Clinical Trials /

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

NCT02299141

Description:

There has been limited benefit with angiogenesis inhibitor drugs when used with molecularly selected 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 (VEGFR1-3, PDGFR-A, PDGFR-B, and FGFR1-3) will have clinically meaningful benefits in terms of response rate (RR) and progression-free survival (PFS). Furthermore the investigators plan to perform exome sequencing of paired tumor (pre and post treatment) in order to better define molecular marker predictors for response and resistance.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: 201412116
  • NCT ID: NCT02299141

Conditions

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

Interventions

DrugSynonymsArms
NintedanibOfev, BIBF 1120, VargatefNintedanib

Purpose

There has been limited benefit with angiogenesis inhibitor drugs when used with molecularly selected 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 (VEGFR1-3, PDGFR-A, PDGFR-B, and FGFR1-3) will have clinically meaningful benefits in terms of response rate (RR) and progression-free survival (PFS). Furthermore the investigators plan to perform exome sequencing of paired tumor (pre and post treatment) in order to better define molecular marker predictors for response and resistance.

Trial Arms

NameTypeDescriptionInterventions
NintedanibExperimental-Nintedanib will be administered orally at a dose of 200 mg twice daily during each 28 day cycle
  • Nintedanib

Eligibility Criteria

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Response rate (RR)
Time Frame:After 2 cycles of therapy (approximately Day 56)
Safety Issue:
Description: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

Secondary Outcome Measures

Measure:Progression-free survival (PFS)
Time Frame:At the time of progression (estimated to be 8 months)
Safety Issue:
Description: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
Measure:Response rate of specific genetic mutation statuses
Time Frame:At the time of progression (estimated to be 8 months)
Safety Issue:
Description:The association between response and specific mutation status will be assessed by permutation analysis. Taking the relationship between FGFR1 expression and RR as an example, for instance, we first compute the observed test statistics, e.g., the sample mean difference between responders versus non-responders. Then to simulate the null distribution of the test statistics, or the distribution of the observed mean differences if there were truly no difference, we repeat the following 10,000 times: we randomly shuffle the response status, and then calculate the sample difference between the newly designated groups. The permutation p-value equals the proportion of simulations from the null distribution that exceed the observed test statistics.
Measure:Unique genetic variations associated with extreme responses (both non-responders and responders)
Time Frame:At the time of progression (estimated to be 8 months)
Safety Issue:
Description:Unbiased exome and transcriptome sequencing performed on tumor samples at time of diagnosis in responders and non-responders will help us identify unique variations that confer susceptibility to nintedanib.
Measure:Genetic mechanisms of secondary resistance
Time Frame:At the time of progression (estimated to be 8 months)
Safety Issue:
Description: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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Washington University School of Medicine

Last Updated