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A Study to Test the Safety and Efficacy of the Drug Larotrectinib for the Treatment of Tumors With NTRK-fusion in Children (SCOUT)

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ClinicalTrials.gov Identifier: NCT02637687
Recruitment Status : Recruiting
First Posted : December 22, 2015
Last Update Posted : May 3, 2019
Sponsor:
Information provided by (Responsible Party):
Bayer

Brief Summary:

The study is being done to test the safety of a cancer drug called larotrectinib in children. The cancer must have a change in a particular gene (NTRK1, NTRK2 or NTRK3). Larotrectinib blocks the actions of these NTRK genes in cancer cells and can therefore be used to treat cancer.

The first study part (Phase 1) is done to determine what dose level of larotrectinib is safe for children, how the drug is absorbed and changed by their bodies and how well the cancer responds to the drug. The main purpose of the second study part (Phase 2) is to investigate how well and how long different cancer types respond to the treatment with larotrectininb.


Condition or disease Intervention/treatment Phase
Solid Tumors Harboring NTRK Fusion Drug: Larotrectinib (Vitravki, BAY2757556) Phase 1 Phase 2

Expanded Access : An investigational treatment associated with this study is available outside the clinical trial.   More info ...

Detailed Description:

The primary objectives are to determine the safety and efficacy of oral larotrectinib in pediatric patients with advanced solid or primary central nervous system (CNS) tumors.

The secondary objectives comprise e.g. the determination of the pharmacokinetic properties, the maximum tolerated dose/ recommended dose and the tumor-type specific efficacy of larotrectinib. In addition, pain status and health-related quality of life of the pediatric patients will be assessed.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 104 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2 Study of the Oral TRK Inhibitor LOXO-101 in Pediatric Patients With Advanced Solid or Primary Central Nervous System Tumors
Actual Study Start Date : December 16, 2015
Estimated Primary Completion Date : September 30, 2020
Estimated Study Completion Date : September 30, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Pediatric patients_Dose 1
Pediatric cancer patients receiving BAY2757556 at an adult-equivalent dose of 50 mg twice daily (dose escalation cohort).
Drug: Larotrectinib (Vitravki, BAY2757556)
BAY2757556 will be administered orally as capsule or in liquid form over continuous 28-day cycles.
Other Name: LOXO-101

Experimental: Pediatric patients_Dose 2
Pediatric cancer patients receiving BAY2757556 at an adult-equivalent dose of 75 mg twice daily (dose escalation cohort).
Drug: Larotrectinib (Vitravki, BAY2757556)
BAY2757556 will be administered orally as capsule or in liquid form over continuous 28-day cycles.
Other Name: LOXO-101

Experimental: Pediatric patients_Dose 3
Pediatric cancer patients receiving BAY2757556 at an adult-equivalent dose of 100 mg twice daily (dose escalation cohort).
Drug: Larotrectinib (Vitravki, BAY2757556)
BAY2757556 will be administered orally as capsule or in liquid form over continuous 28-day cycles.
Other Name: LOXO-101

Experimental: Pediatric patients_Dose 4
Pediatric cancer patients receiving BAY2757556 at an adult-equivalent dose of 150 mg twice daily (dose escalation cohort).
Drug: Larotrectinib (Vitravki, BAY2757556)
BAY2757556 will be administered orally as capsule or in liquid form over continuous 28-day cycles.
Other Name: LOXO-101

Experimental: Pediatric patients_Dose 5
Pediatric cancer patients receiving BAY2757556 at dose of 100 mg/m2 twice daily (dose escalation cohort).
Drug: Larotrectinib (Vitravki, BAY2757556)
BAY2757556 will be administered orally as capsule or in liquid form over continuous 28-day cycles.
Other Name: LOXO-101

Experimental: Pediatric patients_Dose 6
Pediatric cancer patients receiving BAY2757556 at dose of 150 mg/m2 twice daily (dose escalation cohort).
Drug: Larotrectinib (Vitravki, BAY2757556)
BAY2757556 will be administered orally as capsule or in liquid form over continuous 28-day cycles.
Other Name: LOXO-101

