Phase II Open-Label Study of Repotrectinib in Frail or Elderly Patients with ROS1-Rearranged Advanced Non-Small-Cell Lung Cancer

Trial ID: 2023-509073-23-00
Protocol: REPOROS GFPC 04-2023
Sponsor: Centre Hospitalier Intercommunal Toulon / La Seine-Sur-Mer

Trial statistics

science

test molecule

location_city

research sites

public

country

medical_information

disease

person_search

investigators

Diseases & Conditions

Non-small cell lung cancer

Objectives

The primary objective of this study is to evaluate the **objective response rate (ORR)** in patients with stage III/IV non-small-cell lung cancer (NSCLC) harboring an ROS1 gene rearrangement, using the RECIST v1.1 criteria. The ORR is determined by the presence of a radiologically confirmed complete response (CR) or partial response (PR), assessed by a masked, independent central review. This objective is clinically relevant as it provides a direct measure of the treatment's efficacy in shrinking tumors, which is crucial for assessing the potential benefits of the investigational drug, Repotrectinib, in this patient population.

Secondary objectives include:

Progression-free survival (PFS) by masked, independent central review
Disease control rate (DCR) by masked, independent central review
Intracranial ORR by masked, independent central review
Overall survival (OS)
Toxicities occurring during either the induction or maintenance treatment, assessed according to NCI-CTCAE v5.0 criteria
Duration of response (DOR) in patients with an objective response, as determined by the investigator using RECIST v1.1
Time to deterioration in lung-related symptoms
Time to deterioration in quality of life
Subgroup analyses according to Performance Status and age
Investigation of the relationships between treatment efficacy and predictive blood biomarkers
Identification of mechanisms of resistance at tumor progression using blood samples

These secondary objectives aim to provide a comprehensive understanding of the treatment's impact on disease progression, patient quality of life, and potential resistance mechanisms, which are essential for optimizing therapeutic strategies in this patient cohort.

Participants

The clinical trial involves participants diagnosed with **Stage III/IV non-small-cell lung cancer (NSCLC)** harboring an ROS1 gene rearrangement. The study population includes both male and female subjects aged 18 years and older, with no vulnerable populations selected. Participants are required to have a life expectancy of at least three months and must be affiliated with an appropriate social security system. They must demonstrate adequate hematologic and end-organ function, as well as a histologically or cytologically confirmed diagnosis of locally advanced or metastatic NSCLC. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Participants' lifestyle considerations, such as diet and physical activity, are not detailed in the available data. Key inclusion criteria include having at least one measurable target lesion according to RECIST v1.1 and the ability to provide written informed consent. The trial allows prior cytotoxic chemotherapy and immunotherapy, with specific conditions regarding the timing and resolution of side effects. Participants are divided into cohorts based on prior treatment with ROS1 tyrosine kinase inhibitors (TKIs), with specific criteria for TKI-naïve and TKI-pretreated individuals. The trial excludes individuals who have previously received ROS1 TKI for the TKI-naïve cohort, while allowing a maximum of 30% of patients in the TKI-pretreated cohort. Subjects with symptomatic CNS metastases and/or asymptomatic leptomeningeal carcinomatosis are eligible for participation.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of **repotrectinib** in patients with stage III/IV non-small-cell lung cancer (NSCLC) harboring an ROS1 gene rearrangement. This is an open-label, phase II study with a primary objective to assess the objective response rate (ORR) according to RECIST v1.1 criteria. The trial will involve a randomized, controlled design, with participants receiving repotrectinib in the form of hard capsules administered orally. The maximum daily dose is set at 320 mg, with a total treatment period not exceeding 72 weeks. The trial is expected to commence recruitment on September 1, 2024, and conclude by August 31, 2031.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, life expectancy, and adequate hematologic and end-organ function. Following the screening, participants will attend regular follow-up visits to monitor treatment response and safety, with assessments including radiological evaluations and laboratory tests. The end-of-study visit will occur upon completion of the treatment period or earlier if disease progression or unacceptable toxicity is observed.

