A Study to Test the Effect of the Drug Larotrectinib in Adults and Children With NTRK-fusion Positive Solid Tumors

Phase 2

Active, not recruiting

• Conditions: Solid Tumors Harboring NTRK Fusion
• Interventions: Drug: BAY2757556 (Larotrectinib, Vitrakvi)

• Registration Number: NCT02576431
• Lead Sponsor: Bayer

Brief Summary

This research study is done to test how well different types of cancer respond to the drug called larotrectinib. The cancer must have a change in a particular gene (NTRK1, NTRK2 or NTRK3). Larotrectinib is a drug that blocks the actions of these NTRK genes in cancer cells and can therefore be used to treat cancer.

Detailed Description

The primary objective of this study is to investigate the efficacy of larotrectinib for the treatment of advanced solid tumors harboring a fusion of neurotrophic tyrosine receptor kinase (NTRK) of types 1-3 in children and adults.

Secondary objectives comprise the efficacy and safety of larotrectinib in different NTRK-tumor types.

Study Timeline

• Study Start: 2015-09-30
• Study First Submitted: 2015-10-12
• Study First Submitted QC: 2015-10-13
• Study First Posted: 2015-10-15
• Status Verified: 2025-01
• Last Update Submitted: 2025-01-09
• Last Update Posted: 2025-01-10
• Primary Completion: 2025-07-20
• Study Completion: 2025-10-31

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 215

Inclusion Criteria

• Locally-advanced or metastatic malignancy with an NTRK1, NTRK2, or NTRK3 gene fusion, identified through molecular assays as routinely performed at CLIA or other similarly-certified laboratories. Subjects who have an NTRK gene fusion identified in a lab where CLIA or equivalent certification cannot be confirmed by the Sponsor at the time of consent may have been enrolled in Cohort 9 as per protocol versions 1.0 - 8.0. From protocol version 9.0: CLIA or similar certification of the lab performing the fusion assay is required. However, patients may be included after discussion with the sponsor if the lab performing the fusion assay is not CLIA or similar certified.

• Subjects who have received prior standard therapy appropriate for their tumor type and stage of disease, or who have no satisfactory alternative treatments and in the opinion of the Investigator, would be unlikely to tolerate or derive clinically meaningful benefit from appropriate standard of care therapy.

• Subjects must have at least one measurable lesion as defined by RECIST v1.1 (Eisenhauer et al. 2009). Subjects with solid tumors without RECIST v1.1 measurable disease (e.g., evaluable disease only) had been eligible for enrollment to Cohort 8 as per protocol versions 1.0 - 8.0, regardless of tumor type. Subjects with primary CNS tumors should meet the following criteria:

  1. Have received prior treatment including radiation and/or chemotherapy, with radiation completed > 12 weeks prior to C1D1 of therapy, as recommended or appropriate for that CNS tumor type.

  2. Have ≥ 1 site of bi-dimensionally measurable disease (confirmed by magnetic resonance imaging [MRI] and evaluable by RANO criteria), with the size of at least one of the measurable lesions ≥ 1 cm in each dimension and noted on more than one imaging slice.

  3. Imaging study performed within 28 days before enrollment. If on steroid therapy, the dose must be stable for at least 7 days immediately before and during the imaging study.

  4. Must be neurologically stable based on stable neurologic exam for 7 days prior to enrollment.

     For subjects eligible for enrollment to bone health cohort, inclusion criterion 3 is modified as the following:

  5. Subjects must have at least one lesion at baseline (measurable or non-measurable as defined by RECIST v1.1 or RANO criteria, as appropriate to tumor type).

  6. Subjects with primary CNS tumors must be neurologically stable based on stable neurologic exam for 7 days prior to enrollment.

• At least 18 years of age

• Performance Status: Eastern Cooperative Oncology Group (ECOG) score ≤ 3. If enrolled with primary CNS tumor to be assessed by RANO, Karnofsky Performance Score (KPS) ≥ 50%.

• Tumor tissue before treatment (mandatory). If neither fresh tissue can be obtained nor archival tissue is available patients might be enrolled after consultation with the sponsor.

