DS-1205c With Gefitinib 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 gefitinib in the study population and to determine the recommended dose for expansion of DS-1205c when combined with gefitinib in the study population For Dose Expansion, to assess the safety and tolerability of DS-1205c when combined with gefitinib 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 for 36 months unless 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 Gefitinib in Subjects With Metastatic or Unresectable EGFR-Mutant Non-Small Cell Lung Cancer

Conditions
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Non Small Cell Lung Cancer

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


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 tyrosine kinase inhibitor (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 able to interrupt gefitinib or discontinue erlotinib, afatinib, or osimertinib Has been receiving gefitinib, erlotinib, afatinib, or osimertinib for at least 6 weeks with well-controlled related toxicities less than Grade 3 in severity at the time of screening period; participants who have been receiving gefitinib must be taking gefitinib at a dose of 250 mg/day Has radiological documentation of disease progression while receiving continuous treatment with gefitinib, erlotinib, 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 gefitinib, erlotinib, 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 mutation in tumor tissue since progression during gefitinib, erlotinib, afatinib, or osimertinib treatment 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 on antiandrogen therapy) 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). Has 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 corrected QT interval 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 a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required corticosteroid treatment, has current ILD/pneumonitis, or has suspected ILD/pneumonitis which cannot be ruled out by imaging at screening Has history of pancreatitis within the past 6 months

Ages Eligible for Study
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Minimum Age: 20 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 Gefitinib<br>Participants receive DS-1205c (at planned doses given orally twice daily: 200 mg, 400 mg, 800 mg, 1000 mg, 1200 mg) in combination with daily 250 mg oral dose of gefitinib | Drug: DS-1205c<br>* DS-1205c 200 mg capsule for oral administration<br>* Other names: Experimental product;Drug: Gefitinib<br>* Gefitinib 250 mg tablet for oral administration<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 Gefitinib | A dose-limiting toxicity (DLT) was defined as any treatment-emergent adverse event (TEAE) not attributable to disease or disease-related processes that occurs during the DLT-evaluation period (Cycle 0 Day 1 to Cycle 1 Day 21 of Dose Escalation) and is Grade 3 or above, according to NCI-CTCAE version 5.0. | Cycle 0 Day 1 (7-day cycle) to Cycle 1 Day 21 (each cycle is 21 days) | 
| Number of Participants With Treatment-emergent Adverse Events Occurring in Participants Following Administration With DS-1205c in Combination With Gefitinib | An adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A treatment-emergent adverse event (TEAE) was defined as an 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 37 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 1, 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 With Confirmation as Assessed by Investigator Following Administration of DS-1205c in Combination With Gefitinib | 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 was calculated as the number of participants with best objective response (CR + PR) determined by Investigator assessment based on Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1]. | 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 Gefitinib | Disease control rate (DCR) was defined number of participants with CR+PR+SD objective response. 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 Gefitinib | Progression-free survival (PFS) was defined as the time from the date of the first dose to the earlier of the dates of the first objective documentation of radiographic PD 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 Gefitinib | Overall Survival (OS) was defined as the time from the date of first dose to the date of death from 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 | 
| Pharmacokinetic Parameter of Maximum Concentration (Cmax) of DS-1205a Following Administration of DS-1205c in Combination With Gefitinib | Blood samples for pharmacokinetic (PK) analyses of DS-1205a were obtained at specified time points. Plasma concentrations of DS-1205a were measured using validated assays and non-compartmental analysis. | Predose, 1, 2, 4, 6, 8, and 10 hours of Cycle 0 (7-day cycle; DS-1205c alone), Days 1 and 7; Predose of Cycle 1 (21-day cycle), Day 1 (DS-1205c + gefitinib); Predose, 1, 2, 4, 6, 8, and 10 hours of Cycle 2 (21-day cycle; DS-1205c + gefitinib), Day 1 | 
| Pharmacokinetic Parameter Time to Maximum Concentration (Tmax) of DS-1205a Following Administration of DS-1205c in Combination With Gefitinib | Blood samples for pharmacokinetic (PK) analyses of DS-1205a were obtained at specified time points. Plasma concentrations of DS-1205a were measured using validated assays and non-compartmental analysis. | Predose, 1, 2, 4, 6, 8, and 10 hours of Cycle 0 (7-day cycle; DS-1205c alone), Days 1 and 7; Predose of Cycle 1 (21-day cycle), Day 1 (DS-1205c + gefitinib); Predose, 1, 2, 4, 6, 8, and 10 hours of Cycle 2 (21-day cycle; DS-1205c + gefitinib), Day 1 | 
| Pharmacokinetic Parameter Area Under the Plasma Concentration Curve of DS-1205a Following Administration of DS-1205c in Combination With Gefitinib | Blood samples for pharmacokinetic (PK) analyses of DS-1205a were obtained at specified time points. Plasma concentrations of DS-1205a were measured using validated assays and non-compartmental analysis. Area under the plasma concentration curve from time 0 to 8 hours (AUC8h), area under the plasma concentration-time curve from time 0 to 10 hours (AUC10h), and area under the plasma concentration-time curve during a dosing interval (AUCtau) were assessed. | Predose, 1, 2, 4, 6, 8, and 10 hours of Cycle 0 (7-day cycle; DS-1205c alone), Days 1 and 7; Predose of Cycle 1 (21-day cycle), Day 1 (DS-1205c + gefitinib); Predose, 1, 2, 4, 6, 8, and 10 hours of Cycle 2 (21-day cycle; DS-1205c + gefitinib), Day 1 | 
| Pharmacokinetic Parameter Trough Plasma Concentration (Ctrough) of DS-1205a Following Administration of DS-1205c in Combination With Gefitinib | Blood samples for pharmacokinetic (PK) analyses of DS-1205a were obtained at specified time points. Plasma concentrations of DS-1205a were measured using validated assays and non-compartmental analysis. | Predose, 1, 2, 4, 6, 8, and 10 hours of Cycle 0 (7-day cycle; DS-1205c alone), Days 1 and 7; Predose of Cycle 1 (21-day cycle), Day 1 (DS-1205c + gefitinib); Predose, 1, 2, 4, 6, 8, and 10 hours of Cycle 2 (21-day cycle; DS-1205c + gefitinib), Day 1 |