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A Study to Test the Safety of the Investigational Drug Loxo-195 in Children and Adults That May Treat Cancer

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ClinicalTrials.gov Identifier: NCT03215511
Recruitment Status : Recruiting
First Posted : July 12, 2017
Last Update Posted : September 27, 2019
Sponsor:
Information provided by (Responsible Party):
Bayer

Tracking Information
First Submitted Date  ICMJE June 30, 2017
First Posted Date  ICMJE July 12, 2017
Last Update Posted Date September 27, 2019
Actual Study Start Date  ICMJE July 3, 2017
Estimated Primary Completion Date October 28, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 26, 2019)
  • Phase 1: Maximum tolerated dose (MTD) [ Time Frame: Up to 42 days ]
  • Phase 1: Recommended dose [ Time Frame: Up to 12 months ]
  • Phase 2: Overall response rate (ORR) for patients <12 years from Cohort 1 by IRC [ Time Frame: Up to 40 months ]
    ORR is determined by an Independent Review Committee (IRC) 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 IRC [ Time Frame: Up to 40 months ]
    ORR is determined by an Independent Review Committee (IRC) using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
Original Primary Outcome Measures  ICMJE
 (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
Change History Complete list of historical versions of study NCT03215511 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: September 26, 2019)
  • Phase 1: Incidence of adverse events [ Time Frame: Up to 56 months ]
  • Phase 1: Severity of adverse events [ Time Frame: Up to 56 months ]
    Severity is assessed using CTCAE version 4.03
  • Phase 1: Duration of adverse events [ Time Frame: Up to 56 months ]
  • Phase 1: Number of subjects with safety-relevant changes in clinical parameters or vital signs after drug administration [ Time Frame: Up to 56 months ]
  • Phase 1: Severity of safety-relevant changes in clinical parameters or vital signs after drug administration [ Time Frame: Up to 56 months ]
  • Phase 1: Overall response rate (ORR) in patients with NTRK fusion cancer previously treated with TRK inhibitor determined by an IRC [ Time Frame: Up to 56 months ]
    ORR is determined by an Independent Review Committee (IRC) 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 [ Time Frame: 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) [ Time Frame: Up to 56 months ]
    Number of months from the initiation of Loxo-195 to the date of death due to any cause.
  • Phase 1: Maximum concentration of BAY2731954 in plasma (Cmax) [ 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) ]
  • Phase 1: Time to maximum concentration of BAY2731954 in plasma (Tmax) [ 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) ]
  • Phase 1: Area under the concentration versus time curve of BAY2731954 in plasma (AUC(0-t)) [ 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) ]
  • Phase 1: Area under the concentration versus time curve of BAY2731954 in plasma from time 0 to infinity (AUC(0-∞)) [ 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) ]
  • Phase 1: Apparent volume of distribution (Vz/F) [ 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) ]
  • Phase 1: Clearance (CL/F) [ 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) ]
  • Phase 1: Terminal elimination half-life (T1/2) [ 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) ]
  • Phase 2: Incidence of adverse events in patients ≥12 years [ Time Frame: Up to 44 months ]
  • Phase 2: Severity of adverse events in patients ≥12 years [ Time Frame: Up to 44 months ]
    Severity is assessed using CTCAE version 4.03
  • Phase 2: Duration of adverse events in patients ≥12 years [ Time Frame: Up to 44 months ]
  • Phase 2: Incidence of adverse events in patients <12 years [ Time Frame: Up to 44 months ]
  • Phase 2: Severity of adverse events in patients <12 years [ Time Frame: Up to 44 months ]
    Severity is assessed using CTCAE version 4.03
  • Phase 2: Duration of adverse events in patients <12 years [ Time Frame: Up to 44 months ]
  • Phase 2: Number of subjects with safety-relevant changes in clinical parameters or vital signs after drug administration [ Time Frame: Up to 44 months ]
  • Phase 2: Severity of safety-relevant changes in clinical parameters or vital signs after drug administration [ Time Frame: Up to 44 months ]
  • Phase 2: Overall response rate (ORR) in Cohort 2 determined by IRC [ Time Frame: Up to 44 months ]
    ORR is determined by an Independent Review Committee (IRC) using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
  • Phase 2: Overall response rate (ORR) in Cohort 1 determined by investigator [ Time Frame: 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: Overall response rate (ORR) in Cohort 2 determined by investigator [ Time Frame: 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 IRC [ Time Frame: Up to 44 months ]
    Determined by an Independent Review Committee (IRC)
  • Phase 2: Duration of response (DOR) determined by investigator [ Time Frame: Up to 44 months ]
  • Phase 2: Progression free survival (PFS) determined by IRC [ Time Frame: Up to 44 months ]
    Determined by an Independent Review Committee (IRC)
  • Phase 2: Progression free survival (PFS) determined by investigator [ Time Frame: Up to 44 months ]
  • Phase 2: Overall survival (OS) [ Time Frame: Up to 44 months ]
  • Phase 2: Clinical benefit rate (CBR) determined by IRC [ Time Frame: Up to 44 months ]
    Determined by an Independent Review Committee (IRC)
  • Phase 2: Clinical benefit rate (CBR) determined by investigator [ Time Frame: Up to 44 months ]
Original Secondary Outcome Measures  ICMJE
 (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  ICMJE A Study to Test the Safety of the Investigational Drug Loxo-195 in Children and Adults That May Treat Cancer
Official Title  ICMJE A Phase 1/2 Study of the TRK Inhibitor LOXO-195 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 Loxo-195 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 Loxo-195 in humans with cancer, for whom no other effective therapy exists.
Detailed Description

