Phase II Efficacy Study of Repotrectinib in Frail and/or Elderly Patients With ROS1-rearranged Advanced NSCLC

Inclusion Criteria38

• Eligible patients are defined as patients with
• Eastern Cooperative Oncology Group (ECOG) PS ≥ 2 at the time of inclusion and/or
• Age ≥ 70 years
• Age ≥ 18 years
• Histologically or cytologically confirmed diagnosis of locally advanced or metastatic NSCLC harboring an ROS1 gene rearrangement as by any nucleic acid-based diagnostic testing method (e.g., next-generation sequencing \[NGS\], Sanger sequencing, reverse transcription-polymerase chain reaction), Break-apart fluorescence in situ hybridization (FISH) or Immunohistochemistry (IHC) (confirmed by NGS or qPCR test).
• Willing and able to provide written institutional review board (IRB)/institutional ethics committee-approved Informed Consent.
• At least 1 measurable target lesion according to RECIST (v1.1). CNS-only measurable disease as defined by RECIST (v1.1) is allowed.
• Prior cytotoxic chemotherapy for advanced or metastatic disease is allowed. At the time of starting treatment with repotrectinib, at least 14 days or 5 half-lives (whichever is shorter) must have elapsed after discontinuation of prior cytotoxic chemotherapy (or at least 42 days for prior nitrosoureas, mitomycin C, and liposomal doxorubicin) and all side effects from prior treatments must have resolved to grade ≤ \_1 (CTCAE Version 5.0 with the exception of alopecia.
• Prior immunotherapy (e.g., anti-PD-1, anti-PDL1, anti-TIM3, anti-OX40) is allowed. At the time of starting treatment with repotrectinib, at least 14 days must have elapsed after discontinuation of prior immunotherapy treatment and all immune-related side effects from prior treatments must have resolved to grade ≤ \_1.
• No prior ROS1 TKI is allowed for the TKI naïve cohort.
• Prior ROS1 TKI is allowed for the TKI pretreated cohort (max 30% of patients). At least 7 days or 5 half-lives (whichever is shorter) must have elapsed since completion of treatment with the last ROS1i prior to starting treatment with repotrectinib for subjects enrolling into the TKI-pretreated expansion cohorts. All side effects from prior treatments with ROS1i must have resolved to grade ≤ \_1 prior to starting treatment with repotrectinib.
• Prior ROS1i allowed include crizotinib, ceritinib, lorlatinib, brigatinib, entrectinib, ensartinib, cabozantinib.
• Subjects with symptomatic CNS metastases and/or asymptomatic leptomeningeal carcinomatosis are eligible.
• Life expectancy ≥3 months
• Subject affiliated to an appropriate social security system
• Adequate hematologic and end-organ function, defined by the following laboratory
• ANC ≥ 1500 /mm3 without granulocyte colony-stimulating factor support
• Lymphocyte count ≥ 500/mm3
• Platelet count ≥ 100,000/mm3 without transfusion
• Hemoglobin ≥ 9.0 g/dL. Patients may be transfused to meet this criterion.
• INR or aPTT ≤ 1.5, upper limit of normal (ULN)
• This applies only to patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be receiving a stable dose.
• ASAT, ALAT, and alkaline phosphatase ≤ 2.5xULN, with the following exceptions:
• Patients with documented liver metastases: ASAT and/or ALAT ≤ 5xULN
• Patients with documented liver or bone metastases: alkaline phosphatase \< 5xULN
• Serum bilirubin ≤1.25xULN
• Patients with known Gilbert disease who have serum bilirubin level ≤ 3xULN may be enrolled.
• Calculated creatinine clearance (CRCL) ≥ 45 mL/min
• Adequate method of contraception during the treatment period
• For Females:
• All women of childbearing potential (WOCBP) must agree to avoid pregnancy during the study and must use a highly effective method of contraception during study treatment with repotrectinib and for at least 2 months following the final dose.
• Highly effective contraceptive methods consist of prior sterilization, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), injectable or implantable contraceptives and abstinence.
• Hormonal contraception must begin 7 days prior to the first dose of study treatment.
• Due to a potential loss of effectiveness of hormonal contraceptives caused by interaction with study intervention, if WOCBP use hormonal contraceptives (including oral hormonal contraceptives), they must use either another form of non-hormonal highly effective contraception or a reliable barrier method.
• Female subjects must refrain from egg donation from screening through at least 2 months after the last dose of study drug.
• For Males:
• Male participants with WOCBP partners must use latex condoms during treatment with repotrectinib and for 4 months following the final dose even if the participant has undergone a successful vasectomy or if the partner is pregnant or breastfeeding.
• Male subjects must refrain from sperm donation from screening through at least 4 months after the last dose of study drug