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

Conditions

CNS Tumors, Solid Tumors

Keywords

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)

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.

Ami V. Desai, Huanmin Wang, Ellen M. Basu, Michela Casanova, Amy E. Armstrong et al. (15 authors)

Journal of Clinical Oncology2025-05-28

10.1200/jco.2025.43.16_suppl.10050

Efficacy and safety of entrectinib in children with extracranial solid or central nervous system (CNS) tumours harbouring NTRK or ROS1 fusions

Ami V. Desai, Aditi Bagchi, Amy E. Armstrong, Cornelis M. van Tilburg, Ellen M. Basu et al. (20 authors)

European Journal of Cancer2025-02-224 citations

10.1016/j.ejca.2025.115308

TRLS-12. EFFICACY AND SAFETY OF ENTRECTINIB IN CHILDREN WITHNTRK ORROS1 FUSION-POSITIVE (FP) PRIMARY CENTRAL NERVOUS SYSTEM (CNS) TUMORS

Aditi Bagchi, Giles Robinson, Ami V. Desai, Yeming Wu, Huanmin Wang et al. (20 authors)

Neuro-Oncology2024-06-18

10.1093/neuonc/noae064.165

Efficacy and safety of entrectinib in children with extracranial solid or primary central nervous system (CNS) tumors harboring NTRK or ROS1 fusions.

Ami V. Desai, Giles Robinson, Yeming Wu, Huanmin Wang, Ellen M. Basu et al. (20 authors)

Journal of Clinical Oncology2024-06-012 citations

10.1200/jco.2024.42.16_suppl.10000

HGG-24. NTRK-rearranged infantile gliomas of suprasellar/ optic pathway origin

Margot Lazow, Mariam Mathew, Ralph Salloum, Diana Rodriguez, Jeffrey R. Leonard et al. (10 authors)

Neuro-Oncology2022-06-01

10.1093/neuonc/noac079.239

Entrectinib in children and young adults with solid or primary CNS tumors harboring NTRK, ROS1, or ALK aberrations (STARTRK-NG)

Ami V. Desai, Giles Robinson, Karen Gauvain, Ellen M. Basu, Margaret E. Macy et al. (29 authors)

Neuro-Oncology2022-04-08121 citations

10.1093/neuonc/noac087

Updated entrectinib data in children and adolescents with recurrent or refractory solid tumors, including primary CNS tumors.

Ami V. Desai, Giles Robinson, Ellen M. Basu, Jennifer H. Foster, Karen Gauvain et al. (20 authors)

Journal of Clinical Oncology2020-05-2021 citations

10.1200/jco.2020.38.15_suppl.107

Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials.

Doebele RC, Drilon A, Paz-Ares L, Siena S, Shaw AT, Farago AF, Blakely CM, Seto T, Cho BC, Tosi D, Besse B, Chawla SP, Bazhenova L, Krauss JC, Chae YK, Barve M, Garrido-Laguna I, Liu SV, Conkling P, John T, Fakih M, Sigal D, Loong HH, Buchschacher GL, Garrido P, Nieva J, Steuer C, Overbeck TR, Bowles DW, Fox E, Riehl T, Chow-Maneval E, Simmons B, Cui N, Johnson A, Eng S, Wilson TR, Demetri GD, trial investigators.

2019-12-111,148 citations

10.1016/s1470-2045(19)30691-6

Phase 1/1B trial to assess the activity of entrectinib in children and adolescents with recurrent or refractory solid tumors including central nervous system (CNS) tumors.

Giles Robinson, Amar Gajjar, Karen Gauvain, Ellen M. Basu, Margaret E. Macy et al. (20 authors)

Journal of Clinical Oncology2019-05-2060 citations

10.1200/jco.2019.37.15_suppl.10009

Entrectinib in Two Pediatric Patients With Inflammatory Myofibroblastic Tumors Harboring ROS1 or ALK Gene Fusions

Srikanth Ambati, Emily K. Slotkin, Edna Chow‐Maneval, Ellen M. Basu

JCO Precision Oncology2018-09-1316 citations

10.1200/po.18.00095

Phase 1 study of entrectinib (RXDX-101), a TRK, ROS1, and ALK inhibitor, in children, adolescents, and young adults with recurrent or refractory solid tumors.

Ami V. Desai, Garrett M. Brodeur, Jennifer H. Foster, Stacey L. Berg, Ellen M. Basu et al. (14 authors)

Journal of Clinical Oncology2018-05-2015 citations

10.1200/jco.2018.36.15_suppl.10536

Abstract CT030: STARTRK-NG: A phase 1/1b study of entrectinib in children and adolescents with advanced solid tumors and primary CNS tumors, with or without TRK, ROS1, or ALK fusions

Ami V. Desai, Garrett M. Brodeur, Jennifer Foster, Suzanne Shusterman, Amit J. Sabnis et al. (13 authors)

Cancer Research2017-07-016 citations

10.1158/1538-7445.am2017-ct030

TRTH-10. PEDIATRIC PHASE 1/1B STUDY OF ENTRECTINIB IN PATIENTS WITH PRIMARY BRAIN TUMORS, NEUROBLASTOMA, AND NTRK, ROS1, OR ALK FUSIONS

Sunitha Rangaraju, Gang Li, Jason Christiansen, Zachary Hornby, Pratik S. Multani et al. (7 authors)

Neuro-Oncology2017-05-3110 citations

10.1093/neuonc/nox083.222

Interventions

DRUGEntrectinib

TRKA/B/C, ROS1, and ALK inhibitor

Study design

Allocation

NON_RANDOMIZED

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

0 Years to 18 Years

Healthy volunteers

No

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.

Design outcomes

Primary

Measure	Time frame	Description
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 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 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
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
Cohort D: ORR	Approximately 6 months	Assessed by RECIST v1.1 per the BICR

Secondary

Measure	Time frame	Description
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 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
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
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
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
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 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 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
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
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
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 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
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 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
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
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: Clinical Benefit Rate (CBR)	Approximately 6 months	Assessed by RECIST v1.1 per the BICR and investigator
Cohort B or E: CBR	Approximately 6 months	Assessed by RANO per the BICR and investigator
Cohort C: CBR	Approximately 6 months	Assessed by the Curie scale per the BICR and investigator
Cohort A, D, or E: Progression-free Survival (PFS)	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
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 B or E: OS	Approximately 6 months	Assessed by RANO
Cohort A, D, or E: ORR	Approximately 6 months	Assessed by RECIST v1.1 per the BICR and investigator
Cohort B or E: ORR	Approximately 6 months	Assessed by RANO per the BICR and investigator
Cohort C: ORR	Approximately 6 months	Assessed by the Curie scale 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 B or E: TTR	Approximately 6 months	Assessed by RANO per the BICR and investigator
Cohort C: TTR	Approximately 6 months	Assessed by the Curie scale 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
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
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
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 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): 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 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 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 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 or 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 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 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 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 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 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 ROS1 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

Countries

Canada, China, France, Germany, Hong Kong, Italy, Spain, United Kingdom, United States

Contacts

STUDY_DIRECTORClinical Trials

Hoffmann-La Roche

Outcome results

None listed