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

Phase 2Active Not RecruitingNCT02650401

Hoffmann-La Roche69 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Solid Tumors CNS Tumors

Interventions

EntrectinibDRUG

TRKA/B/C, ROS1, and ALK inhibitor

Eligibility

Sex: ALLMin age: 0 YearsMax age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. 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 2. 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 3. Histologic/molecular diagnosis of malignancy at diagnosis or the time of relapse 4. Archival tumor tissue from diagnosis or, preferably, at relapse 5. Performance status: Lansky or Karnofsky score ≥ 60% and minimum life expectancy of at least 4 weeks 6. 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 7. Participants must have recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to enrollment 8. Adequate organ and neurologic function 9. 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. 10. 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: 1. Receiving other experimental therapy 2. Known congenital long QT syndrome 3. History of recent (3 months) symptomatic congestive heart failure or ejection fraction ≤50% at screening 4. Known active infections 5. Familial or personal history of congenital bone disorders, bone metabolism alterations or osteopenia 6. Receiving Enzyme Inducing Antiepileptic Drugs (EIAEDs) within 14 days of first dose. 7. Prior treatment with approved or investigational TRK or ROS1 inhibitors 8. Known hypersensitivity to entrectinib or any of the other excipients of the investigational medicinal product 9. Patients with NB with bone marrow space-only disease 10. Incomplete recovery from acute effects of any surgery prior to treatment. 11. Active gastrointestinal disease or other malabsorption syndromes that would impact drug absorption. 12. 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.

Locations (26)

Outcomes

Primary Outcomes

Maximum Tolerated Dose (MTD)

Assessed by National Cancer Institute Common Terminology for Adverse Events Criteria (NCI CTCAE v4.03)

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: Approximately 6 months

Cohort B: Objective Response Rate (ORR)

Assessed by RANO per the BICR

Time frame: Approximately 6 months

Cohort D: ORR

Assessed by RECIST v1.1 per the BICR

Time frame: Approximately 6 months

Secondary Outcomes

Safety and Tolerability - AE, ECG and Labs assessed by NCI CTCAE v4.03

Data from ClinicalTrials.gov

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University of California San Diego

La Jolla, California, United States

UCSF Benioff Children's Hospital

San Francisco, California, United States

Children's Hospital Colorado

Aurora, Colorado, United States

Egleston Children's Hospital at Emory University Atlanta

Atlanta, Georgia, United States

University of Chicago

Chicago, Illinois, United States

Johns Hopkins University

Baltimore, Maryland, United States

Dana Farber Cancer Institute

Boston, Massachusetts, United States

Washington University,St. Louis Children's Hospital

St Louis, Missouri, United States

Memorial Sloan Kettering Cancer Center

New York, New York, United States

Nationwide Children's Hospital

Columbus, Ohio, United States

...and 16 more locations

AE, ECG and Labs assessed by NCI CTCAE v4.03

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: Approximately 24 months

Cohort A, D, or E: Clinical Benefit Rate (CBR)

Assessed by RECIST v1.1 per the BICR and investigator

Time frame: Approximately 6 months

Cohort B or E: CBR

Assessed by RANO per the BICR and investigator

Time frame: Approximately 6 months

Cohort C: CBR

Assessed by the Curie scale per the BICR and investigator

Time frame: Approximately 6 months

Cohort A, D, or E: Progression-free Survival (PFS)

Assessed by RECIST v1.1 per the BICR and investigator

Time frame: Approximately 6 months

Cohort B or E: PFS

Assessed by RANO per the BICR and investigator

Time frame: Approximately 6 months

Cohort C: PFS

Assessed by the Curie scale per the BICR and investigator

Time frame: Approximately 6 months

Cohort A, D, or E: Overall Survival (OS)

Assessed by RECIST v1.1

Time frame: Approximately 6 months

Cohort B or E: OS

Assessed by RANO

Time frame: Approximately 6 months

Cohort A, D, or E: ORR

Assessed by RECIST v1.1 per the BICR and investigator

Time frame: Approximately 6 months

Cohort B or E: ORR

Assessed by RANO per the BICR and investigator

Time frame: Approximately 6 months

Cohort C: ORR

Assessed by the Curie scale per the BICR and investigator

Time frame: Approximately 6 months

Cohort A, D, or E: Time to response (TTR)

Assessed by RECIST v1.1 per the BICR and investigator

Time frame: Approximately 6 months

Cohort B or E: TTR

Assessed by RANO per the BICR and investigator

Time frame: Approximately 6 months

Cohort C: TTR

Assessed by the Curie scale per the BICR and investigator

Time frame: Approximately 6 months

Cohort A, D, or E: Duration of Response (DOR)

Assessed by RECIST v1.1 per the BICR and investigator

Time frame: Approximately 6 months

Cohort B or E: DOR

Assessed by RANO per the BICR and investigator

Time frame: Approximately 6 months

Cohort C: DOR

Assessed by the Curie scale per the BICR and investigator

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: Approximately 6 months

Phase 1/2 Participants with ROS1 gene fusions (Cohort B or E): ORR

Assessed by RANO per the BICR and investigator

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: Approximately 6 months

Phase 1/2 Participants with ROS1 gene fusions (Cohort B or E): DOR

Assessed by RANO per the BICR and investigator

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: Approximately 6 months

Phase 1/2 Participants with ROS1 gene fusions (Cohort B or E): TTR

Assessed by RANO per the BICR and investigator

Time frame: 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

Time frame: 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

Time frame: Approximately 6 months