Study Of Entrectinib (Rxdx-101) in Children and Adolescents With Locally Advanced Or Metastatic Solid Or Primary CNS Tumors And/Or Who Have No Satisfactory Treatment Options

Study Overview
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Brief Summary
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This is an open-label, Phase 1/2 multicenter dose escalation study in pediatric patients with relapsed or refractory extracranial solid tumors (Phase 1), with additional expansion cohorts (Phase 2) in patients with primary brain tumors harboring NTRK1/2/3 or ROS1 gene fusions, and extracranial solid tumors harboring NTRK1/2/3 or ROS1 gene fusions.

Official Title
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A Phase 1/2, Open-Label, Dose-Escalation And Expansion Study Of Entrectinib (Rxdx-101) In Pediatrics With Locally Advanced Or Metastatic Solid Or Primary CNS Tumors And/Or Who Have No Satisfactory Treatment Options

Conditions
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Solid Tumors, CNS Tumors

Intervention / Treatment
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* Drug: Entrectinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Disease status: Phase 1 portion (closed): Participants must have measurable or evaluable disease, as defined by RECIST v1.1 Phase 2 portion: Part B: Participants must have measurable or evaluable disease, as defined by RANO Part C (closed): Participants must have measurable or evaluable disease, as defined by RECIST v1.1 ± Curie Scale Part D: Participants must have measurable or evaluable disease, as defined by RECIST v1.1 Part E (closed): Participants must have measurable or evaluable disease, as defined by RECIST v1.1 ± Curie Scale or RANO Tumor type: Phase 1 portion: * Part A: Relapsed or refractory extracranial solid tumors Phase 2 portion Part B: Primary brain tumors with NTRK1/2/3 or ROS1 gene fusions; gene fusions are defined as those predicted to translate into a fusion protein with a functional TRKA/B/C or ROS1 kinase domain, without a concomitant second oncodriver as determined by a nucleic acid-based diagnostic testing method Part D: Extracranial solid tumors (including NB) with NTRK1/2/3 or ROS1 gene fusions; gene fusions are defined as those predicted to translate into a fusion protein with a functional TRKA/B/C or ROS1 kinase domain, without a concomitant second oncodriver as determined by a nucleic acid-based diagnostic testing method Histologic/molecular diagnosis of malignancy at diagnosis or the time of relapse Archival tumor tissue from diagnosis or, preferably, at relapse Performance status: Lansky or Karnofsky score ≥ 60% and minimum life expectancy of at least 4 weeks Prior therapy: Participants must have a disease that is locally advanced, metastatic, or where surgical resection is likely to result in severe morbidity, and who have no satisfactory treatment options for solid tumors and primary CNS tumors that are neurotrophic tyrosine receptor kinase (NTRK) or ROS1 fusion-positive Participants must have recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to enrollment Adequate organ and neurologic function Females of childbearing potential must have a negative serum pregnancy test during screening and be neither breastfeeding nor intending to become pregnant during study participation. Agreement to remain abstinent or use use combined contraceptive methods prior to study entry, for the duration of study participation and in the following 90 days after discontinuation of study treatment. For male participants with a female partner of childbearing potential or a pregnant female partner: Agreement to remain abstinent or use a condom during the treatment period and for at least 3 months after the last dose of study drug Exclusion Criteria: Receiving other experimental therapy Known congenital long QT syndrome History of recent (3 months) symptomatic congestive heart failure or ejection fraction ≤50% at screening Known active infections Familial or personal history of congenital bone disorders, bone metabolism alterations or osteopenia Receiving Enzyme Inducing Antiepileptic Drugs (EIAEDs) within 14 days of first dose. Prior treatment with approved or investigational TRK or ROS1 inhibitors Known hypersensitivity to entrectinib or any of the other excipients of the investigational medicinal product Patients with NB with bone marrow space-only disease Incomplete recovery from acute effects of any surgery prior to treatment. Active gastrointestinal disease or other malabsorption syndromes that would impact drug absorption. Other severe acute or chronic medical or psychiatric condition or lab abnormality that may increase the risk associated with study participation, drug administration or may interfere with the interpretation of study results.

Ages Eligible for Study
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Minimum Age: 0 Years
Maximum 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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Extracranial solid tumors harboring NTRK1/2/3,<br>Arm closed for further enrollment ROS1, ALK non-gene fusion molecular alterations Oral entrectinib (RXDX-101) | Drug: Entrectinib<br>* TRKA/B/C, ROS1, and ALK inhibitor<br>* Other names: RXDX-101;|
| Active Comparator: CNS tumors harboring- NTRK1/2/3, ROS1, ALK<br>Arm closed for further enrollment molecular alterations, including gene fusions Oral entrectinib (RXDX-101) | Drug: Entrectinib<br>* TRKA/B/C, ROS1, and ALK inhibitor<br>* Other names: RXDX-101;|
| Active Comparator: Neuroblastoma<br>Arm closed for further enrollment Oral entrectinib (RXDX-101) | Drug: Entrectinib<br>* TRKA/B/C, ROS1, and ALK inhibitor<br>* Other names: RXDX-101;|
| Active Comparator: Non-neuroblastoma, extracranial solid tumors<br>Arm closed for further enrollment harboring - NTRK1/2/3, ROS1, ALK gene fusions Oral entrectinib (RXDX-101) | Drug: Entrectinib<br>* TRKA/B/C, ROS1, and ALK inhibitor<br>* Other names: RXDX-101;|
| Active Comparator: Any participant unable to swallow capsules<br>Arm closed for further enrollment Any participant who otherwise meet all other eligibility criteria Oral entrectinib (RXDX-101) | Drug: Entrectinib<br>* TRKA/B/C, ROS1, and ALK inhibitor<br>* Other names: RXDX-101;|
| Active Comparator: Expansion: CNS tumors harboring NTRK1/2/3, ROS1<br>gene fusions Oral entrectinib (RXDX-101) | Drug: Entrectinib<br>* TRKA/B/C, ROS1, and ALK inhibitor<br>* Other names: RXDX-101;|
| Active Comparator: Expansion: Extracranial solid tumors harboring NTRK1/2/3, ROS1<br>NTRK 1,2,3 and ROS1 fusions 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 |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) | Assessed by National Cancer Institute Common Terminology for Adverse Events Criteria (NCI CTCAE v4.03) | Approximately 6 months | 
| Recommended Phase 2 Dose (RP2D) of F1 Formulation In Pediatric Participants Able To Swallow Intact Capsules | Assessed by NCI CTCAE v4.03 | Approximately 6 months | 
| Recommended Phase 2 Dose (RP2D) of F06 Formulation In Pediatric Participants Able To Swallow Intact Capsules | Assessed by NCI CTCAE v4.03 | Approximately 6 months | 
| Recommended Phase 2 Dose (RP2D) of F06 Formulation In Pediatric In Participants Dosed Via Feeding Tube (Nasogastric Tube Or Gastric Tube) | Assessed by NCI CTCAE v4.03 | Approximately 6 months | 
| Recommended Phase 2 Dose (RP2D) Of Minitablets/F15 Formulation In Pediatric Participants Unable To Swallow Intact Capsules | Assessed by NCI CTCAE v4.03 | Approximately 6 months | 
| Cohort B: Objective Response Rate (ORR) | Assessed by RANO per the BICR | Approximately 6 months | 
| Cohort D: ORR | Assessed by RECIST v1.1 per the BICR | Approximately 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability - AE, ECG and Labs assessed by NCI CTCAE v4.03 | AE, ECG and Labs assessed by NCI CTCAE v4.03 | Approximately 24 months | 
| Maximum observed plasma drug concentration (Cmax) using F1 Formulation | Assessed by plasma concentrations obtained on Days 1, 2, 8, 15, 22 (Cycle 1), Days 1, 2 (Cycle 2) and on Day 1 of every cycle thereafter | Approximately 24 months | 
| Maximum observed plasma drug concentration (Cmax) using F06 Formulation given intact | Assessed by plasma concentrations obtained on Days 1, 2, 8, 15, 22 (Cycle 1), Days 1, 2 (Cycle 2) and on Day 1 of every cycle thereafter | Approximately 24 months | 
