Open-Label Phase Ii Efficacy Study of Repotrectinib in Frail (Ps ≥2) and OR Elderlypatients with ROS1-REARRANGED Advanced NSCLC

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier Intercommunal Toulon, La Seine-Sur-Mer, Groupe Français de Pneumo-Oncologie

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08], Diseases [C] - Neoplasms [C04]

Trial duration

1 Oct 2024 → ongoing

Decision date (initial)

2024-07-24

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Bristol-Myers Squibb (BMS)

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

The primary objective is the objective response rate (ORR) according to RECIST v1.1.
Objective response will be considered in case of radiologically confirmed complete (CR) or partial response (PR) according to RECIST v1.1 criteria (Response Evaluation Criteria in Solid Tumors version 1.1) assessed by masked, independent central review.

Secondary objectives 11

1. Progression free survival (PFS) by masked, independent central review
2. Disease control rate (DCR) by masked, independent central review
3. Intracranial ORR by masked, independent central review
4. Overall survival (OS)
5. Toxicities occurring during either the induction or maintenance treatment in terms of kind, grade, time of onset, reversibility, according to NCI-CTCAE v5.0 criteria
6. Duration of response (DOR) assessed in patients who had an objective response as determined by the investigator using RECIST v1.1
7. Time to deterioration in lung-related symptoms
8. Time to deterioration in quality of life
9. Subgroup analyses according to Performance Status and age
10. To investigate the relationships between treatment efficacy and predictive blood biomarkers
11. To identify the mechanisms of resistance at tumor progression, using blood samples (optional biocollection).

Conditions and MedDRA coding

Stage III/IV non-small-cell lung cancer (NSCLC) harboring an ROS1 gene rearrangement

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Age ≥ 18 years
2. 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).
3. Willing and able to provide written institutional review board (IRB)/institutional ethics committee-approved Informed Consent.
4. At least 1 measurable target lesion according to RECIST (v1.1). CNS-only measurable disease as defined by RECIST (v1.1) is allowed.
5. 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.
6. 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.
7. No prior ROS1 TKI is allowed for the TKI naïve cohort.
8. 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.
9. Subjects with symptomatic CNS metastases and/or asymptomatic leptomeningeal carcinomatosis are eligible.
10. Life expectancy ≥3 months
11. Subject affiliated to an appropriate social security system
12. 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
13. 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.

Exclusion criteria 11

1. 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)
2. 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.
3. Active tuberculosis
4. Severe infections within 2 weeks prior to inclusion, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
5. 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
6. 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
7. 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.
8. Patients with illnesses or conditions that interfere with their capacity to understand, follow and/or comply with study procedures.
9. Concurrent participation in any therapeutic clinical trial
10. Patient deprived of liberty or placed under the authority of a tutor or a curator
11. Assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. ORR, defined as the proportion of patients who achieved a complete response (CR) or partial response (PR) according to RECIST v1.1 from the date of first treatment administration until disease progression (or death if patient died before progression) or the introduction of a new treatment assessed by blinded independent central review (BICR).

Secondary endpoints 11

1. Independent central review of progression free survival (PFS) from Repotrectinib initiation, defined as the time from first dose of Repotrectinib to first documentation of objective disease progression (RECIST v1.1) or to death from any cause. Patients lost to follow-up will be censored as the last date of radiological assessment without progression.
2. DCR, defined as the proportion of patients who achieved a complete response (CR) or partial response (PR) or stable disease (SD) according to RECIST v1.1 assessed by BICR.
3. ic-ORR, defined as the proportion of patients who achieved CR or PR in measurable brain metastases.
4. OS, defined as the time from first dose of Repotrectinib until death from any cause. Patients lost to follow-up will be censored at the last date known to be alive.
5. Proportion (%) of patients with any adverse event (AE) and number of events for all AEs, all serious AEs (SAEs) and all AEs of grade ≥3 according to the National Cancer Institute (NCI) Common terminology criteria for adverse events (CTCAE) v5.0 criteria.
6. DOR, defined as the time from the first documented objective response (CR or PR) until disease progression or death, whichever occurs first.
7. Time to deterioration in lung-related symptoms, defined as the time from inclusion to the time the patient’s score on the EORTC QLQ C30 or QLQ-LC13 shows a ≥10-point increase above baseline in each of the following EORTC-transformed scores for cough, dyspnea (single item), dyspnea (multi-item subscale) and chest pain. Patients lost to follow-up without previous QOL deterioration will be censored at the last EORTC assessment date.
8. Time to deterioration in quality of life, defined as the time from inclusion to the time the patient’s score on the EQ-5D-3L utility score shows a 0.08 point decrease above baseline. Patients lost to follow-up without previous EQ-5D-3L deterioration will be censored at the last EQ-5D-3L assessment.
9. Subgroup analyses: PFS, OS, ORR, DCR, ic-ORR, DOR, duration of treatment and toxicity according to different subgroups : PS ≥ 2 at the time of inclusion ; Age ≥ 70 years
10. Biospecimens (blood components) to support analyses of cellular components (e.g. protein, DNA, RNA, metabolites) and other circulating molecules, which are collected to identify novel biomarkers (optional biocollection).
11. Biospecimens (blood components) to support analyses of cellular components (e.g. protein, DNA, RNA, metabolites) and other circulating molecules, which are collected to identify novel biomarkers (optional biocollection).

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier Intercommunal Toulon / La Seine-Sur-Mer

Sponsor organisation

Centre Hospitalier Intercommunal Toulon / La Seine-Sur-Mer

Address

54 Rue Henri Sainte Claire Deville, Cs 91400 Cs 91400

City

Toulon Cedex

Postcode

83056

Country

France

Scientific contact point

Organisation

Groupe Français de Pneumo-Oncologie

Contact name

Soizic Ferlandin

Public contact point

Organisation

Centre Hospitalier Intercommunal Toulon / La Seine-Sur-Mer

Contact name

Jean-Philippe Suppini

Groupe Français de Pneumo-Oncologie

Sponsor organisation

Groupe Français de Pneumo-Oncologie

Address

84 avenue de la République

City

Clermont-Ferrand

Postcode

63050

Country

France

Sponsor responsibilities

Article 77 compliance

Centre Hospitalier Intercommunal Toulon / La Seine-Sur-Mer

Contact point sponsor

Centre Hospitalier Intercommunal Toulon / La Seine-Sur-Mer

Article 77 implementation

Centre Hospitalier Intercommunal Toulon / La Seine-Sur-Mer

Locations

1 EU/EEA country · 20 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 17 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications