Phase II Evaluation of Repotrectinib Efficacy and Safety in ROS1-Positive NSCLC Patients with Active Brain Metastases

Trial ID: 2023-508112-35-00
Protocol: MEDOPP662
Sponsor: Medica Scientia Innovation Research S.L.

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Diseases & Conditions

Metastases to central nervous system Non-small cell lung cancer

Objectives

The primary objective of this phase II study is to assess the **efficacy** of repotrectinib in terms of intracranial objective response rate (IC-ORR) in patients with **ROS1-positive non-small cell lung cancer (NSCLC)** with active brain metastasis. This is clinically relevant as it aims to determine the potential of repotrectinib to effectively target and reduce intracranial tumor burden, which is a critical concern in this patient population.

Secondary objectives include:

Evaluating efficacy in terms of progression-free survival (PFS), overall survival (OS), extracranial objective response rate (EC-ORR), clinical benefit rate (CBR), time to response (TTR), duration of response (DoR), disease control rate (DCR), and best percentage of change in tumor burden for intracranial lesions as per RANO-BM and RECIST v.1.1 for extracranial and overall lesions (bicompartmental ORR).
Assessing changes in neurocognitive functions and health-related quality of life (QoL) using the EORTC QLQ-C30 and EORTC QLQ-BN20 questionnaires.
Evaluating neurological function according to the Neurologic Assessment in Neuro-Oncology (NANO) scale.
Determining the safety and toxicity profile of repotrectinib treatment according to the NCI-CTCAE v.5.0.

Participants

The clinical trial involves participants diagnosed with **ROS1-positive non-small cell lung cancer (NSCLC)** with active brain metastasis. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a general health status that allows for an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, and a minimum life expectancy of at least 6 weeks. The trial does not limit the number of prior chemotherapies, immunotherapy, or other non-ROS1 TKI regimens, but excludes those who have previously received any ROS1 TKI-based treatment. Participants must have adequate bone marrow, liver, and renal function, and must be capable of swallowing capsules intact. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified. Key inclusion criteria include histologically documented NSCLC, confirmed ROS1 rearrangement, and measurable disease according to Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. Participants must be accessible for treatment and follow-up, and women of childbearing potential must adhere to specific contraceptive guidelines.

Plans and Procedures

The clinical trial is designed to evaluate the **efficacy** and safety of **repotrectinib** in patients with **ROS1-positive non-small cell lung cancer** (NSCLC) with active brain metastasis. This is a phase II, open-label, single-arm study utilizing Simon's two-stage design. The trial aims to assess the intracranial objective response rate (IC-ORR) as the primary endpoint, with secondary endpoints including progression-free survival (PFS), overall survival (OS), and other response metrics. The study is expected to commence recruitment on December 2, 2024, and conclude by April 30, 2027.

Participants will be involved in the study for a maximum treatment period of 36 months, with the administration of **repotrectinib** in the form of hard capsules taken orally. The maximum daily dose is set at 320 mg. The trial includes several key visits: an initial screening visit to confirm eligibility based on criteria such as ECOG performance status, life expectancy, and adequate organ function; regular follow-up visits to monitor treatment response and safety; and an end-of-study visit to assess final outcomes. Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or withdraw consent.

Inclusion criteria require participants to have a confirmed **ROS1 rearrangement**, measurable disease according to RANO-BM criteria, and no prior treatment with ROS1 TKI-based therapies. Exclusion criteria are not explicitly listed. The study will also explore the relationship between treatment efficacy and biomarkers, as well as the association of efficacy outcomes with radiological imaging biomarkers. Safety assessments will include changes in quality of life scales, neurological function, and adverse events as per NCI-CTCAE v.5.0.

Treatment

The clinical trial involves the administration of **Repotrectinib (TPX-0005)**, a **tyrosine kinase inhibitor**, as the experimental medication. Repotrectinib is provided in the form of a hard capsule, with each capsule containing the active chemical substance **repotrectinib**. The medication is administered orally, with a maximum daily dose of 320 mg. The treatment period is set for a maximum of 36 months. The pharmaceutical product is developed by Bristol-Myers Squibb International Corporation and is identified by the sponsor product code BMS-986472. The study aims to evaluate the efficacy of Repotrectinib in patients with ROS1-positive non-small cell lung cancer and active brain metastasis, focusing on the intracranial objective response rate (IC-ORR).

In addition to the experimental treatment, the study may include non-experimental treatments such as standard-of-care therapy or placebo, depending on the specific study design and protocol. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the treatment regimen. The trial does not involve any pediatric formulations, and the product is not classified as an orphan drug. The administration of Repotrectinib is strictly regulated to maintain the integrity and safety of the clinical trial.

Efficacy

The efficacy of Repotrectinib in the treatment of **ROS1-positive non-small cell lung cancer** with active brain metastasis will be assessed primarily through the intracranial objective response rate (IC-ORR). This primary endpoint will be evaluated at any timepoint based on the best central nervous system (CNS) response, as determined by the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. Secondary endpoints include progression-free survival (PFS), overall survival (OS), extracranial objective response rate (EC-ORR), clinical benefit rate (CBR), disease control rate (DCR), time to response (TTR), duration of response (DoR), and the best percentage of change in tumor burden for intracranial and extracranial lesions. These will be assessed using the RECIST v.1.1 criteria.