• Adequate organ function as defined by the following criteria:

  1. Serum AST and serum ALT < 2.5 x upper limit of normal (ULN), or AST and ALT < 5 x ULN if liver function abnormalities are due to underlying malignancy
  2. Total bilirubin < 2.5 x ULN, except in the setting of biliary obstruction. Subjects with a known history of Gilberts Disease and an isolated elevation of indirect bilirubin are eligible
  3. Serum creatinine < 2.0 x ULN OR an estimated glomerular filtration rate ≥ 30 mL/minute using the Cockcroft-Gault formula: (140- age) x body weight (kg) x 0.85 (if female)/serum creatinine (mg/dL) x 72 with either result acceptable for enrollment.

• Ability to comply (or for guardian to ensure compliance) with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation.

• Willingness of men and women of reproductive potential to use double effective birth control methods, defined as one used by the subject and another by his/her partner, for the duration of treatment and for 1 month following study completion.

• For subjects eligible for enrollment to bone health cohort only: life expectancy of at least 6 months, based on investigator assessment.

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Exclusion Criteria

• Investigational agent or anticancer therapy within 2 weeks prior to the planned start of larotrectinib or 5 half-lives, whichever is shorter, and without recovery of acute and/or clinically significant toxicities from that therapy.

• Prior progression while receiving approved or investigational tyrosine kinase inhibitors targeting TRK. Subjects who received less than 28 days of treatment and discontinued because of intolerance or toxicity are eligible.

• Symptomatic or unstable brain metastases. (Note: Subjects with asymptomatic brain metastases are eligible to participate in the study.) Subjects with primary CNS tumors are eligible.

• Uncontrolled concurrent malignancy that would limit assessment of efficacy of larotrectinib. Allowed conditions may include, but are not limited to in situ cancers of cervix, breast, or skin, superficial bladder cancer, limited-stage prostate cancer, and basal or squamous cancers of the skin.

• Active uncontrolled systemic bacterial, viral, or fungal infection CTCAE grade ≥ 2; unstable cardiovascular disease, or other systemic disease that would limit compliance with study procedures. Unstable cardiovascular disease is defined as:

  1. In adults, persistently uncontrolled hypertension defined as systolic blood pressure (BP) > 150 mmHg and/or diastolic BP > 100 mmHg despite antihypertensive therapy.
  2. Myocardial infarction within 3 months of screening.
  3. Stroke within 3 months of screening.

• Inability to discontinue treatment with a strong CYP3A4 inhibitor or inducer

• Currently recovering from AEs/ ADRs due to previous treatments (excluding alopecia). Inclusion is only advised once the AE/ADR resolves or recovers to baseline or at least to CTCAE grade 1.

• Known or suspected hypersensitivity against the active substance or any of the ingredients of the IMP.

• Known history of HIV infection. All patients must be screened for HIV up to 28 days prior to study drug start using a blood test for HIV according to local regulations.

• HBV or HCV infection. All patients must be screened for HBV and HCV up to 28 days prior to study drug start using the routine hepatitis virus laboratorial panel. Patients positive for HBsAg or HBcAb will be eligible if they are negative for HBVDNA. Patients positive for anti-HCV antibody will be eligible if they are negative for HCV-RNA.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm 1_NSCLC	BAY2757556 (Larotrectinib, Vitrakvi)	Patients with solid non-small cell lung cancer (NSCLC) harboring NTRK fusions (arm closed)
Arm 4_Colorectal	BAY2757556 (Larotrectinib, Vitrakvi)	Patients with solid colorectal tumors harboring NTRK fusions (arm closed)
Arm 8_Other tumors	BAY2757556 (Larotrectinib, Vitrakvi)	Patients with e.g. kidney cancer, squamous cell cancer of head or neck or ovarian solid tumors harboring NTRK fusions (arm closed)
Arm 3_Sarcoma	BAY2757556 (Larotrectinib, Vitrakvi)	Patients with soft-tissue sarcoma harboring NTRK fusions (arm closed)
Arm 7_Primary CNS	BAY2757556 (Larotrectinib, Vitrakvi)	Patients with solid tumors in the primary central nervous system (CNS) harboring NTRK fusions (arm closed)
Arm 5_Salivary	BAY2757556 (Larotrectinib, Vitrakvi)	Patients with solid salivary tumors harboring NTRK fusions (arm closed)
Arm 6_Biliary	BAY2757556 (Larotrectinib, Vitrakvi)	Patients with solid biliary tumors harboring NTRK fusions (arm closed)
Arm 11_Bone health cohort	BAY2757556 (Larotrectinib, Vitrakvi)	Patients with all tumor types harboring NTRK fusions, not eligible for the main prospective cohort, including patients with non-measurable disease
Arm 2_Thyroid	BAY2757556 (Larotrectinib, Vitrakvi)	Patients with solid thyroid tumors harboring NTRK fusions (arm closed)
Arm 10_Prospective cohort	BAY2757556 (Larotrectinib, Vitrakvi)	Patients with melanoma, non secretory breast and colorectal cancer or other tumor types harboring NTRK fusions, except soft tissue sarcoma, salivary gland and thyroid cancer (arm closed)
Arm 9_Solid tumors without confirmed NTRK fusion	BAY2757556 (Larotrectinib, Vitrakvi)	Patients eligible for arms 1 to 8, but with documented NTRK fusion from a laboratory where CLIA or equivalent certification cannot be confirmed by the sponsor at the time of consent (arm closed)

Primary Outcome Measures

Name	Time	Method
Best overall response of confirmed complete response (CR) or partial response (PR) as determined by an independent radiology review committee using RECIST v1.1 or RANO criteria, as appropriate to tumor type.	Up to 120 months

Secondary Outcome Measures

Name	Time	Method
Severity of safety-relevant changes in clinical parameters or vital signs after drug administration	Up to 120 months
Best overall response of confirmed CR or PR as determined by the treating Investigator using RECIST v1.1 or RANO criteria, as appropriate to tumor type	Up to 120 months
Number of subjects with safety-relevant changes in clinical parameters or vital signs after drug administration	Up to 120 months
Rate of subjects that have any tumor regression as a best response, measured as shrinkage of target lesions	Up to 120 months
Overall Survival (OS): Number of months from the initiation of larotrectinib to the date of death due to any cause.	Up to 120 months
Clinical benefit rate (CBR): best overall response of confirmed CR, PR, or stable disease lasting 16 or more weeks following the initiation of Larotrectinib	Up to 120 months
Number of subjects with AEs categorized by severity. (including all, serious, and those considered treatment related.)	Up to 120 months
Concordance coefficient	Up to 120 months	Concordance of prior molecular profiling that detected an NTRK fusion within the subject's tumor with the diagnostic test being evaluated by the Sponsor.
Duration of response (DOR): determined for subjects with best overall response of confirmed CR or PR by 1) an independent radiology review committee and 2) the treating Investigator	Up to 120 months	Duration of response is the number of months from the start of confirmed complete response or partial response to disease progression or death. Complete response, partial response and disease progression are assessed by an independent radiology committee (IRC).
PFS: Number of months from initiation of larotrectinib to the earlier of disease progression or death due to any cause	Up to 120 months
Comparison of PFS following initiation of larotrectinib to that following the line of therapy immediately preceding larotrectinib in each subject who has received prior therapy	Up to 120 months

Trial Locations

Locations (98)

Avera Cancer Institute - Sioux Falls; 🇺🇸 Sioux Falls, South Dakota, United States

Karolinska Universitetssjukhuset Solna - Tema Cancer; 🇸🇪 Stockholm, Sweden

Stanford Cancer Center; 🇺🇸 Palo Alto, California, United States

UCLA-Santa Monica Medical Center; 🇺🇸 Santa Monica, California, United States

Memorial Hospital West; 🇺🇸 Pembroke, Florida, United States

The University of Chicago Medical Center (UCMC); 🇺🇸 Chicago, Illinois, United States

Massachusetts General Hospital; 🇺🇸 Boston, Massachusetts, United States

Dana-Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

Memorial Sloan Kettering Cancer Center; 🇺🇸 New York, New York, United States

University of North Carolina Hospitals; 🇺🇸 Chapel Hill, North Carolina, United States

Wake Forest Baptist Health; 🇺🇸 Winston-Salem, North Carolina, United States

Cleveland Clinic Foundation; 🇺🇸 Cleveland, Ohio, United States

Thomas Jefferson University; 🇺🇸 Philadelphia, Pennsylvania, United States

Fox Chase Cancer Center; 🇺🇸 Philadelphia, Pennsylvania, United States

Vanderbilt University Medical Center; 🇺🇸 Nashville, Tennessee, United States

University of Texas MD Anderson Cancer Center; 🇺🇸 Houston, Texas, United States

Inova Schar Cancer Institute; 🇺🇸 Fairfax, Virginia, United States

University of Washington; 🇺🇸 Seattle, Washington, United States

West Virginia University; 🇺🇸 Morgantown, West Virginia, United States

Hospital Alemán; 🇦🇷 Buenos Aires, Ciudad Auton. De Buenos Aires, Argentina

Fundación Cenit para la Investigación en Neurociencias; 🇦🇷 Caba, Ciudad Auton. De Buenos Aires, Argentina

