding/grade 4 lasting \>=7 days. Other non-hematologic toxicity included: Grade 3/4 toxicities (except for alopecia, Grade 3/4 hypophosphatemia, grade 3 hypertension with controlled blood pressure \[less than (\<) 140/90 millimeter of mercury, and Grade 3/4 hyperuricemia without signs and symptoms of gout). Nausea, vomiting/diarrhea must persist at grade 3/4 despite maximal medical therapy.
Time frame: Cycle 1 (28 days)
Dose-Escalation Cohort: Recommended Phase 2 Dose (RP2D) of Crizotinib
RP2D was defined as a dose below or equal to MTD, at which crizotinib was unlikely to cause a significant inhibition of CYP3A4 activity.
Time frame: Cycle 1 (28 days)
Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) of Crizotinib on Day -7
AUCinf = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) extrapolated to infinite time (0-inf).
Time frame: Pre-dose, 1, 2, 4, 6, 8, 9, 24, 48 and any two time points (72, 96, 120 and 144 hours) post-dose on Day -7
Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Crizotinib on Day -7
Area under the plasma concentration versus time curve from time 0 to end of dosing interval (AUCtau), where dosing interval is 12 hours for BID dose and 24 hours for QD dose.
Time frame: Pre-dose, 1, 2, 4, 6, 8, 9, 24, 48 and any two time points (72, 96, 120 and 144 hours) post-dose on Day -7
Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Crizotinib on Cycle 1 Day 1
Area under the plasma concentration versus time curve from time 0 to end of dosing interval (AUCtau), where dosing interval is 12 hours for BID dose and 24 hours for QD dose.
Time frame: Pre-dose, 2, 4 and 6 hours post dose on Cycle 1 Day 1
Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Crizotinib on Cycle 1 Day 15
Area under the plasma concentration versus time curve from time 0 to end of dosing interval (AUCtau), where dosing interval is 12 hours for BID dose and 24 hours for QD dose.
Time frame: Pre-dose, 1, 2, 4, 6, 8, 9 and 24 hours post dose on Cycle 1 Day 15
Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Crizotinib on Cycle 2 Day 1
Area under the plasma concentration versus time curve from time 0 to end of dosing interval (AUCtau), where dosing interval is 12 hours for BID dose and 24 hours for QD dose.
Time frame: Pre-dose, 1, 2, 4, 6, 8, 9 and 24 hours post dose on Cycle 2 Day 1
Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Trough Concentration (Ctrough) of Crizotinib Cycle 1 Day 15
Ctrough refers to plasma concentration of Crizotinib observed just before treatment administration.
Time frame: Pre-dose on Cycle 1 Day 15
Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Trough Concentration (Ctrough) of Crizotinib on Cycle 2 Day 1
Ctrough refers to plasma concentration of Crizotinib observed just before treatment administration.
Time frame: Pre-dose on Cycle 2 Day 1
Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Maximum Observed Plasma Concentration (Cmax) of Crizotinib on Day -7
Cmax is defined as the observed maximum plasma concentration post drug administration.
Time frame: Pre-dose, 1, 2, 4, 6, 8, 9, 24, 48 and any two time points (72, 96, 120 and 144 hours) post-dose on Day -7
Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Maximum Observed Plasma Concentration (Cmax) of Crizotinib on Cycle 1 Day 1
Cmax is defined as the observed maximum plasma concentration post drug administration.
Time frame: Pre-dose, 2, 4 and 6 hours post dose on Cycle 1 Day 1
Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Maximum Observed Plasma Concentration (Cmax) of Crizotinib on Cycle 1 Day 15
Cmax is defined as the observed maximum plasma concentration post drug administration.
Time frame: Pre-dose, 1, 2, 4, 6, 8, 9 and 24 hours post dose on Cycle 1 Day 15
Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Maximum Observed Plasma Concentration (Cmax) of Crizotinib on Cycle 2 Day 1
Cmax is defined as the observed maximum plasma concentration post drug administration.
Time frame: Pre-dose, 1, 2, 4, 6, 8, 9 and 24 hours post dose on Cycle 2 Day 1
Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Crizotinib on Day -7
Tmax was defined as the time to reach the observed maximum plasma concentration (Cmax).
Time frame: Pre-dose, 1, 2, 4, 6, 8, 9, 24, 48 and any two time points (72, 96, 120 and 144 hours) post-dose on Day -7
Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Crizotinib on Cycle 1 Day 1
Tmax was defined as the time to reach the observed maximum plasma concentration (Cmax).
Time frame: Pre-dose, 2, 4 and 6 hours post dose on Cycle 1 Day 1
Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Crizotinib on Cycle 1 Day 15
Tmax was defined as the time to reach the observed maximum plasma concentration (Cmax).
Time frame: Pre-dose, 1, 2, 4, 6, 8, 9 and 24 hours post dose on Cycle 1 Day 15
Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Crizotinib Cycle 2 Day 1
Tmax was defined as the time to reach the observed maximum plasma concentration (Cmax).
Time frame: Pre-dose, 1, 2, 4, 6, 8, 9 and 24 hours post dose on Cycle 2 Day 1
Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Plasma Decay Half-Life (t1/2) of Crizotinib on Day -7
Plasma decay half-life is the time measured for the plasma concentration of Crizotinib to decrease by one half.
Time frame: Pre-dose, 1, 2, 4, 6, 8, 9, 24, 48 and any two time points (72, 96, 120 and 144 hours) post-dose on Day -7
Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Number of Participants With Treatment Emergent Adverse Events (TEAES) and Serious Adverse Events (SAEs)
An AE was any untoward medical occurrence in a participant who received investigational product without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; medically important events. AEs included both serious and all non-serious adverse events. TEAEs were those with initial onset or increasing in severity on or after the first dose of investigational product administration.
Time frame: up to 189 Months
Dose-Escalation Cohort: Number of Participants With Dose-limiting Toxicities (DLT)
Dose-limiting toxicity (DLT) was defined as any of the following: Hematologic- prolonged grade 4 neutropenia for \>7 days. Febrile neutropenia, defined as grade 4 neutropenia with fever greater than (\>)38.5 degree Celsius, both sustained over a 24 hour period, neutropenic infection: greater than or equal to (\>=)Grade 3 neutropenia with Grade \>=3 infection. Grade \>=3 thrombocytopenia with bleeding or grade 4 lasting \>=7 days Lymphopenia was not considered a DLT unless accompanied by infection. Other non-hematologic toxicity: Grade 3 or 4 toxicities (except for alopecia, Grade 3/4 hypophosphatemia, grade 3 hypertension with controlled blood pressure \[less than (\<) 140/90\], and Grade 3/4 hyperuricemia without signs and symptoms of gout). Nausea, vomiting or diarrhea must persist at grade 3 or 4 despite maximal medical therapy.
Time frame: Cycle 1 (28 days)
Midazolam Interaction Cohort: Maximum Observed Plasma Concentration (Cmax) of Midazolam When Taken Alone or Taken With Crizotinib
Cmax is defined as the observed maximum plasma concentration post drug administration.
Time frame: pre-dose, 0.5, 1, 2, 4, 6, 8, 9, and 24 hours post dose on Day -7 (midazolam alone arm), pre-dose, 0.5, 1, 2, 4, 6, 8, 9, and 24 hours post dose on Cycle 2 Day 1 (midazolam with crizotinib arm)
Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) of Midazolam When Taken Alone or Taken With Crizotinib
AUCinf = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf).
Time frame: pre-dose, 0.5, 1, 2, 4, 6, 8, 9, and 24 hours post dose on Day -7 (midazolam alone arm), pre-dose, 0.5, 1, 2, 4, 6, 8, 9, and 24 hours post dose on Cycle 2 Day 1 (midazolam with crizotinib arm)
RP2D Cohort: Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-24)] of Crizotinib When Taken With Food
AUC0-24 of Crizotinib was defined as the area under the free plasma concentration time curve from time 0 to 24 hours post-dose.
Time frame: pre-dose, 1, 2, 4, 6, 8, 9, and 24 hours post-dose on Day -7
RP2D Cohort: Maximum Observed Plasma Concentration (Cmax) of Crizotinib When Taken With Food
Cmax is defined as the observed maximum plasma concentration post drug administration.
Time frame: pre-dose, 1, 2, 4, 6, 8, 9, and 24 hours post-dose on Day -7
Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Crizotinib Alone and When Taken With Rifampin
Area under the plasma concentration versus time curve from time 0 to end of dosing interval (AUCtau).
Time frame: pre-dose, 2, 4, 6, 8 and 10 hours on Cycle 1 Day 15 (Crizotinib alone arm) and Cycle 2 Day 1 (Crizotinib with Rifampin arm)
Rifampin Cohort: Maximum Observed Plasma Concentration (Cmax) of Crizotinib Alone and When Taken With Rifampin
Time frame: pre-dose, 2, 4, 6, 8 and 10 hours on Cycle 1 Day 15 (Crizotinib alone) and Cycle 2 Day 1 (Crizotinib with Rifampin)
Rifampin Cohort: Ctrough of Crizotinib Alone and When Taken With Rifampin
Ctrough refers to plasma concentration of Crizotinib observed just before treatment administration.
Time frame: pre-dose on Cycle 1 Day 15 (Crizotinib alone arm) and Cycle 2 Day 1 (Crizotinib with Rifampin arm)
Itraconazole Cohort: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Crizotinib When Taken Alone and When Taken With Itraconazole
Area under the plasma concentration versus time curve from time 0 to end of dosing interval (AUCtau), where dosing interval is 24 hours.
Time frame: pre-dose, 1, 2, 4, 6, 8, 9 and 24 hours post dose on Cycle 1 Day 15 (Crizotinib with itraconazole) and Cycle 2 Day 1 (itraconazole alone)
Itraconazole Cohort: Maximum Observed Plasma Concentration (Cmax) of Crizotinib When Taken Alone and When Taken With Itraconazole
Time frame: pre-dose, 1, 2, 4, 6, 8, 9 and 24 hours post dose on Cycle 1 Day 15 (Crizotinib with itraconazole) and Cycle 2 Day 1 (itraconazole alone)
Itraconazole Cohort: Trough Plasma Concentration (Ctrough) of Crizotinib When Taken Alone and When Taken With Itraconazole
Ctrough refers to plasma concentration of Crizotinib observed just before treatment administration.
