Clinical trial NCT02637687: A Study to Test the Safety and Efficacy of the Drug Larotrectinib for the Treatment of Tumors With NTRK-fusion in Children
Official title: A Phase 1/2 Study of the Oral TRK Inhibitor Larotrectinib in Pediatric Patients With Advanced Solid or Primary Central Nervous System Tumors
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Solid Tumors Harboring NTRK Fusion
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
Lead sponsor: Bayer
Sponsor class: INDUSTRY
First posted: 2015-12-22
Enrollment: 154
Sex: ALL
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: 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
timeFrame: From Day 1 to Day 28 of Cycle 1 (1 Cycle=28 days)
measure: Phase 1: Number of participants with TEAEs
timeFrame: From first dose of larotrectinib up to 93 months
measure: Phase 1: Severity of TEAEs
timeFrame: From first dose of larotrectinib up to 93 months
measure: Phase 2: Overall response rate (ORR) by IRRC
timeFrame: From first dose of Larotrectinib to disease progression or subsequent therapy or surgical intervention or death, up to 76 months
Secondary outcomes:
measure: Phase 1: Maximum concentration of larotrectinib in plasma (Cmax)
timeFrame: 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
measure: Phase 1: Area under the concentration versus time curve from time 0 to t (AUC0-t) of larotrectinib in plasma
timeFrame: 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
measure: Phase 1: Oral clearance (CL/F)
timeFrame: 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
measure: Phase 1: Cerebral spinal fluid/plasma ratio of larotrectinib
timeFrame: C1D1 in conjunction with the post-dose 1-hour PK sample
measure: Phase 1: Maximum tolerated dose (MTD)
timeFrame: From C1D1 to C1D28 of treatment of each participant in each of the assigned dose cohort, up to 16 months
measure: Phase 1: Recommended dose for Phase 2
timeFrame: 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
measure: Phase 1: Overall Response Rate (ORR)
timeFrame: From first dose of Larotrectinib to disease progression or subsequent therapy or surgical intervention or death (due to any cause), up to 93 months
measure: Phase 1: Mean change from baseline in Pain scores as assessed by the Wong-Baker Faces scale
timeFrame: Baseline and D1 of every cycle (1 Cycle=28 days), up to 93 months
measure: Phase 1: Mean change in Health-related quality of life scores by PedsQL-Core
timeFrame: Baseline and D1 of every cycle (1 Cycle=28 days), Up to 93 months
measure: Phase 2: Best overall response (BOR)
timeFrame: From first dose of Larotrectinib to disease progression or subsequent therapy or surgical intervention or death (due to any cause), up to 76 months
measure: Phase 2: Duration of response (DOR)
timeFrame: From start of first objective response of confirmed CR or PR to progression or death (due to any cause), up to 76 months
measure: 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
timeFrame: From first dose of Larotrectinib, up to 76 months
measure: Phase 2: Progression-free survival (PFS)
timeFrame: From first dose of Larotrectinib to disease progression or subsequent therapy or surgical intervention or death (due to any cause), up to 112 months
measure: Phase 2: Overall survival (OS)
timeFrame: From first dose of Larotrectinib to death (due to any cause), up to 112 months
measure: Phase 2: Number of participants with Treatment emergent adverse events (TEAEs)
timeFrame: From first dose of larotrectinib to discontinuation of treatment or death (due to any cayse), up to 112 months
measure: Phase 2: Severity of adverse events as assessed by NCI-CTCAE grading V 4.03
timeFrame: From first dose of larotrectinib to discontinuation of treatment or death (due to any cause), up to 112 months
measure: Phase 2: Clinical Benefit Rate (CBR)
timeFrame: From first dose of Larotrectinib to disease progression or subsequent therapy or surgical intervention or death (due to any cause), up to 76 months
measure: Phase 2: Concordance coefficient
timeFrame: 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
measure: Phase 2: Post-operative tumor staging
timeFrame: From first dose of Larotrectinib to surgical intervention, up to 112 months
measure: Phase 2: Post-operative surgical margin assessment
timeFrame: From first dose of Larotrectinib to surgical intervention, up to 112 months
measure: Phase 2: Pre-treatment surgical plan to preserve function and cosmetic outcome
timeFrame: From first dose of Larotrectinib to surgical intervention, up to 112 months
measure: Phase 2: Post-treatment plans to conserve function and cosmetic outcome
