A Study to Test the Safety of the Investigational Drug Selitrectinib in Children and Adults That May Treat Cancer

Sponsor

Bayer (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT03215511

Collaborator

(none)

Enrollment

Locations

Arms

96.8

Anticipated Duration (Months)

2.8

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This research study is done to test the safety of the new drug selitrectinib in children and adults with cancer having a change in a particular gene (NTRK1, NTRK2 or NTRK3). The drug may treat cancer by interfering with the effect of the NTRK genes on cancer growth. The study also investigates how the drug is absorbed and processed in the human body, and how well and for how long the cancer responds to the drug. This is the first study to test selitrectinib in humans with cancer, for whom no other effective therapy exists.

Condition or Disease	Intervention/Treatment	Phase
Solid Tumors Harboring NTRK Fusion	Drug: Selitrectinib (BAY2731954)	Phase 1/Phase 2

Detailed Description

The trial will be conducted in 2 parts: dose escalation and expansion (Phase 1) and Phase 2.

The primary objective of Phase 1 is to establish the recommended dose of selitrectinib to treat neurotrophic tyrosine kinase (NTRK) fusion cancers in patients a) aged 12 years and older and b) younger than 12 years. Secondary objectives of Phase 1 are to characterize the pharmakokinetic properties of the test drug, its safety and tolerability, and to assess the objective response rate (ORR) of NTRK-tumors.

The primary objective of Phase 2 is to assess the overall response rate in NTRK fusion cancer patients as determined by an independent radiology committee (IRR). Secondary objectives of Phase 2 comprise the safety and efficacy of selitrectinib at the recommended dose.

Study Design

Study Type:

Interventional

Actual Enrollment :

81 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 1/2 Study of the TRK Inhibitor Selitrectinib in Adult and Pediatric Subjects With Previously Treated NTRK Fusion Cancers

Actual Study Start Date :

Jul 3, 2017

Actual Primary Completion Date :

Apr 11, 2022

Anticipated Study Completion Date :

Jul 26, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase 1: Cancer patients <12 years Dose escalation cohorts with pediatric patients aged <12 years. Dose escalation starts with 43 mg of selitrectinib per m2 body surface twice daily.	Drug: Selitrectinib (BAY2731954) Selitrectinib is administered as capsules or liquid formulation. Other Names: Loxo-195
Experimental: Phase 1: Cancer patients ≥12 years Dose escalation cohorts with patients aged 12 years or older. Dose escalation starts with 100 mg of selitrectinib twice daily.	Drug: Selitrectinib (BAY2731954) Selitrectinib is administered as capsules or liquid formulation. Other Names: Loxo-195
Experimental: Phase 2: Cancer patients_Cohort 1 Expansion cohort consisting of patients with NTRK fusion cancers showing disease progression despite treatment with a TRK inhibitor. Patients receive selitrectinib at recommended dose twice daily.	Drug: Selitrectinib (BAY2731954) Selitrectinib is administered as capsules or liquid formulation. Other Names: Loxo-195
Experimental: Phase 2: Cancer patients_Cohort 2 Expansion cohort consisting of patients with NTRK fusion cancers showing intolerance or unresponsiveness to previous treatment with a TRK inhibitor. Patients receive selitrectinib at recommended dose twice daily.	Drug: Selitrectinib (BAY2731954) Selitrectinib is administered as capsules or liquid formulation. Other Names: Loxo-195

Outcome Measures

Primary Outcome Measures

Phase 1: Maximum tolerated dose (MTD) [Up to 42 days]
Phase 1: Recommended dose [Up to 12 months]
Phase 2: Overall response rate (ORR) for patients <12 years from Cohort 1 by IRR [Up to 40 months]
ORR is determined by an Independent Radiology Committee (IRR) using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
Phase 2: Overall response rate (ORR) for patient ≥12 years from Cohort 1 by IRR [Up to 40 months]
ORR is determined by an Independent Radiology Committee (IRR) using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

Secondary Outcome Measures

Phase 1: Incidence of adverse events [Up to 56 months]
Phase 1: Severity of adverse events [Up to 56 months]
Severity is assessed using CTCAE version 4.03
Phase 1: Duration of adverse events [Up to 56 months]
Phase 1: Number of subjects with safety-relevant changes in clinical parameters or vital signs after drug administration [Up to 56 months]
Phase 1: Severity of safety-relevant changes in clinical parameters or vital signs after drug administration [Up to 56 months]
Phase 1: Overall response rate (ORR) in patients with NTRK fusion cancer previously treated with TRK inhibitor determined by investigator [Up to 56 months]
ORR is determined by the investigator using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
Phase 1: Overall response rate (ORR) in patients with primary central nervous system (CNS) malignancies determined by investigator [Up to 56 months]
ORR is determined by the treating investigator using the Response Assessment in Neuro-Oncology (RANO) criteria.
Phase 1: Overall survival (OS) [Up to 56 months]
Number of months from the initiation of selitrectinib to the date of death due to any cause.
Phase 1: Maximum concentration of BAY2731954 in plasma (Cmax) [Predose, 0.25, 0.5, 1, 2, 4, 6, 8 hours post-dose on Day 1, predose, 0.5, 1, 2, 4 post-dose on Day 8 of Cycle 1 (cycle length 28 days)]
Phase 1: Area under the concentration versus time curve of BAY2731954 in plasma (AUC(0-last)) [Predose, 0.25, 0.5, 1, 2, 4, 5, 8 and 10 hours post-dose on Days 1, 8, 15 and 22 of Cycle 1 (cycle length 28 days)]
Phase 2: Incidence of adverse events in patients ≥12 years [Up to 44 months]
Phase 2: Severity of adverse events in patients ≥12 years [Up to 44 months]
Severity is assessed using CTCAE version 4.03
Phase 2: Duration of adverse events in patients ≥12 years [Up to 44 months]
Phase 2: Incidence of adverse events in patients <12 years [Up to 44 months]
Phase 2: Severity of adverse events in patients <12 years [Up to 44 months]
Severity is assessed using CTCAE version 4.03
Phase 2: Duration of adverse events in patients <12 years [Up to 44 months]
Phase 2: Number of subjects with safety-relevant changes in clinical parameters or vital signs after drug administration [Up to 44 months]
Phase 2: Severity of safety-relevant changes in clinical parameters or vital signs after drug administration [Up to 44 months]
Phase 2: Overall response rate (ORR) in Cohort 2 determined by IRR [Up to 44 months]
ORR is determined by an Independent Radiology Committee (IRR) using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
Phase 2: Overall response rate (ORR) determined by investigator [Up to 44 months]
ORR is determined by the treating investigator using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or the Response Assessment in Neuro-Oncology (RANO) criteria, as appropriate.
Phase 2: Duration of response (DOR) determined by IRR [Up to 44 months]
Determined by an Independent Radiology Committee (IRR)
Phase 2: Duration of response (DOR) determined by investigator [Up to 44 months]
Phase 2: Progression free survival (PFS) determined by IRR [Up to 44 months]
Determined by an Independent Radiology Committee (IRR)
Phase 2: Progression free survival (PFS) determined by investigator [Up to 44 months]
Phase 2: Overall survival (OS) [Up to 44 months]
Phase 2: Clinical benefit rate (CBR) determined by IRR [Up to 44 months]
Determined by an Independent Radiology Committee (IRR)
Phase 2: Clinical benefit rate (CBR) determined by investigator [Up to 44 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