Time frame: pre-dose on Cycle 1 Day 15 (crizotinib with itraconazole) and Cycle 2 Day 1 (itraconazole alone)
Recommended Phase 2 Dose (RP2D) Cohort: Percentage of Participants With Objective Response (OR)
ORR was defined as participants with a best overall response of complete response (CR) or partial response (PR) divided by the total number of evaluable participants per RECIST version 1.0 (RECIST1.1 for ALK-negative NSCLC cohort 1 and ALK-negative NSCLC cohort 2). CR: Disappearance of all target and non-target lesions, normalization of tumor marker levels, and no appearance of new lesions indicated complete response. PR: At least a 30% decrease in the sum of the longest diameters of target lesions (taking as reference the baseline sum), without progression of non-target lesions and no appearance of new lesions indicated partial response.
Time frame: Baseline up to 172 months
Recommended Phase 2 Dose (RP2D) Cohort: Duration of Response (DOR)
Duration of response (DoR) was the time from first documentation of PR or CR to date of first documentation of progressive disease (PD) or death due to any cause. PR: At least a 30% decrease in the sum of the longest diameters of target lesions (taking as reference the baseline sum), without progression of non-target lesions and no appearance of new lesions indicated partial response. CR: Disappearance of all target and non-target lesions, normalization of tumor marker levels, and no appearance of new lesions indicated complete response. PD: \>=20% increase in the sum of the longest diameter of target lesions taking as references the smallest sum longest diameter recorded since the treatment started, unequivocal progression of existing non-target lesions, or the appearance of 1 or more new lesions.
Time frame: From first documentation of response to date of PD or death due to any cause (up to 172 months)
Recommended Phase 2 Dose (RP2D) Cohort: Time to Response (TTR)
TTR: time between first dose until first documented response of PR or CR. PR: At least a 30% decrease in the sum of the longest diameters of target lesions (taking as reference the baseline sum), without progression of non-target lesions and no appearance of new lesions indicated partial response. CR: Disappearance of all target and non-target lesions, normalization of tumor marker levels, and no appearance of new lesions indicated complete response.
Time frame: From first dose until first documented response of PR or CR (up to 172 months)
Recommended Phase 2 Dose (RP2D) Cohort: Percentage of Participants With Disease Control at Week 8
Disease control was defined as the percentage of participants with a confirmed CR, PR, or stable disease (SD) per RECIST version 1.0 (RECIST1.1 for ALK-negative NSCLC cohort 1 and ALK-negative NSCLC cohort 2). PR: At least a 30% decrease in the sum of the longest diameters of target lesions (taking as reference the baseline sum), without progression of non-target lesions and no appearance of new lesions indicated partial response. CR: Disappearance of all target and non-target lesions, normalization of tumor marker levels, and no appearance of new lesions indicated complete response. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Time frame: Week 8
Recommended Phase 2 Dose (RP2D) Cohort: Percentage of Participants With Disease Control at Week 16
Disease control was defined as the percentage of participants with a confirmed CR, PR, or stable disease (SD) per RECIST version 1.0 (RECIST1.1 for ALK-negative NSCLC cohort 1 and ALK-negative NSCLC cohort 2). PR: At least a 30% decrease in the sum of the longest diameters of target lesions (taking as reference the baseline sum), without progression of non-target lesions and no appearance of new lesions indicated partial response. CR: Disappearance of all target and non-target lesions, normalization of tumor marker levels, and no appearance of new lesions indicated complete response. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Time frame: Week 16
Recommended Phase 2 Dose (RP2D) Cohort: Progression Free Survival (PFS)
Progression free survival (PFS) was the time from randomization date to date of first documentation of PD or death due to any cause RECIST version 1.0 (RECIST1.1 for ALK-negative NSCLC cohort 1 and ALK-negative NSCLC cohort 2). PD: \>=20% increase in the sum of the longest diameter of target lesions taking as references the smallest sum longest diameter recorded since the treatment started, unequivocal progression of existing non-target lesions, or the appearance of 1 or more new lesions.
Time frame: From randomization until PD or death, whichever occurred first (up to 172 months)
Recommended Phase 2 Dose (RP2D) Cohort: Probability of Being Event Free at Month 6
Probability of being event free (event defined as PD or death due to any cause) at 6 months after the first dose of crizotinib was reported. PD: \>=20% increase in the sum of the longest diameter of target lesions taking as references the smallest sum longest diameter recorded since the treatment started, unequivocal progression of existing non-target lesions, or the appearance of 1 or more new lesions.
Time frame: From randomization to 6 months
Recommended Phase 2 Dose (RP2D) Cohort: Overall Survival (OS)
OS was defined as the time from randomization to death due to any cause.
Time frame: From randomization date to the date of death (up to 172 Months)
Probability of Participant Survival at Month 6
Probability of survival was defined as the probability of being alive at Month 6.
Time frame: Month 6
Probability of Participant Survival at Month 12
Probability of survival was defined as the probability of being alive at Month 12.
Time frame: Month 12
Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 1 Day 15
Geometric mean of ratio (Cycle1Day15/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts.
Time frame: Baseline, Cycle 1 Day 15
Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 2 Day 1
Geometric mean of ratio (Cycle 2 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts.
Time frame: Baseline, Cycle 2 Day 1
Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 4 Day 1
Geometric mean of ratio (Cycle 4 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts.
Time frame: Baseline, Cycle 4 Day 1
Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 6 Day 1
Geometric mean of ratio (Cycle 6 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts.
Time frame: Baseline, Cycle 6 Day 1
Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 9 Day 1
Geometric mean of ratio (Cycle 9 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts. 95% CI should be interpreted with cautions due to the limited sample size at this time point.
Time frame: Baseline, Cycle 9 Day 1
Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 12 Day 1
Geometric mean of ratio (Cycle 12 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts. 95% CI should be interpreted with cautions due to the limited sample size at this time point.
Time frame: Baseline, Cycle 12 Day 1
Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 15 Day 1
Geometric mean of ratio (Cycle 15 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts. 95% CI should be interpreted with cautions due to the limited sample size at this time point.
Time frame: Baseline, Cycle 15 Day 1
Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 18 Day 1
Geometric mean of ratio (Cycle 18 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts. 95% CI should be interpreted with cautions due to the limited sample size at this time point.
Time frame: Baseline, Cycle 18 Day 1
Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 21 Day 1
Geometric mean of ratio (Cycle 21 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts. 95% CI should be interpreted with cautions due to the limited sample size at this time point.
Time frame: Baseline, Cycle 21 Day 1
Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 24 Day 1
Geometric mean of ratio (Cycle 24 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts. 95% CI should be interpreted with cautions due to the limited sample size at this time point.
Time frame: Baseline, Cycle 24 Day 1
Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 27 Day 1
Geometric mean of ratio (Cycle 27 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts. 95% CI should be interpreted with cautions due to the limited sample size at this time point.
Time frame: Baseline, Cycle 27 Day 1
Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 30 Day 1
Geometric mean of ratio (Cycle 30 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts. 95% CI should be interpreted with cautions due to the limited sample size at this time point.
Time frame: Baseline, Cycle 30 Day 1
Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at End of Treatment
Geometric mean of ratio (End of treatment/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts. 95% CI should be interpreted with cautions due to the limited sample size at this time point.
Time frame: Baseline, End of Treatment (28 days post last dose)
| Milestone | Low Dose Escalation Cohort: Crizotinib 50 mg QD | Low Dose Escalation Cohort: Crizotinib 100 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg BID | Low Dose Escalation Cohort: Crizotinib 250 mg BID | Low Dose Escalation Cohort: Crizotinib 300 mg BID | High Dose Escalation Cohort: Crizotinib 300 mg QD | High Dose Escalation Cohort: Crizotinib 400 mg QD | High Dose Escalation Cohort: Crizotinib 500 mg QD | High Dose Escalation Cohort: Crizotinib 650 mg QD | High Dose Escalation Cohort: Crizotinib 800 mg QD | RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg | RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg | RP2D Cohort: MET Amplification NSCLC: Crizotinib 250 mg | RP2D Cohort: ALK-Negative Cohort 1, NSCLC: Crizotinib 250 mg | RP2D Cohort: ALK-Negative Cohort 2, NSCLC: Crizotinib 250 mg | RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg | RP2D Cohort: Enriched Other: Crizotinib 250 mg | RP2D Cohort: Itraconazole Interaction: Crizotinib 250 mg +Itraconazole | RP2D Cohort: Rifampin Interaction: Crizotinib 250 mg +Rifampin | RP2D Cohort: Midazolam Interaction: Crizotinib 250 mg +Midazolam |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Started | 3 | 4 | 9 | 7 | 9 | 6 | 7 | 5 | 3 | 6 | 11 | 53 | 85 | 41 | 48 | 19 | 154 | 67 | 21 | 18 | 14 |
| Treated | 3 | 4 | 8 | 7 | 8 | 6 | 6 | 5 | 3 | 6 | 9 | 53 | 85 | 41 | 48 | 18 | 154 | 66 | 18 | 18 | 12 |
| Completed | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Not completed | 3 | 4 | 9 | 7 | 9 | 6 | 7 | 5 | 3 | 6 | 11 | 53 | 85 | 41 | 48 | 19 | 154 | 67 | 21 | 18 | 14 |
| Withdrew: Adverse event | 0 | 0 | 0 | 0 | 2 | 1 | 0 | 1 | 0 | 0 | 3 | 0 | 8 | 6 | 4 | 1 | 14 | 9 | 2 | 3 | 1 |
| Withdrew: Progressive disease | 2 | 2 | 5 | 4 | 6 | 4 | 6 | 3 | 0 | 5 | 2 | 25 | 29 | 26 | 21 | 12 | 94 | 42 | 4 | 9 | 8 |
| Withdrew: Withdrawal by subject | 1 | 1 | 2 | 2 | 0 | 0 | 0 | 1 | 0 | 0 | 3 | 8 | 15 | 0 | 3 | 0 | 7 | 1 | 2 | 2 | 0 |
| Withdrew: Other | 0 | 1 | 1 | 1 | 0 | 1 | 0 | 0 | 2 | 1 | 0 | 19 | 24 | 7 | 11 | 3 | 28 | 12 | 10 | 4 | 2 |
| Withdrew: Randomized not treated | 0 | 0 | 1 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 3 | 0 | 2 |
| Withdrew: Death | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 1 | 7 | 2 | 8 | 2 | 11 | 0 | 0 | 0 | 1 |
| Withdrew: Lost to follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 2 | 0 | 0 | 0 |
| Withdrew: Site terminated by sponsor | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Withdrew: Withdrawn due to pregnancy | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
MTD: Dose level at which at most 1 of 6 participants experienced DLT within and including 28 days of treatment (during Cycle 1 \[1 cycle=28 days\]) with next higher dose having at least 2/3 or 2/6 participants experiencing a DLT. DLT was defined as any of following: Hematologic toxicities- 1) prolonged grade 4 neutropenia for \>7 days. 2) Febrile neutropenia: grade 4 neutropenia with fever greater than (\>) 38.5 degree Celsius, both sustained over a 24 hour period (3) neutropenic infection: greater than or equal to (\>=) Grade 3 neutropenia with Grade \>=3 infection. (4) Grade \>=3 thrombocytopenia with bleeding/grade 4 lasting \>=7 days. Other non-hematologic toxicity included: Grade 3/4 toxicities (except for alopecia, Grade 3/4 hypophosphatemia, grade 3 hypertension with controlled blood pressure \[less than (\<) 140/90 millimeter of mercury, and Grade 3/4 hyperuricemia without signs and symptoms of gout). Nausea, vomiting/diarrhea must persist at grade 3/4 despite maximal medical therapy.
| milligram | Low Dose Escalation Cohort: Crizotinib 50 mg QD | Low Dose Escalation Cohort: Crizotinib 100 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg BID | Low Dose Escalation Cohort: Crizotinib 250 mg BID | Low Dose Escalation Cohort: Crizotinib 300 mg BID | High Dose Escalation Cohort: Crizotinib 300 mg QD | High Dose Escalation Cohort: Crizotinib 400 mg QD | High Dose Escalation Cohort: Crizotinib 500 mg QD | High Dose Escalation Cohort: Crizotinib 650 mg QD | High Dose Escalation Cohort: Crizotinib 800 mg QD |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Dose-Escalation Cohort: Maximum Tolerated Dose (MTD) of Crizotinib | 250 | 250 | 250 | 250 | 250 | 250 | 250 | 250 | 250 | 250 | 250 |
RP2D was defined as a dose below or equal to MTD, at which crizotinib was unlikely to cause a significant inhibition of CYP3A4 activity.
| milligram | Low Dose Escalation Cohort: Crizotinib 50 mg QD | Low Dose Escalation Cohort: Crizotinib 100 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg BID | Low Dose Escalation Cohort: Crizotinib 250 mg BID | Low Dose Escalation Cohort: Crizotinib 300 mg BID | High Dose Escalation Cohort: Crizotinib 300 mg QD | High Dose Escalation Cohort: Crizotinib 400 mg QD | High Dose Escalation Cohort: Crizotinib 500 mg QD | High Dose Escalation Cohort: Crizotinib 650 mg QD | High Dose Escalation Cohort: Crizotinib 800 mg QD |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Dose-Escalation Cohort: Recommended Phase 2 Dose (RP2D) of Crizotinib | 250 | 250 | 250 | 250 | 250 | 250 | 250 | 250 | 250 | 250 | 250 |
AUCinf = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) extrapolated to infinite time (0-inf).
| nanogram*hour per milliliter | Low Dose Escalation Cohort: Crizotinib 50 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg BID | Low Dose Escalation Cohort: Crizotinib 250 mg BID | Low Dose Escalation Cohort: Crizotinib 300 mg BID | High Dose Escalation Cohort: Crizotinib 300 mg QD | High Dose Escalation Cohort: Crizotinib 400 mg QD | High Dose Escalation Cohort: Crizotinib 500 mg QD | High Dose Escalation Cohort: Crizotinib 650 mg QD | High Dose Escalation Cohort: Crizotinib 800 mg QD | RP2D Cohort: Crizotinib 250 mg |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) of Crizotinib on Day -7 | 274.43 ± 22 | 1378.05 ± 144 | 946.93 ± 38 | 1817.35 ± 34 | 2320.00 | 3457 ± 42 | 3078 ± 119 | 2107 ± 53 | 3979 ± 39 | 7547 ± 76 | 2489.39 ± 53 |
Area under the plasma concentration versus time curve from time 0 to end of dosing interval (AUCtau), where dosing interval is 12 hours for BID dose and 24 hours for QD dose.
| nanogram*hour per milliliter | Low Dose Escalation Cohort: Crizotinib 50 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg BID | Low Dose Escalation Cohort: Crizotinib 250 mg BID | Low Dose Escalation Cohort: Crizotinib 300 mg BID | High Dose Escalation Cohort: Crizotinib 300 mg QD | High Dose Escalation Cohort: Crizotinib 400 mg QD | High Dose Escalation Cohort: Crizotinib 500 mg QD | High Dose Escalation Cohort: Crizotinib 650 mg QD | High Dose Escalation Cohort: Crizotinib 800 mg QD | RP2D Cohort: Crizotinib 250 mg |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Crizotinib on Day -7 | 137.40 ± 8 | 658.64 ± 136 | 338.39 ± 50 | 558.01 ± 33 | 863.00 | 1731 ± 51 | 1377 ± 114 | 1300 ± 61 | 1906 ± 39 | 3423 ± 57 | 741.50 ± 45 |
Area under the plasma concentration versus time curve from time 0 to end of dosing interval (AUCtau), where dosing interval is 12 hours for BID dose and 24 hours for QD dose.
| nanogram*hour per milliliter | Low Dose Escalation Cohort: Crizotinib 100 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg BID | Low Dose Escalation Cohort: Crizotinib 300 mg BID | RP2D Cohort: Crizotinib 250 mg |
|---|---|---|---|---|
| Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Crizotinib on Cycle 1 Day 1 | 457.55 ± 32 | 383.98 ± 10 | 763.71 ± 57 | 663.39 ± 56 |
Area under the plasma concentration versus time curve from time 0 to end of dosing interval (AUCtau), where dosing interval is 12 hours for BID dose and 24 hours for QD dose.
| nanogram*hour per milliliter | Low Dose Escalation Cohort: Crizotinib 50 mg QD | Low Dose Escalation Cohort: Crizotinib 100 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg BID | Low Dose Escalation Cohort: Crizotinib 250 mg BID | Low Dose Escalation Cohort: Crizotinib 300 mg BID | High Dose Escalation Cohort: Crizotinib 300 mg QD | High Dose Escalation Cohort: Crizotinib 400 mg QD | High Dose Escalation Cohort: Crizotinib 500 mg QD | High Dose Escalation Cohort: Crizotinib 650 mg QD | High Dose Escalation Cohort: Crizotinib 800 mg QD | RP2D Cohort: Crizotinib 250 mg |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Crizotinib on Cycle 1 Day 15 | 206.13 ± 76 | 1086.99 ± 34 | 2047.13 ± 45 | 1780.21 ± 69 | 3083.93 ± 31 | 4066.67 ± 53 | 4375 ± 34 | 3385 ± 24 | 6655 ± 4 | 6362 ± 37 | 10480 ± 76 | 3879.56 ± 45 |
Area under the plasma concentration versus time curve from time 0 to end of dosing interval (AUCtau), where dosing interval is 12 hours for BID dose and 24 hours for QD dose.
| nanogram*hour per milliliter | Low Dose Escalation Cohort: Crizotinib 50 mg QD | Low Dose Escalation Cohort: Crizotinib 100 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg BID | Low Dose Escalation Cohort: Crizotinib 250 mg BID | Low Dose Escalation Cohort: Crizotinib 300 mg BID | High Dose Escalation Cohort: Crizotinib 300 mg QD | High Dose Escalation Cohort: Crizotinib 400 mg QD | High Dose Escalation Cohort: Crizotinib 500 mg QD | High Dose Escalation Cohort: Crizotinib 650 mg QD | High Dose Escalation Cohort: Crizotinib 800 mg QD | RP2D Cohort: Crizotinib 250 mg |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Crizotinib on Cycle 2 Day 1 | 425.90 ± 49 | 1595.58 ± 30 | 1719.30 ± 68 | 2255.70 ± 14 | 3054.45 ± 29 | 3644.72 ± 17 | 4815 ± 23 | 3839 ± 65 | 6330 ± 64 | 7273 ± 48 | 8733 ± 63 | 4163.77 ± 40 |
Ctrough refers to plasma concentration of Crizotinib observed just before treatment administration.
| nanogram per milliliter | Low Dose Escalation Cohort: Crizotinib 50 mg QD | Low Dose Escalation Cohort: Crizotinib 100 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg BID | Low Dose Escalation Cohort: Crizotinib 250 mg BID | Low Dose Escalation Cohort: Crizotinib 300 mg BID | RP2D Cohort: Crizotinib 250 mg |
|---|---|---|---|---|---|---|---|
| Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Trough Concentration (Ctrough) of Crizotinib Cycle 1 Day 15 | 7.29 ± 42 | 32.61 ± 36 | 48.18 ± 58 | 126.76 ± 97 | 232.59 ± 33 | 307.83 ± 59 | 280.43 ± 75 |
Ctrough refers to plasma concentration of Crizotinib observed just before treatment administration.
| nanogram per milliliter | Low Dose Escalation Cohort: Crizotinib 50 mg QD | Low Dose Escalation Cohort: Crizotinib 100 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg BID | Low Dose Escalation Cohort: Crizotinib 250 mg BID | Low Dose Escalation Cohort: Crizotinib 300 mg BID | RP2D Cohort: Crizotinib 250 mg |
|---|---|---|---|---|---|---|---|
| Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Trough Concentration (Ctrough) of Crizotinib on Cycle 2 Day 1 | 12.68 ± 94 | 31.91 ± 34 | 54.04 ± 85 | 157.24 ± 17 | 232.45 ± 32 | 329.50 ± 40 | 312.99 ± 55 |
Cmax is defined as the observed maximum plasma concentration post drug administration.
| nanogram per milliliter | Low Dose Escalation Cohort: Crizotinib 50 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg BID | Low Dose Escalation Cohort: Crizotinib 250 mg BID | Low Dose Escalation Cohort: Crizotinib 300 mg BID | High Dose Escalation Cohort: Crizotinib 300 mg QD | High Dose Escalation Cohort: Crizotinib 400 mg QD | High Dose Escalation Cohort: Crizotinib 500 mg QD | High Dose Escalation Cohort: Crizotinib 650 mg QD | High Dose Escalation Cohort: Crizotinib 800 mg QD | RP2D Cohort: Crizotinib 250 mg |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Maximum Observed Plasma Concentration (Cmax) of Crizotinib on Day -7 | 24.19 ± 36 | 67.64 ± 106 | 55.73 ± 45 | 87.02 ± 34 | 130.00 | 184.7 ± 65 | 115.9 ± 85 | 146.6 ± 31 | 154.3 ± 30 | 270.9 ± 47 | 108.40 ± 42 |
Cmax is defined as the observed maximum plasma concentration post drug administration.