Safety endpoints will be evaluated through changes from baseline in the EORTC QLQ-C30 and EORTC QLQ-BN20 scales, neurological function assessment via the NANO scale, and safety and tolerability as per NCI-CTCAE v.5.0. Exploratory endpoints may include the relationship of treatment efficacy outcomes with biomarkers analyzed in blood samples, association with radiological imaging biomarkers, and efficacy according to ROS1 gene expression level at baseline. The trial is designed as an international, multicenter, open-label, single-arm, one cohort, Simon’s two-stage phase II clinical trial, with an estimated end date of April 30, 2027.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Patient must be capable to understand the purpose of the study and have signed written informed consent form (ICF) prior to beginning specific protocol procedures.
Female or male patients ≥ 18 years of age at the time of signing ICF.
Patients must be capable to swallow capsules intact (without chewing, crushing, or opening).
Histologically documented NSCLC.
Patients may have symptoms attributed to brain metastases.
No indication for immediate local therapy (neurosurgery, brain radiotherapy) of brain metastases per local investigator. Note: in case of immediate local therapy is needed, the study’s medical monitor should be consulted
Type II leptomeningeal disease per ESMO-EANO guidelines are allowed.
Patients with confirmed ROS1 rearrangement. Prior to study enrollment, patients must have had confirmation of ROS1 rearrangement, which should have been determined locally by a certified laboratory using methods such as FISH, NGS, qPCR, or IHC.
Measurable disease according to Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria, with at least one measurable brain lesion of ≥10 mm on T1-weighted, gadoliniumenhanced magnetic resonance imaging (MRI).
ECOG PS of ≤ 2.
Minimum life expectancy of ≥ 6 weeks at screening.
No limit in number of prior chemotherapies, immunotherapy or other non-ROS1 TKI regimens.
Patients must not have previously received any ROS1 TKI-based treatment.
Left ventricular ejection fraction (LVEF) ≥ 50% by echocardiogram (ECHO) or multigated acquisition (MUGA) scan
If feasible, archival tumor biopsy sample at baseline (from primary tissue or any metastatic site) should be provided.
Patient has adequate bone marrow, liver, and renal function: I. Hematological (without platelet, red blood cell transfusion, and/or granulocyte colonystimulating factor support within 7 days before first study treatment dose): White blood cell (WBC) count > 3.0 x 109/L, absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelet count ≥ 100.0 x109/L, and hemoglobin ≥ 8.0 g/dL (≥ 4.96 mmol/L).
Patient has adequate bone marrow, liver, and renal function: II. Hepatic: Total bilirubin ≤ 1.5 times upper limit of normal (ULN) (≤ 3 in patients with liver metastases or know history of Gilbert’s disease); alkaline phosphatase (ALP) ≤ 2.5 times ULN; aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 times ULN (≤ 5 in patients with liver metastases); international normalized ratio (INR) < 1.5.
Patient has adequate bone marrow, liver, and renal function: III. Renal: serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 40 mL/min/1.73 m2 based on Cockcroft−Gault glomerular filtration rate estimation for patients with creatinine levels above institutional normal.
Resolution of all acute toxic effects of prior anti-cancer therapy to grade ≤ 1 as determined by the US National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (v.5.0) (except for alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion).
Women of childbearing potential (WOCBP) who are sexually active with a non-sterilized male partner must have a negative serum pregnancy test within 14 days before study treatment initiation. In addition, they must agree to use one highly effective method of birth control from the time of screening until 2 months after the last dose of study treatments. Female patients must refrain from egg cell donation and breastfeeding during this same period. Note: 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.
Male participants who are sexually active with a WOCBP partner must be surgically sterile or using an acceptable method of contraception from the time of screening until 4 months after the last administration of the study drug. Male participants must not donate or bank sperm during this same period.
Patient must be accessible for treatment and follow-up.

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Exclusion Criteria

Major surgery within four weeks of the start of treatment.
Type I leptomeningeal disease per ESMO-EANO guidelines.
Mean resting corrected QT interval (ECG interval measured from the onset of the QRS complex to the end of the T wave) for heart rate (QTc) > 470 msec obtained from 3 ECGs, using the screening clinic ECG machine-derived QTc value.
Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block, second degree heart block, PR interval > 250 msec).
Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome, or any concomitant medication known to prolong the QT interval.
Clinically significant cardiovascular disease (either active or within 6 months prior to enrollment): myocardial infarction, unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure (New York Heart Association Classification Class ≥ II), cerebrovascular accident or transient ischemic attack, symptomatic bradycardia, requirement for anti-arrhythmic medication. Ongoing cardiac dysrhythmias of NCI CTCAE grade ≥ 2.
Known clinically significant active infections not controlled with systemic treatment (bacterial, fungal, viral including HIV positivity).
Gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gut syndrome) or other malabsorption syndromes that would impact on drug absorption.
Peripheral neuropathy grade ≥ 2.
History of extensive, disseminated, bilateral, or presence of NCI CTCAE grade 3 or 4 interstitial fibrosis or interstitial lung disease (ILD) including a history of pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, ILD, obliterative bronchiolitis, and pulmonary fibrosis. Patients with a history of prior radiation pneumonitis are not excluded.
Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or that may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for entry into this study or could compromise the protocol objectives in the opinion of the Investigator.
Presence or history of any other primary malignancy other than NSCLC within 5 years prior to enrollment into the study. Note: Patients with a history of adequately treated basal or squamous cell carcinoma of the skin or any adequately treated in situ carcinoma may be included in the study
Current use or anticipated need for drugs that are known to be strong Cytochrome P450, family 3, subfamily A (CYP3A) inhibitors or inducers. Note: midazolam requires diligent monitoring in situations where there is an unprecedented necessity for co-administration. These cases should be discussed with the study’s medical monitor.
Patients requiring concomitant use of chronic systemic (intravenously [IV] or oral) corticosteroids at doses higher than 8 mg dexamethasone per day or other immunosuppressive medications except for managing adverse events (AEs); (inhaled steroids or intra articular steroid injections are permitted in this study). Note: The use of stable corticosteroid therapy in patients with brain metastases should be discussed with the Sponsor’s Medical Monitor.