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

Solid Tumors Clinical Trial

— STARTRK-NG  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02650401
• Other study ID #: RXDX-101-03
• Secondary ID: CO40778
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: May 3, 2016
• Est. completion date: June 15, 2025

Study information

• Verified date: June 2024
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 69
• Est. completion date: June 15, 2025
• Est. primary completion date: June 15, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 0 Years to 18 Years

Eligibility

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.

Related Conditions & MeSH terms

• Central Nervous System Neoplasms
• CNS Tumors
• Neoplasms
• Solid Tumors

Intervention

Drug:
• Entrectinib
TRKA/B/C, ROS1, and ALK inhibitor

Locations

Country	Name	City	State
Canada	The Hospital for Sick Children	Toronto	Ontario
China	Beijing Children's Hospital, Capital Medical University; Oncological Surgery Department	Beijing City
China	Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine	Shanghai
France	Centre Leon Berard; Pediatrie	Lyon
France	Hôpital de la Timone, Oncologie Pédiatrique	Marseille
France	Hopital Purpan; Pediatrie - Hematologie - Oncologie pediatrique	Toulouse
France	Institut Gustave Roussy; Service de Pathologie Morphologique	Villejuif
Germany	Universitaetsklinikum Heidelberg	Heidelberg
Hong Kong	Hong Kong Children's Hospital	Hong Kong
Italy	Fondazione IRCCS Istituto Nazionale dei Tumori; Struttura Complessa di Pediatria Oncologica	Milano	Lombardia
Italy	A. O. Città della Salute e della Scienza di Torino; SC Oncoematologia e Centro Trapianti AOOIRM	Torino	Piemonte
Korea, Republic of	Seoul National University Hospital	Seoul
Spain	Hospital Sant Joan de Deu; Servicio de Oncologia y Hematologia	Esplugues de Llobregat	Barcelona
Spain	Hospital Infantil Universitario Nino Jesus	Madrid
Taiwan	National Taiwan University Hospital; Department of Paediatrics	Taipei
Taiwan	Chang Gung Memorial Hospital, Linkou; Department of Pediatric Internal Medicine	Taoyuan City
United Kingdom	Leeds General Infirmary	Leeds
United Kingdom	Royal Victoria Infirmary; Pharmacy	Newcastle upon Tyne
United Kingdom	Royal Marsden NHS Foundation Trust	Sutton
United States	Egleston Children's Hospital at Emory University Atlanta; Pediatric Hematology/Oncology	Atlanta	Georgia
United States	Children's Hospital Colorado; Center For Cancer/Blood Disorder	Aurora	Colorado
United States	Johns Hopkins University	Baltimore	Maryland
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	University of Chicago; Comer Children's Hospital/Department of Pediatrics	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Nationwide Children's Hospital; Dept. of Pulmonology	Columbus	Ohio
United States	Cook Childrens Medical Center	Fort Worth	Texas
United States	Texas Children's Cancer and Hematology Center	Houston	Texas
United States	St. Jude Children'S Research Hospital	Memphis	Tennessee
United States	University of Minnesota Childrens' Hospital	Minneapolis	Minnesota
United States	Memorial Sloan Kettering Cancer Center; Pediatrics	New York	New York
United States	Morgan Stanley Children's Hospital; Herbert Irving Cancer Center	New York	New York
United States	Children'S Hospital of Orange County	Orange	California
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Oregon Health & Science Uni	Portland	Oregon
United States	Washington University,St. Louis Children's Hospital; Neurology, Movement Disorder	Saint Louis	Missouri
United States	Primary Children's Hospital	Salt Lake City	Utah
United States	Rady Childrens Hospital	San Diego	California
United States	UCSF Benioff Children's Hospital; UCSF Pediatrics Hematology Oncology	San Francisco	California
United States	Children's National Medical Center; Department of Pediatrics	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Canada,  China,  France,  Germany,  Hong Kong,  Italy,  Korea, Republic of,  Spain,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum Tolerated Dose (MTD)	Assessed by National Cancer Institute Common Terminology for Adverse Events Criteria (NCI CTCAE v4.03)	Approximately 6 months
Primary	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
Primary	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
Primary	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
Primary	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
Primary	Cohort B: Objective Response Rate (ORR)	Assessed by RANO per the BICR	Approximately 6 months
Primary	Cohort D: ORR	Assessed by RECIST v1.1 per the BICR	Approximately 6 months
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Cohort A, D, or E: Clinical Benefit Rate (CBR)	Assessed by RECIST v1.1 per the BICR and investigator	Approximately 6 months
Secondary	Cohort B or E: CBR	Assessed by RANO per the BICR and investigator	Approximately 6 months
Secondary	Cohort C: CBR	Assessed by the Curie scale per the BICR and investigator	Approximately 6 months
Secondary	Cohort A, D, or E: Progression-free Survival (PFS)	Assessed by RECIST v1.1 per the BICR and investigator	Approximately 6 months
Secondary	Cohort B or E: PFS	Assessed by RANO per the BICR and investigator	Approximately 6 months
Secondary	Cohort C: PFS	Assessed by the Curie scale per the BICR and investigator	Approximately 6 months
Secondary	Cohort A, D, or E: Overall Survival (OS)	Assessed by RECIST v1.1	Approximately 6 months
Secondary	Cohort B or E: OS	Assessed by RANO	Approximately 6 months
Secondary	Cohort A, D, or E: ORR	Assessed by RECIST v1.1 per the BICR and investigator	Approximately 6 months
Secondary	Cohort B or E: ORR	Assessed by RANO per the BICR and investigator	Approximately 6 months
Secondary	Cohort C: ORR	Assessed by the Curie scale per the BICR and investigator	Approximately 6 months
Secondary	Cohort A, D, or E: Time to response (TTR)	Assessed by RECIST v1.1 per the BICR and investigator	Approximately 6 months
Secondary	Cohort B or E: TTR	Assessed by RANO per the BICR and investigator	Approximately 6 months
Secondary	Cohort C: TTR	Assessed by the Curie scale per the BICR and investigator	Approximately 6 months
Secondary	Cohort A, D, or E: Duration of Response (DOR)	Assessed by RECIST v1.1 per the BICR and investigator	Approximately 6 months
Secondary	Cohort B or E: DOR	Assessed by RANO per the BICR and investigator	Approximately 6 months
Secondary	Cohort C: DOR	Assessed by the Curie scale per the BICR and investigator	Approximately 6 months
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Phase 1/2 Participants with ROS1 gene fusions (Cohort B or E): ORR	Assessed by RANO per the BICR and investigator	Approximately 6 months
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Phase 1/2 Participants with ROS1 gene fusions (Cohort B or E): DOR	Assessed by RANO per the BICR and investigator	Approximately 6 months
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Phase 1/2 Participants with ROS1 gene fusions (Cohort B or E): TTR	Assessed by RANO per the BICR and investigator	Approximately 6 months
Secondary	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
Secondary	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