The expected length of participant involvement is up to 72 weeks, contingent upon individual response and tolerability. Conditions that may lead to early termination from the study include disease progression, withdrawal of consent, or adverse events that compromise patient safety. The trial will also collect biospecimens for optional biomarker analysis, contributing to the understanding of treatment effects and potential predictive markers.

Treatment

The clinical trial involves the administration of **Repotrectinib (TPX-0005)**, a chemical compound developed by Bristol-Myers Squibb International Corporation. The pharmaceutical form of Repotrectinib is a hard capsule, designed for oral administration. The maximum daily dose is 320 mg, with the same amount being the maximum total dose allowed per day. The treatment period is set to a maximum of 72 weeks. The active substance in the medication is **repotrectinib**, which is also known by several synonyms, including BMS-986472, FP-247, TPX-0005, CML-478, and TP-01067. The medication is not formulated for pediatric use and is not classified as an orphan drug.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The trial is an open-label Phase II efficacy study focusing on frail and/or elderly patients with ROS1-rearranged advanced non-small cell lung cancer (NSCLC). The primary objective is to assess the objective response rate (ORR) according to RECIST v1.1 criteria, with responses evaluated by a masked, independent central review. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the prescribed regimen.

Efficacy

The efficacy of Repotrectinib in the clinical trial will be primarily assessed through the **Objective Response Rate (ORR)**, which is defined as the proportion of patients achieving a complete response (CR) or partial response (PR) according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). This assessment will be conducted by a masked, independent central review. The ORR will be evaluated from the date of the first treatment administration until disease progression, death, or the introduction of a new treatment.

Secondary efficacy endpoints include the independent central review of **Progression-Free Survival (PFS)**, which measures the time from the first dose of Repotrectinib to the first documentation of objective disease progression or death from any cause. The **Disease Control Rate (DCR)**, defined as the proportion of patients achieving CR, PR, or stable disease (SD) according to RECIST v1.1, will also be assessed. Additionally, the **intracranial Objective Response Rate (ic-ORR)** will be evaluated for patients with measurable brain metastases.

Other secondary endpoints include **Overall Survival (OS)**, defined as the time from the first dose until death from any cause, and the **Duration of Response (DOR)**, which is the time from the first documented objective response until disease progression or death. Patient-reported outcomes will be measured using the EORTC QLQ C30 or QLQ-LC13 for lung-related symptoms and the EQ-5D-3L utility score for quality of life, with specific criteria for deterioration. Subgroup analyses will be conducted for PFS, OS, ORR, DCR, ic-ORR, DOR, duration of treatment, and toxicity according to different subgroups, such as performance status and age.

Inclusion and Exclusion Criteria

check_circle

Inclusion Criteria

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 o 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. o 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.

cancel

Exclusion Criteria

Malignancies other than NSCLC within 2 years prior to inclusion, with the exception of those with a negligible risk of metastasis or death (e.g., expected 5-year OS ≥ 90%) treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous-cell skin cancer, localized prostate cancer treated surgically with curative intent, ductal carcinoma in situ treated surgically with curative intent)
Patients with active hepatitis B (chronic or acute; defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C. Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as the presence of hepatitis B core antibody [HBcAb] and absence of HBsAg) are eligible only if they are negative for HBV DNA. Patients positive for hepatitis C virus (HCV) antibody are eligible only if PCR is negative for HCV RNA.
Active tuberculosis
Severe infections within 2 weeks prior to inclusion, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction, or cerebrovascular accident within 3 months prior to inclusion, unstable arrhythmias, or unstable angina
Major surgical procedure other than for diagnosis within 28 days prior to inclusion or anticipation of need for a major surgical procedure during the course of the study
Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or renders the patient at high risk from treatment complications.
Patients with illnesses or conditions that interfere with their capacity to understand, follow and/or comply with study procedures.
Concurrent participation in any therapeutic clinical trial
Patient deprived of liberty or placed under the authority of a tutor or a curator
Assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol