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TerminatedNCT03255083Updated Jan 19, 2022Results posted

DS-1205c With Osimertinib for Metastatic or Unresectable Epidermal Growth Factor Receptor (EGFR)-Mutant Non-Small Cell Lung Cancer

A Phase 1 interventional study of DS-1205c and Osimertinib in Non-small Cell Lung Cancer (NSCLC), sponsored by Daiichi Sankyo. Terminated at 7 sites in Taiwan. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2022-01-19.

Sponsored by Daiichi Sankyo · Phase 1, Interventional, and Treatment

Why this study was terminated
This study was terminated based on a business decision by the Sponsor.
Phase
Phase 1
Study type
Interventional
Enrollment
13
Allocation
Not applicable
Ages
18 Years and older
Sex
All
01

Study summary

This study has two parts: dose escalation and dose expansion.

The primary objectives are:

  • For Dose Escalation, to assess the safety and tolerability of DS-1205c when combined with osimertinib in the study population and to determine the recommended dose for expansion of DS-1205c when combined with osimertinib in the study population
  • For Dose Expansion, to assess the safety and tolerability of DS-1205c when combined with osimertinib in the study population

In Dose Escalation, after a 7-day run in period (Cycle 0), there will be 21-day cycles (Cycle 1 onward). In Dose Expansion, there will be 21-day cycles.

The number of treatment cycles is not fixed in this study. Participants will continue study treatment until they decide not to (withdraw consent), their disease gets worse [progressive disease (PD)], or side effects become unacceptable (unacceptable toxicity).

02

Conditions studied

  • Non-small Cell Lung Cancer (NSCLC)

Keywords

  • Oncology
  • Advanced Non-small Cell Lung Cancer
  • Inoperable Non-small Cell Lung Cancer
  • Metastatic
  • Non-resectable
  • Epidermal growth factor receptor
  • EGFR
03

Who can participate

Ages eligible
18 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

Inclusion criteria

  1. Has histologically or cytologically documented adenocarcinoma NSCLC.
  2. Has locally advanced or metastatic NSCLC, not amenable to curative surgery or radiation.

  3. Has acquired resistance to EGFR TKI according to the Jackman criteria (PMID: 19949011):

    1. Historical confirmation that the tumor harbors an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) or
    2. Has experienced clinical benefit from an EGFR TKI, followed by systemic progression (Response Evaluation Criteria in Solid Tumors [RECIST version 1.1] or World Health Organization [WHO]) while on continuous treatment with an EGFR TKI.
  4. Is currently receiving, and is able to discontinue erlotinib, gefinitib, or afatinib; or is currently receiving osimertinib at the prescribed 80 mg dose and is able to interrupt osimertinib.
  5. Has been receiving erlotinib, gefitinib, or afatinib for at least 6 weeks with well-controlled related toxicities less than Grade 3 in severity at the time of screening period.
  6. Has radiological documentation of disease progression while receiving continuous treatment with erlotinib, gefitinib, afatinib, or osimertinib.
  7. Has at least one measurable lesion per RECIST version 1.1.
  8. Is willing to provide archival tumor tissue from a biopsy performed after progression during treatment with erlotinib, gefitinib, afatinib , or osimertinib OR has at least one lesion not previously irradiated, amenable to core biopsy, and is willing to undergo screening tumor biopsy.
  9. Demonstrates absence of EGFR T790M. No EGFR mutation testing is required if treated with osimertinib.
  10. Has Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1, with no deterioration over the previous 2 weeks.

Exclusion criteria

Exclusion Criteria:

  1. Has any evidence of small cell histology, or combined small cell and non-small cell histology, in original tumor biopsy or in screening biopsy performed since progression.
  2. Has previously documented evidence of anaplastic lymphoma kinase (ALK) fusion, ROS proto-oncogene 1 (ROS1) fusion, BRAF V600E mutation, rearranged during transfection (RET) rearrangement, human epidermal growth factor receptor 2 (HER2) mutation, or MET exon 14 skipping mutation. No new testing for these genomic alterations is required for Screening.

  3. Has received treatment with any of the following:

    1. Any cytotoxic chemotherapy, immune checkpoint inhibitor therapy, investigational agent or other anticancer drug(s) from a previous cancer treatment regimen or clinical study (other than EGFR TKI), within 14 days of the first dose of study treatment.
    2. Immune checkpoint inhibitor therapy within 30 days of first dose of study treatment.
    3. Major surgery (excluding placement of vascular access) within 4 weeks of the first dose of study treatment.
    4. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks, or palliative radiation therapy within 2 weeks of the first dose of study drug treatment.

