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

Study Overview
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Brief Summary
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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).

Official Title
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A Multicenter, Open-Label Phase 1 Study of DS-1205c in Combination With Osimertinib in Subjects With Metastatic or Unresectable EGFR-Mutant Non-Small Cell Lung Cancer

Conditions
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Non-small Cell Lung Cancer (NSCLC)

Intervention / Treatment
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* Drug: DS-1205c
* Drug: Osimertinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has histologically or cytologically documented adenocarcinoma NSCLC. Has locally advanced or metastatic NSCLC, not amenable to curative surgery or radiation. Has acquired resistance to EGFR TKI according to the Jackman criteria (PMID: 19949011): 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 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. 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. 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. Has radiological documentation of disease progression while receiving continuous treatment with erlotinib, gefitinib, afatinib, or osimertinib. Has at least one measurable lesion per RECIST version 1.1. 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. Demonstrates absence of EGFR T790M. No EGFR mutation testing is required if treated with osimertinib. Has Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1, with no deterioration over the previous 2 weeks. Exclusion Criteria: 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. 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. Has received treatment with any of the following: 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. Immune checkpoint inhibitor therapy within 30 days of first dose of study treatment. Major surgery (excluding placement of vascular access) within 4 weeks of the first dose of study treatment. 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. Has history of other active malignancy within 3 years prior to enrollment, except: Adequately treated non-melanoma skin cancer OR Superficial bladder tumors (tumor stage a [Ta], tumor stage is [Tis], tumor stage 1 [T1]) OR Curatively treated in situ disease OR Low risk non-metastatic prostate cancer (with Gleason score < 7, and following local treatment or undergoing active surveillance) 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). 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). Has history of myocardial infarction within the past 6 months. Has symptomatic congestive heart failure (New York Heart Association [NYHA] Classes II-IV), unstable angina, or cardiac arrhythmia requiring antiarrhythmic treatment. Has left ventricular ejection fraction (LVEF) <45% by either echocardiogram (ECHO) or multigated acquisition (MUGA) scan. 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). 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. Unable or unwilling to discontinue concomitant use of drugs that are known to prolong the QT interval. 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. Has any history of interstitial lung disease (pulmonary fibrosis or severe radiation pneumonitis) or is suspected to have such disease by imaging during screening. Has history of pancreatitis within the past 6 months.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DS-1205c with osimertinib<br>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<br>* DS-1205c 200 mg capsule<br>Drug: Osimertinib<br>* Osimertinib 80 mg tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Cycle 0, Day 1 (7-day cycle) to Cycle 1, Day 21 of Dose Escalation (each cycle was 21 days) | 
| 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. | 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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) | 
| 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. | 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) | 
| 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. | 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) | 
| 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. | 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) | 
| 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. | 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Oncology, Advanced Non-small Cell Lung Cancer, Inoperable Non-small Cell Lung Cancer, Metastatic, Non-resectable, Epidermal growth factor receptor, EGFR