AN OPEN-LABEL, MULTICENTER, GLOBAL PHASE II BASKET STUDY OF ENTRECTINIB FOR THE TREATMENT OF PATIENTS WITH LOCALLY ADVANCED OR METASTATIC SOLID TUMORS THAT HARBOR NTRK1/2/3, ROS1, OR ALK GENE REARRANGEMENTS

The primary objective of this study is to determine the objective response rate of entrectinib, as assessed by blinded independent central review (BICR), in each patient population basket of solid tumors that harbor an NTRK1/2/3, ROS1, or ALK gene rearrangement. This evaluation is clinically relevant for establishing the antitumor activity of entrectinib across molecularly defined tumor types characterized by these specific oncogenic driver mutations.

The secondary objectives include:

• To determine the duration of response, time to response, and clinical benefit rate of entrectinib in each patient population basket of solid tumors.

• To determine the intracranial tumor response of entrectinib and central nervous system progression-free survival (CNS-PFS) in patients presenting with measurable CNS disease at baseline, as assessed by BICR using RECIST v1.1 or RANO for primary CNS tumors as applicable.

• To estimate the progression-free survival and overall survival of patients with solid tumors treated with entrectinib.

• To evaluate the safety and tolerability of entrectinib when administered at the recommended phase 2 dose (RP2D).

• To assess the population pharmacokinetics of entrectinib and to explore correlations between pharmacokinetics, response, and safety findings.

• To evaluate the effect of entrectinib on ventricular repolarization.

• To assess treatment-related symptoms and general health status using validated instruments of patient-reported outcomes.

This clinical trial enrolled a total of **455 participants** with histologically or cytologically confirmed **locally advanced or metastatic solid tumors** harboring **NTRK1/2/3**, **ROS1**, or **ALK gene rearrangements**. The study population consisted of adult patients aged **18 years and older**, including both **male and female** participants. Eligible individuals were required to have an **Eastern Cooperative Oncology Group (ECOG) performance status** of 2 or less and a minimum **life expectancy** of at least 4 weeks. Participants were selected based on molecular testing confirming the presence of specific **gene rearrangements** predicted to translate into fusion proteins with functional kinase domains, without concomitant second oncodrivers. The trial included patients for whom no alternative effective standard therapy was available or for whom standard therapy was considered unsuitable or intolerable. Participants were required to have adequate **liver function**, with specific thresholds for **aspartate transaminase (AST)**, **alanine transaminase (ALT)**, and **total serum bilirubin**. Prior anticancer therapy was permitted, with specified washout periods for chemotherapy, targeted therapy, antibody-directed therapy, and radiotherapy. Patients with **central nervous system (CNS) involvement**, including **leptomeningeal carcinomatosis**, were allowed if asymptomatic or previously treated and controlled. Female participants of childbearing potential were required to use highly effective contraception and have negative pregnancy tests, while male participants with female partners of childbearing potential were also required to use contraception during the study period.

This is an open-label, multicenter, global Phase II basket study evaluating entrectinib for the treatment of patients with locally advanced or metastatic solid tumors that harbor NTRK1/2/3, ROS1, or ALK gene rearrangements. The study follows a basket trial design, grouping patients based on specific molecular alterations rather than tumor type. The primary objective is to determine the objective response rate of entrectinib, as assessed by blinded independent central review, in each patient population basket of solid tumors harboring these gene rearrangements. Secondary endpoints include duration of response, time to response, clinical benefit rate, intracranial tumor response in patients with measurable brain metastases, CNS progression-free survival in patients with measurable CNS disease, progression-free survival, overall survival, safety assessments including type, incidence, severity, timing, seriousness, and relatedness of adverse events and laboratory abnormalities, population pharmacokinetics, ventricular repolarization, quality-of-life and health status, examination of biological markers of bone formation and resorption and markers of calcium metabolism, and assessment of bone mineral density via dual X-ray absorptiometry scans.

