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 for 36 months unless they decide not to (withdraw consent), their disease gets worse [progressive disease (PD)], or side effects become unacceptable (unacceptable toxicity).
Name: DS-1205c
Description: DS-1205c 200 mg capsuleType: DrugDS-1205c with osimertinib
Name: Osimertinib
Description: Osimertinib 80 mg tabletType: DrugDS-1205c with osimertinib
Description: Categories: during dose escalation, during dose expansion
Measure: Number of participants with clinically significant safety measures when taking DS-1205c in combination with osimertinib Time: within 36 monthsDescription: DS-1205a is the free form of DS-1205c when DS-1205c is administered alone
Measure: Area under the plasma concentration time curve (AUC) for DS-1205a Time: during Cycle 0 of the dose escalation period (within 28 days)Description: Categories: DS-1205a, osimertinib, and osimertinib active metabolites (AZ5104 and AZ7550)
Measure: Cmax during a dosing interval (Tau) at steady state (Cmax,ss) Time: during the dose expansion period, within 36 monthsDescription: Categories: DS-1205a, osimertinib, and osimertinib active metabolites (AZ5104 and AZ7550)
Measure: Plasma concentration of DS-1205a versus time Time: during the dose expansion period, within 36 monthsDescription: Categories: DS-1205a, osimertinib, and osimertinib active metabolites (AZ5104 and AZ7550)
Measure: Tmax Time: during the dose expansion period, within 36 monthsDescription: Categories: DS-1205a, osimertinib, and osimertinib active metabolites (AZ5104 and AZ7550)
Measure: Ctrough Time: during the dose expansion period, within 36 monthsDescription: Categories: DS-1205a, osimertinib, and osimertinib active metabolites
Measure: AUCtau Time: during the dose expansion period, within 36 monthsDescription: 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.
Measure: Objective response rate (ORR), graded according to RECIST version 1.1 Time: within 36 monthsDescription: DOR is defined as the time from documentation of tumor response [either CR or PR] to disease progression
Measure: Duration of response (DOR) Time: within 36 monthsDescription: DCR is defined as the sum of CR rate, PR rate, and stable disease (SD) rate
Measure: Disease control rate (DCR) Time: first dose to 36 monthsDescription: PFS is 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
Measure: Progression-free survival (PFS) Time: baseline to objective disease progression or death from any cause (within 36 months)Single Group Assignment
There are 4 SNPs
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. --- L858R ---
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. --- L858R --- --- L861Q ---
9. Demonstrates absence of EGFR T790M. --- T790M ---
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. --- V600E ---