HumRes38470
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SNCTP000002979
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BASEC2018-01159
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NCT02637687
A study on the TRK inhibitor Larotrectinib in children with advanced solid or primary tumors of the central nervous system
Zusammenfassung der Studie
This is an international study conducted in several countries in North America, Europe, and other parts of the world. The study is being conducted to find out whether Larotrectinib is safe in children and to determine how well their cancer responds to treatment with Larotrectinib. The study has two phases: 1. In phase 1 of the study, called dose escalation, a total of 24 patients were enrolled. Based on the data for the patients enrolled in the dose escalation part of the study, it was determined that enrollment in the dose escalation should be stopped and that all patients in the study should receive Larotrectinib at a dose of 100 mg/m2 twice daily, with the dose of 100 mg twice daily not to be exceeded in any case. In phase 1 of the study, there is also a so-called expansion cohort. Up to 18 children may be enrolled in the expansion cohort. 2. In phase 2 of the study, up to 50 patients may be enrolled. In this phase, there will be three cohorts (patient groups), depending on the type of cancer: infantile fibrosarcoma (10-20 patients), solid tumors (10-20 patients), and central nervous system tumors (10 patients). The study is expected to last about 24 months.
(BASEC)
Untersuchte Intervention
Treatment with the study medication Larotrectinib occurs in cycles of 28 days. During each cycle, the patient takes Larotrectinib twice daily as a capsule or solution. In each cycle, the patient is evaluated to assess how the cancer is progressing and how the patient is feeling. Among other things, images of the tumor are taken (using computed tomography or magnetic resonance imaging), blood and urine are collected and analyzed, and questionnaires are completed.
(BASEC)
Untersuchte Krankheit(en)
The study examines certain types of cancer in children and young adults aged up to 21 years. Three patient cohorts (patient groups) with NTRK fusions will participate in the study. Patients with infantile fibrosarcoma (IFS), patients with solid tumors, and patients with central nervous system tumors (brain). An NTRK fusion is a change (alteration) in a specific gene (NTRK1, NTRK2, or NTRK3) in a patient's tumor. Larotrectinib is an investigational (or experimental) drug that inhibits the effects of NTRK fusion genes in cancer cells and may be beneficial in treating cancer.
(BASEC)
Kriterien zur Teilnahme
Phase 1: From birth to 21 years at Z1T1 (cycle 1, day 1) with locally advanced or metastatic solid tumor or primary CNS tumor that has not responded to available therapies or has recurred or progressed and for which there is no standard or available systemic curative therapy or: Children from birth with diagnosed malignant disease and documented NTRK fusion that has not responded to available therapies or has progressed and for which there is no standard or available systemic curative therapy or: Patients with locally advanced infantile fibrosarcoma, for whom the investigator believes that a disfiguring surgery or limb amputation would be necessary to achieve complete surgical resection. Enrollment of patients in phase 1 dose escalation is complete. Phase 1 dose expansion: In addition to the above inclusion criteria, patients who are eligible for enrollment in this cohort must have a malignant disease with a documented NTRK gene fusion, except for patients with IFS (Infantile Fibrosarcoma), CMN (Congenital Mesoblastic Nephroma), or SBC (Secretory Burkitt Lymphoma). Patients with IFS, CMN, or SBC may be included in this cohort with a documented rearrangement of the ETV6 gene or a documented NTRK gene fusion. Phase 2: Children from birth at Z1T1 with locally advanced or metastatic infantile