A Study to Test the Safety and Efficacy of the Drug Larotrectinib for the Treatment of Tumors With NTRK-fusion in Children
- Conditions
- Solid Tumors Harboring NTRK Fusion
- Interventions
- Registration Number
- NCT02637687
- Lead Sponsor
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 154
-
Phase 1 (Closed):
- 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 (or NTRK3 rearrangement after discussion with the sponsor) by FISH or RT-PCR. 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.
-
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
-
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 lestaurtinib. Patients who received a TRK inhibitor for less than 28 days of treatment and discontinued because of intolerance remain eligible.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Phase 1 dose expansion Larotrectinib (Vitrakvi, BAY2757556) Patients who are enrolled in the expansion cohort, following the formal dose escalation phase of the study. Distinct from the Phase 1 dose escalation cohort, the Phase 1 expansion cohort will enroll pediatric patients with advanced solid or primary CNS tumors with a documented NTRK gene fusion, or in the case of IFS, CMN or SBC with documented ETV6 rearrangement by FISH or RT-PCR or a documented NTRK fusion by NGS. This expansion cohort will follow the same schedule of assessments as the dose escalation cohorts. (arm closed) Phase 2: Other extra-cranial solid tumors_Cohort 2 Larotrectinib (Vitrakvi, BAY2757556) Patients will receive larotrectinib dose on Day 1 (BID in accordance with the cohort assignment) at the recommended Phase 2 dose as determined in the Phase 1 portion of this study. Each cycle will consist of 28 days of continuous dosing. Individual patients will continue daily larotrectinib dosing until PD, unacceptable toxicity, or other reason for treatment discontinuation. (arm closed) Phase 2: Primary CNS tumors_Cohort 3 Larotrectinib (Vitrakvi, BAY2757556) Patients will receive larotrectinib dose on Day 1 (BID in accordance with the cohort assignment) at the recommended Phase 2 dose as determined in the Phase 1 portion of this study. Each cycle will consist of 28 days of continuous dosing. Individual patients will continue daily larotrectinib dosing until PD, unacceptable toxicity, or other reason for treatment discontinuation. Phase 2: Bone health assessment_sub-cohort Larotrectinib (Vitrakvi, BAY2757556) Patients will receive larotrectinib dose on Day 1 (BID in accordance with the cohort assignment) at the recommended Phase 2 dose as determined in the Phase 1 portion of this study. Each cycle will consist of 28 days of continuous dosing. Individual patients will continue daily larotrectinib dosing until PD, unacceptable toxicity, or other reason for treatment discontinuation. Patients in this group will undergo bone health assessments in addition to all other efficacy and safety assessments. Phase 1 dose escalation Larotrectinib (Vitrakvi, BAY2757556) Patients will receive the different levels of dose on Day 1 (BID in accordance with the cohort assignment). Each cycle will consist of 28 days of continuous dosing. Individual patients will continue daily larotrectinib dosing until PD, unacceptable toxicity, or other reason for treatment discontinuation. (arm closed) Phase 2: Patients with tumors bearing NTRK fusions (IFS)_Cohort 1 Larotrectinib (Vitrakvi, BAY2757556) Patients will receive larotrectinib dose on Day 1 (BID in accordance with the cohort assignment) at the recommended Phase 2 dose as determined in the Phase 1 portion of this study. Each cycle will consist of 28 days of continuous dosing. Individual patients will continue daily larotrectinib dosing until PD, unacceptable toxicity, or other reason for treatment discontinuation. (arm closed)
- Primary Outcome Measures
Name Time Method Phase 1: Number of participants in an assigned dose cohort with treatment emergent adverse events (TEAEs) by grade assessed by NCI-CTCAE v 4.03 who experience a DLT From Day 1 to Day 28 of Cycle 1 (1 Cycle=28 days) DLT: Dose-limiting toxicity. NCI-CTCAE: National Cancer Institute-Common Terminology Criteria for Adverse Events.
Phase 1: Number of participants with TEAEs From first dose of larotrectinib up to 93 months Phase 1: Severity of TEAEs From first dose of larotrectinib up to 93 months Phase 2: Overall response rate (ORR) by IRRC From first dose of Larotrectinib to disease progression or subsequent therapy or surgical intervention or death, up to 76 months Proportion of participants with a best overall response of complete response (CR) or partial response (PR) as determined by an independent radiology review committee (IRRC) based on Response Evaluation Criteria in Solid Tumours (RECIST) 1.1, Response Assessment in Neuro Oncology (RANO) or International Neuroblastoma Response Criteria (INRC) as appropriate to tumor type who express NTRK gene fusions.