  4. Has history of other active malignancy within 3 years prior to enrollment, except:

    1. Adequately treated non-melanoma skin cancer OR
    2. Superficial bladder tumors (tumor stage "a" [Ta], tumor stage "is" [Tis], tumor stage "1" [T1]) OR
    3. Curatively treated in situ disease OR
    4. Low risk non-metastatic prostate cancer (with Gleason score \< 7, and following local treatment or undergoing active surveillance)
  5. Has spinal cord compression or clinically active brain metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Subjects with clinically inactive brain metastases may be included in the study. Subjects with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy and study enrollment (1 week for stereotactic radiotherapy).
  6. Presence of retinal disease in the eye that is not due to neovascular age-related macular degeneration (nAMD; eg, significant diabetic retinopathy, glaucomatous retinal atrophy, retinal detachment).
  7. Has history of myocardial infarction within the past 6 months.
  8. Has symptomatic congestive heart failure (New York Heart Association [NYHA] Classes II-IV), unstable angina, or cardiac arrhythmia requiring antiarrhythmic treatment.
  9. Has left ventricular ejection fraction (LVEF) \<45% by either echocardiogram (ECHO) or multigated acquisition (MUGA) scan.
  10. Has any clinically important abnormalities in rhythm, conduction or morphology of resting ECG, eg, complete left bundle branch block, third-degree heart block, second-degree heart block, or PR interval >250 milliseconds (ms).
  11. Has a mean QT interval corrected using Fridericia's correction (QTcF) prolongation >470 ms for females and >450 ms for males in three successive Screening measurements.
  12. Unable or unwilling to discontinue concomitant use of drugs that are known to prolong the QT interval.
  13. Has any factors that increase the risk of QTc prolongation or risk of arrhythmic events, such as congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives.
  14. Has any history of interstitial lung disease (pulmonary fibrosis or severe radiation pneumonitis) or is suspected to have such disease by imaging during screening.
  15. Has history of pancreatitis within the past 6 months.
04

Study design

Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrollment
13 participants (actual)

Study arms

  • Experimental
    DS-1205c with osimertinib

    Participants receive DS-1205c (at planned doses given orally twice daily: 200 mg, 400 mg, 800 mg, 1200 mg) in combination with daily 80 mg oral dose of osimertinib

    Drug: DS-1205c · Drug: Osimertinib

Interventions

  • DrugDS-1205c

    DS-1205c 200 mg capsule

  • DrugOsimertinib

    Osimertinib 80 mg tablet

05

What researchers measure

Primary outcomes

  1. Number of Participants With Dose-limiting Toxicities (DLTs) Following Administration With DS-1205c in Combination With Osimertinib

    A dose-limiting toxicity (DLT) was defined as any TEAE not attributable to disease or disease-related processes that occurred during the DLT-evaluation period (Cycle 0, Day 1 to Cycle 1, Day 21 of Dose Escalation) and was Grade 3 or above, according to NCI-CTCAE Version 5.0.

    Time frame: Cycle 0, Day 1 (7-day cycle) to Cycle 1, Day 21 of Dose Escalation (each cycle was 21 days)

  2. Number of Participants With Treatment-emergent Adverse Events Occurring in More Than 1 Participant Following Administration With DS-1205c in Combination With Osimertinib

    Treatment-emergent adverse events were defined as an adverse event (AE) that occurs, having been absent before the first dose of study drug, or has worsened in severity after the initiating the study drug until 30 days after last dose of the study drug.

    Time frame: Screening; Cycle 0 (7-day cycle), Days -1, 1, 2, 4, 6, and 7; Cycle 1 (21-day cycle), Days 4, 8, and 15; Cycle 2 (21-day cycle), Days 1, 2, and 8; Cycle 3 and beyond (21-day cycles), Day 1; and end-of-treatment, 30 days after last dose, up to 1 year

Secondary outcomes

  1. Number of Participants With Best Overall Response Assessed by Investigator Following Administration of DS-1205c in Combination With Osimertinib

    Complete response (CR) was defined as a disappearance of all target lesions, partial response (PR) was defined as at least a 30% decrease in the sum of diameters of target lesions, and stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD; at least a 20% increase in the sum of diameters of target lesions. Objective response rate is calculated as the number of participants with best objective response \[complete response (CR) or partial response (PR) determined by Investigator assessment based on Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1\], divided by the number of participants in the analysis population.

    Time frame: Screening; Cycle 0 (7-day cycle); Cycle 1 and beyond (21-day cycles), Every 6 weeks (± 7 days) in the first 24 weeks after Day 1 of Cycle 1, and every 12 weeks (± 7 days) thereafter; and end-of-treatment, 30 days after last dose, up to 1 year

  2. Disease Control Rate Assessed by Investigator Following Administration of DS-1205c in Combination With Osimertinib

    Disease control rate (DCR) is defined as the sum of complete response (CR) rate, partial response (PR) rate, and stable disease (SD) rate. As per the Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), complete response (CR) was defined as a disappearance of all target lesions, partial response (PR) was defined as at least a 30% decrease in the sum of diameters of target lesions, and stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease.

