Solid Tumors Harboring NTRK Fusion
Conditions
Keywords
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
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.
Interventions
BAY2757556 will be administered orally as capsule or in liquid form over continuous 28-day cycles.
Sponsors
Bayer
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 21 Years
Healthy volunteers
No
Inclusion criteria
* 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
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 lestaurtinib. Patients who received a TRK inhibitor for less than 28 days of treatment and discontinued because of intolerance remain eligible.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 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 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: 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 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 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 |
| Phase 2: Overall survival (OS) | From first dose of Larotrectinib to death (due to any cause), up to 112 months | — |
| 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: 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: Cerebral spinal fluid/plasma ratio of larotrectinib | C1D1 in conjunction with the post-dose 1-hour PK sample | — |
Countries
Australia, Canada, China, Czechia, Denmark, France, Germany, Ireland, Israel, Italy, Japan, Netherlands, Poland, South Korea, Spain, Sweden, Switzerland, Turkey (Türkiye), Ukraine, United Kingdom, United States
Outcome results
None listed