Clinical trial NCT02576431: A Study to Test the Effect of the Drug Larotrectinib in Adults and Children With NTRK-fusion Positive Solid Tumors
Official title: A Study to Learn How Well the Drug Larotrectinib Works in Adults With Different Solid Cancers With a Change in the Genes Called NTRK Fusion
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Solid Tumors Harboring NTRK Fusion
Keywords: Non-small cell lung cancer
Thyroid cancer
Sarcoma
Colorectal cancer
Salivary gland cancer
Biliary cancer
Central nervous system (CNS) Tumor
Breast cancer
Melanoma
Neurotrophic tyrosine receptor kinase (NTRK)
NTRK1
NTRK2
NTRK3
Fusion Positive
TRK fusion
TRKA
TRKB
TRKC
ETV6
Lead sponsor: Bayer
Sponsor class: INDUSTRY
First posted: 2015-10-15
Enrollment: 215
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

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.

Primary outcomes:
measure: 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.
timeFrame: Up to 120 months
Secondary outcomes:
measure: 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
timeFrame: Up to 120 months
measure: 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
timeFrame: Up to 120 months
measure: Clinical benefit rate (CBR): best overall response of confirmed CR, PR, or stable disease lasting 16 or more weeks following the initiation of Larotrectinib
timeFrame: Up to 120 months
measure: Rate of subjects that have any tumor regression as a best response, measured as shrinkage of target lesions
timeFrame: Up to 120 months
measure: PFS: Number of months from initiation of larotrectinib to the earlier of disease progression or death due to any cause
timeFrame: Up to 120 months
measure: Overall Survival (OS): Number of months from the initiation of larotrectinib to the date of death due to any cause.
timeFrame: Up to 120 months
measure: 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
timeFrame: Up to 120 months
measure: Number of subjects with AEs categorized by severity. (including all, serious, and those considered treatment related.)
timeFrame: Up to 120 months
measure: Number of subjects with safety-relevant changes in clinical parameters or vital signs after drug administration
timeFrame: Up to 120 months
measure: Severity of safety-relevant changes in clinical parameters or vital signs after drug administration
timeFrame: Up to 120 months
measure: Concordance coefficient
timeFrame: Up to 120 months
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Stanford Cancer Center
state: California
city: Santa Monica
country: United States
facility: UCLA-Santa Monica Medical Center
state: California
city: Pembroke Pines
country: United States
facility: Memorial Cancer Institute at West
state: Florida
city: Chicago
country: United States
facility: The University of Chicago Medical Center (UCMC)
state: Illinois
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
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: Chapel Hill
country: United States
facility: University of North Carolina Hospitals
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest Baptist Health
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic - Neurology
state: Ohio
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Sioux Falls
country: United States
facility: Avera Cancer Institute - Sioux Falls
state: South Dakota
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
city: Fairfax
country: United States
facility: Inova Schar Cancer Institute
state: Virginia
city: Seattle
country: United States
facility: University of Washington
state: Washington
city: Morgantown
country: United States
facility: West Virginia University
state: West Virginia
city: Buenos Aires
country: Argentina
facility: Hospital Alemán
state: Ciudad Auton. De Buenos Aires
city: Buenos Aires
country: Argentina
facility: Centro Estudios Médicos e Invest. Clínicas "Dr. N. Quirno"
state: Ciudad Auton. De Buenos Aires
city: Caba
country: Argentina
facility: Fundación Cenit para la Investigación en Neurociencias
state: Ciudad Auton. De Buenos Aires
city: TBC
country: Argentina
facility: Centro Medico Austral
state: Ciudad Auton. De Buenos Aires
city: San Miguel de Tucumán
country: Argentina
facility: Centro Médico San Roque
state: Tucuman
city: Sydney
country: Australia
facility: Macquarie University Hospital
state: New South Wales
city: Tiwi
country: Australia
facility: Royal Darwin Hospital
state: Northern Territory
city: Subiaco
country: Australia
facility: St John of God Healthcare
state: Western Australia
city: Bruxelles
country: Belgium
facility: Institut Jules Bordet/Jules Bordet Instituut
city: Goiânia
country: Brazil
facility: Hosp. Araujo Jorge da Associação de Combate ao Câncer
state: Goiás
city: Belo Horizonte
country: Brazil
facility: Cenantron Centro Avançado de Tratamento Oncológico, Ltda.