    Time frame: Screening; Cycle 0 (7-day cycle); Cycle 1 and beyond (21-day cycles), Every 6 weeks (± 7 days) in the first 24 weeks after Day 1 of Cycle 1, and every 12 weeks (± 7 days) thereafter; and end-of-treatment, 30 days after last dose, up to 1 year

  3. Progression-free Survival Assessed by Investigator Following Administration of DS-1205c in Combination With Osimertinib

    Progression-free survival is defined as the time from the date of first dose to the earliest date of the first objective documentation of disease progression or death due to any cause. As per the Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), progressive disease is defined as at least a 20% increase in the sum of diameters of target lesions.

    Time frame: Screening; Cycle 0 (7-day cycle); Cycle 1 and beyond (21-day cycles), Every 6 weeks (± 7 days) in the first 24 weeks after Day 1 of Cycle 1, and every 12 weeks (± 7 days) thereafter; and end-of-treatment, 30 days after last dose, up to 1 year

  4. Overall Survival in Participants Following Administration of DS-1205c in Combination With Osimertinib

    Overall survival was defined as the time from the date of first dose to the date of death due to any cause.

    Time frame: Screening; Cycle 0 (7-day cycle); Cycle 1 and beyond (21-day cycles), Every 6 weeks (± 7 days) in the first 24 weeks after Day 1 of Cycle 1, and every 12 weeks (± 7 days) thereafter; and end-of-treatment, 30 days after last dose, up to 1 year

  5. Maximum Concentration (Cmax) Following Administration of DS-1205c Alone and in Combination With Osimertinib

    The maximum concentration (Cmax) of DS-1205c alone and in combination with osimertinib was assessed. Pharmacokinetic (PK) parameters for each participant were estimated using non-compartmental analysis. Descriptive statistics are provided for all plasma concentration data by analyte/dose/study day/time and for each PK parameter by analyte/dose/study day, as appropriate.

    Time frame: Predose, 1, 2, 4, 6, 8, and 12 hours of Cycle 0 (7-day cycle; DS-1205c alone), Day 1; Predose, 1, 2, 4, 6, 8, and 10 hours of Cycle 0, Day 7 (DS-1205c alone); Predose, 1, 2, 4, 6, 8, 10, and 12 hours of Cycle 2 (21-day cycle), Day 1 (DS-1205c+osimertinib)

  6. Area Under the Plasma Concentration Curve Following Administration of DS-1205c Alone and in Combination With Osimertinib

    The area under the plasma concentration curve from time 0 until last quantifiable time point (AUClast) and the area under the plasma concentration curve over a dosing interval (AUCtau) of DS-1205c alone and in combination with osimertinib were assessed. Pharmacokinetic (PK) parameters for each participant were estimated using non-compartmental analysis. Descriptive statistics are provided for all plasma concentration data by analyte/dose/study day/time and for each PK parameter by analyte/dose/study day, as appropriate.

    Time frame: Predose, 1, 2, 4, 6, 8, and 12 hours of Cycle 0 (7-day cycle; DS-1205c alone), Day 1; Predose, 1, 2, 4, 6, 8, and 10 hours of Cycle 0, Day 7 (DS-1205c alone); Predose, 1, 2, 4, 6, 8, 10, and 12 hours of Cycle 2 (21-day cycle), Day 1 (DS-1205c+osimertinib)

  7. Time to Maximum Concentration (Tmax) Following Administration of DS-1205c Alone and in Combination With Osimertinib

    The time to maximum concentration (Tmax) of DS-1205c alone and in combination with osimertinib was assessed. Pharmacokinetic (PK) parameters for each participant were estimated using non-compartmental analysis. Descriptive statistics are provided for all plasma concentration data by analyte/dose/study day/time and for each PK parameter by analyte/dose/study day, as appropriate.

    Time frame: Predose, 1, 2, 4, 6, 8, and 12 hours of Cycle 0 (7-day cycle; DS-1205c alone), Day 1; Predose, 1, 2, 4, 6, 8, and 10 hours of Cycle 0, Day 7 (DS-1205c alone); Predose, 1, 2, 4, 6, 8, 10, and 12 hours of Cycle 2 (21-day cycle), Day 1 (DS-1205c+osimertinib)

  8. Trough Plasma Concentration (Ctrough) Following Administration of DS-1205c Alone and in Combination With Osimertinib

    The trough plasma concentration (Ctrough) of DS-1205c alone and in combination with osimertinib was assessed. Pharmacokinetic (PK) parameters for each participant were estimated using non-compartmental analysis. Descriptive statistics are provided for all plasma concentration data by analyte/dose/study day/time and for each PK parameter by analyte/dose/study day, as appropriate.

