A Phase 1/2 interventional study of PF-05212384 and FOLFIRI regimen in Metastatic Colorectal Carcinoma, sponsored by Pfizer. Terminated at 39 sites in 3 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2016-08-18.
Sponsored by Pfizer · Phase 1/2, Interventional, and Treatment
This is a multicenter, open label Phase 1b/2 study in patients with metastatic colorectal carcinoma. The Phase 1b will identify the dose of the combination of PF-05212384 plus FOLFIRI. The randomized, two-arm Phase 2 portion will compare the efficacy and safety of PF-05212384 plus FOLFIRI to that of bevacizumab plus FOLFIRI.
The study population will consist of patients with mCRC previously treated with an oxaliplatin-based regimen in the first line setting or who have progressed within 6 months of the end of an adjuvant oxaliplatin-based regimen.
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This study's enrollment of 18 is below the median of 77 across 4,222 interventional studies indexed under Colorectal Neoplasms.
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Exclusion Criteria:
PF-05212384 plus FOLFIRI
Drug: PF-05212384 · Drug: FOLFIRI regimen
Bevacizumab plus FOLFIRI
Biological: Bevacizumab · Drug: FOLFIRI
PF-05212384 at the Recommended phase 2 dose (RP2D/MTD) weekly
The RP2D/MTD dose of FOLFIRI regimen every 2 weeks
5 mg/m\^2 every 2 weeks or 7.5 mg/m\^2 every 3 weeks
Full dose FOLFIRI regimen every 2 weeks
Percentage of Participants With Dose-Limiting Toxicities (DLTs) in First Cycle of Therapy
DLTs were classified according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 and defined as any of the following events judged to be attributed to the combination of PF-05212384 plus FOLFIRI: hematologic (febrile neutropenia or a sustained temperature \>=38 degrees Celcius for \>1 hour, grade \>=3 neutropenic infection, grade 3 thrombocytopenia with bleeding, grade 4 thrombocytopenia); non-hematologic (grade \>=2 pneumonitis, grade \>=3 toxicities, toxicities which resulted in failure to deliver at least 75% of the planned total dose of PF-05212384 and/or 50% of the planned total dose of FOLFIRI during the first cycle, toxicities which resulted in delay of start of Cycle 2 by \>2 weeks of scheduled day (Day 43 of study), Grade 3 QTc prolongation).
Time frame: Day 1 up to Day 28
Progression-Free Survival (PFS)
Progression-free survival was the time from randomization the date to date of first documentation of progression or death due to any cause, whichever occurred first. Documentation of progression was by objective disease assessment as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
Time frame: Baseline (Day 1) up to disease progression or death whichever occurred first (up to 18 months)
Number of Participants With Best Overall Response (Phase 1B)
Best overall response is defined as the best response recorded from randomization (or first dose for patients in the Phase 1B) until disease progression, death, start of new anti-cancer treatment or end of study. The categories for best overall response include: complete response (CR) (complete disappearance of all target lesions with the exception of nodal disease and all target nodes must decrease to normal size (short axis \<10 millimeters (mm)); partial response (PR) (at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters); stable disease (SD) (not qualify for CR, PR or Progression); progressive disease (PD) (20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with a minimum absolute increase of 5 mm); indeterminate (IND) (progression has not been documented).
Time frame: Every 8 weeks from Cycle 1 Day 1 until 28 days of last dose
Number of Participants With All Causality Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), and Discontinuations by Relationship and Seriousness
An AE was any untoward medical occurrence without regard to causality in a participant who received study drug. An 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. An AE was considered treatment emergent if the event occurred for the first time after the start of study treatment and within 28 days after final dose of study treatment and was not seen prior to the start of treatment; or the event was seen prior to the start of treatment but increased in CTCAE version 4.0 grade after the start of study treatment and within 28 days after final dose of study treatment.
Time frame: Baseline up to final study evaluation (within 28 days of last dose)
Number of Participants With All Causality AEs by System Organ Class (SOC)
An AE was any untoward medical occurrence without regard to causality in a participant who received study drug.
Time frame: Baseline up to final study evaluation (within 28 days of last dose)
Number of Participants With Treatment-Emergent AEs by Worst On-Study Grade
An AE was any untoward medical occurrence without regard to causality in a participant who received study drug. AE grades were defined according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 criteria.
Time frame: Baseline up to final study evaluation (within 28 days of last dose)
Number of Participants With Hematological Test Abnormalities
Number of participants with NCI CTCAE version 4.0 grade 1 to 4 hematological test abnormalities.
Time frame: Day 1 and Day 15 of each cycle
Number of Participants With Coagulation Test Abnormalities
Number of participants with NCI CTCAE version 4.0 grade 1 to 4 Coagulation test abnormalities.
Time frame: Day 1 and Day 15 of Cycle 1, Day 1 of Cycle 2 and subsequent cycles
Number of Participants With Chemistry Test Abnormalities
Number of participants with NCI CTCAE version 4.0 grade 1 to 4 Chemistry test abnormalities.
Time frame: Day 1 and Day 15 of each cycle
Number of Participants With Urinalysis Test Abnormalities
Number of participants with NCI CTCAE version 4.0 grade 1 to 4 Urinalysis test abnormalities.
Time frame: Day 1 and Day 15 of Cycle 1, Day 1 of Cycle 2 and subsequent cycles
Maximum Observed Plasma Concentration (Cmax): PF-05212384, Irinotecan, and Fluorouracil
Maximum Plasma Concentration of PF-05212384, Irinotecan, and Fluorouracil
Time frame: PF-05212384: Cycle 1 Day 3. Irinotecan: Cycle 1 Day 1. Fluorouracil: Cycle 1 Day 1.
Time to Reach Maximum Observed Plasma Concentration (Tmax): PF-05212384, Irinotecan, and Fluorouracil
Time to Reach Maximum Observed Plasma Concentration of PF-05212384, Irinotecan, and Fluorouracil
Time frame: PF-05212384: Cycle 1 Day 3. Irinotecan: Cycle 1 Day 1. Fluorouracil: Cycle 1 Day 1.
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast): PF-05212384 and Irinotecan
Area Under the Curve From Time Zero to Last Quantifiable Concentration of PF-05212384, and Irinotecan
Time frame: PF-05212384: Cycle 1 Day 3. Irinotecan: Cycle 1 Day 1.
Area Under the Plasma Concentration-Time Profile From Time 0 Extrapolated to Infinite Time (AUCinf): PF-05212384 and Irinotecan
Area Under the Plasma Concentration-Time Profile From Time 0 Extrapolated to Infinite Time of PF-05212384 and Irinotecan
Time frame: PF-05212384: Cycle 1 Day 3. Irinotecan: Cycle 1 Day 1.
Terminal Elimination Half-Life (t1/2): PF-05212384 and Irinotecan
Terminal Elimination Half-Life of PF-05212384 and Irinotecan
Time frame: PF-05212384: Cycle 1 Day 3. Irinotecan: Cycle 1 Day 1.
Number of Participants Meeting Maximum Post-Baseline QTc Interval Values
Criteria for corrected QT interval using Fridericia's formula (QTcF) meeting potential clinical concern included: an absolute value \>=450 - \<480 msec, \>=480-\<500 msec, \>500 msec; an absolute change 30 - \<60, \>=60 msec.
Time frame: Baseline, Cycle 1 Day 1, and Cycle 2 Day 2
Number of Participants With Expression of Gene Sequences or Gene Amplications in Biopsied Tumor Tissue
Biomarker evaluation were to be performed on fresh biopsies, as well as on archival biopsies collected during the study. Samples were to be analyzed for biomarkers indicative of pathway modulation or for genetic markers correlated to drug sensitivity.
Time frame: Baseline and Cycle 2 Day 17
Number of Participants With Gene and/or Protein Expression Biomarkers Relating to the PI3K and/or mTOR Pathway Activation in Biopsied Tumor Tissue
Biomarker evaluation were to be performed on fresh biopsies, as well as on archival biopsies collected during the study. Samples were to be analyzed for biomarkers indicative of pathway modulation or for genetic markers correlated to drug sensitivity.
Time frame: Baseline and Cycle 2 Day 17
Number of Participants With Best Overall Response (Phase 2)
Best overall response is defined as the best response recorded from randomization (or first dose for patients in the Phase 1B) until disease progression, death, start of new anti-cancer treatment or end of study. The categories for best overall response include: complete response (CR) (complete disappearance of all target lesions with the exception of nodal disease and all target nodes must decrease to normal size (short axis \<10 millimeters (mm)); partial response (PR) (at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters); stable disease (SD) (not qualify for CR, PR or Progression); progressive disease (PD) (20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with a minimum absolute increase of 5 mm); indeterminate (IND) (progression has not been documented).
Time frame: Day 1 up to Day 28
Duration of Response (Phase 2)
Duration of response is the time from first documentation of CR or PR to date of first documentation of objective progression or death.
Time frame: Day 1 to Day 28
Overall Survival (Phase 2)
Overall survival is the time from randomization date to date of death due to any cause.
Time frame: Day 1 up to Day 28
Number of Participants With Evidence of Pathway Signaling Related Genes and/or Proteins in Biopsied Tumor Tissue (Phase 2)
Biomarker evaluation were to be performed on these fresh biopsies, as well as on archival biopsies collected during the study. Samples were to be analyzed for biomarkers indicative of pathway modulation or for genetic markers correlated to drug sensitivity.
Time frame: Baseline and Cycle 2 Day 17
Change From Baseline in Functional Assessment of Cancer Therapy-Colorectal (FACT-C) (Phase 2)
The FACT-C was to assess health-related quality of life and colorectal cancer (CRC)-related symptoms. It includes a total of 36 items, which are summarized into 6 subscales: physical well-being (7 items), functional well-being (7 items), social/family well-being (7 items), emotional well-being (6 items), CRC subscale (9 items) which addresses a subset of CRC concerns such as diarrhea.
Time frame: Day 1 of each cycle
| Milestone | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 1 | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 2A | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 2B | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 3 | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 4 |
|---|---|---|---|---|---|
| Started | 3 | 4 | 3 | 5 | 3 |
| Completed | 3 | 3 | 3 | 1 | 1 |
| Not completed | 0 | 1 | 0 | 4 | 2 |
| Withdrew: Death | 0 | 0 | 0 | 1 | 0 |
| Withdrew: Withdrawal by subject | 0 | 1 | 0 | 0 | 2 |
| Withdrew: Other | 0 | 0 | 0 | 3 | 0 |
DLTs were classified according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 and defined as any of the following events judged to be attributed to the combination of PF-05212384 plus FOLFIRI: hematologic (febrile neutropenia or a sustained temperature \>=38 degrees Celcius for \>1 hour, grade \>=3 neutropenic infection, grade 3 thrombocytopenia with bleeding, grade 4 thrombocytopenia); non-hematologic (grade \>=2 pneumonitis, grade \>=3 toxicities, toxicities which resulted in failure to deliver at least 75% of the planned total dose of PF-05212384 and/or 50% of the planned total dose of FOLFIRI during the first cycle, toxicities which resulted in delay of start of Cycle 2 by \>2 weeks of scheduled day (Day 43 of study), Grade 3 QTc prolongation).
| percentage of participants | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 1 | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 2A | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 2B | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 3 | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 4 |
|---|---|---|---|---|---|
| Percentage of Participants With Dose-Limiting Toxicities (DLTs) in First Cycle of Therapy | 0 | 0 | 0 | 20.0 | 66.7 |
Progression-free survival was the time from randomization the date to date of first documentation of progression or death due to any cause, whichever occurred first. Documentation of progression was by objective disease assessment as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
No measurements were reported for this outcome.
Best overall response is defined as the best response recorded from randomization (or first dose for patients in the Phase 1B) until disease progression, death, start of new anti-cancer treatment or end of study. The categories for best overall response include: complete response (CR) (complete disappearance of all target lesions with the exception of nodal disease and all target nodes must decrease to normal size (short axis \<10 millimeters (mm)); partial response (PR) (at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters); stable disease (SD) (not qualify for CR, PR or Progression); progressive disease (PD) (20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with a minimum absolute increase of 5 mm); indeterminate (IND) (progression has not been documented).
| participants | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 1 | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 2A | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 2B | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 3 | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 4 |
|---|---|---|---|---|---|
| PD | 2 | 2 | 0 | 1 | 1 |
| SD | 0 | 2 | 2 | 3 | 0 |
| PR | 0 | 0 | 1 | 0 | 0 |
| Indeterminant | 0 | 0 | 0 | 1 | 2 |
An AE was any untoward medical occurrence without regard to causality in a participant who received study drug. An 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. An AE was considered treatment emergent if the event occurred for the first time after the start of study treatment and within 28 days after final dose of study treatment and was not seen prior to the start of treatment; or the event was seen prior to the start of treatment but increased in CTCAE version 4.0 grade after the start of study treatment and within 28 days after final dose of study treatment.