timeFrame: From surgical intervention to subsequent therapy, up to 112 months
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles - Hematology/Oncology
state: California
city: Los Angeles
country: United States
facility: UCLA Jonsson Comprehensive Cancer Center
state: California
city: Palo Alto
country: United States
facility: Lucille Packard Children's Hospital Stanford - Pediatric Nephrology
state: California
city: Orlando
country: United States
facility: Nemours Children's Hospital - Florida - Hematology / Oncology
state: Florida
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center New York - Main Campus
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center | Division of Nephrology and Hypertension
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia - Hematology/Oncology
state: Pennsylvania
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Sydney
country: Australia
facility: Sydney Children's Hospital
state: New South Wales
city: North Adelaide
country: Australia
facility: Women's and Children's Hospital
state: South Australia
city: Parkville
country: Australia
facility: Royal Children's Hospital Melbourne
state: Victoria
city: Vancouver
country: Canada
facility: BC Children's Hospital - Hematology/Oncology
state: British Columbia
city: Toronto
country: Canada
facility: The Hospital for Sick Children (SickKids)
state: Ontario
city: Montreal
country: Canada
facility: CHU Sainte-Justine
state: Quebec
city: Beijing
country: China
facility: Beijing Children's Hospital, Capital Medical University
state: Beijing
city: Guangzhou
country: China
facility: Sun Yat-sen University Cancer Center
state: Guangdong
city: Tianjin
country: China
facility: Tianjin Medical University Cancer Institute & Hospital
city: Brno
country: Czechia
facility: FN Brno - Detska nemocnice
city: Praha 5
country: Czechia
facility: Fakultni nemocnice v Motole
city: Copenhagen
country: Denmark
facility: Rigshospitalet - Børn og Unge
city: PARIS cedex 5
country: France
facility: Institut Curie - Ulm - Paris
city: Villejuif Cedex
country: France
facility: Gustave Roussy - Departement Oncologie-Radiotherapie
city: Heidelberg
country: Germany
facility: Universitaetsklinikum Heidelberg - KiTZ | Klinik für Paediatrische Onkologie, Haematologie, Immunologie und Pneumologie
state: Baden-Württemberg
city: Stuttgart
country: Germany
facility: KLINIKUM STUTTGART - Olgahospital | Paediatrie 5 (Onkologie, Haematologie, Immunologie)
state: Baden-Württemberg
city: Berlin
country: Germany
facility: Charité - Campus Virchow-Klinikum (CVK), Klinik für Pädiatrie mit Schwerpunkt Onkologie und Hämatologie
city: Crumlin
country: Ireland
facility: Children's Health Ireland Crumlin
state: Dublin
city: Petach Tikva
country: Israel
facility: Clalit Health Services Schneider Children's Medical Center
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori - S. C. Pediatria Oncologica
state: Lombardia
city: Yokohama
country: Japan
facility: Kanagawa Children's Medical Center
state: Kanagawa
city: Chuo-ku
country: Japan
facility: National Cancer Center Hospital
state: Tokyo
city: Fukuoka
country: Japan
facility: Kyushu University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
state: Seoul Teugbyeolsi
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
state: Seoul Teugbyeolsi
city: Utrecht
country: Netherlands
facility: Prinses Maxima Centrum
city: Gdansk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne
city: Barcelona
country: Spain
facility: Ciutat Sanitaria i Universitaria de la Vall d'Hebron
city: Stockholm
country: Sweden
facility: Karolinska Universitetssjukhuset i Solna
city: Zürich
country: Switzerland
facility: Universitätskinderspital Zürich
city: Istanbul
country: Turkey
facility: Istanbul Universitesi Istanbul Tip Fakultesi
city: Kyiv
country: Ukraine
facility: Governmental Noncommercial Institution "National Cancer Institute
city: Lviv
country: Ukraine
facility: Western Ukrainian Specialized Pediatric Medial Centre, Surgical Department
city: Sutton
country: United Kingdom
facility: Royal Marsden NHS Trust (Surrey)
state: Surrey
Study officials:
References:
citation: Doz F, van Tilburg CM, Geoerger B, Hojgaard M, Ora I, Boni V, Capra M, Chisholm J, Chung HC, DuBois SG, Gallego-Melcon S, Gerber NU, Goto H, Grilley-Olson JE, Hansford JR, Hong DS, Italiano A, Kang HJ, Nysom K, Thorwarth A, Stefanowicz J, Tahara M, Ziegler DS, Gavrilovic IT, Norenberg R, Dima L, De La Cuesta E, Laetsch TW, Drilon A, Perreault S. Efficacy and safety of larotrectinib in TRK fusion-positive primary central nervous system tumors. Neuro Oncol. 2022 Jun 1;24(6):997-1007. doi: 10.1093/neuonc/noab274.