    Time frame: Predose, 1, 2, 4, 6, 8, and 12 hours of Cycle 0 (7-day cycle; DS-1205c alone), Day 1; Predose, 1, 2, 4, 6, 8, and 10 hours of Cycle 0, Day 7 (DS-1205c alone); Predose, 1, 2, 4, 6, 8, 10, and 12 hours of Cycle 2 (21-day cycle), Day 1 (DS-1205c+osimertinib)

  9. Terminal Half-life (t1/2) Following Administration of DS-1205c Alone and in Combination With Osimertinib

    The terminal half-life (t1/2) of DS-1205c alone and in combination with osimertinib was assessed. Pharmacokinetic (PK) parameters for each participant were estimated using non-compartmental analysis. Descriptive statistics are provided for all plasma concentration data by analyte/dose/study day/time and for each PK parameter by analyte/dose/study day, as appropriate.

    Time frame: Predose, 1, 2, 4, 6, 8, and 12 hours of Cycle 0 (7-day cycle; DS-1205c alone), Day 1; Predose, 1, 2, 4, 6, 8, and 10 hours of Cycle 0, Day 7 (DS-1205c alone); Predose, 1, 2, 4, 6, 8, 10, and 12 hours of Cycle 2 (21-day cycle), Day 1 (DS-1205c+osimertinib)

06

Results

Posted Jan 11, 2022
Limitations and caveats
This study was terminated based on a business decision by the Sponsor.

Participant flow

A total of 13 participants who met all inclusion criteria and no exclusion criteria were enrolled from 10 April 2019 to 04 September 2020 in the study at 7 clinical sites in Taiwan.

Participant flow — Overall Study
MilestoneDS-1205c 200 mg + OsimertinibDS-1205c 400 mg + OsimertinibDS-1205c 800 mg + OsimertinibDS-1205c 1200 mg + Osimertinib
Started6331
Completed0000
Not completed6331
Withdrew: Clinical progression1000
Withdrew: Adverse event0100
Withdrew: Progressive disease by recist version 1.14121
Withdrew: Withdrawal by subject1110

Outcome measures

PrimaryNumber of Participants With Dose-limiting Toxicities (DLTs) Following Administration With DS-1205c in Combination With Osimertinib

A dose-limiting toxicity (DLT) was defined as any TEAE not attributable to disease or disease-related processes that occurred during the DLT-evaluation period (Cycle 0, Day 1 to Cycle 1, Day 21 of Dose Escalation) and was Grade 3 or above, according to NCI-CTCAE Version 5.0.

Time frame:
Cycle 0, Day 1 (7-day cycle) to Cycle 1, Day 21 of Dose Escalation (each cycle was 21 days)
Reported as:
Count of participants · Participants
Number of Participants With Dose-limiting Toxicities (DLTs) Following Administration With DS-1205c in Combination With Osimertinib
ParticipantsDS-1205c 200 mg + OsimertinibDS-1205c 400 mg + OsimertinibDS-1205c 800 mg + OsimertinibDS-1205c 1200 mg + Osimertinib
Number of Participants With Dose-limiting Toxicities (DLTs) Following Administration With DS-1205c in Combination With Osimertinib1000
PrimaryNumber of Participants With Treatment-emergent Adverse Events Occurring in More Than 1 Participant Following Administration With DS-1205c in Combination With Osimertinib

Treatment-emergent adverse events were defined as an adverse event (AE) that occurs, having been absent before the first dose of study drug, or has worsened in severity after the initiating the study drug until 30 days after last dose of the study drug.

Time frame:
Screening; Cycle 0 (7-day cycle), Days -1, 1, 2, 4, 6, and 7; Cycle 1 (21-day cycle), Days 4, 8, and 15; Cycle 2 (21-day cycle), Days 1, 2, and 8; Cycle 3 and beyond (21-day cycles), Day 1; and end-of-treatment, 30 days after last dose, up to 1 year
Reported as:
Count of participants · Participants
Number of Participants With Treatment-emergent Adverse Events Occurring in More Than 1 Participant Following Administration With DS-1205c in Combination With Osimertinib
ParticipantsDS-1205c 200 mg + OsimertinibDS-1205c 400 mg + OsimertinibDS-1205c 800 mg + OsimertinibDS-1205c 1200 mg + Osimertinib
Any TEAEs6331
Upper respiratory tract infection2010
Urinary tract infection2100
Pneumonia1001
Anaemia0111
Insomnia1210
Dizziness1100
Headache1010
Cough1100
Dyspnoea1100
Haemoptysis1100
Vomiting3100
Diarrhoea0120
Constipation2000
Rash1100
Fatigue1200
Pyrexia0020
Alanine aminotransferase increased1011
Aspartate aminotransferase increased1011
Blood Creatinine Phosphokinase Increased0111
Blood Creatinine Increased0110
Ejection Fraction Decreased0110
Lipase Increased0011
Overdose0020
SecondaryNumber of Participants With Best Overall Response Assessed by Investigator Following Administration of DS-1205c in Combination With Osimertinib

Complete response (CR) was defined as a disappearance of all target lesions, partial response (PR) was defined as at least a 30% decrease in the sum of diameters of target lesions, and stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD; at least a 20% increase in the sum of diameters of target lesions. Objective response rate is calculated as the number of participants with best objective response \[complete response (CR) or partial response (PR) determined by Investigator assessment based on Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1\], divided by the number of participants in the analysis population.