fibrosarcoma, patients with locally advanced infantile fibrosarcoma, for whom the investigator believes that a disfiguring surgery or limb amputation would be necessary to achieve complete surgical resection, or: From birth to 21 years at Z1T1 with locally advanced or metastatic solid tumor or primary CNS tumor that has not responded to available therapies or has recurred or progressed and for which there is no standard or available systemic curative therapy. The tumor must have a documented NTRK fusion or, in the case of IFS, CMN, or SBC, patients must have a documented rearrangement of the ETV6 gene or a documented NTRK gene fusion. Patients with benign tumors with NTRK gene fusion are also eligible. or: (including expansion phase) Potential patients over 21 years with a diagnosis of a tumor that has a histology typical of pediatric patients and an NTRK fusion may be considered for enrollment after discussion between the investigator at the local trial center and the medical monitor of the sponsor. (BASEC)
Ausschlusskriterien
Patients meeting the following criteria will be excluded from participation in the study: 1. Major surgery within the last 14 days (2 weeks) prior to Z1T1. 2. Clinically significant active cardiovascular disease or history of myocardial infarction in the last 6 months prior to Z1T1, existing cardiomyopathy, or currently prolonged heart contraction duration (corrected QT interval (QTc) > 480 milliseconds) 3. Active uncontrolled systemic bacterial, viral, or fungal infection. (BASEC)
Phase 1: From birth to 21 years at Z1T1 (cycle 1, day 1) with locally advanced or metastatic solid tumor or primary CNS tumor that has not responded to available therapies or has recurred or progressed and for which there is no standard or available systemic curative therapy or: Children from birth with diagnosed malignant disease and documented NTRK fusion that has not responded to available therapies or has progressed and for which there is no standard or available systemic curative therapy or: Patients with locally advanced infantile fibrosarcoma, for whom the investigator believes that a disfiguring surgery or limb amputation would be necessary to achieve complete surgical resection. Enrollment of patients in phase 1 dose escalation is complete. Phase 1 dose expansion: In addition to the above inclusion criteria, patients who are eligible for enrollment in this cohort must have a malignant disease with a documented NTRK gene fusion, except for patients with IFS (Infantile Fibrosarcoma), CMN (Congenital Mesoblastic Nephroma), or SBC (Secretory Burkitt Lymphoma). Patients with IFS, CMN, or SBC may be included in this cohort with a documented rearrangement of the ETV6 gene or a documented NTRK gene fusion. Phase 2: Children from birth at Z1T1 with locally advanced or metastatic infantile fibrosarcoma, patients with locally advanced infantile fibrosarcoma, for whom the investigator believes that a disfiguring surgery or limb amputation would be necessary to achieve complete surgical resection, or: From birth to 21 years at Z1T1 with locally advanced or metastatic solid tumor or primary CNS tumor that has not responded to available therapies or has recurred or progressed and for which there is no standard or available systemic curative therapy. The tumor must have a documented NTRK fusion or, in the case of IFS, CMN, or SBC, patients must have a documented rearrangement of the ETV6 gene or a documented NTRK gene fusion. Patients with benign tumors with NTRK gene fusion are also eligible. or: (including expansion phase) Potential patients over 21 years with a diagnosis of a tumor that has a histology typical of pediatric patients and an NTRK fusion may be considered for enrollment after discussion between the investigator at the local trial center and the medical monitor of the sponsor. (BASEC)
Ausschlusskriterien
