DS-1205c With Gefitinib for Metastatic or Unresectable Epidermal Growth Factor Receptor (EGFR)-Mutant Non-Small Cell Lung Cancer
Condition: Non Small Cell Lung Cancer
MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
Intervention: DS-1205c; Gefitinib
Intervention description: DS-1205c 200 mg capsule for oral administration; Gefitinib 250 mg tablet for oral administration
Intervention MeSH terms: Gefitinib
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 20.0
Sex: All
Minimum age: 20 Years
Healthy volunteers: No

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 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).
    

Eligibility criteria:

        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 tyrosine kinase inhibitor (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 able to interrupt gefitinib or discontinue erlotinib,
             afatinib, or osimertinib

          5. 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

          6. Has radiological documentation of disease progression while receiving continuous
             treatment with gefitinib, erlotinib, 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 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

          9. Demonstrates absence of EGFR T790M mutation in tumor tissue since progression during
             gefitinib, erlotinib, afatinib, or osimertinib treatment

         10. Has Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1, with
             no deterioration over the previous 2 weeks

        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 on antiandrogen
                  therapy)

          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. 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)

          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 corrected QT interval 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 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

         15. Has history of pancreatitis within the past 6 months