Time frame:
Screening; Cycle 0 (7-day cycle); Cycle 1 and beyond (21-day cycles), Every 6 weeks (± 7 days) in the first 24 weeks after Day 1 of Cycle 1, and every 12 weeks (± 7 days) thereafter; and end-of-treatment, 30 days after last dose, up to 1 year
Reported as:
Count of participants · Participants
Number of Participants With Best Overall Response Assessed by Investigator Following Administration of DS-1205c in Combination With Osimertinib
ParticipantsDS-1205c 200 mg + OsimertinibDS-1205c 400 mg + OsimertinibDS-1205c 800 mg + OsimertinibDS-1205c 1200 mg + Osimertinib
Complete response (CR)0000
Partial response (PR)0000
Stable disease (SD)2331
Progressive disease (PD)3000
Not evaluable (NE)1000
Overall response rate (ORR)0000
SecondaryDisease Control Rate Assessed by Investigator Following Administration of DS-1205c in Combination With Osimertinib

Disease control rate (DCR) is defined as the sum of complete response (CR) rate, partial response (PR) rate, and stable disease (SD) rate. As per the Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), complete response (CR) was defined as a disappearance of all target lesions, partial response (PR) was defined as at least a 30% decrease in the sum of diameters of target lesions, and stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease.

Time frame:
Screening; Cycle 0 (7-day cycle); Cycle 1 and beyond (21-day cycles), Every 6 weeks (± 7 days) in the first 24 weeks after Day 1 of Cycle 1, and every 12 weeks (± 7 days) thereafter; and end-of-treatment, 30 days after last dose, up to 1 year
Reported as:
Count of participants · Participants
Disease Control Rate Assessed by Investigator Following Administration of DS-1205c in Combination With Osimertinib
ParticipantsDS-1205c 200 mg + OsimertinibDS-1205c 400 mg + OsimertinibDS-1205c 800 mg + OsimertinibDS-1205c 1200 mg + Osimertinib
Disease Control Rate Assessed by Investigator Following Administration of DS-1205c in Combination With Osimertinib2331
SecondaryProgression-free Survival Assessed by Investigator Following Administration of DS-1205c in Combination With Osimertinib

Progression-free survival is defined as the time from the date of first dose to the earliest date of the first objective documentation of disease progression or death due to any cause. As per the Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), progressive disease is defined as at least a 20% increase in the sum of diameters of target lesions.

Time frame:
Screening; Cycle 0 (7-day cycle); Cycle 1 and beyond (21-day cycles), Every 6 weeks (± 7 days) in the first 24 weeks after Day 1 of Cycle 1, and every 12 weeks (± 7 days) thereafter; and end-of-treatment, 30 days after last dose, up to 1 year
Reported as:
Median · weeks
Progression-free Survival Assessed by Investigator Following Administration of DS-1205c in Combination With Osimertinib
weeksDS-1205c 200 mg + OsimertinibDS-1205c 400 mg + OsimertinibDS-1205c 800 mg + OsimertinibDS-1205c 1200 mg + Osimertinib
Progression-free Survival Assessed by Investigator Following Administration of DS-1205c in Combination With Osimertinib7.1 (5.4 to 36.6)NA (12.3 to NA)22.0 (12.1 to 22.0)12.4 (NA to NA)
SecondaryOverall Survival in Participants Following Administration of DS-1205c in Combination With Osimertinib

Overall survival was defined as the time from the date of first dose to the date of death due to any cause.

Time frame:
Screening; Cycle 0 (7-day cycle); Cycle 1 and beyond (21-day cycles), Every 6 weeks (± 7 days) in the first 24 weeks after Day 1 of Cycle 1, and every 12 weeks (± 7 days) thereafter; and end-of-treatment, 30 days after last dose, up to 1 year
Reported as:
Median · weeks
Overall Survival in Participants Following Administration of DS-1205c in Combination With Osimertinib
weeksDS-1205c 200 mg + OsimertinibDS-1205c 400 mg + OsimertinibDS-1205c 800 mg + OsimertinibDS-1205c 1200 mg + Osimertinib
Overall Survival in Participants Following Administration of DS-1205c in Combination With Osimertinib46.9 (34.0 to NA)NA (14 to NA)NA (32 to NA)NA (NA to NA)
SecondaryMaximum Concentration (Cmax) Following Administration of DS-1205c Alone and in Combination With Osimertinib

The maximum concentration (Cmax) of DS-1205c alone and in combination with osimertinib was assessed. Pharmacokinetic (PK) parameters for each participant were estimated using non-compartmental analysis. Descriptive statistics are provided for all plasma concentration data by analyte/dose/study day/time and for each PK parameter by analyte/dose/study day, as appropriate.

Time frame:
Predose, 1, 2, 4, 6, 8, and 12 hours of Cycle 0 (7-day cycle; DS-1205c alone), Day 1; Predose, 1, 2, 4, 6, 8, and 10 hours of Cycle 0, Day 7 (DS-1205c alone); Predose, 1, 2, 4, 6, 8, 10, and 12 hours of Cycle 2 (21-day cycle), Day 1 (DS-1205c+osimertinib)
Reported as:
Mean · ng/mL
Maximum Concentration (Cmax) Following Administration of DS-1205c Alone and in Combination With Osimertinib
ng/mLDS-1205c 200 mg + OsimertinibDS-1205c 400 mg + OsimertinibDS-1205c 800 mg + OsimertinibDS-1205c 1200 mg + Osimertinib
Cycle 0: Day 1292 ± 94.8413 ± 94.0499 ± 222703 ± NA
Cycle 0: Day 7561 ± 191827 ± 2991041 ± 4601070 ± NA
Cycle 2: Day 1544 ± 176845 ± 328921 ± 2601150 ± NA
SecondaryArea Under the Plasma Concentration Curve Following Administration of DS-1205c Alone and in Combination With Osimertinib

The area under the plasma concentration curve from time 0 until last quantifiable time point (AUClast) and the area under the plasma concentration curve over a dosing interval (AUCtau) of DS-1205c alone and in combination with osimertinib were assessed. Pharmacokinetic (PK) parameters for each participant were estimated using non-compartmental analysis. Descriptive statistics are provided for all plasma concentration data by analyte/dose/study day/time and for each PK parameter by analyte/dose/study day, as appropriate.

Time frame:
Predose, 1, 2, 4, 6, 8, and 12 hours of Cycle 0 (7-day cycle; DS-1205c alone), Day 1; Predose, 1, 2, 4, 6, 8, and 10 hours of Cycle 0, Day 7 (DS-1205c alone); Predose, 1, 2, 4, 6, 8, 10, and 12 hours of Cycle 2 (21-day cycle), Day 1 (DS-1205c+osimertinib)
Reported as:
Mean · h*ng/mL
Area Under the Plasma Concentration Curve Following Administration of DS-1205c Alone and in Combination With Osimertinib
h*ng/mLDS-1205c 200 mg + OsimertinibDS-1205c 400 mg + OsimertinibDS-1205c 800 mg + OsimertinibDS-1205c 1200 mg + Osimertinib
AUClast, Cycle 0: Day 11916 ± 5302493 ± 2772891 ± 13985050 ± NA
AUClast, Cycle 0: Day 74193 ± 15145716 ± 19317385 ± 45628602 ± NA
AUClast, Cycle 2: Day 14445 ± 13896852 ± 27167220 ± 26299495 ± NA
AUCtau, Cycle 0: Day 11975 ± 5632557 ± 2573002 ± 14725255 ± NA
AUCtau, Cycle 0: Day 74818 ± 17726496 ± 22086972 ± NA10300 ± NA
AUCtau, Cycle 2: Day 14596 ± 14887117 ± 28837640 ± 291810000 ± NA
SecondaryTime to Maximum Concentration (Tmax) Following Administration of DS-1205c Alone and in Combination With Osimertinib

The time to maximum concentration (Tmax) of DS-1205c alone and in combination with osimertinib was assessed. Pharmacokinetic (PK) parameters for each participant were estimated using non-compartmental analysis. Descriptive statistics are provided for all plasma concentration data by analyte/dose/study day/time and for each PK parameter by analyte/dose/study day, as appropriate.

Time frame:
Predose, 1, 2, 4, 6, 8, and 12 hours of Cycle 0 (7-day cycle; DS-1205c alone), Day 1; Predose, 1, 2, 4, 6, 8, and 10 hours of Cycle 0, Day 7 (DS-1205c alone); Predose, 1, 2, 4, 6, 8, 10, and 12 hours of Cycle 2 (21-day cycle), Day 1 (DS-1205c+osimertinib)
Reported as:
Median · hours
Time to Maximum Concentration (Tmax) Following Administration of DS-1205c Alone and in Combination With Osimertinib
hoursDS-1205c 200 mg + OsimertinibDS-1205c 400 mg + OsimertinibDS-1205c 800 mg + OsimertinibDS-1205c 1200 mg + Osimertinib
Cycle 0: Day 14.1 (2.0 to 6.0)4.0 (3.9 to 4.0)3.9 (2.0 to 4.0)6.2 (6.2 to 6.2)
Cycle 0: Day 74.0 (2.0 to 4.2)4.0 (2.1 to 4.0)4.0 (3.9 to 5.9)4.0 (4.0 to 4.0)
Cycle 2: Day 14.1 (4.0 to 4.2)4.0 (2.0 to 4.1)2.1 (0 to 4.0)3.9 (3.9 to 3.9)
SecondaryTrough Plasma Concentration (Ctrough) Following Administration of DS-1205c Alone and in Combination With Osimertinib