| participants | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 1 | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 2A | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 2B | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 3 | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 4 |
|---|---|---|---|---|---|
| Number (#) of Participants with AEs | 3 | 4 | 3 | 5 | 3 |
| # of Participants with SAEs | 0 | 0 | 2 | 2 | 3 |
| # of Participants with Grade 3 or 4 AEs | 0 | 3 | 3 | 3 | 3 |
| # of Participants with Grade 5 AEs | 0 | 0 | 0 | 0 | 0 |
| # of Participants D/C'd Study Due to AEs | 0 | 0 | 0 | 0 | 0 |
| # of Participants D/C'd PF-05212384 Due to AEs | 0 | 0 | 0 | 0 | 1 |
| Number of Participants D/C'd FOLFIRI Due to AEs | 0 | 0 | 0 | 0 | 1 |
An AE was any untoward medical occurrence without regard to causality in a participant who received study drug.
| participants | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 1 | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 2A | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 2B | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 3 | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 4 |
|---|---|---|---|---|---|
| Blood and lymphatic system disorders | 0 | 2 | 0 | 1 | 0 |
| Eye disorders | 0 | 1 | 0 | 0 | 1 |
| Gastrointestinal disorders | 3 | 4 | 3 | 5 | 3 |
| General disorders & administration site conditions | 2 | 2 | 2 | 4 | 2 |
| Hepatobiliary disorders | 0 | 0 | 0 | 1 | 0 |
| Immune system disorders | 0 | 0 | 1 | 0 | 0 |
| Infections and infestations | 1 | 3 | 1 | 1 | 1 |
| Injury, poisoning and procedural complications | 0 | 3 | 0 | 0 | 0 |
| Investigations | 1 | 4 | 1 | 2 | 2 |
| Metabolism and nutrition disorders | 2 | 3 | 1 | 3 | 2 |
| Musculoskeletal and connective tissue disorders | 1 | 4 | 1 | 1 | 1 |
| Nervous system disorders | 0 | 2 | 3 | 2 | 1 |
| Psychiatric disorders | 3 | 2 | 0 | 0 | 2 |
| Renal and urinary disorders | 0 | 2 | 0 | 1 | 0 |
| Respiratory, thoracic and mediastinal disorders | 1 | 1 | 3 | 3 | 1 |
| Skin and subcutaneous tissue disorders | 1 | 3 | 2 | 2 | 3 |
| Vascular disorders | 0 | 1 | 1 | 1 | 1 |
An AE was any untoward medical occurrence without regard to causality in a participant who received study drug. AE grades were defined according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 criteria.
| participants | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 1 | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 2A | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 2B | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 3 | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 4 |
|---|---|---|---|---|---|
| Any AEs, Grade 1 | 0 | 0 | 0 | 1 | 0 |
| Any AEs, Grade 2 | 3 | 1 | 0 | 1 | 0 |
| Any AEs, Grade 3 | 0 | 3 | 3 | 2 | 3 |
| Any AEs, Grade 4 | 0 | 0 | 0 | 1 | 0 |
| Any AEs, Grade 5 | 0 | 0 | 0 | 0 | 0 |
| Any AEs, total | 3 | 4 | 3 | 5 | 3 |
Number of participants with NCI CTCAE version 4.0 grade 1 to 4 hematological test abnormalities.
| participants | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 1 | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 2A | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 2B | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 3 | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 4 |
|---|---|---|---|---|---|
| Anemia | 3 | 4 | 3 | 5 | 2 |
| Hemoglobin increased | 0 | 0 | 0 | 0 | 0 |
| Lymphocyte count increased | 0 | 1 | 0 | 0 | 0 |
| Lymphopenia | 2 | 2 | 2 | 3 | 0 |
| Neutrophils (Absolute) | 0 | 4 | 2 | 2 | 2 |
| Platelets | 0 | 2 | 0 | 2 | 0 |
| White blood cells | 1 | 3 | 3 | 3 | 2 |
Number of participants with NCI CTCAE version 4.0 grade 1 to 4 Coagulation test abnormalities.
| participants | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 1 | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 2A | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 2B | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 3 | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 4 |
|---|---|---|---|---|---|
| Partial thromboplastin time (N=3, 4, 3, 5, 2) | 1 | 0 | 1 | 2 | 2 |
| Prothrombin time (PT) (N=3, 3,2, 5, 1) | 1 | 0 | 2 | 1 | 1 |
| PT INR (N=3, 4, 3, 5, 2) | 1 | 0 | 2 | 0 | 1 |
Number of participants with NCI CTCAE version 4.0 grade 1 to 4 Chemistry test abnormalities.
| participants | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 1 | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 2A | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 2B | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 3 | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 4 |
|---|---|---|---|---|---|
| Alanine aminotransferase | 0 | 1 | 1 | 3 | 1 |
| Alkaline phosphatase | 3 | 2 | 0 | 3 | 1 |
| Aspartate aminotransferase | 2 | 2 | 2 | 4 | 1 |
| Bilirubin (total) | 0 | 2 | 0 | 1 | 0 |
| Creatinine | 1 | 2 | 3 | 4 | 2 |
| Hyperglycemia | 2 | 3 | 1 | 5 | 2 |
| Hypermagnesemia | 0 | 0 | 1 | 0 | 0 |
| Hypoalbuminemia | 2 | 2 | 0 | 3 | 1 |
| Hypocalcemia | 0 | 0 | 0 | 2 | 0 |
| Hypoglycemia | 1 | 0 | 0 | 0 | 0 |
| Hypokalemia | 2 | 2 | 1 | 0 | 1 |
| Hypomagnesemia | 0 | 1 | 1 | 1 | 0 |
| Hyponatremia | 3 | 2 | 1 | 4 | 0 |
| Hypohphosphatemia | 1 | 0 | 0 | 1 | 0 |
| Hyperkalemia | 0 | 1 | 0 | 0 | 0 |
Number of participants with NCI CTCAE version 4.0 grade 1 to 4 Urinalysis test abnormalities.
| participants | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 1 | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 2A | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 2B | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 3 | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 4 |
|---|---|---|---|---|---|
| Number of Participants With Urinalysis Test Abnormalities | 2 | 1 | 1 | 2 | 2 |
Maximum Plasma Concentration of PF-05212384, Irinotecan, and Fluorouracil
| nanogram (ng)/milliliter (mL) | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 1 | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 2A | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 2B | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 3 | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 4 |
|---|---|---|---|---|---|
| PF-05212384 (n=3,4,2,5,3) | 8245 ± 25 | 6554 ± 66 | 33470 ± NA | 8222 ± 35 | 10250 ± 11 |
| Irinotecan (n=3,4,1,5,3) | 1782 ± 4 | 1323 ± 43 | 1550 ± NA | 1585 ± 17 | 1755 ± 6 |
| Fluorouracil (n=3,4,1,4,3) | 18390 ± 85 | 18950 ± 41 | 44000 ± NA | 26790 ± 18 | 26920 ± 3 |
Time to Reach Maximum Observed Plasma Concentration of PF-05212384, Irinotecan, and Fluorouracil
| hour (hr) | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 1 | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 2A | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 2B | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 3 | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 4 |
|---|---|---|---|---|---|
| PF-05212384 (n=3,4,2,5,3) | 0.500 (0.450 to 0.500) | 0.550 (0.450 to 0.617) | 0.500 (0.500 to 0.500) | 0.500 (0.383 to 0.500) | 0.500 (0.483 to 1.03) |
| Irinotecan (n=3,4,1,5,3) | 2.02 (1.98 to 2.02) | 2.04 (2.00 to 2.15) | 1.95 (1.95 to 1.95) | 2.25 (1.98 to 2.50) | 2.00 (1.98 to 2.02) |
| Fluorouracil (n=3,4,1,4,3) | 0.0830 (0.0330 to 0.150) | 0.167 (0.167 to 0.233) | 0.0830 (0.0830 to 0.0830) | 0.125 (0.0670 to 0.250) | 0.150 (0.150 to 46.2) |
Area Under the Curve From Time Zero to Last Quantifiable Concentration of PF-05212384, and Irinotecan
| ng*hr/mL | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 1 | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 2A | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 2B | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 3 | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 4 |
|---|---|---|---|---|---|
| PF-05212384 (n=3,4,1,5,3) | 11460 ± 22 | 9129 ± 33 | 30700 ± NA | 13570 ± 40 | 14760 ± 34 |
| Irinotecan (n=3,4,1,4,3) | 12510 ± 8 | 9164 ± 53 | 8050 ± NA | 10340 ± 15 | 11030 ± 28 |