Centro Medico Austral; 🇦🇷 TBC, Ciudad Auton. De Buenos Aires, Argentina

Centro Médico San Roque; 🇦🇷 San Miguel de Tucumán, Tucuman, Argentina

Macquarie University Hospital; 🇦🇺 Sydney, New South Wales, Australia

Centro Estudios Médicos e Invest. Clínicas "Dr. N. Quirno"; 🇦🇷 Buenos Aires, Ciudad Auton. De Buenos Aires, Argentina

Royal Darwin Hospital; 🇦🇺 Tiwi, Northern Territory, Australia

St John of God Healthcare; 🇦🇺 Subiaco, Western Australia, Australia

Institut Jules Bordet/Jules Bordet Instituut; 🇧🇪 Bruxelles, Belgium

Hosp. Araujo Jorge da Associação de Combate ao Câncer; 🇧🇷 Goiânia, Goiás, Brazil

Cenantron Centro Avançado de Tratamento Oncológico, Ltda.; 🇧🇷 Belo Horizonte, Minas Gerais, Brazil

Fundacao Pio XII - Hospital de Cancer de Barretos; 🇧🇷 Barretos/SP, Sao Paulo, Brazil

Instituto do Cancer do Estado de Sao Paulo; 🇧🇷 São Paulo, Sao Paulo, Brazil

Real e Benemérita Associação Portuguesa de Beneficência; 🇧🇷 São Paulo, Sao Paulo, Brazil

IBCC - Instituto Brasileiro de Controle do Cancer; 🇧🇷 São Paulo, Sao Paulo, Brazil

INCA - Hospital do Cancer III; 🇧🇷 Rio de Janeiro, Brazil

Oncoclínicas Rio de Janeiro S.A; 🇧🇷 Rio de Janeiro, Brazil

Instituto Nacional do Câncer - INCA - HC II; 🇧🇷 Rio de Janeiro, Brazil

Hospital Sirio Libanes; 🇧🇷 Sao Paulo, Brazil

Tom Baker Cancer Centre; 🇨🇦 Calgary, Alberta, Canada

Beijing Cancer Hospital; 🇨🇳 Beijing, Beijing, China

Sun Yat-sen University Cancer Center; 🇨🇳 Guangzhou, Guangdong, China

Sichuan University West China Hospital; 🇨🇳 Chengdu, Sichuan, China

Zhongshan Hospital, Fudan University; 🇨🇳 Shanghai, China

Instituto Nacional de Cancerología INC Colombia; 🇨🇴 Bogota, Cundinamarca, Colombia

Oncomédica S.A.; 🇨🇴 Montería, Córdoba, Colombia

Fundación Oftalmológica de Santander Carlos Ardila Lule; 🇨🇴 Florida Blanca, Santander, Colombia

Fakultní Nemocnice Olomouc; 🇨🇿 Olomouc, Czechia

Rigshospitalet - Kræftbehandling; 🇩🇰 Copenhagen OE, Denmark

Hopital Jean Minjoz; 🇫🇷 Besancon, France

Institut Bergonié - Unicancer Nouvelle Aquitaine; 🇫🇷 Bordeaux Cedex, France

Hopital Saint Antoine - Paris; 🇫🇷 Clamart, France

Centre Antoine Lacassagne; 🇫🇷 Nice Cedex 2, France

Hôpital de la Pitié-Salpétrière; 🇫🇷 Paris, France

Hôpital de la Milétrie; 🇫🇷 Poitiers, France

Institut de Cancérologie de l'Ouest - Saint Herblain; 🇫🇷 Saint-Herblain, France

ICANS - Institut de Cancérologie de Strasbourg Europe; 🇫🇷 Strasbourg, France

Charité Comprehensive Cancer Center (CCCC); 🇩🇪 Berlin, Germany

All India Institute of Medical Sciences; 🇮🇳 Bhubaneswar, Odisha, India

Jawaharlal Institute Of Postgraduate Medical Education and R; 🇮🇳 Gorimedu, Pondicherry, India

