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
- Registration Number
- NCT02650401
- Lead Sponsor
- Hoffmann-La Roche
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 69
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Disease status:
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Phase 1 portion (closed): Participants must have measurable or evaluable disease, as defined by RECIST v1.1
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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
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Tumor type:
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Phase 1 portion:
* Part A: Relapsed or refractory extracranial solid tumors
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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
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Histologic/molecular diagnosis of malignancy at diagnosis or the time of relapse
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Archival tumor tissue from diagnosis or, preferably, at relapse
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Performance status: Lansky or Karnofsky score ≥ 60% and minimum life expectancy of at least 4 weeks
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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
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Participants must have recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to enrollment
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Adequate organ and neurologic function
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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.
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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
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Expansion: CNS tumors harboring NTRK1/2/3, ROS1 Entrectinib gene fusions Oral entrectinib (RXDX-101) Any participant unable to swallow capsules Entrectinib Arm closed for further enrollment Any participant who otherwise meet all other eligibility criteria Oral entrectinib (RXDX-101) Extracranial solid tumors harboring NTRK1/2/3, Entrectinib Arm closed for further enrollment ROS1, ALK non-gene fusion molecular alterations Oral entrectinib (RXDX-101) CNS tumors harboring- NTRK1/2/3, ROS1, ALK Entrectinib Arm closed for further enrollment molecular alterations, including gene fusions Oral entrectinib (RXDX-101) Non-neuroblastoma, extracranial solid tumors Entrectinib Arm closed for further enrollment harboring - NTRK1/2/3, ROS1, ALK gene fusions Oral entrectinib (RXDX-101) Expansion: Extracranial solid tumors harboring NTRK1/2/3, ROS1 Entrectinib NTRK 1,2,3 and ROS1 fusions Oral entrectinib (RXDX-101) Neuroblastoma Entrectinib Arm closed for further enrollment Oral entrectinib (RXDX-101)
- Primary Outcome Measures
Name Time Method Maximum Tolerated Dose (MTD) Approximately 6 months Assessed by National Cancer Institute Common Terminology for Adverse Events Criteria (NCI CTCAE v4.03)
Recommended Phase 2 Dose (RP2D) Of Minitablets/F15 Formulation In Pediatric Participants Unable To Swallow Intact Capsules Approximately 6 months Assessed by NCI CTCAE v4.03
Cohort B: Objective Response Rate (ORR) Approximately 6 months Assessed by RANO per the BICR
Recommended Phase 2 Dose (RP2D) of F06 Formulation In Pediatric Participants Able To Swallow Intact Capsules Approximately 6 months Assessed by NCI CTCAE v4.03
Recommended Phase 2 Dose (RP2D) of F1 Formulation In Pediatric Participants Able To Swallow Intact Capsules Approximately 6 months Assessed by NCI CTCAE v4.03
Recommended Phase 2 Dose (RP2D) of F06 Formulation In Pediatric In Participants Dosed Via Feeding Tube (Nasogastric Tube Or Gastric Tube) Approximately 6 months Assessed by NCI CTCAE v4.03
Cohort D: ORR Approximately 6 months Assessed by RECIST v1.1 per the BICR
- Secondary Outcome Measures
Name Time Method Cohort B or E: OS Approximately 6 months Assessed by RANO
Maximum observed plasma drug concentration (Cmax) using F1 Formulation Approximately 24 months 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
AUC at steady state (AUCss) using F1 Formulation Approximately 24 months 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
Safety and Tolerability - AE, ECG and Labs assessed by NCI CTCAE v4.03 Approximately 24 months AE, ECG and Labs assessed by NCI CTCAE v4.03
Maximum observed plasma drug concentration (Cmax) using minitablets/F15 Approximately 24 months 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
