Phase II Efficacy Study of Repotrectinib in Frail and/or Elderly Patients With ROS1-rearranged Advanced NSCLC
NCT Number: NCT06552234
Acronym: REPOROS
Status: NOT_YET_RECRUITING
Study Type: INTERVENTIONAL
Phases: PHASE2
Conditions: NSCLC Stage IV|NSCLC, Stage III
Interventions: DRUG: Repotrectinib
Sponsor: Centre Hospitalier Intercommunal de Toulon La Seyne sur Mer
Collaborators: Groupe Français de Pneumo-Cancérologie|Hospices Civils de Lyon
Sex: ALL
Age: ADULT, OLDER_ADULT
Enrollment: 30
Study Design: Allocation: NA|Intervention Model: SINGLE_GROUP|Masking: NONE|Primary Purpose: TREATMENT
Start Date: 2024-09-01
Completion Date: 2031-08-01
Locations: CH Aix-en-Provence, Aix-en-Provence, Bouches Du Rhône, France|AP-HM, Marseille, Bouches Du Rhône, France|HIA Sainte Anne, Toulon, Var, France|CHU Angers, Angers, France|CHU Bordeaux, Bordeaux, France|CHU Brest, Brest, France|Centre François Baclesse, Caen, France|CH Chambéry, Chambéry, France|Hôpitaux civils de Colmar, Colmar, France|CHI Créteil, Créteil, France|CHD Vendée, La Roche-sur-Yon, France|CHRU Lille, Lille, France|CHU Limoges, Limoges, France|Hospices Civils de Lyon, Lyon, France|CH Cornouaille, Quimper, France|CHU Rennes, Rennes, France|CHU Rouen, Rouen, France|Hôpital Foch, Suresnes, France|CHU Toulouse, Toulouse, France|Hôpitaux Nord-Ouest, Villefranche-sur-Saône, France

Summary:
ROS1 rearrangements are rare, accounting for only 1-2% of NSCLC cases, but have been associated with response to ROS1 inhibitors, such as crizotinib and entrectinib. However, many patients develop resistance to the tyrosine-kinase inhibitors (TKIs), creating a need for new treatments.

Repotrectinib is a new-generation TKI designed against ROS1 or NTRK rearranged malignancies (Drilon 2018). Early phase clinical data support activity of repotrectinib in patients with NSCLC harboring such gene rearrangements (TRIDENT-1 study), but there are limited evidence in frail populations, such as poor performance status patients and/or elderly patients, who are classically excluded from clinical trials or underrepresented.

The present study aims to assess the activity and tolerability of repotrectinib in frail (PS ≥2) and/or elderly patients with ROS1-rearranged advanced NSCLC.

Primary Outcome Measures: Objective response rate (ORR) according to RECIST v1.1., ORR defined as the proportion of patients who achieved a complete or partial response 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.

Tumor assessments will be performed at Screening, every 2 Months during the first year then every 3 months thereafter until documented progression, death or the introduction of a new treatment.

Patients who discontinue treatment for reasons other than radiographic disease progression per RECIST v1.1 (toxicity, symptomatic deterioration) will continue scheduled tumor assessments until radiographic disease progression per RECIST v1.1, withdrawal of consent, death, or study termination by the co-Sponsors, whichever occurs first, From the date of first treatment administration until the date of disease progression or death if patient died before progression) or the introduction of a new treatment, which ever occurs earlier, assessed up to 7 years
Secondary Outcome Measures: Progression free survival (PFS) by masked, independent central review, 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.

Tumor assessments will be performed at Screening, every 2 Months during the first year then every 3 months thereafter until documented progression, death or the introduction of a new treatment.

Patients who discontinue treatment for reasons other than radiographic disease progression per RECIST v1.1 (e.g., toxicity, symptomatic deterioration) will continue scheduled tumor assessments until radiographic disease progression per RECIST v1.1, withdrawal of consent, death, or study termination by the co-Sponsors, whichever occurs first., From the date of first treatment administration until the date of disease progression (or death if patient died before progression), which ever occurs earlier, assessed up to 7 years|Disease control rate (DCR) by masked, independent central review, 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.

Tumor assessments will be performed at Screening, every 2 Months during the first year then every 3 months thereafter until documented progression, death or the introduction of a new treatment.