Experimental: Pediatric patients_Dose 7
Pediatric cancer patients receiving BAY2757556 at dose of 200 mg/m2 twice daily (dose escalation cohort).
Drug: Larotrectinib (Vitravki, BAY2757556)
BAY2757556 will be administered orally as capsule or in liquid form over continuous 28-day cycles.
Other Name: LOXO-101

Experimental: Pediatric patients_Recommended dose
Pediatric cancer patients receiving BAY2757556 at the recommended dose of 100 mg/m2 twice daily as determined in the dose escalation part (dose expansion cohort, Phase 1).
Drug: Larotrectinib (Vitravki, BAY2757556)
BAY2757556 will be administered orally as capsule or in liquid form over continuous 28-day cycles.
Other Name: LOXO-101

Experimental: Pediatric patients_Fibrosarcoma
Pediatric patients with infantile fibrosarcoma (IFS) and confirmed ETV6 rearrangement receiving BAY2757556 at the recommended dose of 100 mg/m2 twice daily (efficacy cohort, Phase 2).
Drug: Larotrectinib (Vitravki, BAY2757556)
BAY2757556 will be administered orally as capsule or in liquid form over continuous 28-day cycles.
Other Name: LOXO-101

Experimental: Pediatric patients_Extracranial
Pediatric patients with other extra-cranial solid tumors and confirmed NTRK-fusion receiving BAY2757556 at the recommended dose of 100 mg/m2 twice daily (efficacy cohort, Phase 2).
Drug: Larotrectinib (Vitravki, BAY2757556)
BAY2757556 will be administered orally as capsule or in liquid form over continuous 28-day cycles.
Other Name: LOXO-101

Experimental: Pediatric patients_CNS tumors
Pediatric patients with primary central nervous system (CNS) tumors and confirmed NTRK-fusion receiving BAY2757556 at the recommended dose of 100 mg/m2 twice daily (efficacy cohort, Phase 2).
Drug: Larotrectinib (Vitravki, BAY2757556)
BAY2757556 will be administered orally as capsule or in liquid form over continuous 28-day cycles.
Other Name: LOXO-101




Primary Outcome Measures :
  1. Phase 1: Number of participants with adverse events [ Time Frame: Up to 5 years ]
  2. Phase 1: Severity of adverse events [ Time Frame: Up to 5 years ]
  3. Phase 2: Overall response rate (ORR) by IRRC [ Time Frame: Up to 5 years ]
    Proportion of subjects with confirmed best overall response of complete response or partial response, assessed by an independent radiology review committee (IRRC) using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or Response Assessment in Neuro-Oncology (RANO) as appropriate.


Secondary Outcome Measures :
  1. Phase 1: Maximum concentration of larotrectinib in plasma (Cmax) [ Time Frame: Pre-dose, 1 hour and 4 hours after drug on Day 1 of Cycles 1 - 12 ]
  2. Phase 1: Area under the concentration versus time curve of larotrectinib in plasma (AUC) [ Time Frame: Pre-dose, 1 hour and 4 hours after drug on Day 1 of Cycles 1 - 12 ]
  3. Phase 1: Oral clearance (CL/F) [ Time Frame: Pre-dose, 1 hour and 4 hours after drug on Day 1 of Cycles 1 - 12 ]
  4. Phase 1: Cerebral spinal fluid/plasma ratio of larotrectinib [ Time Frame: Pre-dose, 1 hour and 4 hours after drug on Day 1 of Cycles 1 - 12 ]
  5. Phase 1: Maximum tolerated dose (MTD) [ Time Frame: 15 months ]
  6. Phase 1: Recommended dose for Phase 2 [ Time Frame: 15 months ]
  7. Phase 1: Overall response rate (ORR) [ Time Frame: 15 months ]
  8. Phase 1: Pain level [ Time Frame: Up to 5 years ]
    Pain Status is assessed by the Wong-Baker Faces Scale giving a pain scale between 0 (no hurt) to 10 (hurts worst).