Cohort B or E: DOR Approximately 6 months Assessed by RANO per the BICR and investigator
Cohort C: DOR Approximately 6 months Assessed by the Curie scale per the BICR and investigator
Maximum observed plasma drug concentration (Cmax) using F06 Formulation given intact Approximately 24 months 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
Maximum observed plasma drug concentration (Cmax) using F06 Formulation administered via feeding tube Approximately 24 months 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 to Cmax, by inspection (Tmax) using F1 Formulation Approximately 24 months 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 to Cmax, by inspection (Tmax) using F06 Formulation given intact Approximately 24 months 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
Terminal half life (t½) using F06 Formulation given intact Approximately 24 months 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
Terminal half life (t½) using F06 Formulation administered via feeding tube Approximately 24 months 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
Cohort A, D, or E: Clinical Benefit Rate (CBR) Approximately 6 months Assessed by RECIST v1.1 per the BICR and investigator
Cohort B or E: PFS Approximately 6 months Assessed by RANO per the BICR and investigator
Phase 1/2 Participants with NTRK1/2/3 gene fusions (Cohort B or E): ORR Approximately 6 months Assessed by RANO per the BICR and investigator
Phase 1/2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort A, D, or E): ORR Approximately 6 months Assessed by RECIST v1.1 per the BICR and investigator
Phase 1/2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort B or E): ORR Approximately 6 months Assessed by RANO per the BICR and investigator
Phase 2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort B or E): DOR Approximately 6 months Assessed by RANO per the BICR and investigator
Phase 1/2 Participants with ROS1 gene fusions (Cohort A, D, or E): DOR Approximately 6 months Assessed by RECIST v1.1 per the BICR and investigator
Phase 1/2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort A, D, or E): DOR Approximately 6 months Assessed by RECIST v1.1 per the BICR and investigator
Cohort B or E: TTR Approximately 6 months Assessed by RANO per the BICR and investigator
Time to Cmax, by inspection (Tmax) using F06 Formulation administered via feeding tube Approximately 24 months 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 to Cmax, by inspection (Tmax) using minitablets/F15 Approximately 24 months 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
AUC at steady state (AUCss) using F06 Formulation administered via feeding tube Approximately 24 months 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
Terminal half life (t½) using F1 Formulation Approximately 24 months 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
Terminal half life (t½) using minitablets/F15 Approximately 24 months 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
Area under the drug concentration by time curve (AUC) using F1 Formulation Approximately 24 months 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
Area under the drug concentration by time curve (AUC) using F06 Formulation administered via feeding tube Approximately 24 months 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
Cohort C: CBR Approximately 6 months Assessed by the Curie scale per the BICR and investigator
Cohort A, D, or E: ORR Approximately 6 months Assessed by RECIST v1.1 per the BICR and investigator
Cohort A, D, or E: Time to response (TTR) Approximately 6 months Assessed by RECIST v1.1 per the BICR and investigator
Cohort C: TTR Approximately 6 months Assessed by the Curie scale per the BICR and investigator
Phase 2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort B or E): ORR Approximately 6 months Assessed by RANO per the investigator
Phase 2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort D or E): ORR Approximately 6 months Assessed by RECIST v1.1 per the investigator
Phase 1/2 Participants with NTRK1/2/3 gene fusions (Cohort A, D, or E): ORR Approximately 6 months Assessed by RECIST v1.1 per the BICR and investigator
AUC at steady state (AUCss) using minitablets/F15 Approximately 24 months 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
Area under the drug concentration by time curve (AUC) using minitablets/F15 Approximately 24 months 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
Cohort A, D, or E: Progression-free Survival (PFS) Approximately 6 months Assessed by RECIST v1.1 per the BICR and investigator