state: Minas Gerais
city: Barretos/SP
country: Brazil
facility: Fundacao Pio XII - Hospital de Cancer de Barretos
state: Sao Paulo
city: São Paulo
country: Brazil
facility: Instituto do Cancer do Estado de Sao Paulo
state: Sao Paulo
city: São Paulo
country: Brazil
facility: Real e Benemérita Associação Portuguesa de Beneficência
state: Sao Paulo
city: São Paulo
country: Brazil
facility: IBCC - Instituto Brasileiro de Controle do Cancer
state: Sao Paulo
city: Rio de Janeiro
country: Brazil
facility: Instituto Nacional do Câncer - INCA - HC II
city: Rio de Janeiro
country: Brazil
facility: INCA - Hospital do Cancer III
city: Rio de Janeiro
country: Brazil
facility: Oncoclínicas Rio de Janeiro S.A
city: Sao Paulo
country: Brazil
facility: Hospital Sirio Libanes
city: Calgary
country: Canada
facility: Tom Baker Cancer Centre
state: Alberta
city: Beijing
country: China
facility: Beijing Cancer Hospital
state: Beijing
city: Guangzhou
country: China
facility: Sun Yat-sen University Cancer Center
state: Guangdong
city: Chengdu
country: China
facility: Sichuan University West China Hospital
state: Sichuan
city: Shanghai
country: China
facility: Zhongshan Hospital, Fudan University
city: Bogota
country: Colombia
facility: Instituto Nacional de Cancerología INC Colombia
state: Cundinamarca
city: Montería
country: Colombia
facility: Oncomédica S.A.
state: Córdoba
city: Florida Blanca
country: Colombia
facility: Fundación Oftalmológica de Santander Carlos Ardila Lule
state: Santander
city: Olomouc
country: Czechia
facility: Fakultní Nemocnice Olomouc
city: Copenhagen OE
country: Denmark
facility: Rigshospitalet - Kræftbehandling
city: Besancon
country: France
facility: Hopital Jean Minjoz
city: Bordeaux
country: France
facility: Institut Bergonie - Unicancer Nouvelle Aquitaine - Service Oncologie medicale
city: Nice
country: France
facility: Centre Antoine Lacassagne - Departement Oncologie
city: Paris
country: France
facility: Hopital Saint Antoine APHP - Departement Oncologie
city: Paris
country: France
facility: APHP-Hopital la Pitie Salpetriere-Departement oncologie
city: Poitiers
country: France
facility: Hôpital de la Milétrie
city: Saint-Herblain
country: France
facility: Institut de Cancerologie Ouest - Saint-Herblain
city: Strasbourg
country: France
facility: ICANS - Institut de Cancerologie de Strasbourg Europe - service oncologie medicale
city: Berlin
country: Germany
facility: Charité Comprehensive Cancer Center (CCCC)
city: Bhubaneswar
country: India
facility: All India Institute of Medical Sciences
state: Odisha
city: Gorimedu
country: India
facility: Jawaharlal Institute Of Postgraduate Medical Education and R
state: Pondicherry
city: Dublin 4
country: Ireland
facility: St Vincents University Hospital
city: Avellino
country: Italy
facility: A.O.R.N. San Giuseppe Moscati
state: Campania
city: Bologna
country: Italy
facility: A.O.U. di Bologna Policlinico S.Orsola Malpighi
state: Emilia-Romagna
city: Udine
country: Italy
facility: A.S.U. Friuli Centrale - A. Regionale Coordinamento Salute
state: Friuli-Venezia Giulia
city: Roma
country: Italy
facility: IRCCS Istituti Fisioterapici Ospitalieri - IFO
state: Lazio
city: Milano
country: Italy
facility: Istituto Europeo di Oncologia s.r.l
state: Lombardia
city: Padova
country: Italy