Eligible patients must have histologically or cytologically confirmed diagnosis of locally advanced or metastatic solid tumor harboring an NTRK1/2/3, ROS1, or ALK gene rearrangement predicted to translate into a fusion protein with a functional TrkA/B/C, ROS1, or ALK kinase domain, without a concomitant second oncodriver, as determined by nucleic acid-based diagnostic testing at a CLIA-certified or equivalently-accredited diagnostic laboratory. Patients must be those for whom no alternative effective standard therapy is available or for whom standard therapy is considered unsuitable or intolerable. Patients diagnosed with anaplastic large cell lymphoma harboring a gene rearrangement of interest are no longer eligible. Additional key inclusion criteria include age ≥ 18 years, Eastern Cooperative Oncology Group performance status ≤ 2 with minimum life expectancy of at least 4 weeks, adequate liver function defined by serum aspartate transaminase and serum alanine transaminase ≤ 3.0 × upper limit of normal (≤ 5.0 × ULN if liver metastases are present), total serum bilirubin ≤ 2.0 × ULN (patients with known history of Gilbert's syndrome and/or isolated elevations of indirect bilirubin are eligible), and measurable disease as assessed locally using RECIST v1.1. Patients with non-measurable disease will be eligible for enrollment in the non-evaluable for the primary endpoint basket and will mainly contribute to assessment of safety, pharmacokinetics, and other secondary endpoints. Patients with CNS involvement, including leptomeningeal carcinomatosis, which is either asymptomatic or previously treated and controlled, are allowed, with seizure prophylaxis permitted as long as patients are taking non-enzyme-inducing anti-epileptic drugs. Prior anticancer therapy is allowed, excluding approved or investigational Trk, ROS1, or ALK inhibitors in patients who have tumors that harbor those respective gene rearrangements. At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed after prior chemotherapy or small molecule targeted therapy at the time of the start of entrectinib treatment, with at least 4 weeks since completion of antibody-directed therapy. Prior radiotherapy is allowed if more than 14 days have elapsed since the end of treatment, with patients who received brain irradiation having completed whole brain radiotherapy at least 14 days prior and/or stereotactic radiosurgery at least 7 days prior to the start of entrectinib treatment. Women of childbearing potential must have a negative serum pregnancy test during screening, must not be breastfeeding or intending to become pregnant during the study, and must agree to use contraception methods with failure rate < 1% per year prior to entering the study and for 5 weeks following the last dose of study drug. Male patients with female partners of childbearing potential must agree to use highly effective contraception during the study and for 3 months following the last dose. Patients must have ability to swallow entrectinib intact without chewing, crushing, or opening the capsules. For patients enrolled via local molecular testing, archival or fresh tumor tissue is required to be submitted for independent central molecular testing unless medically contraindicated.

The investigational medicinal product is Rozlytrek 200 mg hard capsules containing entrectinib as the active substance, administered via the oral route. The maximum daily dose is 800 mg, with a maximum total dose of 2044000 mg over a maximum treatment period of 84 months. The estimated recruitment start date was November 19, 2015, with an estimated end date of November 19, 2025, indicating an overall trial duration of approximately 10 years. Participant involvement extends throughout the treatment period and follow-up phases as defined by the study protocol. Early termination from the study may occur under conditions such as disease progression, unacceptable toxicity, withdrawal of consent, investigator decision, or other protocol-specified criteria.

The experimental medication evaluated in this clinical trial is **Rozlytrek** (**entrectinib**, also known by the sponsor product code **RO7102122**), formulated as **200 mg hard capsules**. The **active substance** is entrectinib, a chemical compound with the European substance number SUB177830. The **pharmaceutical form** is hard capsules, administered via the **oral route**. The **maximum daily dose** is **800 mg**, with a **maximum total dose** of **2,044,000 mg** over the course of treatment. The **maximum treatment period** is **84 months**. The product is authorized under the European Union marketing authorization number EU/1/20/1460/002 and is manufactured by Roche Registration GmbH. This medicinal product is not classified as a paediatric formulation and holds orphan drug designation for specific indications. The study follows an open-label design, with entrectinib serving as the test intervention for patients with locally advanced or metastatic solid tumors harboring **NTRK1/2/3**, **ROS1**, or **ALK gene rearrangements**. Participant compliance monitoring and adherence to the prescribed dosing schedule are essential components of the trial protocol to ensure accurate assessment of the objective response rate as determined by blinded independent central review.

Efficacy will be assessed using the objective response rate (ORR) as the primary endpoint, defined as the proportion of patients achieving complete response (CR) or partial response (PR). Response assessments will be conducted by blinded independent central review (BICR) for each patient population basket of solid tumors harboring NTRK1/2/3, ROS1, or ALK gene rearrangements. Measurable disease will be evaluated locally using RECIST version 1.1 criteria.

Secondary efficacy endpoints include duration of response (DOR), time to response (TTR), clinical benefit rate (CBR), and progression-free survival (PFS). Overall survival (OS) will also be assessed as a secondary endpoint. For patients with measurable brain metastases, intracranial tumor response will be determined by BICR using RANO or RANO-BM criteria as applicable. CNS progression-free survival (CNS-PFS) will be evaluated in patients with measurable CNS disease. Additional assessments will include quality-of-life and health status measures, evaluation of biological markers of bone formation and resorption, markers of calcium metabolism, and bone mineral density (BMD) via dual X-ray absorptiometry (DXA) scans.