| nanogram per milliliter | Low Dose Escalation Cohort: Crizotinib 100 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg BID | Low Dose Escalation Cohort: Crizotinib 300 mg BID | RP2D Cohort: Crizotinib 250 mg |
|---|---|---|---|---|
| Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Maximum Observed Plasma Concentration (Cmax) of Crizotinib on Cycle 1 Day 1 | 54.89 ± 53 | 64.14 ± 2 | 114.09 ± 48 | 98.86 ± 55 |
Cmax is defined as the observed maximum plasma concentration post drug administration.
| nanogram per milliliter | Low Dose Escalation Cohort: Crizotinib 50 mg QD | Low Dose Escalation Cohort: Crizotinib 100 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg BID | Low Dose Escalation Cohort: Crizotinib 250 mg BID | Low Dose Escalation Cohort: Crizotinib 300 mg BID | High Dose Escalation Cohort: Crizotinib 300 mg QD | High Dose Escalation Cohort: Crizotinib 400 mg QD | High Dose Escalation Cohort: Crizotinib 500 mg QD | High Dose Escalation Cohort: Crizotinib 650 mg QD | High Dose Escalation Cohort: Crizotinib 800 mg QD | RP2D Cohort: Crizotinib 250 mg |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Maximum Observed Plasma Concentration (Cmax) of Crizotinib on Cycle 1 Day 15 | 24.44 ± 68 | 85.66 ± 66 | 149.06 ± 29 | 188.84 ± 56 | 326.51 ± 24 | 420.15 ± 46 | 315.2 ± 50 | 215.5 ± 26 | 395.3 ± 16 | 379.2 ± 28 | 671.3 ± 76 | 411.11 ± 51 |
Cmax is defined as the observed maximum plasma concentration post drug administration.
| nanogram per milliliter | Low Dose Escalation Cohort: Crizotinib 50 mg QD | Low Dose Escalation Cohort: Crizotinib 100 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg BID | Low Dose Escalation Cohort: Crizotinib 250 mg BID | Low Dose Escalation Cohort: Crizotinib 300 mg BID | High Dose Escalation Cohort: Crizotinib 300 mg QD | High Dose Escalation Cohort: Crizotinib 400 mg QD | High Dose Escalation Cohort: Crizotinib 500 mg QD | High Dose Escalation Cohort: Crizotinib 650 mg QD | High Dose Escalation Cohort: Crizotinib 800 mg QD | RP2D Cohort: Crizotinib 250 mg |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Maximum Observed Plasma Concentration (Cmax) of Crizotinib on Cycle 2 Day 1 | 47.99 ± 23 | 133.69 ± 48 | 146.26 ± 38 | 238.84 ± 12 | 327.94 ± 25 | 474.68 ± 43 | 275.0 ± 28 | 248.2 ± 60 | 327.9 ± 47 | 419.8 ± 36 | 700.0 ± 37 | 477.85 ± 44 |
Tmax was defined as the time to reach the observed maximum plasma concentration (Cmax).
| hour | Low Dose Escalation Cohort: Crizotinib 50 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg BID | Low Dose Escalation Cohort: Crizotinib 250 mg BID | Low Dose Escalation Cohort: Crizotinib 300 mg BID | High Dose Escalation Cohort: Crizotinib 300 mg QD | High Dose Escalation Cohort: Crizotinib 400 mg QD | High Dose Escalation Cohort: Crizotinib 500 mg QD | High Dose Escalation Cohort: Crizotinib 650 mg QD | High Dose Escalation Cohort: Crizotinib 800 mg QD | RP2D Cohort: Crizotinib 250 mg |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Crizotinib on Day -7 | 2.00 (1.75 to 4.08) | 4.09 (1.08 to 6.00) | 4.00 (4.00 to 4.08) | 4.00 (1.00 to 8.95) | 2.02 (2.02 to 2.02) | 4.00 (2.00 to 6.00) | 2.15 (1.00 to 6.00) | 4.00 (2.00 to 8.00) | 4.00 (1.98 to 6.00) | 4.99 (2.15 to 6.13) | 4.00 (2.00 to 9.33) |
Tmax was defined as the time to reach the observed maximum plasma concentration (Cmax).
| hour | Low Dose Escalation Cohort: Crizotinib 100 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg BID | Low Dose Escalation Cohort: Crizotinib 300 mg BID | RP2D Cohort: Crizotinib 250 mg |
|---|---|---|---|---|
| Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Crizotinib on Cycle 1 Day 1 | 2.52 (1.00 to 4.02) | 4.00 (4.00 to 4.00) | 4.00 (2.05 to 8.02) | 4.05 (1.00 to 9.08) |
Tmax was defined as the time to reach the observed maximum plasma concentration (Cmax).
| hour | Low Dose Escalation Cohort: Crizotinib 50 mg QD | Low Dose Escalation Cohort: Crizotinib 100 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg BID | Low Dose Escalation Cohort: Crizotinib 250 mg BID | Low Dose Escalation Cohort: Crizotinib 300 mg BID | High Dose Escalation Cohort: Crizotinib 300 mg QD | High Dose Escalation Cohort: Crizotinib 400 mg QD | High Dose Escalation Cohort: Crizotinib 500 mg QD | High Dose Escalation Cohort: Crizotinib 650 mg QD | High Dose Escalation Cohort: Crizotinib 800 mg QD | RP2D Cohort: Crizotinib 250 mg |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Crizotinib on Cycle 1 Day 15 | 2.00 (1.00 to 4.00) | 2.51 (0.00 to 6.08) | 4.07 (1.00 to 6.00) | 5.01 (2.08 to 8.03) | 4.00 (0.97 to 6.07) | 4.99 (3.98 to 6.22) | 5.13 (1.93 to 7.88) | 5.17 (0.933 to 6.00) | 4.00 (4.00 to 9.00) | 5.98 (4.00 to 6.00) | 5.03 (4.00 to 6.03) | 4.00 (0.00 to 9.03) |
Tmax was defined as the time to reach the observed maximum plasma concentration (Cmax).
| hour | Low Dose Escalation Cohort: Crizotinib 50 mg QD | Low Dose Escalation Cohort: Crizotinib 100 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg BID | Low Dose Escalation Cohort: Crizotinib 250 mg BID | Low Dose Escalation Cohort: Crizotinib 300 mg BID | High Dose Escalation Cohort: Crizotinib 300 mg QD | High Dose Escalation Cohort: Crizotinib 400 mg QD | High Dose Escalation Cohort: Crizotinib 500 mg QD | High Dose Escalation Cohort: Crizotinib 650 mg QD | High Dose Escalation Cohort: Crizotinib 800 mg QD | RP2D Cohort: Crizotinib 250 mg |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Crizotinib Cycle 2 Day 1 | 1.02 (1.00 to 4.00) | 3.98 (2.00 to 4.02) | 4.00 (2.00 to 4.17) | 4.00 (3.95 to 4.00) | 4.00 (4.00 to 6.00) | 4.05 (3.98 to 9.00) | 3.00 (1.00 to 5.95) | 4.00 (2.08 to 6.00) | 7.59 (6.18 to 9.00) | 4.30 (4.00 to 9.00) | 5.00 (4.00 to 6.00) | 4.00 (0.00 to 9.02) |
Plasma decay half-life is the time measured for the plasma concentration of Crizotinib to decrease by one half.
| hour | Low Dose Escalation Cohort: Crizotinib 50 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg BID | Low Dose Escalation Cohort: Crizotinib 250 mg BID | Low Dose Escalation Cohort: Crizotinib 300 mg BID | High Dose Escalation Cohort: Crizotinib 300 mg QD | High Dose Escalation Cohort: Crizotinib 400 mg QD | High Dose Escalation Cohort: Crizotinib 500 mg QD | High Dose Escalation Cohort: Crizotinib 650 mg QD | High Dose Escalation Cohort: Crizotinib 800 mg QD | RP2D Cohort: Crizotinib 250 mg |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Plasma Decay Half-Life (t1/2) of Crizotinib on Day -7 | 48.20 (45.50 to 56.80) | 46.70 (30.40 to 67.20) | 52.60 (51.70 to 53.50) | 47.35 (36.80 to 57.70) | 45.70 (45.70 to 45.70) | 43.33 (35.4 to 52.3) | 49.06 (33.2 to 79.3) | 46.36 (43.0 to 49.8) | 42.17 (28.3 to 53.8) | 38.78 (30.9 to 55.3) | 43.20 (27.10 to 63.40) |
An AE was any untoward medical occurrence in a participant who received investigational product without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; medically important events. AEs included both serious and all non-serious adverse events. TEAEs were those with initial onset or increasing in severity on or after the first dose of investigational product administration.
| Participants | Low Dose Escalation Cohort: Crizotinib 50 mg QD | Low Dose Escalation Cohort: Crizotinib 100 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg BID | Low Dose Escalation Cohort: Crizotinib 250 mg BID | Low Dose Escalation Cohort: Crizotinib 300 mg BID | High Dose Escalation Cohort: Crizotinib 300 mg QD | High Dose Escalation Cohort: Crizotinib 400 mg QD | High Dose Escalation Cohort: Crizotinib 500 mg QD | High Dose Escalation Cohort: Crizotinib 650 mg QD | High Dose Escalation Cohort: Crizotinib 800 mg QD | RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 | RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg | RP2D Cohort: MET Amplification NSCLC: Crizotinib 250 mg | RP2D Cohort: ALK-Negative Cohort 1, NSCLC: Crizotinib 250 mg | RP2D Cohort: ALK-Negative Cohort 2, NSCLC: Crizotinib 250 mg | RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg | RP2D Cohort: Enriched Other: Crizotinib 250 mg | RP2D Cohort: Itraconazole Interaction: Crizotinib 250 mg +Itraconazole | RP2D Cohort: Rifampin Interaction: Crizotinib 250 mg +Rifampin | RP2D Cohort: Midazolam Interaction: Crizotinib 250 mg +Midazolam |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| AEs | 3 | 4 | 8 | 7 | 8 | 6 | 6 | 4 | 3 | 6 | 9 | 53 | 85 | 41 | 47 | 18 | 154 | 66 | 18 | 18 | 12 |
| SAEs | 0 | 0 | 1 | 2 | 4 | 2 | 2 | 2 | 1 | 2 | 4 | 24 | 54 | 25 | 22 | 9 | 75 | 29 | 7 | 6 | 6 |
Dose-limiting toxicity (DLT) was defined as any of the following: Hematologic- prolonged grade 4 neutropenia for \>7 days. Febrile neutropenia, defined as grade 4 neutropenia with fever greater than (\>)38.5 degree Celsius, both sustained over a 24 hour period, neutropenic infection: greater than or equal to (\>=)Grade 3 neutropenia with Grade \>=3 infection. Grade \>=3 thrombocytopenia with bleeding or grade 4 lasting \>=7 days Lymphopenia was not considered a DLT unless accompanied by infection. Other non-hematologic toxicity: Grade 3 or 4 toxicities (except for alopecia, Grade 3/4 hypophosphatemia, grade 3 hypertension with controlled blood pressure \[less than (\<) 140/90\], and Grade 3/4 hyperuricemia without signs and symptoms of gout). Nausea, vomiting or diarrhea must persist at grade 3 or 4 despite maximal medical therapy.
| Participants | Low Dose Escalation Cohort: Crizotinib 50 mg QD | Low Dose Escalation Cohort: Crizotinib 100 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg BID | Low Dose Escalation Cohort: Crizotinib 250 mg BID | Low Dose Escalation Cohort: Crizotinib 300 mg BID | High Dose Escalation Cohort: Crizotinib 300 mg QD | High Dose Escalation Cohort: Crizotinib 400 mg QD | High Dose Escalation Cohort: Crizotinib 500 mg QD | High Dose Escalation Cohort: Crizotinib 650 mg QD | High Dose Escalation Cohort: Crizotinib 800 mg QD |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Dose-Escalation Cohort: Number of Participants With Dose-limiting Toxicities (DLT) | 0 | 0 | 1 | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 |
Cmax is defined as the observed maximum plasma concentration post drug administration.
| nanogram per milliliter | Low Dose Escalation Cohort: Crizotinib 100 mg QD (Midazolam Alone) | Low Dose Escalation Cohort: Crizotinib 100 mg QD + Midazolam | Low Dose Escalation Cohort: Crizotinib 300 mg BID (Midazolam Alone) | Low Dose Escalation Cohort: Crizotinib 300 mg BID + Midazolam | RP2D Cohort: Crizotinib 250 mg (Midazolam Alone) | RP2D Cohort: Crizotinib 250 mg + Midazolam |
|---|---|---|---|---|---|---|
| Midazolam Interaction Cohort: Maximum Observed Plasma Concentration (Cmax) of Midazolam When Taken Alone or Taken With Crizotinib | 14.98 ± 19 | 19.26 ± 38 | 13.65 ± 10 | 32.62 ± 40 | 12.78 ± 41 | 25.37 ± 67 |
AUCinf = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf).
| nanogram*hour per milliliter | Low Dose Escalation Cohort: Crizotinib 100 mg QD (Midazolam Alone) | Low Dose Escalation Cohort: Crizotinib 100 mg QD + Midazolam | Low Dose Escalation Cohort: Crizotinib 300 mg BID (Midazolam Alone) | Low Dose Escalation Cohort: Crizotinib 300 mg BID + Midazolam | RP2D Cohort: Crizotinib 250 mg (Midazolam Alone) | RP2D Cohort: Crizotinib 250 mg +Midazolam |
|---|---|---|---|---|---|---|
| Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) of Midazolam When Taken Alone or Taken With Crizotinib | 41.77 ± 27 | 90.78 ± 33 | 37.71 ± 38 | 151.45 ± 31 | 32.10 ± 36 | 112.78 ± 87 |
AUC0-24 of Crizotinib was defined as the area under the free plasma concentration time curve from time 0 to 24 hours post-dose.
| nanogram*hour per milliliter | RP2D Cohort: Crizotinib 250 mg With Food |
|---|---|
| RP2D Cohort: Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-24)] of Crizotinib When Taken With Food | 1212.86 ± 46 |
Cmax is defined as the observed maximum plasma concentration post drug administration.
| nanogram per milliliter | RP2D Cohort: Crizotinib 250 mg With Food |
|---|---|
| RP2D Cohort: Maximum Observed Plasma Concentration (Cmax) of Crizotinib When Taken With Food | 106.24 ± 51 |
Area under the plasma concentration versus time curve from time 0 to end of dosing interval (AUCtau).
| nanogram*hour per milliliter | RP2D Cohort: Rifampin Interaction: Crizotinib 250 mg Alone | RP2D Cohort: Rifampin Interaction: Crizotinib 250 mg With Rifampin |
|---|---|---|
| Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Crizotinib Alone and When Taken With Rifampin | 3110 ± 49 | 509.6 ± 35 |
| nanogram per milliliter | RP2D Cohort: Rifampin Interaction: Crizotinib 250 mg Alone | RP2D Cohort: Rifampin Interaction: Crizotinib 250 mg With Rifampin |
|---|---|---|
| Rifampin Cohort: Maximum Observed Plasma Concentration (Cmax) of Crizotinib Alone and When Taken With Rifampin | 326.4 ± 48 | 71.53 ± 49 |
Ctrough refers to plasma concentration of Crizotinib observed just before treatment administration.
| nanogram per milliliter | RP2D Cohort: Rifampin Interaction: Crizotinib 250 mg Alone | RP2D Cohort: Rifampin Interaction: Crizotinib 250 mg With Rifampin |
|---|---|---|
| Rifampin Cohort: Ctrough of Crizotinib Alone and When Taken With Rifampin | 251.7 ± 46 | 26.67 ± 50 |
Area under the plasma concentration versus time curve from time 0 to end of dosing interval (AUCtau), where dosing interval is 24 hours.
| nanogram*hour per milliliter | RP2D Cohort: Itraconazole Interaction: Crizotinib 250 mg Alone | Itraconazole Interaction Cohort: Crizotinib 250 mg + Itraconazole |
|---|---|---|
| Itraconazole Cohort: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Crizotinib When Taken Alone and When Taken With Itraconazole | 4102 ± 31 | 6665 ± 16 |
| nanogram per milliliter | RP2D Cohort: Itraconazole Interaction: Crizotinib 250 mg Alone | RP2D Cohort: Itraconazole Interaction: Crizotinib 250 mg With Itraconazole |
|---|---|---|
| Itraconazole Cohort: Maximum Observed Plasma Concentration (Cmax) of Crizotinib When Taken Alone and When Taken With Itraconazole | 259.9 ± 23 | 353.2 ± 14 |
Ctrough refers to plasma concentration of Crizotinib observed just before treatment administration.
| nanogram per milliliter | RP2D Cohort: Itraconazole Interaction: Crizotinib 250 mg Alone | RP2D Cohort: Itraconazole Interaction: Crizotinib 250 mg With Itraconazole |
|---|---|---|
| Itraconazole Cohort: Trough Plasma Concentration (Ctrough) of Crizotinib When Taken Alone and When Taken With Itraconazole | 136.0 ± 36 | 214.0 ± 30 |
ORR was defined as participants with a best overall response of complete response (CR) or partial response (PR) divided by the total number of evaluable participants per RECIST version 1.0 (RECIST1.1 for ALK-negative NSCLC cohort 1 and ALK-negative NSCLC cohort 2). CR: Disappearance of all target and non-target lesions, normalization of tumor marker levels, and no appearance of new lesions indicated complete response. PR: At least a 30% decrease in the sum of the longest diameters of target lesions (taking as reference the baseline sum), without progression of non-target lesions and no appearance of new lesions indicated partial response.
| percentage of participants | RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg | RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg | RP2D Cohort: MET Amplification NSCLC: Crizotinib 250 mg | RP2D Cohort: ALK-Negative Cohort 2, NSCLC: Crizotinib 250 mg | RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg | RP2D Cohort: Enriched Other: Crizotinib 250 mg |
|---|---|---|---|---|---|---|
| Recommended Phase 2 Dose (RP2D) Cohort: Percentage of Participants With Objective Response (OR) | 71.7 (57.7 to 83.2) | 32.3 (21.2 to 45.1) | 31.6 (17.5 to 48.7) | 19.0 (5.4 to 41.9) | 61.2 (51.7 to 70.1) | 8.3 (0.2 to 38.5) |
Duration of response (DoR) was the time from first documentation of PR or CR to date of first documentation of progressive disease (PD) or death due to any cause. PR: At least a 30% decrease in the sum of the longest diameters of target lesions (taking as reference the baseline sum), without progression of non-target lesions and no appearance of new lesions indicated partial response. CR: Disappearance of all target and non-target lesions, normalization of tumor marker levels, and no appearance of new lesions indicated complete response. PD: \>=20% increase in the sum of the longest diameter of target lesions taking as references the smallest sum longest diameter recorded since the treatment started, unequivocal progression of existing non-target lesions, or the appearance of 1 or more new lesions.
| Weeks | RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg | RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg | RP2D Cohort: MET Amplification NSCLC: Crizotinib 250 mg | RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg |
|---|---|---|---|---|
| Recommended Phase 2 Dose (RP2D) Cohort: Duration of Response (DOR) | 14.5 (2.8 to 45.4) | 6.8 (2.8 to 13.4) | 5.2 (3.8 to 12.2) | 26.2 (8.1 to 72.9) |
TTR: time between first dose until first documented response of PR or CR. PR: At least a 30% decrease in the sum of the longest diameters of target lesions (taking as reference the baseline sum), without progression of non-target lesions and no appearance of new lesions indicated partial response. CR: Disappearance of all target and non-target lesions, normalization of tumor marker levels, and no appearance of new lesions indicated complete response.
| Weeks | RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg | RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg | RP2D Cohort: MET Amplification NSCLC: Crizotinib 250 mg | RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg |
|---|---|---|---|---|
| Recommended Phase 2 Dose (RP2D) Cohort: Time to Response (TTR) | 7.9 (4.3 to 103.6) | 7.6 (3.7 to 47.3) | 8.0 (7.1 to 23.6) | 7.7 (4.3 to 39.6) |
Disease control was defined as the percentage of participants with a confirmed CR, PR, or stable disease (SD) per RECIST version 1.0 (RECIST1.1 for ALK-negative NSCLC cohort 1 and ALK-negative NSCLC cohort 2). PR: At least a 30% decrease in the sum of the longest diameters of target lesions (taking as reference the baseline sum), without progression of non-target lesions and no appearance of new lesions indicated partial response. CR: Disappearance of all target and non-target lesions, normalization of tumor marker levels, and no appearance of new lesions indicated complete response. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
| percentage of participants | RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg | RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg | RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg | RP2D Cohort: ALK-Negative Cohort 2, NSCLC: Crizotinib 250 mg |
|---|---|---|---|---|
| Recommended Phase 2 Dose (RP2D) Cohort: Percentage of Participants With Disease Control at Week 8 | 86.8 (74.7 to 94.5) | 71.8 (61.0 to 81.0) | 79.3 (70.8 to 86.3) | 47.6 (25.7 to 70.2) |
Disease control was defined as the percentage of participants with a confirmed CR, PR, or stable disease (SD) per RECIST version 1.0 (RECIST1.1 for ALK-negative NSCLC cohort 1 and ALK-negative NSCLC cohort 2). PR: At least a 30% decrease in the sum of the longest diameters of target lesions (taking as reference the baseline sum), without progression of non-target lesions and no appearance of new lesions indicated partial response. CR: Disappearance of all target and non-target lesions, normalization of tumor marker levels, and no appearance of new lesions indicated complete response. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
| percentage of participants | RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg | RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg | RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg | RP2D Cohort: ALK-Negative Cohort 2, NSCLC: Crizotinib 250 mg |
|---|---|---|---|---|
| Recommended Phase 2 Dose (RP2D) Cohort: Percentage of Participants With Disease Control at Week 16 | 79.2 (65.9 to 89.2) | 51.8 (40.7 to 62.7) | 67.2 (57.9 to 75.7) | 42.9 (21.8 to 66.0) |
Progression free survival (PFS) was the time from randomization date to date of first documentation of PD or death due to any cause RECIST version 1.0 (RECIST1.1 for ALK-negative NSCLC cohort 1 and ALK-negative NSCLC cohort 2). PD: \>=20% increase in the sum of the longest diameter of target lesions taking as references the smallest sum longest diameter recorded since the treatment started, unequivocal progression of existing non-target lesions, or the appearance of 1 or more new lesions.
| Months | RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg | RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg | RP2D Cohort: MET Amplification NSCLC: Crizotinib 250 mg | RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg |
|---|---|---|---|---|
| Recommended Phase 2 Dose (RP2D) Cohort: Progression Free Survival (PFS) | 19.3 (15.2 to 39.1) | 7.6 (5.6 to 9.1) | 4.0 (1.9 to 6.9) | 10.0 (8.2 to 14.7) |
Probability of being event free (event defined as PD or death due to any cause) at 6 months after the first dose of crizotinib was reported. PD: \>=20% increase in the sum of the longest diameter of target lesions taking as references the smallest sum longest diameter recorded since the treatment started, unequivocal progression of existing non-target lesions, or the appearance of 1 or more new lesions.
| Probability of being event-free | RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg | RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg | RP2D Cohort: MET Amplification NSCLC: Crizotinib 250 mg | RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg |
|---|---|---|---|---|
| Recommended Phase 2 Dose (RP2D) Cohort: Probability of Being Event Free at Month 6 | 76.9 (62.8 to 86.1) | 57.5 (45.3 to 68.0) | 39.0 (22.8 to 54.9) | 71.9 (61.8 to 79.7) |
OS was defined as the time from randomization to death due to any cause.
| Months | RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg | RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg | RP2D Cohort: MET Amplification NSCLC: Crizotinib 250 mg | RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg |
|---|---|---|---|---|
| Recommended Phase 2 Dose (RP2D) Cohort: Overall Survival (OS) | 51.4 (29.3 to NA) | 20.0 (13.2 to 25.7) | 10.1 (7.1 to 12.9) | NA (NA to NA) |
Probability of survival was defined as the probability of being alive at Month 6.
| Probability of participants survival | RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg | RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg | RP2D Cohort: MET Amplification NSCLC: Crizotinib 250 mg | RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg |
|---|---|---|---|---|
| Probability of Participant Survival at Month 6 | 90.5 (78.7 to 95.9) | 86.7 (77.3 to 92.4) | 67.8 (51.1 to 79.9) | 90.0 (82.7 to 94.4) |
Probability of survival was defined as the probability of being alive at Month 12.
| probability of participants survival | RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg | RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg | RP2D Cohort: MET Amplification NSCLC: Crizotinib 250 mg | RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg |
|---|---|---|---|---|
| Probability of Participant Survival at Month 12 | 78.8 (65.0 to 87.7) | 66.0 (54.0 to 75.5) | 37.1 (22.4 to 51.8) | 80.5 (70.9 to 87.2) |
Geometric mean of ratio (Cycle1Day15/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts.
| Ratio | RP2D Cohort: Crizotinib 250 mg |
|---|---|
| Testosterone | 0.46 (0.34 to 0.62) |
| Estradiol | 0.53 (0.42 to 0.66) |
| Prolactin | 1.19 (0.91 to 1.55) |
| Luteinizing Hormone (LH) Serum | 0.58 (0.47 to 0.73) |
| Follicle Stimulating Hormone | 0.77 (0.66 to 0.91) |
| Free Testosterone | 0.96 (0.66 to 1.40) |
| Sex Hormone Binding Globulin | 0.36 (0.32 to 0.41) |
| Dihydroepiandrosterone Sulfate | 0.97 (0.85 to 1.11) |
Geometric mean of ratio (Cycle 2 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts.
| Ratio | RP2D Cohort: Crizotinib 250 mg |
|---|---|
| Testosterone | 0.47 (0.38 to 0.58) |
| Estradiol | 0.72 (0.56 to 0.93) |
| Prolactin | 0.89 (0.71 to 1.12) |
| LH Serum | 0.42 (0.26 to 0.70) |
| Follicle Stimulating Hormone | 0.69 (0.48 to 1.00) |
| Free Testosterone | 1.31 (0.97 to 1.77) |
| Sex Hormone Binding Globulin | 0.24 (0.18 to 0.31) |
| Dihydroepiandrosterone Sulfate | 0.85 (0.75 to 0.96) |
Geometric mean of ratio (Cycle 4 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts.
| Ratio | RP2D Cohort: Crizotinib 250 mg |
|---|---|
| Testosterone | 0.48 (0.27 to 0.84) |
| Estradiol | 0.66 (0.49 to 0.89) |
| Prolactin | 0.84 (0.55 to 1.28) |
| LH Serum | 0.75 (0.57 to 1.00) |
| Follicle Stimulating Hormone | 0.88 (0.68 to 1.15) |
| Free Testosterone | 1.63 (0.88 to 3.01) |
| Sex Hormone Binding Globulin | 0.22 (0.18 to 0.28) |
| Dihydroepiandrosterone Sulfate | 0.81 (0.69 to 0.97) |
Geometric mean of ratio (Cycle 6 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts.
| Ratio | RP2D Cohort: Crizotinib 250 mg |
|---|---|
| Testosterone | 0.49 (0.24 to 1.01) |
| Estradiol | 0.75 (0.58 to 0.97) |
| Prolactin | 0.69 (0.48 to 1.00) |
| LH Serum | 0.78 (0.60 to 1.02) |
| Follicle Stimulating Hormone | 1.07 (0.78 to 1.46) |
| Free Testosterone | 1.71 (1.01 to 2.90) |
| Sex Hormone Binding Globulin | 0.25 (0.15 to 0.43) |
| Dihydroepiandrosterone Sulfate | 0.87 (0.68 to 1.12) |
Geometric mean of ratio (Cycle 9 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts. 95% CI should be interpreted with cautions due to the limited sample size at this time point.
| Ratio | RP2D Cohort: Crizotinib 250 mg |
|---|---|
| Testosterone | 0.38 (0.26 to 0.57) |
| Estradiol | 0.56 (0.49 to 0.65) |
| Prolactin | 1.19 (0.65 to 2.18) |
| LH Serum | 0.72 (0.56 to 0.93) |
| Follicle Stimulating Hormone | 0.83 (0.67 to 1.03) |
| Free Testosterone | 1.23 (1.08 to 1.40) |
| Sex Hormone Binding Globulin | 0.19 (0.09 to 0.39) |
| Dihydroepiandrosterone Sulfate | 0.72 (0.51 to 1.00) |
Geometric mean of ratio (Cycle 12 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts. 95% CI should be interpreted with cautions due to the limited sample size at this time point.
| Ratio | RP2D Cohort: Crizotinib 250 mg |
|---|---|
| Testosterone | 0.38 (0.14 to 1.04) |
| Estradiol | 0.66 (0.32 to 1.37) |
| Prolactin | 1.06 (0.72 to 1.57) |
| LH Serum | 0.88 (0.59 to 1.32) |
| Follicle Stimulating Hormone | 1.02 (0.63 to 1.65) |
| Free Testosterone | 1.39 (0.68 to 2.86) |
| Sex Hormone Binding Globulin | 0.23 (0.11 to 0.46) |
| Dihydroepiandrosterone Sulfate | 0.75 (0.42 to 1.34) |
Geometric mean of ratio (Cycle 15 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts. 95% CI should be interpreted with cautions due to the limited sample size at this time point.
| Ratio | RP2D Cohort: Crizotinib 250 mg |
|---|---|
| Testosterone | 0.49 (0.21 to 1.14) |
| Estradiol | 1.03 (0.47 to 2.25) |
| Prolactin | 1.32 (0.86 to 2.03) |
| LH Serum | 0.90 (0.56 to 1.45) |
| Follicle Stimulating Hormone | 0.81 (0.53 to 1.22) |
| Free Testosterone | 1.71 (0.57 to 5.13) |
| Sex Hormone Binding Globulin | 0.24 (0.12 to 0.49) |
| Dihydroepiandrosterone Sulfate | 0.76 (0.57 to 0.99) |
Geometric mean of ratio (Cycle 18 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts. 95% CI should be interpreted with cautions due to the limited sample size at this time point.
| Ratio | RP2D Cohort: Crizotinib 250 mg |
|---|---|
| Testosterone | 0.32 (0.22 to 0.48) |
| Estradiol | 0.55 (0.03 to 8.69) |
| Prolactin | 1.64 (1.12 to 2.39) |
| LH Serum | 0.69 (0.58 to 0.82) |
| Follicle Stimulating Hormone | 0.89 (0.53 to 1.47) |
| Free Testosterone | 1.10 (0.42 to 2.91) |
| Sex Hormone Binding Globulin | 0.18 (0.07 to 0.45) |
| Dihydroepiandrosterone Sulfate | 0.69 (0.20 to 2.35) |
Geometric mean of ratio (Cycle 21 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts. 95% CI should be interpreted with cautions due to the limited sample size at this time point.
| Ratio | RP2D Cohort: Crizotinib 250 mg |
|---|---|
| Testosterone | 0.23 (0.09 to 0.60) |
| Estradiol | 0.48 |
| Prolactin | 1.46 (0.62 to 3.41) |
| LH Serum | 0.53 (0.12 to 2.42) |
| Follicle Stimulating Hormone | 0.77 (0.44 to 1.33) |
| Free Testosterone | 1.23 (0.00 to 797.68) |
| Sex Hormone Binding Globulin | 0.15 (0.00 to 20.43) |
| Dihydroepiandrosterone Sulfate | 0.72 (0.09 to 5.76) |
Geometric mean of ratio (Cycle 24 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts. 95% CI should be interpreted with cautions due to the limited sample size at this time point.