Patients who discontinue treatment for reasons other than radiographic disease progression per RECIST v1.1 (e.g., toxicity, symptomatic deterioration) will continue scheduled tumor assessments until radiographic disease progression per RECIST v1.1, withdrawal of consent, death, or study termination by the co-Sponsors, whichever occurs first., From the date of first treatment administration until the date of disease progression (or death if patient died before progression), which ever occurs earlier, assessed up to 7 years|Intracranial ORR (ic-ORR) by masked, independent central review, ic-ORR, defined as the proportion of patients who achieved CR or PR in measurable brain metastases based on RECIST 1.1 criteria, From the date of first treatment administration until the date of disease progression (or death if patient died before progression), which ever occurs earlier, assessed up to 7 years|Overall survival (OS), 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.

OS will be evaluated every 3 months (until death or lost to follow-up) in patients who:

* Discontinue the study treatment due to disease progression
* Discontinue the study treatment due to an unacceptable toxicity or any other reason, and who start a new therapy
* Reach the End-of-study Time Point., From the date of first treatment administration until the date of death from any cause, assessed up to 7 years|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, 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., From the date of first treatment administration up to 30 days after the last dose of study treatment|Duration of response (DOR) assessed in patients who had an objective response as determined by the investigator using RECIST v1.1, DOR, defined as the time from the first documented objective response (CR or PR) until disease progression or death, whichever occurs first., From the date of first documented objective response (CR or PR) until disease progression or death, which ever occurs earlier, assessed up to 7 years|Time to deterioration in lung-related symptoms, 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.

QoL/PRO questionnaires may be filled out up until D1 every 8 weeks ±7 days during the first year, then every 12 weeks ±7 days thereafter at Progression., From the date of inclusion to the date the patient's score on the EORTC QLQ C30 or QLQ-LC13 shows a ≥10-point increase above baseline, assessed up to 7 years|Time to deterioration in quality of life, 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.

QoL/PRO questionnaires may be filled out up until D1 every 8 weeks ±7 days during the first year, then every 12 weeks ±7 days thereafter at Progression., From the date of inclusion to the date the patient's score on the EQ-5D-3L utility score shows a 0.08 point decrease above baseline, assessed up to 7 years|PFS subgroup analysis according to Performance Status and age, PFS according to different subgroups :

* PS ≥ 2 at the time of inclusion
* Age ≥ 70 years, From the date of first treatment administration until the date of disease progression (or death if patient died before progression), which ever occurs earlier, assessed up to 7 years|OS subgroup analysis according to Performance Status and age, OS according to different subgroups :

* PS ≥ 2 at the time of inclusion
* Age ≥ 70 years, From the date of first treatment administration until the date of death from any cause, assessed up to 7 years|ORR subgroup analysis according to Performance Status and age, ORR according to different subgroups :

* PS ≥ 2 at the time of inclusion
* Age ≥ 70 years, From the date of first treatment administration until the date of disease progression or death if patient died before progression) or the introduction of a new treatment, which ever occurs earlier, assessed up to 7 years|DCR subgroup analysis according to Performance Status and age, DCR according to different subgroups :

* PS ≥ 2 at the time of inclusion
* Age ≥ 70 years, From the date of first treatment administration until the date of disease progression (or death if patient died before progression), which ever occurs earlier, assessed up to 7 years|ic-ORR subgroup analysis according to Performance Status and age, ic-ORR according to different subgroups :

* PS ≥ 2 at the time of inclusion
* Age ≥ 70 years, From the date of first treatment administration until the date of disease progression (or death if patient died before progression), which ever occurs earlier, assessed up to 7 years|DOR subgroup analysis according to Performance Status and age, DOR according to different subgroups :

* PS ≥ 2 at the time of inclusion
* Age ≥ 70 years, From the date of first documented objective response (CR or PR) until disease progression or death, which ever occurs earlier, assessed up to 7 years|Duration of study treatment subgroup analysis according to Performance Status and age, Duration of treatment according to different subgroups :

* PS ≥ 2 at the time of inclusion
* Age ≥ 70 years, From the date of first treatment administration until the date of last treatment administration, up to 7 years|Toxicities occurring during study treatment assessed by the NCI-CTCAE v5.0, analysed in subgroups according to Performance Status and age, Proportion (%) of patients with any AE and number of events for all AEs, all SAEs and all AEs of grade ≥3 assessed by the NCI-CTCAE v5.0 criteria, according to different subgroups :

* PS ≥ 2 at the time of inclusion
* Age ≥ 70 years, From the date of first treatment administration up to 30 days after the last dose of study treatment