| Maximum observed plasma drug concentration (Cmax) using F06 Formulation administered via feeding tube | Assessed by plasma concentrations obtained on Days 1, 2, 8, 15, 22 (Cycle 1), Days 1, 2 (Cycle 2) and on Day 1 of every cycle thereafter | Approximately 24 months | 
| Maximum observed plasma drug concentration (Cmax) using minitablets/F15 | Assessed by plasma concentrations obtained on Days 1, 2, 8, 15, 22 (Cycle 1), Days 1, 2 (Cycle 2) and on Day 1 of every cycle thereafter | Approximately 24 months | 
| Time to Cmax, by inspection (Tmax) using F1 Formulation | Assessed by plasma concentrations obtained on Days 1, 2, 8, 15, 22 (Cycle 1), Days 1, 2 (Cycle 2) and on Day 1 of every cycle thereafter | Approximately 24 months | 
| Time to Cmax, by inspection (Tmax) using F06 Formulation given intact | Assessed by plasma concentrations obtained on Days 1, 2, 8, 15, 22 (Cycle 1), Days 1, 2 (Cycle 2) and on Day 1 of every cycle thereafter | Approximately 24 months | 
| Time to Cmax, by inspection (Tmax) using F06 Formulation administered via feeding tube | Assessed by plasma concentrations obtained on Days 1, 2, 8, 15, 22 (Cycle 1), Days 1, 2 (Cycle 2) and on Day 1 of every cycle thereafter | Approximately 24 months | 
| Time to Cmax, by inspection (Tmax) using minitablets/F15 | Assessed by plasma concentrations obtained on Days 1, 2, 8, 15, 22 (Cycle 1), Days 1, 2 (Cycle 2) and on Day 1 of every cycle thereafter | Approximately 24 months | 
| AUC at steady state (AUCss) using F1 Formulation | Assessed by plasma concentrations obtained on Days 1, 2, 8, 15, 22 (Cycle 1), Days 1, 2 (Cycle 2) and on Day 1 of every cycle thereafter | Approximately 24 months | 
| AUC at steady state (AUCss) using F06 Formulation given intact | Assessed by plasma concentrations obtained on Days 1, 2, 8, 15, 22 (Cycle 1), Days 1, 2 (Cycle 2) and on Day 1 of every cycle thereafter | Approximately 24 months | 
| AUC at steady state (AUCss) using F06 Formulation administered via feeding tube | Assessed by plasma concentrations obtained on Days 1, 2, 8, 15, 22 (Cycle 1), Days 1, 2 (Cycle 2) and on Day 1 of every cycle thereafter | Approximately 24 months | 
| AUC at steady state (AUCss) using minitablets/F15 | Assessed by plasma concentrations obtained on Days 1, 2, 8, 15, 22 (Cycle 1), Days 1, 2 (Cycle 2) and on Day 1 of every cycle thereafter | Approximately 24 months | 
| Terminal half life (t½) using F1 Formulation | Assessed by plasma concentrations obtained on Days 1, 2, 8, 15, 22 (Cycle 1), Days 1, 2 (Cycle 2) and on Day 1 of every cycle thereafter | Approximately 24 months | 
| Terminal half life (t½) using F06 Formulation given intact | Assessed by plasma concentrations obtained on Days 1, 2, 8, 15, 22 (Cycle 1), Days 1, 2 (Cycle 2) and on Day 1 of every cycle thereafter | Approximately 24 months | 
| Terminal half life (t½) using F06 Formulation administered via feeding tube | Assessed by plasma concentrations obtained on Days 1, 2, 8, 15, 22 (Cycle 1), Days 1, 2 (Cycle 2) and on Day 1 of every cycle thereafter | Approximately 24 months | 
| Terminal half life (t½) using minitablets/F15 | Assessed by plasma concentrations obtained on Days 1, 2, 8, 15, 22 (Cycle 1), Days 1, 2 (Cycle 2) and on Day 1 of every cycle thereafter | Approximately 24 months | 