facility: Istituto Oncologico Veneto
state: Veneto
city: Nagoya
country: Japan
facility: Nagoya University Hospital
state: Aichi
city: Kashiwa
country: Japan
facility: National Cancer Center Hospital East
state: Chiba
city: Sapporo
country: Japan
facility: Hokkaido University Hospital
state: Hokkaido
city: Koto-ku
country: Japan
facility: The Cancer Institute Hospital of JFCR
state: Tokyo
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
state: Seoul Teugbyeolsi
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
state: Seoul Teugbyeolsi
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
state: Seoul Teugbyeolsi
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Porto
country: Portugal
facility: IPO Porto
city: Arkhangelsk
country: Russian Federation
facility: Arkhangelsk Clinical Oncology Dispensary
city: Kazan
country: Russian Federation
facility: Republican Clinical Oncology Dispensary Kazan
city: Moscow
country: Russian Federation
facility: Russian Oncological Scientific Center n.a. N.N. Blokhin RAMS
city: Moscow
country: Russian Federation
facility: 1st Moscow State Medical University n.a. I.M.Sechenov
city: Nizhny Novgorod
country: Russian Federation
facility: Clinical Diagnostical Center
city: St. Petersburg
country: Russian Federation
facility: St. Petersburg Clinical Onc. Cent. of Spec. Types of Care
city: Singapore
country: Singapore
facility: National Cancer Center Singapore
city: Bratislava
country: Slovakia
facility: Onkologicky Ustav Svatej Alzbety, s.r.o.
city: Bratislava
country: Slovakia
facility: Narodny onkologicky ustav
city: Barcelona
country: Spain
facility: Institut Catala D'oncologia - Oncologia
state: L Hospitalet De Llobregat
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Ciutat Sanitaria i Universitaria de la Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Maranon | Oncologia
city: Madrid
country: Spain
facility: Fundacion Jimenez Diaz (Clinica de la Concepcion)
city: Madrid
country: Spain
facility: Centro Integral Oncológico Clara Campal
city: Stockholm
country: Sweden
facility: Karolinska Universitetssjukhuset Solna - Tema Cancer
city: Taipei City
country: Taiwan
facility: Tri-Service General Hospital
city: Ankara
country: Turkey
facility: Health Ministry Of Türkiye Republic Ankara Bilkent City Hospital
city: Edirne
country: Turkey
facility: Trakya Univ. Tip Fak.
city: Istanbul
country: Turkey
facility: Istanbul Universitesi Istanbul Tip Fakultesi
city: Istanbul
country: Turkey
facility: Istanbul Universitesi Cerrahpasa-Cerrahpasa Tip Fakultesi
city: Istanbul
country: Turkey
facility: TC Saglik Bakanligi Goztepe ProfDr Suleyman Yalcin Sehir Has
city: Izmir
country: Turkey
facility: Izmir Katip Celebi Universitesi Ataturk Egitim ve Arastirma
city: Kayseri
country: Turkey
facility: Erciyes Universitesi Tip Fakultesi
Study officials:
References:
citation: Waguespack SG, Drilon A, Lin JJ, Brose MS, McDermott R, Almubarak M, Bauman J, Casanova M, Krishnamurthy A, Kummar S, Leyvraz S, Oh DY, Park K, Sohal D, Sherman E, Norenberg R, Silvertown JD, Brega N, Hong DS, Cabanillas ME. Efficacy and safety of larotrectinib in patients with TRK fusion-positive thyroid carcinoma. Eur J Endocrinol. 2022 Apr 29;186(6):631-643. doi: 10.1530/EJE-21-1259.
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