- Secondary Outcome Measures
Name Time Method Phase 1: Oral clearance (CL/F) Cohort 1 and 2: C1D1 at 1 and 4 hours post-dose and C2D1 at pre-dose, and at 1 and 4 hours post-dose; Cohort 3 and Dose Expansion Cohort: C1D1 at 1 and 4 hours post-dose and C4D1 at pre-dose, 1 and 4 hours post-dos Phase 1: Maximum concentration of larotrectinib in plasma (Cmax) Cohort 1 and 2: Cycle 1 Day 1 (C1D1) at 1 and 4 hours post-dose and C2D1 at pre-dose, and at 1 and 4 hours post-dose; Cohort 3 and Dose Expansion Cohort: C1D1 at 1 and 4 hours post-dose and C4D1 at pre-dose, 1 and 4 hours post-dose Phase 1: Area under the concentration versus time curve from time 0 to t (AUC0-t) of larotrectinib in plasma Cohort 1 and 2: C1D1 at 1 and 4 hours post-dose and C2D1 at pre-dose, and at 1 and 4 hours post-dose; Cohort 3 and Dose Expansion Cohort: C1D1 at 1 and 4 hours post-dose and C4D1 at pre-dose, 1 and 4 hours post-dose Phase 1: Cerebral spinal fluid/plasma ratio of larotrectinib C1D1 in conjunction with the post-dose 1-hour PK sample Phase 1: Maximum tolerated dose (MTD) From C1D1 to C1D28 of treatment of each participant in each of the assigned dose cohort, up to 16 months Phase 1: Recommended dose for Phase 2 From the date a participants from assigned Cohort was administered the first dose to the date of the last dose for the last patient from the dose escalation phase, up to 16 months Phase 1: Overall Response Rate (ORR) From first dose of Larotrectinib to disease progression or subsequent therapy or surgical intervention or death (due to any cause), up to 93 months Proportion of participants with best overall response (BOR) of CR and PR; PFS, CBR and maximum change in tumor burden as assessed based on RECIST 1.1, INRC or RANO as appropriate for tumor type by IRRC.
Phase 1: Mean change from baseline in Pain scores as assessed by the Wong-Baker Faces scale Baseline and D1 of every cycle (1 Cycle=28 days), up to 93 months Wong-Baker Faces Scale giving a pain scale between 0 (no hurt) to 10 (hurts worst).
Phase 1: Mean change in Health-related quality of life scores by PedsQL-Core Baseline and D1 of every cycle (1 Cycle=28 days), Up to 93 months The health-related quality of life (HRQoL) is assessed with the Pediatrics Quality of Life - Core Module (PedsQL-Core) questionnaire 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).
Phase 2: Best overall response (BOR) From first dose of Larotrectinib to disease progression or subsequent therapy or surgical intervention or death (due to any cause), up to 76 months Participants with best overall response (BOR) of either CR or PR determined by Investigator's or IRC's response assessment based on RANO, INRC and RECIST 1.1 as appropriate for tumor type
Phase 2: Duration of response (DOR) From start of first objective response of confirmed CR or PR to progression or death (due to any cause), up to 76 months DOR determined by 1) an independent radiology review committee and 2) the treating Investigator.
Phase 2: Proportion of patients with any tumor regression (i.e., any decrease from baseline of the longest diameters of target lesions) as a best response From first dose of Larotrectinib, up to 76 months Phase 2: Progression-free survival (PFS) From first dose of Larotrectinib to disease progression or subsequent therapy or surgical intervention or death (due to any cause), up to 112 months Phase 2: Overall survival (OS) From first dose of Larotrectinib to death (due to any cause), up to 112 months Phase 2: Number of participants with Treatment emergent adverse events (TEAEs) From first dose of larotrectinib to discontinuation of treatment or death (due to any cayse), up to 112 months Phase 2: Severity of adverse events as assessed by NCI-CTCAE grading V 4.03 From first dose of larotrectinib to discontinuation of treatment or death (due to any cause), up to 112 months Phase 2: Clinical Benefit Rate (CBR) From first dose of Larotrectinib to disease progression or subsequent therapy or surgical intervention or death (due to any cause), up to 76 months CBR (i.e., best overall response of CR, PR or SD lasting 16 weeks or more as determined by 1) an independent radiology review committee (IRC) and 2) by the treating Investigator.
Phase 2: Concordance coefficient From baseline/screening and if feasible end of treatment (EOT) and or PD and or at re-start of study treatment following a "drug holiday" and disease recurrence, up to 112 months Concordance coefficient of intra-patient molecular profile
Phase 2: Post-operative tumor staging From first dose of Larotrectinib to surgical intervention, up to 112 months Post-operative stage in patients treated with larotrectinib according to the TNM Classification of malignant tumors of the Union for International Cancer Control (UICC).
Phase 2: Post-operative surgical margin assessment From first dose of Larotrectinib to surgical intervention, up to 112 months Surgical margin status in patients treated with larotrectinib using the International Cancer Control (UICC)-R classification and the Intergroup Rhabdomyosarcoma Staging (IRS) systems.
Phase 2: Pre-treatment surgical plan to preserve function and cosmetic outcome From first dose of Larotrectinib to surgical intervention, up to 112 months Descriptive analysis of pretreatment surgical plan.
