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

Solid Tumors Harboring NTRK Fusion Clinical Trial

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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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02576431
• Other study ID #: 20289
• Secondary ID: LOXO-TRK-1500220
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: September 30, 2015
• Est. completion date: October 31, 2025

Study information

• Verified date: March 2024
• Source: Bayer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 215
• Est. completion date: October 31, 2025
• Est. primary completion date: July 20, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Solid Tumors Harboring NTRK Fusion

Intervention

Drug:
• BAY2757556 (Larotrectinib, Vitrakvi)
Larotrectinib will be administered orally as capsule or liquid solution at a dose of 100 mg twice daily in continuing 28-days cycles.

Locations

Country	Name	City	State
Argentina	Hospital Alemán	Buenos Aires	Ciudad Auton. De Buenos Aires
Brazil	Fundacao Pio XII Hospital de Cancer de Barretos	Barretos/SP	Sao Paulo
Brazil	IBCC - Instituto Brasileiro de Controle do Cancer	São Paulo	Sao Paulo
China	Beijing Cancer Hospital	Beijing
China	Sichuan University West China Hospital	Chengdu	Sichuan
China	Sun Yat-sen University Cancer Center	Guangzhou	Guangdong
China	Zhongshan Hospital, Fudan University	Shanghai
Czechia	Fakultni Nemocnice Olomouc	Olomouc
Denmark	Finsen Centre	Copenhagen
France	Institut Bergonié - Unicancer Nouvelle Aquitaine	Bordeaux Cedex
France	Centre Antoine Lacassagne	Nice Cedex 2
France	Hôpital de la Pitié-Salpétrière	Paris
France	Hopital Saint Antoine - Paris	Paris
France	Institut de Cancérologie de l'Ouest - Saint Herblain	Saint-Herblain
France	ICANS - Institut de Cancérologie de Strasbourg Europe	Strasbourg
Germany	Charité Comprehensive Cancer Center (CCCC)	Berlin
India	All India Institute of Medical Sciences	Bhubaneswar	Delhi
India	Jawaharlal Institute Of Postgraduate Medical Education and R	Gorimedu	Pondicherry
Ireland	St Vincents University Hospital	Dublin
Japan	National Cancer Center Hospital East	Kashiwa	Chiba
Japan	The Cancer Institute Hospital of JFCR	Koto-ku	Tokyo
Japan	Nagoya University Hospital	Nagoya	Aichi
Japan	Hokkaido University Hospital	Sapporo	Hokkaido
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital, Yonsei University Health System	Seoul
Portugal	IPO Porto	Porto
Singapore	National Cancer Center Singapore	Singapore
Spain	Ciutat Sanitaria i Universitaria de la Vall d'Hebron	Barcelona
Spain	Institut Català d'Oncologia Hospitalet	Hospitalet de Llobregat	Barcelona
Spain	Centro Integral Oncológico Clara Campal	Madrid
Spain	Fundacion Jimenez Diaz (Clinica de la Concepcion)	Madrid
Spain	Hospital General Universitario Gregorio Maranon | Oncologia	Madrid
Sweden	Karolinska Universitetssjukhuset i Solna	Stockholm
Taiwan	Tri-Service General Hospital	Taipei City
Turkey	Health Ministry Of Türkiye Republic Ankara Bilkent City Hospital	Ankara
Turkey	Trakya Univ. Tip Fak.	Edirne
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
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	University of North Carolina Hospitals	Chapel Hill	North Carolina
United States	University of Chicago	Chicago	Illinois
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Inova Schar Cancer Institute	Fairfax	Virginia
United States	University of Texas MD Anderson Cancer Center	Houston	Texas
United States	West Virginia University	Morgantown	West Virginia
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	Stanford Cancer Center	Palo Alto	California
United States	Memorial Hospital West	Pembroke	Florida
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	Thomas Jefferson University	Philadelphia	Pennsylvania
United States	UCLA-Santa Monica Medical Center	Santa Monica	California
United States	University of Washington	Seattle	Washington
United States	Avera Cancer Institute	Sioux Falls	South Dakota
United States	Wake Forest Baptist Health	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Bayer

Countries where clinical trial is conducted

United States,  Argentina,  Brazil,  China,  Czechia,  Denmark,  France,  Germany,  India,  Ireland,  Japan,  Korea, Republic of,  Portugal,  Singapore,  Spain,  Sweden,  Taiwan,  Turkey, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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	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).	Up to 120 months
Secondary	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
Secondary	Rate of subjects that have any tumor regression as a best response, measured as shrinkage of target lesions		Up to 120 months
Secondary	PFS: Number of months from initiation of larotrectinib to the earlier of disease progression or death due to any cause		Up to 120 months
Secondary	Overall Survival (OS): Number of months from the initiation of larotrectinib to the date of death due to any cause.		Up to 120 months
Secondary	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
Secondary	Number of subjects with AEs categorized by severity. (including all, serious, and those considered treatment related.)		Up to 120 months
Secondary	Number of subjects with safety-relevant changes in clinical parameters or vital signs after drug administration		Up to 120 months
Secondary	Severity of safety-relevant changes in clinical parameters or vital signs after drug administration		Up to 120 months
Secondary	Concordance coefficient	Concordance of prior molecular profiling that detected an NTRK fusion within the subject's tumor with the diagnostic test being evaluated by the Sponsor.	Up to 120 months

External Links

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