  9. Phase 1: Health-related quality of life by PedsQL-Core [ Time Frame: Up to 5 years ]
    The health-related quality of life (HRQoL) is assessed with the Pediatrics Quality of Life - Core Module (PedsQL-Core) questionaire that consists of various age-related items regarding physical, emotional, social and school functioning and gives an overall score between 0 (highest HRQoL) and 144 (lowest HRQoL).

  10. Phase 2: Overall Response Rate (ORR) by investigator [ Time Frame: Up to 5 years ]
    Proportion of subjects with confirmed best overall response of complete response or partial response, assessed by the treating investigator using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or Response Assessment in Neuro-Oncology (RANO) as appropriate.

  11. Phase 2: Duration of response (DOR) by IRRC [ Time Frame: Up to 5 years ]
    Duration of response is the number of months from the start of confirmed complete response or partial response to disease progression or death. Complete response, partial response and disease progression are assessed by an independent radiology review committee (IRRC).

  12. Phase 2: Duration of response (DOR) by investigator [ Time Frame: Up to 5 years ]
    Duration of response is the number of months from the start of confirmed complete response or partial response to disease progression or death. Complete response, partial response and disease Progression are assessed by the treating investigator.

  13. Phase 2: Proportion of subjects with any tumor regression as a best response [ Time Frame: Up to 5 years ]
  14. Phase 2: Progression-free survival (PFS) after larotrectinib [ Time Frame: Up to 5 years ]
    Number of months from initiation of larotrectinib to either disease progression or death due to any cause.

  15. Phase 2: Overall survival time [ Time Frame: Up to 5 years ]
    Number of months from the initiation of larotrectinib to the date of death due to any cause.

  16. Phase 2: Number of participants with adverse events [ Time Frame: Up to 5 years ]
  17. Phase 2: Severity of adverse events [ Time Frame: Up to 5 years ]
  18. Phase 2: Clinical benefit rate (CBR) by IRRC [ Time Frame: Up to 5 years ]
    Proportion of subjects with best overall response of complete response, partial response or stable disease lasting 16 or more weeks following the initiation of larotrectinib, assessed by an independent radiology review committee (IRRC).

  19. Phase 2: Clinical benefit rate (CBR) by investigator [ Time Frame: Up to 5 years ]
    Proportion of subjects with best overall response of complete response, partial response or stable disease lasting 16 or more weeks following the initiation of larotrectinib, assessed by investigator.

  20. Phase 2: Concordance coefficient [ Time Frame: Up to 5 years ]
    Describes the concordance of prior molecular profiling that detected an NTRK fusion within the subject's tumor and a diagnostic test being evaluated by the sponsor.

  21. Phase 2: Post-operative stage in patients treated with larotrectinib [ Time Frame: Up to 5 years ]
    Tumor stage is described according to the TNM Classification of malignant tumors of the Union for International Cancer Control (UICC).

  22. Phase 2: Surgical margin status in patients treated with larotrectinib [ Time Frame: Up to 5 years ]
    Tumor margins after surgery are classified into four groups using the International Cancer Control (UICC)-R classification and the Intergroup Rhabdomyosarcoma Staging (IRS) systems: 1) Complete tumor resection with histologically free margins, 2) Macroscopic resection but invaded margins on histology, 3) Macroscopic residual tumor and 4) Distant metastatic tumor.

  23. Phase 2: Descriptive analysis of pretreatment surgical plan [ Time Frame: Up to 5 years ]
  24. Phase 2: Descriptive analysis of post-treatment plans [ Time Frame: Up to 5 years ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   up to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Phase 1:

    • Dose escalation: Birth through 21 years of age at C1D1 with a locally advanced or metastatic solid tumor or primary CNS tumor that has relapsed, progressed or was nonresponsive to available therapies and for which no standard or available systemic curative therapy exists; OR Infants from birth and older with a diagnosis of malignancy and with a documented NTRK fusion that has progressed or was nonresponsive to available therapies, and for which no standard or available curative therapy exists; OR Patients with locally advanced infantile fibrosarcoma who would require, in the opinion of the investigator, disfiguring surgery or limb amputation to achieve a complete surgical resection. Phase I dose escalation cohorts are closed to enrollment.
    • Dose expansion: In addition to the above stated inclusion criteria, patients must have a malignancy with a documented NTRK gene fusion with the exception of patients with infantile fibrosarcoma, congenital mesoblastic nephroma or secretory breast cancer. Patients with infantile fibrosarcoma, congenital mesoblastic nephroma or secretory breast cancer may enroll into this cohort with documentation of an ETV6 rearrangement by FISH or RT-PCR or a documented NTRK fusion by next generation sequencing.
  • Phase 2:

    • Infants from birth and older at C1D1 with a locally advanced or metastatic infantile fibrosarcoma, patients with locally advanced infantile fibrosarcoma who would require, in the opinion of the investigator, disfiguring surgery or limb amputation to achieve a complete surgical resection; OR Birth through 21 years of age at C1D1 with a locally advanced or metastatic solid tumor or primary CNS tumor that has relapsed, progressed or was nonresponsive to available therapies and for which no standard or available systemic curative therapy exists with a documented NTRK gene fusion (or in the case of infantile fibrosarcoma, congenital mesoblastic nephroma or secretory breast cancer with documented ETV6 rearrangement by FISH or RT-PCR or a documented NTRK fusion by next generation sequencing) (identified through molecular assays as routinely performed at CLIA or other similarly certified laboratories). Patients with NTRK-fusion positive benign tumors are also eligible; OR Potential patients older than 21 years of age with a tumor diagnosis with histology typical of a pediatric patient and an NTRK fusion may be considered for enrollment following discussion between the local site Investigator and the Sponsor's Medical Monitor.
  • Patients with primary CNS tumors or cerebral metastasis
  • Karnofsky (those 16 years and older) or Lansky (those younger than 16 years) performance score of at least 50.
  • Adequate hematologic function
  • Adequate hepatic and renal function

Exclusion Criteria:

  • Major surgery within 14 days (2 weeks) prior to C1D1
  • Clinically significant active cardiovascular disease or history of myocardial infarction within 6 months prior to C1D1, ongoing cardiomyopathy; current prolonged QTc interval > 480 milliseconds
  • Active uncontrolled systemic bacterial, viral, or fungal infection
  • Current treatment with a strong CYP3A4 inhibitor or inducer. Enzyme-inducing anti-epileptic drugs (EIAEDs) and dexamethasone for CNS tumors or metastases, on a stable dose, are allowed.
  • Phase 2 only:

    • Prior progression while receiving approved or investigational tyrosine kinase inhibitors targeting TRK, including entrectinib, crizotinib and lestaurtanib. Patients who received a TRK inhibitor for less than 28 days of treatment and discontinued because of intolerance remain eligible.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02637687


Contacts
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Contact: Bayer Clinical Trials Contact (+)1-888-84 22937 clinical-trials-contact@bayer.com

  Show 40 Study Locations
Sponsors and Collaborators
Bayer

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT02637687     History of Changes
Other Study ID Numbers: 20290
LOXO-TRK-15003 ( Other Identifier: Loxo Oncology, Inc )
2016-003498-16 ( EudraCT Number )
First Posted: December 22, 2015    Key Record Dates
Last Update Posted: May 3, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
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.


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

Keywords provided by Bayer:
Advanced solid tumors
Central nervous system (CNS) tumor
Extra-cranial tumor
Infantile fibrosarcoma (IFS)
Neurotrophic tyrosine receptor kinase (NTRK)
NTRK1
NTRK2
NTRK3
Fusion Positive
TRK fusion
TRKA
TRKB
TRKC
ETV6