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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02299141
Recruitment Status : Active, not recruiting
First Posted : November 24, 2014
Last Update Posted : January 13, 2020
Sponsor:
Collaborator:
National Comprehensive Cancer Network
Information provided by (Responsible Party):
Washington University School of Medicine

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Carcinoma, Non-Small-Cell Lung Non-Small Cell Lung Cancer Nonsmall Cell Lung Cancer Drug: Nintedanib Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 20 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Pilot Study of Nintedanib in Molecularly Selected Patients With Advanced Non-Small Cell Lung Cancer (NSCLC)
Actual Study Start Date : May 7, 2015
Actual Primary Completion Date : January 9, 2020
Estimated Study Completion Date : August 31, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Nintedanib
-Nintedanib will be administered orally at a dose of 200 mg twice daily during each 28 day cycle
Drug: Nintedanib
Other Names:
  • Ofev
  • BIBF 1120
  • Vargatef




Primary Outcome Measures :
  1. Response rate (RR) [ Time Frame: After 2 cycles of therapy (approximately Day 56) ]
    • 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 :
  1. Progression-free survival (PFS) [ Time Frame: At the time of progression (estimated to be 8 months) ]
    • 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

  2. Response rate of specific genetic mutation statuses [ Time Frame: At the time of progression (estimated to be 8 months) ]
    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.

  3. Unique genetic variations associated with extreme responses (both non-responders and responders) [ Time Frame: At the time of progression (estimated to be 8 months) ]
    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.

  4. Genetic mechanisms of secondary resistance [ Time Frame: At the time of progression (estimated to be 8 months) ]
    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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02299141


Locations
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United States, Missouri
Washington University School of Medicine
Saint Louis, Missouri, United States, 63110
Sponsors and Collaborators
Washington University School of Medicine
National Comprehensive Cancer Network
Investigators
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Principal Investigator: Ramaswamy Govindan, M.D. Washington University School of Medicine
Additional Information:
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Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT02299141    
Other Study ID Numbers: 201412116
First Posted: November 24, 2014    Key Record Dates
Last Update Posted: January 13, 2020
Last Verified: January 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Nintedanib
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action