citation: Bebb DG, Banerji S, Blais N, Desmeules P, Gill S, Grin A, Feilotter H, Hansen AR, Hyrcza M, Krzyzanowska M, Melosky B, Noujaim J, Purgina B, Ruether D, Simmons CE, Soulieres D, Torlakovic EE, Tsao MS. Canadian Consensus for Biomarker Testing and Treatment of TRK Fusion Cancer in Adults. Curr Oncol. 2021 Jan 15;28(1):523-548. doi: 10.3390/curroncol28010053.
citation: Perreault S, Chami R, Deyell RJ, El Demellawy D, Ellezam B, Jabado N, Morgenstern DA, Narendran A, Sorensen PHB, Wasserman JD, Yip S. Canadian Consensus for Biomarker Testing and Treatment of TRK Fusion Cancer in Pediatric Patients. Curr Oncol. 2021 Jan 9;28(1):346-366. doi: 10.3390/curroncol28010038.
citation: Bielack SS, Cox MC, Nathrath M, Apel K, Blattmann C, Holl T, Jenewein R, Klenk U, Klothaki P, Muller-Abt P, Ortega-Lawerenz S, Reynolds M, Scheer M, Simon-Klingenstein K, Stegmaier S, Tupper R, Vokuhl C, von Kalle T. Rapid, complete and sustained tumour response to the TRK inhibitor larotrectinib in an infant with recurrent, chemotherapy-refractory infantile fibrosarcoma carrying the characteristic ETV6-NTRK3 gene fusion. Ann Oncol. 2019 Nov;30 Suppl 8:viii31-viii35. doi: 10.1093/annonc/mdz382. Epub 2019 Dec 24.
citation: Hong DS, DuBois SG, Kummar S, Farago AF, Albert CM, Rohrberg KS, van Tilburg CM, Nagasubramanian R, Berlin JD, Federman N, Mascarenhas L, Geoerger B, Dowlati A, Pappo AS, Bielack S, Doz F, McDermott R, Patel JD, Schilder RJ, Tahara M, Pfister SM, Witt O, Ladanyi M, Rudzinski ER, Nanda S, Childs BH, Laetsch TW, Hyman DM, Drilon A. Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials. Lancet Oncol. 2020 Apr;21(4):531-540. doi: 10.1016/S1470-2045(19)30856-3. Epub 2020 Feb 24.
citation: Bielack SS, Cox MC, Nathrath M, Apel K, Blattmann C, Holl T, Jenewein R, Klenk U, Klothaki P, Muller-Abt P, Ortega-Lawerenz S, Reynolds M, Scheer M, Simon-Klingenstein K, Stegmaier S, Tupper R, Vokuhl C, von Kalle T. Rapid, complete and sustained tumour response to the TRK inhibitor larotrectinib in an infant with recurrent, chemotherapy-refractory infantile fibrosarcoma carrying the characteristic ETV6-NTRK3 gene fusion. Ann Oncol. 2019 Nov 1;30(Suppl_8):viii31-viii35. doi: 10.1093/annonc/mdz382.
citation: DuBois SG, Laetsch TW, Federman N, Turpin BK, Albert CM, Nagasubramanian R, Anderson ME, Davis JL, Qamoos HE, Reynolds ME, Cruickshank S, Cox MC, Hawkins DS, Mascarenhas L, Pappo AS. The use of neoadjuvant larotrectinib in the management of children with locally advanced TRK fusion sarcomas. Cancer. 2018 Nov 1;124(21):4241-4247. doi: 10.1002/cncr.31701. Epub 2018 Sep 11.
citation: Laetsch TW, DuBois SG, Mascarenhas L, Turpin B, Federman N, Albert CM, Nagasubramanian R, Davis JL, Rudzinski E, Feraco AM, Tuch BB, Ebata KT, Reynolds M, Smith S, Cruickshank S, Cox MC, Pappo AS, Hawkins DS. Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions: phase 1 results from a multicentre, open-label, phase 1/2 study. Lancet Oncol. 2018 May;19(5):705-714. doi: 10.1016/S1470-2045(18)30119-0. Epub 2018 Mar 29.
citation: Drilon A, Laetsch TW, Kummar S, DuBois SG, Lassen UN, Demetri GD, Nathenson M, Doebele RC, Farago AF, Pappo AS, Turpin B, Dowlati A, Brose MS, Mascarenhas L, Federman N, Berlin J, El-Deiry WS, Baik C, Deeken J, Boni V, Nagasubramanian R, Taylor M, Rudzinski ER, Meric-Bernstam F, Sohal DPS, Ma PC, Raez LE, Hechtman JF, Benayed R, Ladanyi M, Tuch BB, Ebata K, Cruickshank S, Ku NC, Cox MC, Hawkins DS, Hong DS, Hyman DM. Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. N Engl J Med. 2018 Feb 22;378(8):731-739. doi: 10.1056/NEJMoa1714448.