The trough plasma concentration (Ctrough) of DS-1205c alone and in combination with osimertinib was assessed. Pharmacokinetic (PK) parameters for each participant were estimated using non-compartmental analysis. Descriptive statistics are provided for all plasma concentration data by analyte/dose/study day/time and for each PK parameter by analyte/dose/study day, as appropriate.

Time frame:
Predose, 1, 2, 4, 6, 8, and 12 hours of Cycle 0 (7-day cycle; DS-1205c alone), Day 1; Predose, 1, 2, 4, 6, 8, and 10 hours of Cycle 0, Day 7 (DS-1205c alone); Predose, 1, 2, 4, 6, 8, 10, and 12 hours of Cycle 2 (21-day cycle), Day 1 (DS-1205c+osimertinib)
Reported as:
Mean · ng/mL
Trough Plasma Concentration (Ctrough) Following Administration of DS-1205c Alone and in Combination With Osimertinib
ng/mLDS-1205c 200 mg + OsimertinibDS-1205c 400 mg + OsimertinibDS-1205c 800 mg + OsimertinibDS-1205c 1200 mg + Osimertinib
Cycle 0: Day 7376 ± 143460 ± 219688 ± 631816 ± NA
Cycle 2: Day 1359 ± 137576 ± 275722 ± 406903 ± NA
SecondaryTerminal Half-life (t1/2) Following Administration of DS-1205c Alone and in Combination With Osimertinib

The terminal half-life (t1/2) of DS-1205c alone and in combination with osimertinib was assessed. Pharmacokinetic (PK) parameters for each participant were estimated using non-compartmental analysis. Descriptive statistics are provided for all plasma concentration data by analyte/dose/study day/time and for each PK parameter by analyte/dose/study day, as appropriate.

Time frame:
Predose, 1, 2, 4, 6, 8, and 12 hours of Cycle 0 (7-day cycle; DS-1205c alone), Day 1; Predose, 1, 2, 4, 6, 8, and 10 hours of Cycle 0, Day 7 (DS-1205c alone); Predose, 1, 2, 4, 6, 8, 10, and 12 hours of Cycle 2 (21-day cycle), Day 1 (DS-1205c+osimertinib)
Reported as:
Mean · hours
Terminal Half-life (t1/2) Following Administration of DS-1205c Alone and in Combination With Osimertinib
hoursDS-1205c 200 mg + OsimertinibDS-1205c 400 mg + OsimertinibDS-1205c 800 mg + OsimertinibDS-1205c 1200 mg + Osimertinib
Cycle 0: Day 16.98 ± 1.895.3 ± 1.04.7 ± 0.63.3 ± NA
Cycle 0: Day 711.6 ± 6.77.1 ± 1.06.9 ± NA—
Cycle 2: Day 19.8 ± 3.37.9 ± 0.87.0 ± 1.311.7 ± NA

