Basket Study of Entrectinib (RXDX-101) for the Treatment of Patients With Solid Tumors Harboring NTRK 1/2/3 (Trk A/B/C), ROS1, or ALK Gene Rearrangements (Fusions)

Study Overview
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Brief Summary
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This is an open-label, multicenter, global Phase 2 basket study of entrectinib (RXDX-101) for the treatment of patients with solid tumors that harbor an NTRK1/2/3, ROS1, or ALK gene fusion. Patients will be assigned to different baskets according to tumor type and gene fusion.

Official Title
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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

Conditions
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Breast Cancer, Cholangiocarcinoma, Colorectal Cancer, Head and Neck Neoplasms, Lymphoma, Large-Cell, Anaplastic, Melanoma, Neuroendocrine Tumors, Non-Small Cell Lung Cancer, Ovarian Cancer, Pancreatic Cancer, Papillary Thyroid Cancer, Primary Brain Tumors, Renal Cell Carcinoma, Sarcomas, Salivary Gland Cancers, Adult Solid Tumor

Intervention / Treatment
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* Drug: Entrectinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically- or cytologically-confirmed diagnosis of locally advanced or metastatic solid tumor that harbors an NTRK1/2/3, ROS1, or ALK gene rearrangement For patients enrolled via local molecular testing, an archival or fresh tumor tissue (unless medically contraindicated) is required to be submitted for independent central molecular testing at Ignyta's CLIA laboratory post-enrollment Measurable or evaluable disease Patients with CNS involvement, including leptomeningeal carcinomatosis, which is either asymptomatic or previously-treated and controlled, are allowed 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) - Note: prior treatment with crizotinib is permitted only in ALK- or ROS1-rearranged NSCLC patients presenting with CNS-only progression. Other ALK inhibitors are prohibited. At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed after prior chemotherapy or small molecule targeted therapy At least 4 weeks must have elapsed since completion of antibody-directed therapy Prior radiotherapy is allowed if more than 14 days have elapsed since the end of treatment Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 and minimum life expectancy of 4 weeks Adequate organ function as defined per protocol Ability to swallow entrectinib intact Other protocol specified criteria Exclusion Criteria: Current participation in another therapeutic clinical trial Prior treatment with approved or investigational Trk, ROS1, or ALK inhibitors in patients who have tumors that harbor those respective gene rearrangements - Note: prior treatment with crizotinib is permitted only in ALK- or ROS1-rearranged NSCLC patients presenting with CNS-only progression. Other ALK inhibitors are prohibited. History of other previous cancer that would interfere with the determination of safety or efficacy Familial or personal history of congenital bone disorders, or bone metabolism alterations Incomplete recovery from any surgery History of recent (within the past 3 months) symptomatic congestive heart failure or ejection fraction ≤50% observed during screening for the study History of non-pharmacologically induced prolonged QTc interval History of additional risk factors for torsades de pointes Peripheral neuropathy Grade ≥ 2 Known active infections Active gastrointestinal disease or other malabsorption syndromes Known interstitial lung disease, interstitial fibrosis, or history of tyrosine kinase inhibitor-induced pneumonitis Other protocol specified criteria

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NTRK1/2/3-rearranged NSCLC<br>Oral entrectinib (RXDX-101) | Drug: Entrectinib<br>* TrkA/B/C, ROS1, and ALK inhibitor<br>* Other names: RXDX-101;|
| Experimental: ROS1-rearranged NSCLC<br>Oral entrectinib (RXDX-101) | Drug: Entrectinib<br>* TrkA/B/C, ROS1, and ALK inhibitor<br>* Other names: RXDX-101;|
| Experimental: ALK- or ROS1-rearranged NSCLC<br>with CNS-only progression previously treated with crizotinib (NOTE: The ALK-rearranged portion of this arm is now closed to enrollment.) Oral entrectinib (RXDX-101) | Drug: Entrectinib<br>* TrkA/B/C, ROS1, and ALK inhibitor<br>* Other names: RXDX-101;|
| Experimental: NTRK/1/2/3-rearranged mCRC<br>Oral entrectinib (RXDX-101) | Drug: Entrectinib<br>* TrkA/B/C, ROS1, and ALK inhibitor<br>* Other names: RXDX-101;|
| Experimental: ROS1-rearranged mCRC<br>Oral entrectinib (RXDX-101) | Drug: Entrectinib<br>* TrkA/B/C, ROS1, and ALK inhibitor<br>* Other names: RXDX-101;|
| Experimental: ALK-rearranged mCRC<br>Oral entrectinib (RXDX-101) | Drug: Entrectinib<br>* TrkA/B/C, ROS1, and ALK inhibitor<br>* Other names: RXDX-101;|
| Experimental: NTRK1/2/3-rearranged other solid tumor<br>Oral entrectinib (RXDX-101) | Drug: Entrectinib<br>* TrkA/B/C, ROS1, and ALK inhibitor<br>* Other names: RXDX-101;|
| Experimental: ROS1-rearranged other solid tumor<br>Oral entrectinib (RXDX-101) | Drug: Entrectinib<br>* TrkA/B/C, ROS1, and ALK inhibitor<br>* Other names: RXDX-101;|
| Experimental: ALK-rearranged other solid tumor<br>Oral entrectinib (RXDX-101) | Drug: Entrectinib<br>* TrkA/B/C, ROS1, and ALK inhibitor<br>* Other names: RXDX-101;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate | Assessed by blinded independent central review (BICR) using RECIST v1.1 | Approximately 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response | Assessed by blinded independent central review (BICR) using RECIST v1.1 | Approximately 24 months | 
| Time to Response | Assessed by blinded independent central review (BICR) using RECIST v1.1 | Approximately 24 months | 
| Clinical Benefit Rate | Assessed by blinded independent central review (BICR) using RECIST v1.1 | Approximately 24 months | 
| Intracranial Tumor Response | Assessed by blinded independent central review (BICR) using RANO or RANO-BM, as applicable | Approximately 24 months | 
| CNS Progression-free Survival | Assessed by blinded independent central review (BICR) using RANO or RANO-BM, as applicable | Approximately 24 months | 
| Progression-free Survival | Assessed by Kaplan-Meier method | Approximately 30 months | 
| Overall Survival | Assessed by Kaplan-Meier method | Approximately 36 months | 
| Population PK | Assessed by Kaplan-Meier method | Approximately 24 months | 
| Adverse Events | Type, incidence, severity, timing, seriousness, and relatedness of adverse events and laboratory abnormalities, graded by the NCI CTCAE | Approximately 36 months | 
| Quality of Life | Assessed with the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire (QLQ-C30) and the Euro-QoL Group EQ-5D. NSCLC and mCRC patients will complete the lung cancer and colorectal cancer specific modules, QLQ-LC13 and QLQ-CR29, respectively | Approximately 24 months | 
| Bone Growth and Bone Mineral Density | Assessed with DHA scans | Approximately 30 months | 
| Bone Biomarkers | Measured by blood | Approximately 30 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Entrectinib, RXDX-101, TrkA, TrkB, TrkC, NTRK1, NTRK2, NTRK3, ROS1, ALK, Trk Fusions, NTRK Gene Rearrangements, ROS1 Fusions, ROS1 Gene Rearrangements, ALK Fusions, ALK Gene Rearrangements, Basket study, Non-small cell lung cancer, Colorectal cancer, Salivary gland cancers, Primary brain tumors, Melanoma, Sarcomas, Papillary thyroid cancer, Renal cell cancer, Pancreatic cancer, Breast cancer, Cholangiocarcinoma, Head & Neck cancers, Ovarian cancer, Neuroendocrine tumors