Phase 2: Post-treatment plans to conserve function and cosmetic outcome From surgical intervention to subsequent therapy, up to 112 months Descriptive analysis of post-treatment plans
Trial Locations
- Locations (45)
Children's Hospital of Los Angeles
🇺🇸Los Angeles, California, United States
UCLA Jonsson Comprehensive Cancer Center
🇺🇸Los Angeles, California, United States
Lucille Salter Packard Children's Hospital at Stanford
🇺🇸Palo Alto, California, United States
Nemours Children's Hospital (Orlando)
🇺🇸Orlando, Florida, United States
Boston Children's Hospital
🇺🇸Boston, Massachusetts, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
Cincinnati Children's Hospital Medical Center | Division of Nephrology and Hypertension
🇺🇸Cincinnati, Ohio, United States
Children's Hospital of Philadelphia
🇺🇸Philadelphia, Pennsylvania, United States
St. Jude Children's Research Hospital
🇺🇸Memphis, Tennessee, United States
University of Texas Southwestern Medical Center
🇺🇸Dallas, Texas, United States
Seattle Children's Hospital
🇺🇸Seattle, Washington, United States
Sydney Children's Hospital
🇦🇺Sydney, New South Wales, Australia
Women's and Children's Hospital
🇦🇺North Adelaide, South Australia, Australia
Royal Children's Hospital Melbourne
🇦🇺Parkville, Victoria, Australia
British Columbia Childrens Hospital
🇨🇦Vancouver, British Columbia, Canada
The Hospital for Sick Children (SickKids)
🇨🇦Toronto, Ontario, Canada
CHU Sainte-Justine
🇨🇦Montreal, Quebec, Canada
Beijing Children's Hospital, Capital Medical University
🇨🇳Beijing, Beijing, China
Sun Yat-sen University Cancer Center
🇨🇳Guangzhou, Guangdong, China
Tianjin Medical University Cancer Institute & Hospital
🇨🇳Tianjin, China
FN Brno - Detska nemocnice
🇨🇿Brno, Czechia
Fakultni nemocnice v Motole
🇨🇿Praha 5, Czechia
Rigshospitalet - Børn og Unge
🇩🇰Copenhagen, Denmark
Institut Curie - Ulm - Paris
🇫🇷PARIS cedex 5, France
Institut Gustave Roussy - Département de Médecine Oncologique
🇫🇷Villejuif Cedex, France
Universitaetsklinikum Heidelberg - KiTZ | Klinik für Paediatrische Onkologie, Haematologie, Immunologie und Pneumologie
🇩🇪Heidelberg, Baden-Württemberg, Germany
KLINIKUM STUTTGART - Olgahospital | Paediatrie 5 (Onkologie, Haematologie, Immunologie)
🇩🇪Stuttgart, Baden-Württemberg, Germany
Charité - Campus Virchow-Klinikum (CVK), Klinik für Pädiatrie mit Schwerpunkt Onkologie und Hämatologie
🇩🇪Berlin, Germany
Children's Health Ireland Crumlin
🇮🇪Crumlin, Dublin, Ireland
Clalit Health Services Schneider Children's Medical Center
🇮🇱Petach Tikva, Israel
Fondazione IRCCS Istituto Nazionale dei Tumori - S. C. Pediatria Oncologica
🇮🇹Milano, Lombardia, Italy
Kanagawa Children's Medical Center
🇯🇵Yokohama, Kanagawa, Japan
National Cancer Center Hospital
🇯🇵Chuo-ku, Tokyo, Japan
Kyushu University Hospital
🇯🇵Fukuoka, Japan
Severance Hospital, Yonsei University Health System
🇰🇷Seoul, Seoul Teugbyeolsi, Korea, Republic of
Seoul National University Hospital
🇰🇷Seoul, Seoul Teugbyeolsi, Korea, Republic of
Prinses Maxima Centrum
🇳🇱Utrecht, Netherlands
Uniwersyteckie Centrum Kliniczne
🇵🇱Gdansk, Poland
Ciutat Sanitaria i Universitaria de la Vall d'Hebron
🇪🇸Barcelona, Spain
Karolinska Universitetssjukhuset i Solna
🇸🇪Stockholm, Sweden
Universitätskinderspital Zürich
🇨🇭Zürich, Switzerland
Istanbul Universitesi Istanbul Tip Fakultesi
🇹🇷Istanbul, Turkey
Governmental Noncommercial Institution "National Cancer Institute
🇺🇦Kyiv, Ukraine
CNE of Lviv Regional Council "Clinical center of Children's healthcare", Clinic of pediatric oncology and BMT
🇺🇦Lviv, Ukraine
Royal Marsden NHS Trust (Surrey)
🇬🇧Sutton, Surrey, United Kingdom
Related News
Larotrectinib Induces Rapid, Durable Responses in Pediatric Patients With TRK Fusion+ ...
- Prev
- 1
- Next