(20289) A Phase 2 Basket Study of the Oral TRK Inhibitor larotrectinib in Subjects with NTRK Fusion-Positive Tumors
- Trial ID
- 2022-502667-38-00
- Protocol
- 20289
- Sponsor
- Bayer Consumer Care AG
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to determine the **overall response rate (ORR)** in subjects with advanced cancer harboring an NTRK fusion, following treatment with larotrectinib. This is assessed by an independent radiology review committee and measured by the proportion of subjects achieving a best overall confirmed response of complete response (CR) or partial response (PR) according to the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) or Response Assessment in Neuro-Oncology (RANO) criteria, as appropriate. This objective is clinically relevant as it evaluates the efficacy of larotrectinib in targeting NTRK fusion-positive tumors, which can lead to improved treatment outcomes for patients with these specific genetic alterations.
Secondary objectives include: - Determining the ORR based on the treating Investigator’s response assessment using RECIST v1.1 or RANO criteria, as appropriate to tumor type. - Evaluating the duration of response (DOR) in subjects with best overall response of CR or PR as determined by both an independent radiology review committee and the treating Investigator. - Estimating the proportion of subjects with any tumor regression as a best response. - Evaluating the duration of progression-free survival (PFS) and overall survival (OS) following initiation of larotrectinib. - Assessing the safety profile and tolerability of larotrectinib. - Comparing the duration of PFS following initiation of larotrectinib to that following the line of therapy immediately preceding larotrectinib in subjects who have received prior therapy. - Evaluating the clinical benefit rate (CBR) based on the proportion of subjects with best overall response of CR, PR, or stable disease lasting 16 or more weeks following initiation of larotrectinib. - Evaluating the concordance of prior molecular profiling that detected an NTRK fusion within the subject’s tumor with the diagnostic test being evaluated by the Sponsor.
Participants
The clinical trial involves a total of **169 participants** diagnosed with **solid tumors harboring NTRK fusion**. The study population includes both male and female subjects, aged 18 years and older, with a performance status of Eastern Cooperative Oncology Group (ECOG) score ≤ 3. Participants were selected based on the presence of locally-advanced or metastatic malignancy with an NTRK1, NTRK2, or NTRK3 gene fusion, identified through molecular assays performed at certified laboratories. The trial includes individuals who have received prior standard therapy appropriate for their tumor type and stage of disease or those with no satisfactory alternative treatments. Participants are required to have adequate organ function and the ability to comply with outpatient treatment and monitoring. The study also considers lifestyle factors, requiring the willingness of men and women of reproductive potential to use double effective birth control methods during the study and for one month following its completion. The trial population includes a vulnerable population, ensuring comprehensive ethical considerations are in place.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **larotrectinib sulfate** in subjects with solid tumors harboring NTRK fusion. This is a Phase 2, randomized, double-blind, controlled study. The trial aims to determine the overall response rate (ORR) as assessed by an independent radiology review committee, using the Response Evaluation Criteria in Solid Tumors (RECIST v1.1) or Response Assessment in Neuro-Oncology (RANO) criteria, as appropriate. The study is expected to run from August 30, 2016, to October 31, 2025, with a maximum treatment period of 120 days per participant.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as the presence of an NTRK gene fusion, adequate organ function, and a performance status of ECOG ≤ 3. Following the screening, participants will be randomized to receive larotrectinib in either oral solution or capsule form, with a maximum daily dose of 200 mg. Study visits will include regular assessments to monitor response to treatment, adverse events, and compliance with the study protocol. Follow-up visits will be scheduled at regular intervals to evaluate the duration of response, progression-free survival, and overall survival.
The end-of-study visit will occur after the completion of the treatment period or upon early termination. Conditions that may lead to early termination include significant adverse events, disease progression, or withdrawal of consent. Participants are expected to be involved in the study for the duration of the treatment period, with additional follow-up as required. The trial will also assess secondary endpoints such as the clinical benefit rate, rate of tumor regression, and changes in clinical safety laboratory values and vital signs.
Treatment
The clinical trial involves the administration of **Larotrectinib Bayer**, an investigational medication formulated as an **oral solution**. The active substance in this formulation is **larotrectinib sulfate**, a chemical compound developed by Bayer AG. The oral solution is administered via the oral route, with a maximum daily dose of 200 mg and a total maximum dose of 730 g over a treatment period of up to 120 days. The medication is not a pediatric formulation and is not classified as an orphan drug. The primary objective of the trial is to evaluate the overall response rate in subjects with NTRK fusion-positive tumors.