1 Month and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Advanced solid tumor for which, in the opinion of the investigator, no other standard therapy offers greater benefit.
A solid tumor diagnosis in the setting of:
1. a documented NTRK fusion and a clinical history of relapse following a response to a prior TRK inhibitor
1. a documented NTRK fusion unresponsive to a prior TRK inhibitor
1. a documented NTRK fusion and a clinical history of intolerance to a prior TRK inhibitor
NTRK gene fusions will be identified in a CLIA-certified (or equivalently-accredited diagnostic) laboratory. If such a report cannot be provided, other available certifications/accreditations are required and need to be documented. Patients with infantile fibrosarcoma (IFS) or congenital mesoblastic nephroma (CMN) may be enrolled based on an ETV6+ FISH test without identifying NTRK3.
Performance Status: Eastern Cooperative Oncology Group (ECOG) score ≤ 2 in adults or Karnofsky Performance Score (KPS) Score≥50% (age ≥ 16 years) or Lansky Performance Score (LPS) ≥ 40% (age < 16 years).
Life expectancy of at least 3 months.
Adequate hematologic, hepatic and renal function.
Patients with stable central nervous system (CNS) primary tumor, brain metastases, or treated spinal cord compression are eligible if neurological symptoms have been stable for 7 days prior to the first dose of selitrectinib.
Ability to receive study drug orally or by enteral administration

Exclusion Criteria:

Prior exposure to second generation TRK inhibitor (e.g. selitrectinib, repotrectinib (TPX-0005)), taletrectinib (DS-6501b/AB-106)). Exception is in case patient presented intolerance to the second generation TRK inhibitor agent and the duration of exposure was less than 28 days. No previous treatment with selitrectinib is allowed.
Concurrent treatment with a strong CYP3A4 inhibitor or inducer, consumption of grapefruit juice or Seville oranges, or drugs associated with QT prolongation.
Clinically significant active cardiovascular disease or history of myocardial infarction within 3 months prior to planned start of selitrectinib, or prolongation of QT interval corrected for heart rate (QTc interval) >480 milliseconds within past 6 months
Major surgery within 7 days of enrollment
Uncontrolled systemic bacterial, fungal or viral infection.
Pregnancy or lactation.
Known hypersensitivity to selitrectinib or Ora-Sweet® SF and OraPlus® for patients receiving liquid formulation.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Univ.of California-San Diego Moores Cancer Center	La Jolla	California	United States	92093
2	UCLA Jonsson Comprehensive Cancer Center	Los Angeles	California	United States	90095
3	Stanford Cancer Center	Palo Alto	California	United States	94304
4	Children's Healthcare of Atlanta	Atlanta	Georgia	United States	30329
5	Midwestern Regional Medical Center	Zion	Illinois	United States	60099
6	Massachusetts General Hospital	Boston	Massachusetts	United States	02114-2696
7	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
8	University of Michigan	Ann Arbor	Michigan	United States	48109
9	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10065
10	Oregon Health and Science University	Portland	Oregon	United States	97239
11	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
12	Avera Cancer Institute	Sioux Falls	South Dakota	United States	57105
13	St. Jude Children's Research Hospital	Memphis	Tennessee	United States	38105
14	Sarah Cannon Research Institute	Nashville	Tennessee	United States	37203
15	University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030-4000
16	Virginia Oncology Associates	Norfolk	Virginia	United States	23502
17	Seattle Children's Hospital	Seattle	Washington	United States	98105
18	Sydney Children's Hospital	Sydney	New South Wales	Australia	2031
19	Royal Children's Hospital Melbourne	Parkville	Victoria	Australia	3052
20	UZ Antwerpen	Edegem		Belgium	2650
21	Finsen Centre	Copenhagen		Denmark	2100
22	Institut Curie - Ulm - Paris	Paris		France	75005
23	Institut Gustave Roussy	Villejuif		France	94805
24	Universitätsklinikum Heidelberg	Heidelberg	Baden-Württemberg	Germany	69120
25	Tallaght Hospital	Dublin		Ireland	24
26	Fondazione IRCCS Istituto Nazionale dei Tumori	Milano	Lombardia	Italy	20133
27	National Cancer Center Singapore	Singapore		Singapore	169610
28	Ciutat Sanitària i Universitaria de la Vall d'Hebron	Barcelona		Spain	08035
29	Fundacion Jimenez Diaz (Clinica de la Concepcion)	Madrid		Spain	28040