| Area under the drug concentration by time curve (AUC) using F1 Formulation | Assessed by plasma concentrations obtained on Days 1, 2, 8, 15, 22 (Cycle 1), Days 1, 2 (Cycle 2) and on Day 1 of every cycle thereafter | Approximately 24 months | 
| Area under the drug concentration by time curve (AUC) using F06 Formulation given intact | Assessed by plasma concentrations obtained on Days 1, 2, 8, 15, 22 (Cycle 1), Days 1, 2 (Cycle 2) and on Day 1 of every cycle thereafter | Approximately 24 months | 
| Area under the drug concentration by time curve (AUC) using F06 Formulation administered via feeding tube | Assessed by plasma concentrations obtained on Days 1, 2, 8, 15, 22 (Cycle 1), Days 1, 2 (Cycle 2) and on Day 1 of every cycle thereafter | Approximately 24 months | 
| Area under the drug concentration by time curve (AUC) using minitablets/F15 | Assessed by plasma concentrations obtained on Days 1, 2, 8, 15, 22 (Cycle 1), Days 1, 2 (Cycle 2) and on Day 1 of every cycle thereafter | Approximately 24 months | 
| Cohort A, D, or E: Clinical Benefit Rate (CBR) | Assessed by RECIST v1.1 per the BICR and investigator | Approximately 6 months | 
| Cohort B or E: CBR | Assessed by RANO per the BICR and investigator | Approximately 6 months | 
| Cohort C: CBR | Assessed by the Curie scale per the BICR and investigator | Approximately 6 months | 
| Cohort A, D, or E: Progression-free Survival (PFS) | Assessed by RECIST v1.1 per the BICR and investigator | Approximately 6 months | 
| Cohort B or E: PFS | Assessed by RANO per the BICR and investigator | Approximately 6 months | 
| Cohort C: PFS | Assessed by the Curie scale per the BICR and investigator | Approximately 6 months | 
| Cohort A, D, or E: Overall Survival (OS) | Assessed by RECIST v1.1 | Approximately 6 months | 
| Cohort B or E: OS | Assessed by RANO | Approximately 6 months | 
| Cohort A, D, or E: ORR | Assessed by RECIST v1.1 per the BICR and investigator | Approximately 6 months | 
| Cohort B or E: ORR | Assessed by RANO per the BICR and investigator | Approximately 6 months | 
| Cohort C: ORR | Assessed by the Curie scale per the BICR and investigator | Approximately 6 months | 
| Cohort A, D, or E: Time to response (TTR) | Assessed by RECIST v1.1 per the BICR and investigator | Approximately 6 months | 
| Cohort B or E: TTR | Assessed by RANO per the BICR and investigator | Approximately 6 months | 
| Cohort C: TTR | Assessed by the Curie scale per the BICR and investigator | Approximately 6 months | 
| Cohort A, D, or E: Duration of Response (DOR) | Assessed by RECIST v1.1 per the BICR and investigator | Approximately 6 months | 
| Cohort B or E: DOR | Assessed by RANO per the BICR and investigator | Approximately 6 months | 
| Cohort C: DOR | Assessed by the Curie scale per the BICR and investigator | Approximately 6 months | 
| Phase 2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort B or E): ORR | Assessed by RANO per the investigator | Approximately 6 months | 
| Phase 2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort D or E): ORR | Assessed by RECIST v1.1 per the investigator | Approximately 6 months | 
| Phase 1/2 Participants with NTRK1/2/3 gene fusions (Cohort A, D, or E): ORR | Assessed by RECIST v1.1 per the BICR and investigator | Approximately 6 months | 
| Phase 1/2 Participants with NTRK1/2/3 gene fusions (Cohort B or E): ORR | Assessed by RANO per the BICR and investigator | Approximately 6 months | 
| Phase 1/2 Participants with ROS1 gene fusions (Cohort A, D, or E): ORR | Assessed by RECIST v1.1 per the BICR and investigator | Approximately 6 months | 