| Ratio | RP2D Cohort: Crizotinib 250 mg |
|---|---|
| Testosterone | 0.39 (0.00 to 70772.27) |
| Estradiol | 0.70 (0.00 to 11581.59) |
| Prolactin | 1.13 (0.10 to 12.55) |
| LH Serum | 0.69 (0.09 to 5.23) |
| Follicle Stimulating Hormone | 0.53 (0.07 to 3.81) |
| Free Testosterone | 2.35 |
| Sex Hormone Binding Globulin | 0.20 (0.00 to 33217.86) |
| Dihydroepiandrosterone Sulfate | 0.90 (0.48 to 1.66) |
Geometric mean of ratio (Cycle 27 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts. 95% CI should be interpreted with cautions due to the limited sample size at this time point.
| Ratio | RP2D Cohort: Crizotinib 250 mg |
|---|---|
| Testosterone | 0.46 (0.00 to 61000.31) |
| Estradiol | 0.97 (0.00 to 9022.66) |
| Prolactin | 1.48 (0.11 to 20.69) |
| LH Serum | 0.70 (0.11 to 4.50) |
| Follicle Stimulating Hormone | 0.66 (0.06 to 7.53) |
| Free Testosterone | 1.86 (0.02 to 147.95) |
| Sex Hormone Binding Globulin | 0.24 (0.00 to 22059.61) |
| Dihydroepiandrosterone Sulfate | 0.95 (0.24 to 3.78) |
Geometric mean of ratio (Cycle 30 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts. 95% CI should be interpreted with cautions due to the limited sample size at this time point.
| Ratio | RP2D Cohort: Crizotinib 250 mg |
|---|---|
| Testosterone | 0.16 |
| Estradiol | 0.38 |
| Prolactin | 1.14 |
| LH Serum | 0.85 |
| Follicle Stimulating Hormone | 0.80 |
| Free Testosterone | 1.25 |
| Sex Hormone Binding Globulin | 0.09 |
| Dihydroepiandrosterone Sulfate | 0.71 |
Geometric mean of ratio (End of treatment/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts. 95% CI should be interpreted with cautions due to the limited sample size at this time point.
| Ratio | RP2D Cohort: Crizotinib 250 mg |
|---|---|
| Testosterone | 0.40 (0.08 to 2.08) |
| Estradiol | 0.66 (0.39 to 1.13) |
| Prolactin | 1.48 (0.49 to 4.50) |
| LH Serum | 0.52 (0.14 to 1.98) |
| Follicle Stimulating Hormone | 0.85 (0.26 to 2.72) |
| Free Testosterone | 0.62 (0.20 to 1.93) |
| Sex Hormone Binding Globulin | 0.64 (0.24 to 1.71) |
| Dihydroepiandrosterone Sulfate | 0.41 (0.21 to 0.78) |
Collected over Up to maximum of 189 months. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Low Dose Escalation Cohort: Crizotinib 50 mg QD | 0/3 (0%) | 0/3 (0%) | 3/3 (100%) |
| Low Dose Escalation Cohort: Crizotinib 100 mg QD | 0/4 (0%) | 0/4 (0%) | 4/4 (100%) |
| Low Dose Escalation Cohort: Crizotinib 200 mg QD | 0/8 (0%) | 1/8 (12.5%) | 8/8 (100%) |
| Low Dose Escalation Cohort: Crizotinib 200 mg BID | 0/7 (0%) | 2/7 (28.6%) | 7/7 (100%) |
| Low Dose Escalation Cohort: Crizotinib 250 mg BID | 0/8 (0%) | 4/8 (50%) | 8/8 (100%) |
| Low Dose Escalation Cohort: Crizotinib 300 mg BID | 0/6 (0%) | 2/6 (33.3%) | 6/6 (100%) |
| High Dose Escalation Cohort: Crizotinib 300 mg QD | 1/6 (16.7%) | 2/6 (33.3%) | 6/6 (100%) |
| High Dose Escalation Cohort: Crizotinib 400 mg QD | 0/5 (0%) | 2/5 (40%) | 4/5 (80%) |
| High Dose Escalation Cohort: Crizotinib 500 mg QD | 1/3 (33.3%) | 1/3 (33.3%) | 3/3 (100%) |
| High Dose Escalation Cohort: Crizotinib 650 mg QD | 1/6 (16.7%) | 2/6 (33.3%) | 6/6 (100%) |
| High Dose Escalation Cohort: Crizotinib 800 mg QD | 1/9 (11.1%) | 4/9 (44.4%) | 9/9 (100%) |
| RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg | 10/53 (18.9%) | 24/53 (45.3%) | 53/53 (100%) |
| RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg | 15/85 (17.6%) | 54/85 (63.5%) | 85/85 (100%) |
| RP2D Cohort: MET Amplification NSCLC: Crizotinib 250 mg | 8/41 (19.5%) | 25/41 (61%) | 41/41 (100%) |
| RP2D Cohort: ALK-Negative Cohort 1, NSCLC: Crizotinib 250 mg | 13/48 (27.1%) | 22/48 (45.8%) | 46/48 (95.8%) |
| RP2D Cohort: ALK-Negative Cohort 2, NSCLC: Crizotinib 250 mg | 9/18 (50%) | 9/18 (50%) | 18/18 (100%) |
| RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg | 25/154 (16.2%) | 75/154 (48.7%) | 154/154 (100%) |
| RP2D Cohort: Enriched Other: Crizotinib 250 mg | 15/66 (22.7%) | 29/66 (43.9%) | 66/66 (100%) |
| Itraconazole Interaction Sub-study: Crizotinib 250 mg | 0/18 (0%) | 7/18 (38.9%) | 18/18 (100%) |
| RP2D Cohort: Rifampin Interaction: Crizotinib 250 mg +Rifampin | 1/18 (5.6%) | 6/18 (33.3%) | 18/18 (100%) |
| Midazolam Interaction Cohort: Crizotinib 250 | 4/12 (33.3%) | 6/12 (50%) | 12/12 (100%) |
| Event | Low Dose Escalation Cohort: Crizotinib 50 mg QD | Low Dose Escalation Cohort: Crizotinib 100 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg BID | Low Dose Escalation Cohort: Crizotinib 250 mg BID | Low Dose Escalation Cohort: Crizotinib 300 mg BID | High Dose Escalation Cohort: Crizotinib 300 mg QD | High Dose Escalation Cohort: Crizotinib 400 mg QD | High Dose Escalation Cohort: Crizotinib 500 mg QD | High Dose Escalation Cohort: Crizotinib 650 mg QD | High Dose Escalation Cohort: Crizotinib 800 mg QD | RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg | RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg | RP2D Cohort: MET Amplification NSCLC: Crizotinib 250 mg | RP2D Cohort: ALK-Negative Cohort 1, NSCLC: Crizotinib 250 mg | RP2D Cohort: ALK-Negative Cohort 2, NSCLC: Crizotinib 250 mg | RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg | RP2D Cohort: Enriched Other: Crizotinib 250 mg | Itraconazole Interaction Sub-study: Crizotinib 250 mg | RP2D Cohort: Rifampin Interaction: Crizotinib 250 mg +Rifampin | Midazolam Interaction Cohort: Crizotinib 250 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Disease progressionGeneral disorders | 0/3 | 0/4 | 0/8 | 0/7 | 2/8 | 1/6 | 1/6 | 0/5 | 0/3 | 1/6 | 1/9 | 10/53 | 8/85 | 6/41 | 8/48 | 1/18 | 19/154 | 12/66 | 0/18 | 0/18 | 4/12 |
| Cardiac arrestCardiac disorders | 0/3 | 0/4 | 0/8 | 0/7 | 0/8 | 0/6 | 0/6 | 0/5 | 1/3 | 0/6 | 0/9 | 0/53 | 1/85 | 0/41 | 0/48 | 0/18 | 0/154 | 0/66 | 0/18 | 0/18 | 0/12 |
| Gastrointestinal necrosisGastrointestinal disorders | 0/3 | 0/4 | 0/8 | 0/7 | 0/8 | 0/6 | 0/6 | 0/5 | 1/3 | 0/6 | 0/9 | 0/53 | 0/85 | 0/41 | 0/48 | 0/18 | 0/154 | 0/66 | 0/18 | 0/18 | 0/12 |
| Intestinal obstructionGastrointestinal disorders | 0/3 | 0/4 | 0/8 | 0/7 | 0/8 | 0/6 | 0/6 | 0/5 | 1/3 | 0/6 | 0/9 | 0/53 | 0/85 | 0/41 | 0/48 | 0/18 | 0/154 | 0/66 | 0/18 | 1/18 | 0/12 |
| MegacolonGastrointestinal disorders | 0/3 | 0/4 | 0/8 | 0/7 | 0/8 | 0/6 | 0/6 | 0/5 | 1/3 | 0/6 | 0/9 | 0/53 | 0/85 | 0/41 | 0/48 | 0/18 | 0/154 | 0/66 | 0/18 | 0/18 | 0/12 |
| Hypoxic-ischaemic encephalopathyNervous system disorders | 0/3 | 0/4 | 0/8 | 0/7 | 0/8 | 0/6 | 0/6 | 0/5 | 1/3 | 0/6 | 0/9 | 0/53 | 0/85 | 0/41 | 0/48 | 0/18 | 0/154 | 0/66 | 0/18 | 0/18 | 0/12 |
| ConstipationGastrointestinal disorders | 0/3 | 0/4 | 0/8 | 0/7 | 0/8 | 0/6 | 0/6 | 1/5 | 0/3 | 0/6 | 0/9 | 0/53 | 1/85 | 1/41 | 0/48 | 0/18 | 3/154 | 0/66 | 0/18 | 0/18 | 0/12 |
| Cerebral haematomaNervous system disorders | 0/3 | 0/4 | 0/8 | 0/7 | 0/8 | 0/6 | 0/6 | 1/5 | 0/3 | 0/6 | 0/9 | 0/53 | 0/85 | 0/41 | 0/48 | 0/18 | 1/154 | 0/66 | 0/18 | 0/18 | 0/12 |
| Small intestinal obstructionGastrointestinal disorders | 0/3 | 0/4 | 1/8 | 0/7 | 0/8 | 0/6 | 0/6 | 0/5 | 0/3 | 1/6 | 0/9 | 0/53 | 0/85 | 0/41 | 0/48 | 0/18 | 0/154 | 1/66 | 0/18 | 0/18 | 0/12 |
| PyrexiaGeneral disorders | 0/3 | 0/4 | 0/8 | 0/7 | 0/8 | 0/6 | 1/6 | 0/5 | 0/3 | 0/6 | 0/9 | 0/53 | 4/85 | 1/41 | 0/48 | 0/18 | 2/154 | 1/66 | 0/18 | 0/18 | 1/12 |