St Vincents University Hospital; 🇮🇪 Dublin 4, Ireland

A.O.R.N. San Giuseppe Moscati; 🇮🇹 Avellino, Campania, Italy

A.O.U. di Bologna Policlinico S.Orsola Malpighi; 🇮🇹 Bologna, Emilia-Romagna, Italy

A.S.U. Friuli Centrale - A. Regionale Coordinamento Salute; 🇮🇹 Udine, Friuli-Venezia Giulia, Italy

IRCCS Istituti Fisioterapici Ospitalieri - IFO; 🇮🇹 Roma, Lazio, Italy

Istituto Europeo di Oncologia s.r.l; 🇮🇹 Milano, Lombardia, Italy

Istituto Oncologico Veneto; 🇮🇹 Padova, Veneto, Italy

Nagoya University Hospital; 🇯🇵 Nagoya, Aichi, Japan

National Cancer Center Hospital East; 🇯🇵 Kashiwa, Chiba, Japan

Hokkaido University Hospital; 🇯🇵 Sapporo, Hokkaido, Japan

The Cancer Institute Hospital of JFCR; 🇯🇵 Koto-ku, Tokyo, Japan

Severance Hospital, Yonsei University Health System; 🇰🇷 Seoul, Seoul Teugbyeolsi, Korea, Republic of

Asan Medical Center; 🇰🇷 Seoul, Seoul Teugbyeolsi, Korea, Republic of

Seoul National University Hospital; 🇰🇷 Seoul, Seoul Teugbyeolsi, Korea, Republic of

Samsung Medical Center; 🇰🇷 Seoul, Korea, Republic of

IPO Porto; 🇵🇹 Porto, Portugal

Arkhangelsk Clinical Oncology Dispensary; 🇷🇺 Arkhangelsk, Russian Federation

Republican Clinical Oncology Dispensary Kazan; 🇷🇺 Kazan, Russian Federation

Russian Oncological Scientific Center n.a. N.N. Blokhin RAMS; 🇷🇺 Moscow, Russian Federation

1st Moscow State Medical University n.a. I.M.Sechenov; 🇷🇺 Moscow, Russian Federation

Clinical Diagnostical Center; 🇷🇺 Nizhny Novgorod, Russian Federation

St. Petersburg Clinical Onc. Cent. of Spec. Types of Care; 🇷🇺 St. Petersburg, Russian Federation

National Cancer Center Singapore; 🇸🇬 Singapore, Singapore

Onkologicky Ustav Svatej Alzbety, s.r.o.; 🇸🇰 Bratislava, Slovakia

Narodny onkologicky ustav; 🇸🇰 Bratislava, Slovakia

Institut Català d'Oncologia Hospitalet; 🇪🇸 Hospitalet de Llobregat, Barcelona, Spain

Hospital del Mar; 🇪🇸 Barcelona, Spain

Ciutat Sanitaria i Universitaria de la Vall d'Hebron; 🇪🇸 Barcelona, Spain

Hospital General Universitario Gregorio Maranon | Oncologia; 🇪🇸 Madrid, Spain

Fundacion Jimenez Diaz (Clinica de la Concepcion); 🇪🇸 Madrid, Spain

Centro Integral Oncológico Clara Campal; 🇪🇸 Madrid, Spain

Tri-Service General Hospital; 🇨🇳 Taipei City, Taiwan

Health Ministry Of Türkiye Republic Ankara Bilkent City Hospital; 🇹🇷 Ankara, Turkey

Trakya Univ. Tip Fak.; 🇹🇷 Edirne, Turkey

Istanbul Universitesi Istanbul Tip Fakultesi; 🇹🇷 Istanbul, Turkey

Istanbul Universitesi Cerrahpasa-Cerrahpasa Tip Fakultesi; 🇹🇷 Istanbul, Turkey

TC Saglik Bakanligi Goztepe ProfDr Suleyman Yalcin Sehir Has; 🇹🇷 Istanbul, Turkey

Izmir Katip Celebi Universitesi Ataturk Egitim ve Arastirma; 🇹🇷 Izmir, Turkey

Erciyes Universitesi Tip Fakultesi; 🇹🇷 Kayseri, Turkey