In addition to the oral solution, **Larotrectinib Bayer** is also available in a **hard capsule** form. This formulation also contains **larotrectinib sulfate** as the active ingredient, with the same dosing regimen as the oral solution: a maximum daily dose of 200 mg and a total maximum dose of 730 g over a 120-day treatment period. The capsules are administered orally and are chemically identical to the oral solution, ensuring consistency in the active substance across different pharmaceutical forms. Both formulations are intended for use in the same patient population and are evaluated under the same clinical trial protocol.
No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in this trial. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the prescribed regimen. The trial aims to provide comprehensive data on the efficacy and safety of **larotrectinib sulfate** in treating advanced cancers with NTRK fusions.
Efficacy
The efficacy of the clinical trial involving the oral TRK inhibitor **larotrectinib** will be assessed primarily through the overall response rate (ORR). This will be determined by an independent radiology review committee, measuring the proportion of subjects achieving a best overall confirmed response of complete response (CR) or partial response (PR). The evaluation will utilize the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1), or the Response Assessment in Neuro-Oncology (RANO) criteria, as appropriate for the tumor type. Secondary endpoints include the best overall response of confirmed CR or PR as determined by the treating Investigator, duration of response (DOR), clinical benefit rate (CBR), rate of tumor regression, progression-free survival (PFS), and overall survival (OS). Additionally, the trial will compare PFS following the initiation of **larotrectinib** to that following the line of therapy immediately preceding **larotrectinib** in subjects who have received prior therapy. The number of subjects experiencing adverse events (AEs), categorized by severity, and changes from baseline in clinical safety laboratory values and vital signs will also be monitored. The concordance of prior molecular profiling that detected NTRK fusion within the subject’s tumor with the diagnostic test being evaluated by the sponsor will be assessed. These efficacy parameters will be collected and analyzed at specified intervals throughout the trial duration, ensuring a comprehensive evaluation of the treatment's impact on subjects with NTRK fusion-positive tumors.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Locally-advanced or metastatic malignancy with an NTRK1, NTRK2, or NTRK3 gene fusion, identified through molecular assays as routinely performed at Clinical Laboratory Improvement Amendments (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 central nervous system (CNS) tumors should meet the following criteria: a. 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. b. 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. c. 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. d. 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: e. 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). f. 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: a. Serum aspartate aminotransferase (AST) and serum alanine aminotransferase (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 b. 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 c. 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.
- Capable of giving signed informed consent as described in protocol which includes compliance with the requirements, restrictions listed in the informed consent form (ICF), and in this protocol.
- " 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 tropomyosin receptor kinase (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 Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 2; unstable cardiovascular disease, or other systemic disease that would limit compliance with study procedures. Unstable cardiovascular disease is defined as: a. In adults, persistently uncontrolled hypertension defined as systolic blood pressure (BP) > 150 mmHg and/or diastolic BP > 100 mmHg despite antihypertensive therapy. b. Myocardial infarction within 3 months of screening. c. Stroke within 3 months of screening."
- Inability to discontinue treatment with a strong cytochrome P450 3A4 (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 Investigational Medicinal Product (IMP).
- Known history of Human immunodeficiency virus (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.
- Hepatitis B Virus (HBV) or Hepatitis C Virus (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 HBV-DNA. Patients positive for anti-HCV antibody will be eligible if they are negative for HCV-RNA.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Denmark | Not Recruiting | 30 Aug 2016 | 7 |
 France | Not Recruiting | 30 Aug 2016 | 18 |
 Germany | Not Recruiting | 30 Aug 2016 | 4 |
 Portugal | Not Recruiting | 30 Aug 2016 | 1 |
 Spain | Not Recruiting | 30 Aug 2016 | 10 |
 Sweden | Not Recruiting | 30 Aug 2016 | 1 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Larotrectinib Bayer | Test | ORAL SOLUTION | ORAL USE | 200 | 120 | PRD10414174 |
Larotrectinib Bayer | Test | CAPSULE, HARD | ORAL USE | 200 | 120 | PRD10414185 |
Larotrectinib Bayer | Test | CAPSULE, HARD | ORAL USE | 200 | 120 | PRD10414175 |