Area Under the Plasma Concentration-Time Profile From Time 0 Extrapolated to Infinite Time of PF-05212384 and Irinotecan
| ng*hr/mL | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 1 | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 2A | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 2B | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 3 | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 4 |
|---|---|---|---|---|---|
| PF-05212384 | 11820 ± 22 | 9289 ± 32 | 30900 ± NA | 13830 ± 40 | 15270 ± 34 |
| Irinotecan | 13120 ± 10 | 9709 ± 54 | 8350 ± NA | 10900 ± 16 | 11560 ± 29 |
Terminal Elimination Half-Life of PF-05212384 and Irinotecan
| hour | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 1 | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 2A | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 2B | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 3 | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 4 |
|---|---|---|---|---|---|
| PF-05212384 | 33.63 ± 1.3503 | 27.90 ± 3.3695 | 29.2 ± NA | 29.18 ± 6.9909 | 36.97 ± 1.9035 |
| Irinotecan | 5.127 ± 0.70692 | 5.533 ± 1.1621 | 4.97 ± NA | 5.360 ± 0.40817 | 5.107 ± 0.40427 |
Criteria for corrected QT interval using Fridericia's formula (QTcF) meeting potential clinical concern included: an absolute value \>=450 - \<480 msec, \>=480-\<500 msec, \>500 msec; an absolute change 30 - \<60, \>=60 msec.
| participants | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 1 | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 2A | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 2B | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 3 | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 4 |
|---|---|---|---|---|---|
| QTcF Interval <450 msec | 3 | 4 | 3 | 3 | 3 |
| QTcF Interval 450-480 msec | 0 | 0 | 0 | 2 | 0 |
| QTcF Interval >480-500 msec | 0 | 0 | 0 | 0 | 0 |
| QTcF Interval >500 msec | 0 | 0 | 0 | 0 | 0 |
| QTcF Interval increase =< 30 msec | 2 | 3 | 3 | 4 | 3 |
| QTcF Interval increase >30 to =<60 msec | 1 | 1 | 0 | 1 | 0 |
| QTcF Interval increase >60 | 0 | 0 | 0 | 0 | 0 |
Biomarker evaluation were to be performed on fresh biopsies, as well as on archival biopsies collected during the study. Samples were to be analyzed for biomarkers indicative of pathway modulation or for genetic markers correlated to drug sensitivity.
No measurements were reported for this outcome.
Biomarker evaluation were to be performed on fresh biopsies, as well as on archival biopsies collected during the study. Samples were to be analyzed for biomarkers indicative of pathway modulation or for genetic markers correlated to drug sensitivity.
No measurements were reported for this outcome.
Best overall response is defined as the best response recorded from randomization (or first dose for patients in the Phase 1B) until disease progression, death, start of new anti-cancer treatment or end of study. The categories for best overall response include: complete response (CR) (complete disappearance of all target lesions with the exception of nodal disease and all target nodes must decrease to normal size (short axis \<10 millimeters (mm)); partial response (PR) (at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters); stable disease (SD) (not qualify for CR, PR or Progression); progressive disease (PD) (20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with a minimum absolute increase of 5 mm); indeterminate (IND) (progression has not been documented).
No measurements were reported for this outcome.
Duration of response is the time from first documentation of CR or PR to date of first documentation of objective progression or death.
No measurements were reported for this outcome.
Overall survival is the time from randomization date to date of death due to any cause.
No measurements were reported for this outcome.
Biomarker evaluation were to be performed on these fresh biopsies, as well as on archival biopsies collected during the study. Samples were to be analyzed for biomarkers indicative of pathway modulation or for genetic markers correlated to drug sensitivity.
No measurements were reported for this outcome.