Patients meeting the following criteria will be excluded from participation in the study: 1. Major surgery within the last 14 days (2 weeks) prior to Z1T1. 2. Clinically significant active cardiovascular disease or history of myocardial infarction in the last 6 months prior to Z1T1, existing cardiomyopathy, or currently prolonged heart contraction duration (corrected QT interval (QTc) > 480 milliseconds) 3. Active uncontrolled systemic bacterial, viral, or fungal infection. (BASEC)
Studienstandort
Zürich
(BASEC)
Australia, Canada, China, Czechia, Denmark, France, Germany, Ireland, Israel, Italy, Japan, Korea, Republic of, Netherlands, Poland, Russian Federation, Spain, Sweden, Switzerland, Turkey, Ukraine, United Kingdom, United States (ICTRP)
Sponsor
Sophia Birnbaum
(BASEC)
Kontakt für weitere Auskünfte zur Studie
Kontaktperson Schweiz
Sophia Birnbaum
+41 44 266 74 55
nicolas.gerber@clutterkispi.uzh.chUniversitätsspital Zürich
(BASEC)
Name der bewilligenden Ethikkommission (bei multizentrischen Studien nur die Leitkommission)
Ethikkommission Zürich
(BASEC)
Datum der Bewilligung durch die Ethikkommission
28.10.2021
(BASEC)
ICTRP Studien-ID
NCT02637687 (ICTRP)
Offizieller Titel (Genehmigt von der Ethikkommission)
SCOUT - A Phase 1/2 Study of the Oral TRK Inhibitor LOXO-101 in Pediatric Patients with Advanced Solid or Primary Central Nervous System Tumors (BASEC)
Wissenschaftlicher Titel
A Phase 1/2 Study of the Oral TRK Inhibitor Larotrectinib in Pediatric Patients With Advanced Solid or Primary Central Nervous System Tumors (ICTRP)
Öffentlicher Titel
A Study to Test the Safety and Efficacy of the Drug Larotrectinib for the Treatment of Tumors With NTRK-fusion in Children (ICTRP)
Untersuchte Krankheit(en)
Solid Tumors Harboring NTRK Fusion (ICTRP)
Untersuchte Intervention
Drug: Larotrectinib (Vitrakvi, BAY2757556) (ICTRP)
Studientyp
Interventional (ICTRP)
Studiendesign
Allocation: Non-Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: None (Open Label). (ICTRP)
Ein-/Ausschlusskriterien
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. (ICTRP)
nicht verfügbar
Primäre und sekundäre Endpunkte
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;Phase 1: Number of participants with TEAEs;Phase 1: Severity of TEAEs;Phase 2: Overall response rate (ORR) by IRRC (ICTRP)
Phase 2: Overall survival (OS);Phase 2: Number of participants with Treatment emergent adverse events (TEAEs);Phase 2: Severity of adverse events as assessed by NCI-CTCAE grading V 4.03;Phase 2: Clinical Benefit Rate (CBR);Phase 2: Concordance coefficient;Phase 2: Post-operative tumor staging;Phase 2: Post-operative surgical margin assessment;Phase 2: Pre-treatment surgical plan to preserve function and cosmetic outcome;Phase 2: Post-treatment plans to conserve function and cosmetic outcome;Phase 1: Maximum concentration of larotrectinib in plasma (Cmax);Phase 1: Area under the concentration versus time curve from time 0 to t (AUC0-t) of larotrectinib in plasma;Phase 1: Oral clearance (CL/F);Phase 1: Cerebral spinal fluid/plasma ratio of larotrectinib;Phase 1: Maximum tolerated dose (MTD);Phase 1: Recommended dose for Phase 2;Phase 1: Overall Response Rate (ORR);Phase 1: Mean change from baseline in Pain scores as assessed by the Wong-Baker Faces scale;Phase 1: Mean change in Health-related quality of life scores by PedsQL-Core;Phase 2: Best overall response (BOR);Phase 2: Duration of response (DOR);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;Phase 2: Progression-free survival (PFS) (ICTRP)
Registrierungsdatum
10.12.2015 (ICTRP)
Einschluss des ersten Teilnehmers
nicht verfügbar
Sekundäre Sponsoren
nicht verfügbar
Weitere Kontakte
Bayer Clinical Trials Contact, clinical-trials-contact@bayer.com, (+)1-888-84 22937 (ICTRP)
Sekundäre IDs
LOXO-TRK-15003, 2022-502668-20-00, 2016-003498-16, 20290 (ICTRP)
Angaben zur Verfügbarkeit von individuellen Teilnehmerdaten
nicht verfügbar
Weitere Informationen zur Studie
https://clinicaltrials.gov/ct2/show/NCT02637687 (ICTRP)
Ergebnisse der Studie
Zusammenfassung der Ergebnisse
nicht verfügbar
Link zu den Ergebnissen im Primärregister
nicht verfügbar