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GO40782 28Aug2018.Pdf PROTOCOL TITLE: AN OPEN-LABEL, MULTICENTER, GLOBAL PHASE 2 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 PROTOCOL NUMBER: GO40782 (RXDX-101-02) VERSION NUMBER: 5 EUDRACT NUMBER: 2015 003385 84 IND NUMBER: 120500,- 135124- TEST PRODUCT: Entrectinib MEDICAL MONITOR: Simonetta Mocci, M.D., Ph.D. SPONSOR: F. Hoffmann-La Roche Ltd DATE FINAL: Version 1: 30 July 2015 DATES AMENDED: Version 2: 2 November 2015 Version 3: 9 September 2016 Version 4: 3 August 2017 Version 5: See electronic date stamp below PROTOCOL AMENDMENT APPROVAL Approver's Name Title Date and Time (UTC) Reddy, Josina (josina) Company Signatory 28-Aug-2018 21:48:56 CONFIDENTIAL This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, Switzerland. However, it may be implemented in individual countries by Roche’s local affiliates, including Genentech, Inc. in the United States. The information contained in this document, especially any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore is provided to you in confidence as an investigator, potential investigator, or consultant, for review by you, your staff, and an applicable Ethics Committee or Institutional Review Board. It is understood that this information will not be disclosed to others without written authorization from Roche except to the extent necessary to obtain informed consent from persons to whom the drug may be administered. Entrectinib—F. Hoffmann-La Roche Ltd Protocol GO40782 (RXDX-101-02), Version 5 PROTOCOL AMENDMENT, VERSION 5: RATIONALE Protocol GO40782 has been amended to reflect Roche as the new Sponsor of this study. Changes to the protocol, along with a rationale for each change, are summarized below: • The Sponsor and signatories have been updated to reflect Roche as the new Sponsor of this study. • Screening diagnostic testing has been updated throughout the protocol to reflect the change in laboratory from the Ignyta Pharos Lab to Foundation Medicine. • Section 6 has been updated to include the description of the foreseen commercial formulation of entrectinib, which may be introduced in the study at a later point in time. • Section 8 has been updated to remove urine collection from the study assessments, as it is no longer being analyzed. • Section 9.3 has been updated to align the immediate reporting requirements with Roche safety standards due to the Sponsor update. • Appendix 1 has been removed, as the Ignyta Pharos testing will no longer be used. Foundation Medicine testing information is located in the study laboratory manual. Subsequent appendices have been renumbered accordingly. • Reduced frequency of follow-up for patients after 1 year has been implemented in the schedule of assessments (previously Appendix 2, now Appendix 1) to align with tumor assessments and to reduce the impact on patients. Additional minor changes have been made to improve clarity and consistency. Substantive new information appears in italics. This amendment represents cumulative changes to the original protocol. Entrectinib—F. Hoffmann-La Roche Ltd 2/Protocol GO40782 (RXDX-101-02), Version 5 PROTOCOL AMENDMENT ACCEPTANCE FORM TITLE: AN OPEN-LABEL, MULTICENTER, GLOBAL PHASE 2 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 PROTOCOL NUMBER: GO40782 (RXDX-101-02) VERSION NUMBER: 5 EUDRACT NUMBER: 2015 003385 84 IND NUMBER: 120500,- 135124- TEST PRODUCT: Entrectinib MEDICAL MONITOR: Simonetta Mocci, M.D., Ph.D. SPONSOR: F. Hoffmann-La Roche Ltd I agree to conduct the study in accordance with the current protocol. Principal Investigator’s Name (print) Principal Investigator’s Signature Date Please retain the signed original of this form for your study files. Please provide a copy of this form to your local CRA at their next monitoring visit. Entrectinib—F. Hoffmann-La Roche Ltd 3/Protocol GO40782 (RXDX-101-02), Version 5 PROTOCOL SYNOPSIS TITLE: AN OPEN-LABEL, MULTICENTER, GLOBAL PHASE 2 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 PROTOCOL NUMBER: GO40782 (RXDX-101-02) VERSION NUMBER: 5 EUDRACT NUMBER: 2015-003385-84 IND NUMBER: 120500, 135124 TEST PRODUCT: Entrectinib PHASE: II INDICATION: Locally Advanced or Metastatic Solid Tumors SPONSOR: F. Hoffmann-La Roche Ltd Rationale Entrectinib (RO7102122, previously known as RXDX-101) is a potent inhibitor of the tyrosine kinases TrkA (encoded by the gene NTRK1), TrkB (encoded by the gene NTRK2), TrkC (encoded by the gene NTRK3), ROS1 (encoded by the gene ROS1), and ALK (encoded by the gene ALK), with IC50 values for kinase inhibition in the low nanomolar range (1.7, 0.1, 0.1, 0.2, and 1.6 nM, respectively). While these enzymes play various roles in normal cellular function, gene rearrangements (fusions) in these target kinases have the potential to be oncogenic drivers, tend to be mutually exclusive, and are present in small percentages (< 10%; Vaishnavi et al., 2015) in a variety of tumor types, including non-small cell lung cancer (NSCLC), colorectal cancer (CRC), salivary gland cancer, papillary thyroid cancer, melanoma, and sarcoma. As such, in the two Phase 1 clinical studies (Study GO40783 [ALKA- 372-001] and Study GO40784 [STARTRK-1]) that were conducted to determine the recommended Phase 2 dose (RP2D) of entrectinib, patients with locally advanced or metastatic solid tumors were enrolled irrespective of tumor type. Among 18 ALK-, ROS1-, or Trk-inhibitor- naïve patients (1 patient was ALK-inhibitor intolerant) with NTRK1/2/3, ROS1, or ALK gene rearrangements who were treated at or above the RP2D, a response rate of 72% (13/18; Siena et al., ECC 2015) was reported. Furthermore, when subset by molecular alteration and tumor type where antitumor activity was observed, these data suggest that patients with NSCLC, metastatic CRC (mCRC), renal cell carcinoma, melanoma, and salivary gland cancers that harbor NTRK1/2/3, ROS1, or ALK gene rearrangements may potentially benefit from treatment with entrectinib. Entrectinib—F. Hoffmann-La Roche Ltd 4/Protocol GO40782 (RXDX-101-02), Version 5 In light of the potentially favorable preliminary benefit-risk profile for entrectinib combined with the low incidence of the targeted gene rearrangements and their presence across a variety of tumor types, this Phase 2 study was designed to demonstrate the efficacy of entrectinib by enrolling patients with any solid tumor that harbors NTRK1/2/3, ROS1, or ALK gene rearrangements, for whom no alternative effective standard therapy is available. Patients will be enrolled across multiple solid tumor “baskets” that will be individually analyzed as separate cohorts. Study Design 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 Entrectinib—F. Hoffmann-La Roche Ltd 5/Protocol
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