The FACT-C was to assess health-related quality of life and colorectal cancer (CRC)-related symptoms. It includes a total of 36 items, which are summarized into 6 subscales: physical well-being (7 items), functional well-being (7 items), social/family well-being (7 items), emotional well-being (6 items), CRC subscale (9 items) which addresses a subset of CRC concerns such as diarrhea.
No measurements were reported for this outcome.
Collected over Baseline to end of treatment. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 1 | — | 0/3 (0%) | 3/3 (100%) |
| PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 2A | — | 0/4 (0%) | 4/4 (100%) |
| PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 2B | — | 2/3 (66.7%) | 3/3 (100%) |
| PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 3 | — | 2/5 (40%) | 5/5 (100%) |
| PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 4 | — | 3/3 (100%) | 3/3 (100%) |
| Event | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 1 | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 2A | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 2B | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 3 | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 4 |
|---|---|---|---|---|---|
| Anal fistulaGastrointestinal disorders | 0/3 | 0/4 | 0/3 | 0/5 | 1/3 |
| StomatitisGastrointestinal disorders | 0/3 | 0/4 | 0/3 | 0/5 | 1/3 |
| Periorbital infectionInfections and infestations | 0/3 | 0/4 | 1/3 | 0/5 | 0/3 |
| Transient ischaemic attackNervous system disorders | 0/3 | 0/4 | 1/3 | 0/5 | 0/3 |
| Pulmonary embolismRespiratory, thoracic and mediastinal disorders | 0/3 | 0/4 | 1/3 | 0/5 | 1/3 |
| AnaemiaBlood and lymphatic system disorders | 0/3 | 0/4 | 0/3 | 1/5 | 0/3 |
| PyrexiaGeneral disorders | 0/3 | 0/4 | 0/3 | 1/5 | 0/3 |
| CholangitisHepatobiliary disorders | 0/3 | 0/4 | 0/3 | 1/5 | 0/3 |
| SepsisInfections and infestations | 0/3 | 0/4 | 0/3 | 1/5 | 0/3 |
| PneumonitisRespiratory, thoracic and mediastinal disorders | 0/3 | 0/4 | 0/3 | 1/5 | 0/3 |
| Event | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 1 | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 2A | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 2B | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 3 | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 4 |
|---|---|---|---|---|---|
| DiarrhoeaGastrointestinal disorders | 1/3 | 3/4 | 3/3 | 3/5 | 3/3 |
| NauseaGastrointestinal disorders | 2/3 | 2/4 | 1/3 | 3/5 | 3/3 |
| Neutrophil count decreasedInvestigations | 0/3 | 4/4 | 1/3 | 0/5 | 2/3 |
| Bone painMusculoskeletal and connective tissue disorders | 0/3 | 3/4 | 0/3 | 0/5 | 0/3 |
| ConstipationGastrointestinal disorders | 0/3 | 1/4 | 2/3 | 1/5 | 2/3 |
| StomatitisGastrointestinal disorders | 1/3 | 2/4 | 1/3 | 3/5 | 2/3 |
| VomitingGastrointestinal disorders | 2/3 | 2/4 | 0/3 | 2/5 | 2/3 |
| FatigueGeneral disorders | 1/3 | 2/4 | 2/3 | 2/5 | 1/3 |
| InsomniaPsychiatric disorders | 2/3 | 2/4 | 0/3 | 0/5 | 1/3 |
| CoughRespiratory, thoracic and mediastinal disorders | 0/3 | 1/4 | 2/3 | 1/5 | 0/3 |
The baseline analysis population included all participants who received at least 1 dose of study treatment.
| Age, Continuous(years) | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 1 | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 2A | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 2B | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 3 | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 4 | Total |
|---|---|---|---|---|---|---|
| Mean | 41.7 ± 11.7 | 54.3 ± 10.1 | 63.3 ± 11.6 | 65.8 ± 9 | 54.3 ± 5.5 | 56.9 ± 12.1 |
| Sex: Female, Male(Participants) | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 1 | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 2A | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 2B | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 3 | PF-05212384+5-FU+Irinotecan+Leucovorin:Dose Level 4 | Total |
|---|---|---|---|---|---|---|
| Female | 1 | 3 | 0 | 0 | 3 | 7 |
| Male | 2 | 1 | 3 | 5 | 0 | 11 |
This study is terminated, as verified in Jul 2016. You cannot join it, but the record below documents what was studied.
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Studies of the drug tested here: Gedatolisib