Cohort C: PFS Approximately 6 months Assessed by the Curie scale per the BICR and investigator
Cohort A, D, or E: Overall Survival (OS) Approximately 6 months Assessed by RECIST v1.1
Cohort C: ORR Approximately 6 months Assessed by the Curie scale per the BICR and investigator
AUC at steady state (AUCss) using F06 Formulation given intact Approximately 24 months 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
Cohort B or E: ORR Approximately 6 months Assessed by RANO per the BICR and investigator
Phase 1/2 Participants with ROS1 gene fusions (Cohort B or E): ORR Approximately 6 months Assessed by RANO per the BICR and investigator
Phase 1/2 Participants with ROS1 gene fusions (Cohort B or E): TTR Approximately 6 months Assessed by RANO per the BICR and investigator
Area under the drug concentration by time curve (AUC) using F06 Formulation given intact Approximately 24 months 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
Cohort B or E: CBR Approximately 6 months Assessed by RANO per the BICR and investigator
Cohort A, D, or E: Duration of Response (DOR) Approximately 6 months Assessed by RECIST v1.1 per the BICR and investigator
Phase 1/2 Participants with ROS1 gene fusions (Cohort A, D, or E): ORR Approximately 6 months Assessed by RECIST v1.1 per the BICR and investigator
Phase 1/2 Participants with ROS1 gene fusions (Cohort B or E): DOR Approximately 6 months Assessed by RANO per the BICR and investigator
Phase 2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort D or E): DOR Approximately 6 months Assessed by RECIST v1.1 per the BICR and investigator
Phase 1/2 Participants with NTRK1/2/3 gene fusions (Cohort A, D, or E): DOR Approximately 6 months Assessed by RECIST v1.1 per the BICR and investigator
Phase 1/2 Participants with NTRK1/2/3 gene fusions (Cohort B or E): DOR Approximately 6 months Assessed by RANO per the BICR and investigator
Phase 1/2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort B or E): DOR Approximately 6 months Assessed by RANO per the BICR and investigator
Phase 1/2 Participants with NTRK1/2/3 gene fusions (Cohort A, D, or E): TTR Approximately 6 months Assessed by RECIST v1.1 per the BICR and investigator
Phase 2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort B or E): TTR Approximately 6 months Assessed by RANO per the BICR and investigator
Phase 2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort D or E): TTR Approximately 6 months Assessed by RECIST v1.1 per the BICR and investigator
Phase 1/2 Participants with ROS1 gene fusions (Cohort A, D, or E): TTR Approximately 6 months Assessed by RECIST v1.1 per the BICR and investigator
Phase 1/2 Participants with NTRK1/2/3 gene fusions (Cohort B or E): TTR Approximately 6 months Assessed by RANO per the BICR and investigator
Phase 1/2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort A, D, or E): TTR Approximately 6 months Assessed by RECIST v1.1 per the BICR and investigator
Phase 1/2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort B or E): TTR Approximately 6 months Assessed by RANO per the BICR and investigator
Trial Locations
- Locations (26)
Texas Children's Cancer and Hematology Center
🇺🇸Houston, Texas, 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
Washington University,St. Louis Children's Hospital
🇺🇸Saint Louis, Missouri, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
Nationwide Children's Hospital
🇺🇸Columbus, Ohio, United States
Beijing Children's Hospital, Capital Medical University
🇨🇳Beijing, China
Centre Leon Berard
🇫🇷Lyon, France
Fondazione IRCCS Istituto Nazionale dei Tumori
🇮🇹Milano, Lombardia, Italy
Royal Victoria Infirmary
🇬🇧Newcastle upon Tyne, United Kingdom
Rady Childrens Hospital
🇺🇸San Diego, California, United States
Johns Hopkins University
🇺🇸Baltimore, Maryland, United States
Dana Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
Oregon Health & Science Uni
🇺🇸Portland, Oregon, United States
Children's Hospital of Philadelphia
🇺🇸Philadelphia, Pennsylvania, United States
St. Jude Children'S Research Hospital
🇺🇸Memphis, Tennessee, United States
Primary Children's Hospital
🇺🇸Salt Lake City, Utah, United States
The Hospital for Sick Children
🇨🇦Toronto, Ontario, Canada
Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
🇨🇳Shanghai, China
Hôpital de la Timone, Oncologie Pédiatrique
🇫🇷Marseille, France
Universitaetsklinikum Heidelberg
🇩🇪Heidelberg, Baden Wuerttemberg, Germany
Hong Kong Children's Hospital
🇭🇰Hong Kong, Hong Kong
Hospital Infantil Universitario Nino Jesus
🇪🇸Madrid, Spain
Royal Marsden NHS Foundation Trust
🇬🇧Sutton, United Kingdom