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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Solid Tumors Harboring NTRK Fusion

Intervention / Treatment
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* Drug: BAY2757556 (Larotrectinib, Vitrakvi)


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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1_NSCLC<br>Patients with solid non-small cell lung cancer (NSCLC) harboring NTRK fusions (arm closed) | Drug: BAY2757556 (Larotrectinib, Vitrakvi)<br>* Larotrectinib will be administered orally as capsule or liquid solution at a dose of 100 mg twice daily in continuing 28-days cycles.<br>* Other names: LOXO-101;|
| Experimental: Arm 2_Thyroid<br>Patients with solid thyroid tumors harboring NTRK fusions (arm closed) | Drug: BAY2757556 (Larotrectinib, Vitrakvi)<br>* Larotrectinib will be administered orally as capsule or liquid solution at a dose of 100 mg twice daily in continuing 28-days cycles.<br>* Other names: LOXO-101;|
| Experimental: Arm 3_Sarcoma<br>Patients with soft-tissue sarcoma harboring NTRK fusions (arm closed) | Drug: BAY2757556 (Larotrectinib, Vitrakvi)<br>* Larotrectinib will be administered orally as capsule or liquid solution at a dose of 100 mg twice daily in continuing 28-days cycles.<br>* Other names: LOXO-101;|
| Experimental: Arm 4_Colorectal<br>Patients with solid colorectal tumors harboring NTRK fusions (arm closed) | Drug: BAY2757556 (Larotrectinib, Vitrakvi)<br>* Larotrectinib will be administered orally as capsule or liquid solution at a dose of 100 mg twice daily in continuing 28-days cycles.<br>* Other names: LOXO-101;|
| Experimental: Arm 5_Salivary<br>Patients with solid salivary tumors harboring NTRK fusions (arm closed) | Drug: BAY2757556 (Larotrectinib, Vitrakvi)<br>* Larotrectinib will be administered orally as capsule or liquid solution at a dose of 100 mg twice daily in continuing 28-days cycles.<br>* Other names: LOXO-101;|
| Experimental: Arm 6_Biliary<br>Patients with solid biliary tumors harboring NTRK fusions (arm closed) | Drug: BAY2757556 (Larotrectinib, Vitrakvi)<br>* Larotrectinib will be administered orally as capsule or liquid solution at a dose of 100 mg twice daily in continuing 28-days cycles.<br>* Other names: LOXO-101;|
| Experimental: Arm 7_Primary CNS<br>Patients with solid tumors in the primary central nervous system (CNS) harboring NTRK fusions (arm closed) | Drug: BAY2757556 (Larotrectinib, Vitrakvi)<br>* Larotrectinib will be administered orally as capsule or liquid solution at a dose of 100 mg twice daily in continuing 28-days cycles.<br>* Other names: LOXO-101;|
| Experimental: Arm 8_Other tumors<br>Patients with e.g. kidney cancer, squamous cell cancer of head or neck or ovarian solid tumors harboring NTRK fusions (arm closed) | Drug: BAY2757556 (Larotrectinib, Vitrakvi)<br>* Larotrectinib will be administered orally as capsule or liquid solution at a dose of 100 mg twice daily in continuing 28-days cycles.<br>* Other names: LOXO-101;|
| Experimental: Arm 9_Solid tumors without confirmed NTRK fusion<br>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) | Drug: BAY2757556 (Larotrectinib, Vitrakvi)<br>* Larotrectinib will be administered orally as capsule or liquid solution at a dose of 100 mg twice daily in continuing 28-days cycles.<br>* Other names: LOXO-101;|
| Experimental: Arm 10_Prospective cohort<br>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) | Drug: BAY2757556 (Larotrectinib, Vitrakvi)<br>* Larotrectinib will be administered orally as capsule or liquid solution at a dose of 100 mg twice daily in continuing 28-days cycles.<br>* Other names: LOXO-101;|
| Experimental: Arm 11_Bone health cohort<br>Patients with all tumor types harboring NTRK fusions, not eligible for the main prospective cohort, including patients with non-measurable disease | Drug: BAY2757556 (Larotrectinib, Vitrakvi)<br>* Larotrectinib will be administered orally as capsule or liquid solution at a dose of 100 mg twice daily in continuing 28-days cycles.<br>* Other names: LOXO-101;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| Rate of subjects that have any tumor regression as a best response, measured as shrinkage of target lesions |  | Up to 120 months | 
| PFS: Number of months from initiation of larotrectinib to the earlier of disease progression or death due to any cause |  | 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 | 
| 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 | 
| Number of subjects with AEs categorized by severity. (including all, serious, and those considered treatment related.) |  | Up to 120 months | 
| Number of subjects with safety-relevant changes in clinical parameters or vital signs after drug administration |  | Up to 120 months | 
| Severity of safety-relevant changes in clinical parameters or vital signs after drug administration |  | Up to 120 months | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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