| Phase 1/2 Participants with ROS1 gene fusions (Cohort B or E): ORR | Assessed by RANO per the BICR and investigator | Approximately 6 months | 
| Phase 1/2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort A, D, or E): ORR | Assessed by RECIST v1.1 per the BICR and investigator | Approximately 6 months | 
| Phase 1/2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort B or E): ORR | Assessed by RANO per the BICR and investigator | Approximately 6 months | 
| Phase 2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort B or E): DOR | Assessed by RANO per the BICR and investigator | Approximately 6 months | 
| Phase 2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort D or E): DOR | Assessed by RECIST v1.1 per the BICR and investigator | Approximately 6 months | 
| Phase 1/2 Participants with NTRK1/2/3 gene fusions (Cohort A, D, or E): DOR | Assessed by RECIST v1.1 per the BICR and investigator | Approximately 6 months | 
| Phase 1/2 Participants with NTRK1/2/3 gene fusions (Cohort B or E): DOR | Assessed by RANO per the BICR and investigator | Approximately 6 months | 
| Phase 1/2 Participants with ROS1 gene fusions (Cohort A, D, or E): DOR | Assessed by RECIST v1.1 per the BICR and investigator | Approximately 6 months | 
| Phase 1/2 Participants with ROS1 gene fusions (Cohort B or E): DOR | Assessed by RANO per the BICR and investigator | Approximately 6 months | 
| Phase 1/2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort A, D, or E): DOR | Assessed by RECIST v1.1 per the BICR and investigator | Approximately 6 months | 
| Phase 1/2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort B or E): DOR | Assessed by RANO per the BICR and investigator | Approximately 6 months | 
| Phase 2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort B or E): TTR | Assessed by RANO per the BICR and investigator | Approximately 6 months | 
| Phase 2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort D or E): TTR | Assessed by RECIST v1.1 per the BICR and investigator | Approximately 6 months | 
| Phase 1/2 Participants with NTRK1/2/3 gene fusions (Cohort A, D, or E): TTR | Assessed by RECIST v1.1 per the BICR and investigator | Approximately 6 months | 
| Phase 1/2 Participants with NTRK1/2/3 gene fusions (Cohort B or E): TTR | Assessed by RANO per the BICR and investigator | Approximately 6 months | 
| Phase 1/2 Participants with ROS1 gene fusions (Cohort A, D, or E): TTR | Assessed by RECIST v1.1 per the BICR and investigator | Approximately 6 months | 
| Phase 1/2 Participants with ROS1 gene fusions (Cohort B or E): TTR | Assessed by RANO per the BICR and investigator | Approximately 6 months | 
| Phase 1/2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort A, D, or E): TTR | Assessed by RECIST v1.1 per the BICR and investigator | Approximately 6 months | 
| Phase 1/2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort B or E): TTR | Assessed by RANO per the BICR and investigator | Approximately 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TRK, Tyrosine kinase, NTRK, NTRK1, NTRK2, NTRK3, ROS1, ALK, Pediatric, Relapsed, Refractory, Solid Tumor, Metastatic Cancer, Gene rearrangement, Neuroblastoma, Infantile fibrosarcoma, Secretory breast cancer, Congenital mesoblastic nephroma, Pontine glioma, Brain tumors, CNS tumors, Sarcoma, Ewing sarcoma, Glial tumors, Salivary Gland Cancer (MASC), Papillary thyroid cancer, Medulloblastoma, Wilms tumor (anaplastic)