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This is an open-label, multicenter, global Phase 2 basket study of entrectinib for the treatment of patients with solid tumors that harbor an NTRK1/2/3, ROS1, or ALK gene rearrangement. NTRK1, NTRK2, and NTRK3 gene rearrangements will be treated as a combined NTRK1/2/3 gene rearrangement basket.

An overview of the study design is provided in Figure 2 of the main protocol.

In order to determine enrollment eligibility and assignment to a specific basket, patients will be screened for gene rearrangements at Foundation Medicine, Inc. laboratory in Cambridge, Massachusetts, USA. Alternatively, local testing using any nucleic acid-based diagnostic testing method that relies on direct assessment of gene rearrangements and is performed at a CLIA-certified or equivalently- accredited diagnostic laboratory will be accepted.

Depending on each particular patient population basket, prior treatment will be allowed; however, prior treatment with Trk, ROS1, or ALK inhibitors (approved or investigational) will not be allowed in patients who have tumors that harbor those respective gene rearrangements, e.g., no prior ROS1-inhibitors will be allowed in patients with ROS1 gene rearrangements. The single exception is for patients with ALK- or ROS1-rearranged NSCLC who have been previously treated with crizotinib and have CNS-only progression.

Note: The ALK-rearranged NSCLC basket for patients previously treated with crizotinib and presenting with CNS-only progression is closed for further enrollment.

Entrectinib will be administered orally on a continuous daily dosing regimen, at a dose of 600 mg once-daily in repeated 4-week cycles.

Safety will be assessed by monitoring of adverse events, clinical laboratory tests (hematology, biochemistry, coagulation, lipid panel, and urinalysis), and physician visits, including physical examination, eye exam, vital signs, and ECGs.

Tumor assessments (computed tomography [CT] or magnetic resonance imaging [MRI]) of the chest, abdomen, pelvis (depending on tumor type), plus bone and/or brain as applicable, will be performed at the end of Cycle 1 and every 8 weeks thereafter. All CT and MRI scans will be read by a central independent imaging laboratory using the Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 and the Response Assessment in Neuro-Oncology Criteria (RANO) or RANO- Brain Metastases (RANO-BM), as applicable for patients with primary or secondary CNS disease, respectively.

Patients will be followed for safety and efficacy as per the schedule of assessments and will remain on study treatment until documented radiographic progression as assessed by blinded independent central review (BICR), development of unacceptable toxicity, or withdrawal of consent. At the discretion of the Investigator and with the Sponsor’s approval, patients may continue treatment with entrectinib after BICR- confirmed disease progression if the patient is perceived to be deriving clinical benefit. For these patients, tumor assessments will no longer be submitted for BICR, but Investigators are encouraged to evaluate patients following a similar 8-week schedule.

Patients discontinuing study treatment due to documented radiographic progression will enter the survival follow-up period, where survival status and subsequent anticancer therapy information (including best response) will be collected every 3 months until death, loss of follow-up, or withdrawal of consent, whichever comes first.

Patients discontinuing study treatment prior to documented radiographic progression will also enter the survival follow-up period, where they will continue to have scheduled disease assessments approximately every 8 weeks until BICR-confirmed disease progression, the start of a subsequent anticancer therapy, or decision to no longer treat (e.g., supportive care only), whichever is first. At that time, survival status (and subsequent anticancer therapy information, including best response, if appropriate) will be collected every 3 months until death, loss of follow-up, or withdrawal of consent, whichever comes first.



Ospedale S.Maria della Misericordia - Centro Operativo Studi Clinici S.C.Oncologia Medica