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

Study Purpose

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.

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	No
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Interventional
Eligible Ages	N/A - 21 Years
Gender	All

More Inclusion & Exclusion 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.

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT02637687
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.	Phase 1/Phase 2
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	Bayer
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	N/A
Principal Investigator Affiliation	N/A
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	Industry
Overall Status	Active, not recruiting
Countries	Australia, Canada, China, Czechia, Denmark, France, Germany, Ireland, Israel, Italy, Japan, Korea, Republic of, Netherlands, Poland, Spain, Sweden, Switzerland, Turkey, Ukraine, United Kingdom, United States
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	Solid Tumors Harboring NTRK Fusion

Arms & Interventions

Arms

Experimental: Phase 1 dose escalation

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)

Experimental: Phase 1 dose expansion

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)

Experimental: Phase 2: Patients with tumors bearing NTRK fusions (IFS)_Cohort 1

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)

Experimental: Phase 2: Other extra-cranial solid tumors_Cohort 2

Experimental: Phase 2: Primary CNS tumors_Cohort 3

Experimental: Phase 2: Bone health assessment_sub-cohort

Interventions

Drug: - Larotrectinib (Vitrakvi, BAY2757556)

BAY2757556 will be administered orally as capsule or in liquid form over continuous 28-day cycles.

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

Children's Hospital of Los Angeles, Los Angeles, California

Status

Address

Children's Hospital of Los Angeles

Los Angeles, California, 90027

UCLA Jonsson Comprehensive Cancer Center, Los Angeles, California

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Address

UCLA Jonsson Comprehensive Cancer Center

Los Angeles, California, 90095

Palo Alto, California

Status

Address

Lucille Salter Packard Children's Hospital at Stanford

Palo Alto, California, 94304

Nemours Children's Hospital (Orlando), Orlando, Florida

Status

Address

Nemours Children's Hospital (Orlando)

Orlando, Florida, 32827

Boston Children's Hospital, Boston, Massachusetts

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Address

Boston Children's Hospital

Boston, Massachusetts, 02115

Memorial Sloan Kettering Cancer Center, New York, New York

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Address

Memorial Sloan Kettering Cancer Center

New York, New York, 10065

Cincinnati, Ohio

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Address

Cincinnati Children's Hospital and Medical Center

Cincinnati, Ohio, 45229-3039

Children's Hospital of Philadelphia, Philadelphia, Pennsylvania

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Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104

St. Jude Children's Research Hospital, Memphis, Tennessee

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St. Jude Children's Research Hospital

Memphis, Tennessee, 38105

Dallas, Texas

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University of Texas Southwestern Medical Center

Dallas, Texas, 75235

Seattle Children's Hospital, Seattle, Washington

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Seattle Children's Hospital

Seattle, Washington, 98105

International Sites

Sydney Children's Hospital, Sydney, New South Wales, Australia

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Address

Sydney Children's Hospital

Sydney, New South Wales, 2031

Women's and Children's Hospital, North Adelaide, South Australia, Australia

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Women's and Children's Hospital

North Adelaide, South Australia, 5006

Royal Children's Hospital Melbourne, Parkville, Victoria, Australia

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Address

Royal Children's Hospital Melbourne

Parkville, Victoria, 3052

British Columbia Childrens Hospital, Vancouver, British Columbia, Canada

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Address

British Columbia Childrens Hospital

Vancouver, British Columbia, V6H 3V4

Toronto, Ontario, Canada

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Address

The Hospital for Sick Children (SickKids)

Toronto, Ontario, M5G 1X8

CHU Sainte-Justine, Montreal, Quebec, Canada

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CHU Sainte-Justine

Montreal, Quebec, H3T 1C5

Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China

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Sun Yat-sen University Cancer Center

Guangzhou, Guangdong, 510000

Beijing, China

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Address

Beijing Children's Hospital, Capital Medical University

Beijing, , 100045

Tianjin, China

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Address

Tianjin Medical University Cancer Institute & Hospital

Tianjin, , 300060

Fakultni nemocnice v Motole, Praha 5, Czechia

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Address

Fakultni nemocnice v Motole

Praha 5, , 150 06

Copenhagen, Denmark

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Address

Rigshospitalet, Dept Pediatrics & Adelescent Med.

Copenhagen, , 2100

Institut Curie - Ulm - Paris, PARIS cedex 5, France

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Institut Curie - Ulm - Paris

PARIS cedex 5, , 75248

Villejuif Cedex, France

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Address

Institut Gustave Roussy - Département de Médecine Oncologique

Villejuif Cedex, , 94805

Universitätsklinikum Heidelberg, Heidelberg, Baden-Württemberg, Germany

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Universitätsklinikum Heidelberg

Heidelberg, Baden-Württemberg, 69120

Stuttgart, Baden-Württemberg, Germany

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Address

KLINIKUM STUTTGART - Olgahospital | Paediatrie 5 (Onkologie, Haematologie, Immunologie)

Stuttgart, Baden-Württemberg, 70174

Charité - Campus Virchow-Klinikum (CVK), Berlin, Germany

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Charité - Campus Virchow-Klinikum (CVK)

Berlin, , 13353

Our Lady's Hospital For Sick Children, Crumlin, Dublin, Ireland

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Our Lady's Hospital For Sick Children

Crumlin, Dublin, 12

Petach Tikva, Israel

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Clalit Health Services Schneider Children's Medical Center

Petach Tikva, , 4920235

Milano, Lombardia, Italy

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Fondazione IRCCS Istituto Nazionale dei Tumori

Milano, Lombardia, 20133

Kanagawa Children's Medical Center, Yokohama, Kanagawa, Japan

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Kanagawa Children's Medical Center

Yokohama, Kanagawa, 232-8555

National Cancer Center Hospital, Chuo-ku, Tokyo, Japan

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National Cancer Center Hospital

Chuo-ku, Tokyo, 104-0045

Kyushu University Hospital, Fukuoka, Japan

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Kyushu University Hospital

Fukuoka, , 812-8582

Seoul National University Hospital, Seoul, Seoul Teugbyeolsi, Korea, Republic of

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Seoul National University Hospital

Seoul, Seoul Teugbyeolsi, 3080

Prinses Maxima Centrum, Utrecht, Netherlands

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Prinses Maxima Centrum

Utrecht, , 3584 CS

Uniwersyteckie Centrum Kliniczne, Gdansk, Poland

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Uniwersyteckie Centrum Kliniczne

Gdansk, , 80-952

Barcelona, Spain

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Ciutat Sanitaria i Universitaria de la Vall d'Hebron

Barcelona, , 08035

Karolinska Universitetssjukhuset i Solna, Stockholm, Sweden

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Address

Karolinska Universitetssjukhuset i Solna

Stockholm, , 171 76

Universitätskinderspital Zürich, Zürich, Switzerland

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Universitätskinderspital Zürich

Zürich, , 8032

Istanbul, Turkey

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Address

Istanbul Universitesi Istanbul Tip Fakultesi

Istanbul, , 34093

Lviv, Ukraine

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Western Ukrainian Specialized Pediatric Medical Centre

Lviv, , 79035

Royal Marsden NHS Trust (Surrey), Sutton, Surrey, United Kingdom

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Address

Royal Marsden NHS Trust (Surrey)

Sutton, Surrey, SM2 5PT

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