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

The primary objective of Phase 1 is to establish the recommended dose of Loxo-195 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 review committee (IRC). Secondary objectives of Phase 2 comprise the safety and efficacy of Loxo-195 at the recommended dose.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Solid Tumors Harboring NTRK Fusion
Intervention  ICMJE Drug: BAY2731954
BAY2731954 is administered as capsules or liquid formulation.
Other Name: Loxo-195
Study Arms  ICMJE
  • Experimental: Phase 1: Cancer patients <12 years
    Dose escalation cohorts with pediatric patients aged <12 years. Dose escalation starts with 43 mg of BAY2731954 per m2 body surface twice daily (children <3 years: once daily).
    Intervention: Drug: BAY2731954
  • Experimental: Phase 1: Cancer patients ≥12 years
    Dose escalation cohorts with patients aged 12 years or older. Dose escalation starts with 100 mg of BAY2731954 twice daily.
    Intervention: Drug: BAY2731954
  • 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 BAY2731954 at recommended dose twice daily.
    Intervention: Drug: BAY2731954
  • 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 BAY2731954 at recommended dose twice daily.
    Intervention: Drug: 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 Oct 11. pii: mdz385. doi: 10.1093/annonc/mdz385. [Epub ahead of print]

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 27, 2018)
93
Original Estimated Enrollment  ICMJE
 (submitted: July 10, 2017)
120
Estimated Study Completion Date  ICMJE February 24, 2022
Estimated Primary Completion Date October 28, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 equivalent) laboratory. 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 ≤ 3 (age ≥ 16 years) or Lansky Performance Score (LPS) ≥ 40% (age < 16 years). If enrolled with primary CNS tumor to be assessed by RANO, Karnofsky Performance Score (KPS) (age ≥ 16 years) or LPS (age < 16 years) ≥ 50%.
  • Life expectancy > 4 weeks.
  • Adequate hematologic, hepatic and renal function.
  • Patients with stable 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 LOXO-195
  • Ability to receive study drug orally or by enteral administration

Exclusion Criteria:

  • Concurrent treatment with a strong CYP3A4 inhibitor or inducer or drugs associated with QT prolongation.
  • Clinically significant active cardiovascular disease or history of myocardial infarction within 3 months prior to planned start of LOXO-195, 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 LOXO-195 or Ora-Sweet® SF and OraPlus® for patients receiving liquid formulation.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 1 Month and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Bayer Clinical Trials Contact (+)1-888-84 22937 clinical-trials-contact@bayer.com
Listed Location Countries  ICMJE Australia,   Denmark,   France,   Germany,   Hong Kong,   Italy,   Korea, Republic of,   Singapore,   Spain,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03215511
Other Study ID Numbers  ICMJE 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  ICMJE
Plan to Share IPD: Undecided
Plan Description: Availability of this study's data will 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.clinicalstudydatarequest.com 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 Study sponsors section of the portal.
Responsible Party Bayer
Study Sponsor  ICMJE Bayer
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Bayer
Verification Date September 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP