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

• ClinicalTrials.gov Identifier: NCT03215511
• Recruitment Status: Completed
• First Posted: July 12, 2017
• Last Update Posted: March 26, 2024
• Sponsor: Bayer
• Information provided by (Responsible Party): Bayer

Tracking Information

• First Submitted Date: June 30, 2017
• First Posted Date: July 12, 2017
• Last Update Posted Date: March 26, 2024
• Actual Study Start Date: July 3, 2017
• Actual Primary Completion Date: April 11, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 2, 2022)

• Maximum tolerated dose (MTD) [ Time Frame: Up to 42 days ]
• Recommended dose [ Time Frame: Up to 12 months ]

Original Primary Outcome Measures (submitted: July 10, 2017)

• Maximum Tolerated Dose (MTD) [ Time Frame: The first 28 days of treatment (Cycle 1) ]
  For Phase 1
• Recommended dose for further study [ Time Frame: The first 28 days of treatment (Cycle 1) and every cycle (28 days) for approximately 12 months (or earlier if the patient discontinues from the study) ]
  For Phase 1
• Best overall response of confirmed PR or CR by independent radiology review in NTRK fusion cancer patients previously treated with TRK inhibitor who have progressed [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks while on treatment, and every 12 weeks after the last dose (for up to 2 years) in patients who have not progressed ]
  For Phase 2

Current Secondary Outcome Measures (submitted: November 2, 2022)

• Incidence of adverse events [ Time Frame: Up to 56 months ]
• Severity of adverse events [ Time Frame: Up to 56 months ]
  Severity is assessed using CTCAE version 4.03
• Duration of adverse events [ Time Frame: Up to 56 months ]
• Number of subjects with safety-relevant changes in clinical parameters or vital signs after drug administration [ Time Frame: Up to 56 months ]
• Severity of safety-relevant changes in clinical parameters or vital signs after drug administration [ Time Frame: Up to 56 months ]
• Overall response rate (ORR) in subjects with NTRK fusion cancer previously treated with TRK inhibitor determined by investigator [ Time Frame: Up to 56 months ]
  ORR is determined by the investigator using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
• Overall response rate (ORR) in subjects with primary central nervous system (CNS) malignancies determined by investigator [ Time Frame: Up to 56 months ]
  ORR is determined by the treating investigator using the Response Assessment in Neuro-Oncology (RANO) criteria.
• Maximum concentration (Cmax) of BAY2731954 in plasma [ Time Frame: 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) ]
• Area under the concentration versus time curve of BAY2731954 in plasma (AUC (0-10), AUC(0-12) for BID dosing and AUC(0-24) for QD dosing) [ Time Frame: At defined time points for different cohort, up to 10 hours post-dose ]

Original Secondary Outcome Measures (submitted: July 10, 2017)

• Incidence of AEs [ Time Frame: From the time of informed consent, for approximately 24 months (or earlier if the patient discontinues from the study), and through Safety Follow-up (28 days after the last dose) ]
  For Phase 1 and Phase 2
• Severity of AEs [ Time Frame: From the time of informed consent, for approximately 24 months (or earlier if the patient discontinues from the study), and through Safety Follow-up (28 days after the last dose) ]
  For Phase 1 and Phase 2
• Duration of AEs [ Time Frame: From the time of informed consent, for approximately 24 months (or earlier if the patient discontinues from the study), and through Safety Follow-up (28 days after the last dose) ]
  For Phase 1 and Phase 2
• Changes in clinical laboratory results compared to baseline [ Time Frame: For approximately 24 months (or earlier if the patient discontinues from the study), and through Safety Follow-up (28 days after the last dose) ]
  For Phase 1 and Phase 2
• Changes in vital signs compared to baseline [ Time Frame: For approximately 24 months (or earlier if the patient discontinues from the study), and through Safety Follow-up (28 days after the last dose) ]
  For Phase 1 and Phase 2
• Best overall response of confirmed PR or CR by independent radiology review in NTRK fusion cancer patients previously treated with TRK inhibitor [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks while on treatment, and every 12 weeks after the last dose (for up to 2 years) in patients who have not progressed ]
  For Phase 1
• Best overall response of confirmed CR or PR as determined by treating investigators using RECIST v1.1 in patients with non-fusion NTRK altered cancers or RANO in patients with primary CNS malignancies. [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks while on treatment, and every 12 weeks after the last dose (for up to 2 years) in patients who have not progressed ]
  For Phase 1
• Best overall response of confirmed PR or CR using RECIST v1.1 or RANO criteria as appropriate in patients with non-fusion NTRK altered cancers who have demonstration of progression following or during receipt of previous anticancer therapy [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks while on treatment, and every 12 weeks after the last dose (for up to 2 years) in patients who have not progressed ]
  For Phase 2
• Best overall response of confirmed PR or CR using RECIST v1.1 or RANO criteria as appropriate in patients with documented NTRK alterations, including TRK fusions, who discontinued previous anticancer therapy including TRK inhibitors due to intolerance [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks while on treatment, and every 12 weeks after the last dose (for up to 2 years) in patients who have not progressed ]
  For Phase 2
• Duration or response (DOR) for patients with best overall response of confirmed CR or PR by an independent radiology review committee [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks while on treatment, and every 12 weeks after the last dose (for up to 2 years) in patients who have not progressed ]
  For Phase 2
• Duration or response (DOR) for patients with best overall response of confirmed CR or PR by the treating Investigator [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks while on treatment, and every 12 weeks after the last dose (for up to 2 years) in patients who have not progressed ]
  For Phase 2
• Progression-free survival (PFS) [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks while on treatment, and every 12 weeks after the last dose (for up to 2 years) in patients who have not progressed ]
  For Phase 2
• Overall survival (OS) [ Time Frame: Up to 24 months ]
  For Phase 2
• Clinical benefit rate (CBR) [ Time Frame: Up to 24 months ]
  For Phase 2

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study to Test the Safety of the Investigational Drug Selitrectinib in Children and Adults That May Treat Cancer
• Official Title: A Phase 1 Study of the TRK Inhibitor Selitrectinib (BAY 2731954) in Adult and Pediatric Subjects With Previously Treated NTRK Fusion Cancers
• 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.
• Detailed Description: The primary objective is to determine the recommended dose for further study of oral selitrectinib with previously treated neurotrophic tyrosine kinase (NTRK) cancers in 2 patient groups: a) aged 12 years and older and b) younger than 12 years. Secondary objectives of Phase I 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.
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Solid Tumors Harboring NTRK Fusion

Intervention

Drug: Selitrectinib (BAY2731954)

Selitrectinib is administered as capsules or liquid formulation.

Other Name: Loxo-195

Study Arms

• Experimental: Cancer participants <12 years
  A Rolling-6 dose escalation design will be used. The starting dose for participants age < 12 years will be 25% below the highest dose level cohort divided by 1.73 m^2 cleared by the Safety Review Committee (SRC) for subjects age 12 years and older.
  Intervention: Drug: Selitrectinib (BAY2731954)
• Experimental: Cancer participants ≥12 years
  A 3+3 dose escalation design will be used to determine the maximum tolerated dose (MTD)/recommended dose for further study, enrolling 3 to 6 participants per cohort with a starting dose level of 100 mg twice daily (BID).
  Intervention: Drug: Selitrectinib (BAY2731954)

• Publications *: O'Reilly EM, Hechtman JF. Tumour response to TRK inhibition in a patient with pancreatic adenocarcinoma harbouring an NTRK gene fusion. Ann Oncol. 2019 Nov 1;30(Suppl_8):viii36-viii40. doi: 10.1093/annonc/mdz385. Epub 2019 Dec 24.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 15, 2022): 81
• Original Estimated Enrollment (submitted: July 10, 2017): 120
• Actual Study Completion Date: January 30, 2023
• Actual Primary Completion Date: April 11, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

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:

  • a) a documented NTRK fusion and a clinical history of relapse following a response to a prior TRK inhibitor
  • b) a documented NTRK fusion unresponsive to a prior TRK inhibitor
  • c) 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 Status (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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 1 Month and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Belgium, Denmark, France, Germany, Ireland, Italy, Singapore, Spain, United States
• Removed Location Countries: Canada, China, Hong Kong, Korea, Republic of, United Kingdom

Administrative Information

• NCT Number: NCT03215511
• Other Study ID Numbers: 20810; LOXO-EXT-17005 ( Other Identifier: Loxo Oncology, Inc. ); 2017-004246-20 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

Plan Description

Availability of this study's data will later be determined according to Bayer's commitment to the EFPIA/PhRMA "Principles for responsible clinical trial data sharing". This pertains to scope, timepoint and process of data access. As such, Bayer commits to sharing upon request from qualified researchers patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials in patients for medicines and indications approved in the US and EU as necessary for conducting legitimate research. This applies to data on new medicines and indications that have been approved by the EU and US regulatory agencies on or after January 01, 2014.

Interested researchers can use www.vivli.org to request access to anonymized patient-level data and supporting documents from clinical studies to conduct research. Information on the Bayer criteria for listing studies and other relevant information is provided in the member section of the portal.

• Current Responsible Party: Bayer
• Original Responsible Party: Loxo Oncology, Inc.
• Current Study Sponsor: Bayer
• Original Study Sponsor: Loxo Oncology, Inc.
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Bayer
• Verification Date: March 2024