Nintedanib in Molecularly Selected Patients With Advanced Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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There has been limited benefit with angiogenesis inhibitor drugs in molecularly unselected patients in non-small cell lung cancer (NSCLC). The investigators propose that patients who are molecularly selected for treatment with nintedanib based on the presence of mutations in the following genes: VEGFR1-3, PDGFR-A, PDGFR-B, FGFR1-3, and TP53, will have clinically meaningful benefit in terms of response rate (RR) and progression-free survival (PFS). Furthermore the investigators plan to correlate outcomes with specific mutations and evaluate mechanisms of resistance.

Official Title
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A Pilot Study of Nintedanib in Molecularly Selected Patients With Advanced Non-Small Cell Lung Cancer (NSCLC)

Conditions
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Carcinoma, Non-Small-Cell Lung, Non-Small Cell Lung Cancer, Nonsmall Cell Lung Cancer

Intervention / Treatment
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* Drug: Nintedanib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed diagnosis of advanced (metastatic or unresectable) NSCLC with mutations, rearrangement and fusion involving RET oncogene, or abnormalities (non-synonymous SNV or amplification) in the nintedanib target genes VEGFR1-3, TP53, PDGFR-A, PDGFR-B, and FGFR1-3. CLIA certified lab testing for nintedanib target genes using cell free DNA from peripheral blood and/or assays performed on tumor tissues are acceptable. Patients with EGFR mutations or ALK rearrangements must have disease progression on appropriate FDA-approved therapy for these genomic aberrations prior to enrollment. Disease progression on platinum-doublet chemotherapy prior to enrollment. At least one measurable lesion or evaluable disease. Measurable disease is defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥10 mm with CT scan, as ≥20 mm by chest x-ray, or ≥10 mm with calipers by clinical exam. Prior treatment of cancer (chemotherapy, radiation therapy, and surgery) is allowed if completed at least 3 weeks prior to start of treatment with nintedanib and if all treatment-related toxicities are resolved. At least 18 years of age. ECOG performance status 0-1 Normal bone marrow and organ function as defined below: Leukocytes ≥ 3,000/mcL Absolute neutrophil count ≥ 1,500/mcL Platelets ≥ 100,000/mcL Hemoglobin ≥ 9.0 g/dL INR < 2.0 PT and PTT < 50% of deviation from IULN Total bilirubin ≤ 1.5 x IULN AST(SGOT)/ALT(SGPT) ≤ 1.5 x IULN for patients without liver metastases and ≤ 2.5 x IULN for patients with liver metastases Urine protein < 2+ Creatinine within normal institutional limits OR Creatinine clearance > 45 mL/min for patients with creatinine levels above institutional normal Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry, for the duration of study participation, and for 3 months after the end of treatment. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Able to understand and willing to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable). Exclusion Criteria: Prior treatment with VEGFR tyrosine kinase inhibitors. A history of other malignancy ≤ 5 years previous with the exception of basal cell or squamous cell carcinoma of the skin which were treated with local resection only or carcinoma in situ of the cervix. Currently receiving any other investigational agents, or received an investigational agent within 3 weeks of the first dose of nintedanib. Radiotherapy to the target lesion within the past 3 months prior to baseline imaging. Symptomatic brain metastases. Patients with known brain metastases are eligible if the metastases are asymptomatic and previously treated. Leptomeningeal disease. Radiographic evidence of cavitary or necrotic tumors. Centrally located tumors with radiographic evidence (CT or MRI) of local invasion of major blood vessels. A history of allergic reactions attributed to compounds of similar chemical or biologic composition to nintedanib or other agents used in the study. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure > NYHA II, active coronary artery disease, unstable angina pectoris, serious cardiac arrhythmia, uncontrolled hypertension (defined as systolic pressures > 150 mmHg or diastolic pressure > 90 mmHg), pericardial effusion, uncontrolled seizure disorder, or psychiatric illness/social situations that would limit compliance with study requirements. Major injuries and/or surgery with then past 4 weeks prior to the start of study treatment with incomplete wound healing and/or planned surgery during the on-treatment study period. History of clinically significant hemorrhagic or thromboembolic event in the past 6 months. Known inherited predisposition to bleeding or thrombosis. History of cardiac infarction within the past 12 months prior to the start of study treatment. Receiving therapeutic anticoagulation (except low-dose heparin and/or heparin flush as needed for maintenance of an in-dwelling intravenous device) or anti-platelet therapy (except for low-dose therapy with acetylsalicylic acid < 325 mg QD). Pregnant and/or breastfeeding. Patients of childbearing potential must have a negative pregnancy test within 14 days of study entry. Significant weight loss (> 10% of BW) within past 6 months prior to inclusion into the trial. Known active or chronic hepatitis B or C infection. Active alcohol or drug abuse. Gastrointestinal disorder or abnormality that would interfere with absorption of the study drug. Known HIV-positivity on combination antiretroviral therapy because of the potential for pharmacokinetic interactions with nintedanib. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nintedanib<br>-Nintedanib will be administered orally at a dose of 200 mg twice daily during each 28 day cycle | Drug: Nintedanib<br> <br> * Other names: Vargatef;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate (RR) | RR = Partial response plus complete response using RECIST 1.1 Complete response (CR) = disappearance of all target lesions, non-target lesions, and normalization of tumor marker level Partial response (PR) = at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline of sum diameters | After 2 cycles of therapy (approximately Day 56) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Progression-free Survival (PFS) | PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. Progressive disease (PD) = at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study, appearance of one or more non-target lesion(s) and/or unequivocal progression of existing non-target lesions | 12 months follow-up minimum | 
| Response Rate by Mutation Type |  | At the time of response (approximately day 56) | 
| Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | Correlate baseline genetic mutations with treatment response and progression of disease | Baseline and at the time of response (approximately Day 56) | 
| Genetic Mechanisms of Secondary Resistance | Genomic analysis at time of progression after treatment with nintedanib (after response (complete response/partial response/stable disease) lasting for 6 months or longer) will provide some unique insights into mechanisms underlying acquired resistance. | At the time of progression (estimated to be 8 months) |