Merestinib In Non-Small Cell Lung Cancer And Solid Tumors

Study Overview
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Brief Summary
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This research study is examining merestinib (a targeted therapy) as a possible treatment for non-small cell lung cancer (NSCLC) that was found to have a specific change in the MET gene (a MET exon 14 mutation); or as a treatment for solid tumors that have an alteration in the NTRK gene (an NTRK1, 2, or 3 rearrangement).

Detailed Description
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This is an open-label, phase II study of merestinib in patients with advanced NSCLC with a MET exon 14 mutation or patients with advanced cancer harboring an NTRK1, 2, or 3 rearrangement. Twenty patients with a MET mutation will be evaluated in a single-arm design. A small separate cohort of 5 NTRK patients will be evaluated for exploratory purposes. Merestinib (LY2801653) is a small molecule that has been shown in vitro to be a reversible type II ATP-competitive inhibitor of MET. Pre-clinical testing also has shown merestinib to inhibit several other receptor tyrosine oncokinases including MST1R, FLT3, AXL, MERTK, TEK, ROS1, NTRK1/2/3, and DDR1/2 and the serine/threonine kinases MKNK1/2.

Official Title
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A Phase II Study of Merestinib in Non-Small Cell Lung Cancers Harboring MET Exon 14 Mutations and Solid Tumors With NTRK Rearrangements

Conditions
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Carcinoma, Non-Small-Cell Lung, Solid Tumor

Intervention / Treatment
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* Drug: Merestinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Baseline evaluations are to be conducted within 14 days prior to start of protocol therapy, with the exception of the informed consent and baseline tumor imaging which may be obtained up to 28 days prior to the start of protocol therapy. For enrollment into the MET cohort: Participants must have a histologically or cytologically confirmed advanced NSCLC and must have received at least one prior line of therapy in the metastatic setting. For enrollment into the NTRK cohort: Participants must have a histologically or cytologically confirmed advanced solid tumor and must have received at least one prior line of therapy in the metastatic setting. Participants enrolling into the MET cohort must have a MET exon 14 mutation as confirmed by targeted NextGen Sequencing using the DFCI/BWH OncoPanel or another CLIA-certified method. Participants whose NSCLC specimens contain actionable genetic mutations/alterations (e.g. ALK/EGFR) should receive appropriate targeted therapies prior to enrollment in the trial. Participants enrolling into the NTRK cohort must have an NTRK1, 2, or 3 rearrangement as confirmed by targeted NextGen Sequencing using the DFCI/BWH OncoPanel or another CLIA-certified method. Participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥ 20 mm with conventional techniques or as ≥ 10 mm with spiral CT scan, MRI, or calipers by clinical exam. Participants enrolling to the MET cohort who have received treatment with a prior MET inhibitor must be able and willing to undergo a baseline tumor biopsy. Participants enrolling to the NTRK cohort who have received treatment with a prior NTRK inhibitor must be able and willing to undergo a baseline tumor biopsy. Age ≥ 18 years. As no dosing or adverse event data are currently available in participants < 18 years of age, children are excluded from this study but will be eligible for future pediatric trials. ECOG performance status ≤ 1 (see Appendix A). Participants must have normal organ and marrow function as defined below: Absolute neutrophil count ≥ 1.5 K/uL Platelets ≥ 100 K/uL Hemoglobin ≥ 9 g/dL (with or without transfusion support) Total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN) AST(SGOT)/ALT(SGPT)≤ 2.5 × institutional ULN, unless liver metastases are present and then ≤ 5 × institutional ULN is acceptable Serum creatinine ≤ 1.5 × institutional ULN The effects of merestinib on the developing human fetus are unknown. For this reason and because MET inhibitor agents are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of merestinib administration. Ability to understand and the willingness to sign a written informed consent document. Participants must be able to swallow and retain oral medication or have an enteral feeding tube in place for study drug administration. Participants who have received prior oral tyrosine kinase inhibitors (TKIs) will be allowed on study if at least 5 half-lives have elapsed since the date of their last dose of TKI. Exclusion Criteria: Participants who have had chemotherapy, immune therapy, other investigational therapy, major surgery, or radiotherapy within 3 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study. Participants who have not recovered to eligibility levels from adverse events due to agents administered more than 3 weeks earlier. Participants who are receiving any other investigational agents. Participants with untreated brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Participants with a history of brain metastases that have been treated, are no longer taking corticosteroids, and have been stable on imaging for ≥ 4 weeks following the last date of treatment are permitted. Note: a brain MRI is required during the screening period. History of allergic reactions attributed to compounds of similar chemical or biologic composition to merestinib. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Pregnant women are excluded from this study because merestinib is an agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with merestinib, breastfeeding should be discontinued if the mother is treated with merestinib. Known HIV-positive participants are ineligible because these participants are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated. Participants enrolling to the MET cohort who have received a prior MET inhibitor may not be on anticoagulant therapy unless the investigator has deemed it safe to temporarily hold to facilitate the baseline tumor biopsy. Participants enrolling to the NTRK cohort who have received a prior NTRK inhibitor may not be on anticoagulant therapy unless the investigator has deemed it safe to temporarily hold to facilitate the baseline tumor biopsy. Participants with uncontrolled high blood pressure, defined as a blood pressure during screening of ≥ 160/100 despite medical management. Participants must not have any clinically significant gastrointestinal abnormalities that in the opinion of the treating investigator may alter absorption of oral medications, such as malabsorption syndrome or major resection of the stomach or bowels. Participants with a history of a second primary malignancy. Exceptions include: patients with a history of malignancies that were treated curatively and have not recurred within 3 years prior to study entry; resected basal and squamous cell carcinomas of the skin, and completely resected carcinoma in situ of any type.

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: NSCLC (Met Exon 14 Mutation)<br>Merestinib at the recommended phase II dose of 120 mg by mouth daily. | Drug: Merestinib<br>* Oral, predetermined dosage per protocol, once daily per 28 day treatment cycle<br>* Other names: LY2801653;|
| Experimental: Solid Tumor (NTRK1,2,3 Rearrangement)<br>Merestinib at the recommended phase II dose of 120 mg by mouth daily. | Drug: Merestinib<br>* Oral, predetermined dosage per protocol, once daily per 28 day treatment cycle<br>* Other names: LY2801653;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) - MET Exon 14 Cohort | Measured by RECIST 1.1 criteria. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) Rate - MET Exon 14 Cohort | Measured by RECIST 1.1 criteria | From date of registration until the date of death from any cause, assessed up to 2 years | 
| Progression-free survival (PFS) Rate - MET Exon 14 Cohort | Measured by RECIST 1.1 criteria. | From date of registration until disease progression, assessed up to 2 years | 
| Duration of response (DoR) - MET Exon 14 Cohort | Measured by RECIST 1.1 criteria. | From date of documentation of radiological response until disease progression, assessed up to 2 years. | 
| Toxicities | Adverse event data in all participants, by CTCAE 4.03 criteria. | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MET exon 14, NSCLC, MET, Non-small cell lung cancer, MET mutation, NTRK rearrangement, NTRK, targeted therapy, NTRK1, NTRK2, NTRK3, merestinib, LY2801653