| Event | Low Dose Escalation Cohort: Crizotinib 50 mg QD | Low Dose Escalation Cohort: Crizotinib 100 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg BID | Low Dose Escalation Cohort: Crizotinib 250 mg BID | Low Dose Escalation Cohort: Crizotinib 300 mg BID | High Dose Escalation Cohort: Crizotinib 300 mg QD | High Dose Escalation Cohort: Crizotinib 400 mg QD | High Dose Escalation Cohort: Crizotinib 500 mg QD | High Dose Escalation Cohort: Crizotinib 650 mg QD | High Dose Escalation Cohort: Crizotinib 800 mg QD | RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg | RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg | RP2D Cohort: MET Amplification NSCLC: Crizotinib 250 mg | RP2D Cohort: ALK-Negative Cohort 1, NSCLC: Crizotinib 250 mg | RP2D Cohort: ALK-Negative Cohort 2, NSCLC: Crizotinib 250 mg | RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg | RP2D Cohort: Enriched Other: Crizotinib 250 mg | Itraconazole Interaction Sub-study: Crizotinib 250 mg | RP2D Cohort: Rifampin Interaction: Crizotinib 250 mg +Rifampin | Midazolam Interaction Cohort: Crizotinib 250 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| NauseaGastrointestinal disorders | 1/3 | 3/4 | 6/8 | 3/7 | 3/8 | 3/6 | 2/6 | 1/5 | 3/3 | 3/6 | 5/9 | 33/53 | 49/85 | 14/41 | 20/48 | 10/18 | 97/154 | 41/66 | 10/18 | 12/18 | 7/12 |
| Visual impairmentEye disorders | 0/3 | 0/4 | 0/8 | 1/7 | 0/8 | 0/6 | 1/6 | 2/5 | 0/3 | 4/6 | 3/9 | 43/53 | 11/85 | 6/41 | 26/48 | 9/18 | 92/154 | 22/66 | 3/18 | 10/18 | 1/12 |
| PyrexiaGeneral disorders | 1/3 | 3/4 | 1/8 | 0/7 | 0/8 | 0/6 | 0/6 | 0/5 | 0/3 | 2/6 | 2/9 | 15/53 | 12/85 | 2/41 | 6/48 | 2/18 | 34/154 | 3/66 | 3/18 | 3/18 | 1/12 |
| ConstipationGastrointestinal disorders | 0/3 | 0/4 | 1/8 | 2/7 | 3/8 | 2/6 | 3/6 | 3/5 | 2/3 | 4/6 | 4/9 | 24/53 | 45/85 | 10/41 | 21/48 | 11/18 | 68/154 | 15/66 | 11/18 | 7/18 | 1/12 |
| DiarrhoeaGastrointestinal disorders | 2/3 | 0/4 | 2/8 | 1/7 | 1/8 | 1/6 | 1/6 | 1/5 | 0/3 | 3/6 | 2/9 | 25/53 | 50/85 | 17/41 | 17/48 | 5/18 | 93/154 | 32/66 | 7/18 | 7/18 | 4/12 |
| VomitingGastrointestinal disorders | 2/3 | 2/4 | 5/8 | 4/7 | 4/8 | 1/6 | 3/6 | 2/5 | 1/3 | 2/6 | 5/9 | 28/53 | 35/85 | 15/41 | 26/48 | 9/18 | 81/154 | 34/66 | 8/18 | 10/18 | 8/12 |
| FatigueGeneral disorders | 2/3 | 2/4 | 3/8 | 3/7 | 4/8 | 3/6 | 3/6 | 1/5 | 2/3 | 2/6 | 3/9 | 20/53 | 35/85 | 11/41 | 23/48 | 8/18 | 59/154 | 26/66 | 8/18 | 6/18 | 5/12 |
| Decreased appetiteMetabolism and nutrition disorders | 1/3 | 2/4 | 4/8 | 2/7 | 2/8 | 4/6 | 1/6 | 1/5 | 2/3 | 1/6 | 3/9 | 16/53 | 24/85 | 7/41 | 9/48 | 3/18 | 50/154 | 20/66 | 5/18 | 6/18 | 3/12 |
| DyspnoeaRespiratory, thoracic and mediastinal disorders | 2/3 | 0/4 | 0/8 | 2/7 | 0/8 | 3/6 | 2/6 | 0/5 | 0/3 | 0/6 | 1/9 | 12/53 | 27/85 | 10/41 | 11/48 | 4/18 | 34/154 | 14/66 | 8/18 | 1/18 | 1/12 |
| Oedema peripheralGeneral disorders | 0/3 | 0/4 | 0/8 | 2/7 | 1/8 | 0/6 | 2/6 | 1/5 | 0/3 | 2/6 | 0/9 | 27/53 | 49/85 | 14/41 | 15/48 | 4/18 | 69/154 | 18/66 | 3/18 | 5/18 | 1/12 |
Safety analysis (SA) set included all enrolled participants who received at least one dose of Crizotinib on Cycle 1 Day 1.
| Age, Customized(Participants) | Low Dose Escalation Cohort: Crizotinib 50 mg QD | Low Dose Escalation Cohort: Crizotinib 100 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg BID | Low Dose Escalation Cohort: Crizotinib 250 mg BID | Low Dose Escalation Cohort: Crizotinib 300 mg BID | High Dose Escalation Cohort: Crizotinib 300 mg QD | High Dose Escalation Cohort: Crizotinib 400 mg QD | High Dose Escalation Cohort: Crizotinib 500 mg QD | High Dose Escalation Cohort: Crizotinib 650 mg QD | High Dose Escalation Cohort: Crizotinib 800 mg QD | RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg | RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg | RP2D Cohort: MET Amplification NSCLC: Crizotinib 250 mg | RP2D Cohort: ALK-Negative Cohort 1, NSCLC: Crizotinib 250 mg | RP2D Cohort: ALK-Negative Cohort 2, NSCLC: Crizotinib 250 mg | RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg | RP2D Cohort: Enriched Other: Crizotinib 250 mg | RP2D Cohort: Itraconazole Interaction: Crizotinib 250 mg +Itraconazole | RP2D Cohort: Rifampin Interaction: Crizotinib 250 mg +Rifampin | RP2D Cohort: Midazolam Interaction: Crizotinib 250 mg +Midazolam | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| less than 65 years | 3 | 4 | 5 | 5 | 8 | 6 | 3 | 5 | 3 | 6 | 5 | 23 | 18 | 20 | 30 | 12 | 131 | 51 | 9 | 12 | 9 | 368 |
| greater than or equals to 65 years | 0 | 0 | 3 | 2 | 0 | 0 | 3 | 0 | 0 | 0 | 4 | 30 | 67 | 21 | 18 | 6 | 23 | 15 | 9 | 6 | 3 | 210 |
| Sex: Female, Male(Participants) | Low Dose Escalation Cohort: Crizotinib 50 mg QD | Low Dose Escalation Cohort: Crizotinib 100 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg BID | Low Dose Escalation Cohort: Crizotinib 250 mg BID | Low Dose Escalation Cohort: Crizotinib 300 mg BID | High Dose Escalation Cohort: Crizotinib 300 mg QD | High Dose Escalation Cohort: Crizotinib 400 mg QD | High Dose Escalation Cohort: Crizotinib 500 mg QD | High Dose Escalation Cohort: Crizotinib 650 mg QD | High Dose Escalation Cohort: Crizotinib 800 mg QD | RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg | RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg | RP2D Cohort: MET Amplification NSCLC: Crizotinib 250 mg | RP2D Cohort: ALK-Negative Cohort 1, NSCLC: Crizotinib 250 mg | RP2D Cohort: ALK-Negative Cohort 2, NSCLC: Crizotinib 250 mg | RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg | RP2D Cohort: Enriched Other: Crizotinib 250 mg | RP2D Cohort: Itraconazole Interaction: Crizotinib 250 mg +Itraconazole | RP2D Cohort: Rifampin Interaction: Crizotinib 250 mg +Rifampin | RP2D Cohort: Midazolam Interaction: Crizotinib 250 mg +Midazolam | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Female | 3 | 1 | 2 | 3 | 4 | 2 | 3 | 5 | 0 | 1 | 3 | 30 | 48 | 19 | 24 | 8 | 80 | 25 | 11 | 9 | 8 | 289 |
| Male | 0 | 3 | 6 | 4 | 4 | 4 | 3 | 0 | 3 | 5 | 6 | 23 | 37 | 22 | 24 | 10 | 74 | 41 | 7 | 9 | 4 | 289 |
| Race/Ethnicity, Customized(Participants) | Low Dose Escalation Cohort: Crizotinib 50 mg QD | Low Dose Escalation Cohort: Crizotinib 100 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg QD | Low Dose Escalation Cohort: Crizotinib 200 mg BID | Low Dose Escalation Cohort: Crizotinib 250 mg BID | Low Dose Escalation Cohort: Crizotinib 300 mg BID | High Dose Escalation Cohort: Crizotinib 300 mg QD | High Dose Escalation Cohort: Crizotinib 400 mg QD | High Dose Escalation Cohort: Crizotinib 500 mg QD | High Dose Escalation Cohort: Crizotinib 650 mg QD | High Dose Escalation Cohort: Crizotinib 800 mg QD | RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg | RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg | RP2D Cohort: MET Amplification NSCLC: Crizotinib 250 mg | RP2D Cohort: ALK-Negative Cohort 1, NSCLC: Crizotinib 250 mg | RP2D Cohort: ALK-Negative Cohort 2, NSCLC: Crizotinib 250 mg | RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg | RP2D Cohort: Enriched Other: Crizotinib 250 mg | RP2D Cohort: Itraconazole Interaction: Crizotinib 250 mg +Itraconazole | RP2D Cohort: Rifampin Interaction: Crizotinib 250 mg +Rifampin | RP2D Cohort: Midazolam Interaction: Crizotinib 250 mg +Midazolam | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| White | 2 | 3 | 7 | 6 | 8 | 6 | 6 | 4 | 2 | 5 | 8 | 30 | 60 | 38 | 35 | 11 | 98 | 49 | 13 | 16 | 11 | 418 |
| Black | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 2 | 2 | 2 | 1 | 3 | 5 | 4 | 3 | 2 | 0 | 27 |
| Asian | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 21 | 15 | 1 | 9 | 2 | 43 | 9 | 0 | 0 | 0 | 102 |
| Other | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 8 | 0 | 3 | 2 | 8 | 4 | 2 | 0 | 1 | 31 |
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