Adverse events

Collected over Treatment-emergent adverse events (TEAEs) were collected at Screening, Cycle 0 (7-day cycle), Days -1, 1, 2, 4, 6, and 7; Cycle 1 (21-day cycle), Days 4, 8, and 15; Cycle 2 (21-day cycle), Days 1, 2, and 8; Cycle 3 and beyond (21-day cycles), Day 1; and end-of-treatment, 30 days after last dose, up to 1 year.. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
DS-1205c 200 mg + Osimertinib0/6 (0%)2/6 (33.3%)6/6 (100%)
DS-1205c 400 mg + Osimertinib0/3 (0%)1/3 (33.3%)3/3 (100%)
DS-1205c 800 mg + Osimertinib0/3 (0%)2/3 (66.7%)3/3 (100%)
DS-1205c 1200 mg + Osimertinib0/1 (0%)1/1 (100%)1/1 (100%)
Most frequent serious events
Most frequent serious events
EventDS-1205c 200 mg + OsimertinibDS-1205c 400 mg + OsimertinibDS-1205c 800 mg + OsimertinibDS-1205c 1200 mg + Osimertinib
PneumoniaInfections and infestations1/60/30/31/1
Cardiac failureCardiac disorders0/60/31/30/1
Coronary artery diseaseCardiac disorders0/60/31/30/1
Pneumonia aspirationRespiratory, thoracic and mediastinal disorders0/61/30/30/1
DysphagiaGastrointestinal disorders0/61/30/30/1
PancreatitisGastrointestinal disorders0/60/31/30/1
Metastases to MeningesNeoplasms benign, malignant and unspecified (incl cysts and polyps)1/60/30/30/1
Alanine aminotransferase increasedInvestigations1/60/30/30/1
Aspartate aminotransferase increasedInvestigations1/60/30/30/1
Most frequent other events
Showing 10 of 83
Most frequent other events
EventDS-1205c 200 mg + OsimertinibDS-1205c 400 mg + OsimertinibDS-1205c 800 mg + OsimertinibDS-1205c 1200 mg + Osimertinib
Alanine aminotransferase increasedInvestigations1/60/31/31/1
AnaemiaBlood and lymphatic system disorders0/61/31/31/1
Aspartate aminotransferase increasedInvestigations1/60/31/31/1
Blood creatinine phosphokinase increasedInvestigations0/61/31/31/1
Lipase increasedInvestigations0/60/31/31/1
PneumoniaInfections and infestations1/60/30/31/1
Lymph node painBlood and lymphatic system disorders0/60/30/31/1
Traumatic haematomaInjury, poisoning and procedural complications0/60/30/31/1
InsomniaPsychiatric disorders1/62/31/30/1
DiarrhoeaGastrointestinal disorders0/61/32/30/1

Baseline characteristics

Demographic and baseline characteristics were assessed in the Full Analysis Set.

Age, Categorical
Age, Categorical(Participants)DS-1205c 200 mg + OsimertinibDS-1205c 400 mg + OsimertinibDS-1205c 800 mg + OsimertinibDS-1205c 1200 mg + OsimertinibTotal
<=18 years00000
Between 18 and 65 years41207
>=65 years22116
Age, Continuous
Age, Continuous(years)DS-1205c 200 mg + OsimertinibDS-1205c 400 mg + OsimertinibDS-1205c 800 mg + OsimertinibDS-1205c 1200 mg + OsimertinibTotal
Median57.5 (45 to 77)73.0 (61 to 88)64.0 (63 to 68)70 (70 to 70)64.0 (45 to 88)
Sex: Female, Male
Sex: Female, Male(Participants)DS-1205c 200 mg + OsimertinibDS-1205c 400 mg + OsimertinibDS-1205c 800 mg + OsimertinibDS-1205c 1200 mg + OsimertinibTotal
Female621110
Male01203
Race (NIH/OMB)
Race (NIH/OMB)(Participants)DS-1205c 200 mg + OsimertinibDS-1205c 400 mg + OsimertinibDS-1205c 800 mg + OsimertinibDS-1205c 1200 mg + OsimertinibTotal
American Indian or Alaska Native00000
Asian633113
Native Hawaiian or Other Pacific Islander00000
Black or African American00000
White00000
More than one race00000
Unknown or Not Reported00000
Region of Enrollment
Region of Enrollment(participants)DS-1205c 200 mg + OsimertinibDS-1205c 400 mg + OsimertinibDS-1205c 800 mg + OsimertinibDS-1205c 1200 mg + OsimertinibTotal
Taiwan633113
07

Study locations

7 sites
  • Taipei Medical University, Shuang Ho Hospital
    New Taipei City, 23561, Taiwan
  • China Medical University Hospital
    Taichung, 40447, Taiwan
  • Taichung Veterans General Hospital
    Taichung, 40705, Taiwan
  • National Cheng-Kung University Hospital
    Tainan, 70457, Taiwan
  • National Taiwan University Hospital
    Taipei, 10048, Taiwan
  • Taipei Medical University Hospital
    Taipei, 11031, Taiwan
  • Taipei Veterans General Hospital
    Taipei, 11217, Taiwan
08

References and documents

Publications

  • Jackman D, Pao W, Riely GJ, Engelman JA, Kris MG, Janne PA, Lynch T, Johnson BE, Miller VA. Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. J Clin Oncol. 2010 Jan 10;28(2):357-60. doi: 10.1200/JCO.2009.24.7049. Epub 2009 Nov 30. PubMed 19949011 ↗

Study documents

  • Protocol and statistical analysis plan · Mar 5, 2019

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Yes — De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/

Supporting information: Study protocol, Sap, Csr

09

Registry details

Key details

Study ID
NCT03255083
Lead sponsor
Daiichi Sankyo
Responsible party
Sponsor
First posted
Aug 21, 2017
Start date
Apr 10, 2019
Primary completion
Sep 4, 2020
Completion
Sep 4, 2020
Results posted
Jan 11, 2022
Last update
Jan 19, 2022

Study contacts

Global Clinical Leader
study director · Daiichi Sankyo

Oversight

Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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