Carcinoma, Non-Small-Cell Lung, Nonsmall Cell Lung Cancer, Non-Small Cell Lung Cancer
Conditions
Brief summary
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.
Interventions
DRUGNintedanib
Sponsors
National Comprehensive Cancer Network
Washington University School of Medicine
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Response Rate (RR) | 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
| Measure | Time frame | Description |
|---|---|---|
| Median Progression-free Survival (PFS) | 12 months follow-up minimum | * 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 |
| 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) | Baseline and at the time of response (approximately Day 56) | Correlate baseline genetic mutations with treatment response and progression of disease |
| Genetic Mechanisms of Secondary Resistance | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Nintedanib -Nintedanib will be administered orally at a dose of 200 mg twice daily during each 28 day cycle | 20 |
| Total | 20 |
Baseline characteristics
| Characteristic | Nintedanib |
|---|---|
| Age, Continuous | 66 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 18 Participants |
| Region of Enrollment United States | 20 participants |
| Sex: Female, Male Female | 15 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 12 / 20 |
| other Total, other adverse events | 10 / 20 |
| serious Total, serious adverse events | 12 / 20 |
Outcome results
Primary
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
Time frame: After 2 cycles of therapy (approximately Day 56)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Nintedanib | Response Rate (RR) | 3 Participants |
Secondary
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.
Time frame: At the time of progression (estimated to be 8 months)
Population: -Samples are available for 2 patients (1 patient with stable disease and 1 with partial response) but sample quantity not sufficient for genomic analysis.
Secondary
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
Time frame: 12 months follow-up minimum
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nintedanib | Median Progression-free Survival (PFS) | 4.3 months |
Secondary
Response Rate by Mutation Type
Time frame: At the time of response (approximately day 56)
Population: Only 3 participants had a response to treatment and are evaluable for this outcome measure
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Nintedanib | Response Rate by Mutation Type | TP53 mutation | 3 Participants |
| Nintedanib | Response Rate by Mutation Type | PDGFR-A mutation | 0 Participants |
| Nintedanib | Response Rate by Mutation Type | PDGFR-B mutation | 0 Participants |
| Nintedanib | Response Rate by Mutation Type | FGFR1-3 mutation | 1 Participants |
| Nintedanib | Response Rate by Mutation Type | VEGFR1-3 mutation | 0 Participants |
| Nintedanib | Response Rate by Mutation Type | RET alteration | 0 Participants |
Secondary
Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders)
Correlate baseline genetic mutations with treatment response and progression of disease
Time frame: Baseline and at the time of response (approximately Day 56)
Population: Only 7 participants are evaluable for this outcome measure as they were considered extreme responders.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Nintedanib | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 D281E | 0 mutations |
| Nintedanib | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | PDGFRA G166E | 0 mutations |
| Nintedanib | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 D207fs | 0 mutations |
| Nintedanib | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 R342P | 0 mutations |
| Nintedanib | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 A159V | 0 mutations |
| Nintedanib | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 C242F | 1 mutations |
| Nintedanib | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 A27V | 0 mutations |
| Nintedanib | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | FGFR1 amplification | 0 mutations |
| Nintedanib | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 P72R | 0 mutations |
| Nintedanib | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | FGFR3 S249C | 1 mutations |
| Nintedanib | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 M160_A161del | 0 mutations |
| Nintedanib | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 Tyr234* | 0 mutations |
| Responder B | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 C242F | 0 mutations |
| Responder B | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | PDGFRA G166E | 0 mutations |
| Responder B | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 A27V | 1 mutations |
| Responder B | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | FGFR3 S249C | 0 mutations |
| Responder B | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 D281E | 0 mutations |
| Responder B | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 R342P | 0 mutations |
| Responder B | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 Tyr234* | 0 mutations |
| Responder B | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 D207fs | 0 mutations |
| Responder B | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 A159V | 1 mutations |
| Responder B | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 P72R | 1 mutations |
| Responder B | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | FGFR1 amplification | 0 mutations |
| Responder B | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 M160_A161del | 0 mutations |
| Responder C | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | PDGFRA G166E | 0 mutations |
| Responder C | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 M160_A161del | 1 mutations |
| Responder C | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 A27V | 0 mutations |
| Responder C | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | FGFR3 S249C | 0 mutations |
| Responder C | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 P72R | 0 mutations |
| Responder C | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | FGFR1 amplification | 0 mutations |
| Responder C | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 D281E | 0 mutations |
| Responder C | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 D207fs | 0 mutations |
| Responder C | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 Tyr234* | 0 mutations |
| Responder C | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 R342P | 0 mutations |
| Responder C | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 A159V | 0 mutations |
| Responder C | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 C242F | 0 mutations |
| Progressive Disease A | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | FGFR1 amplification | 0 mutations |
| Progressive Disease A | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 C242F | 0 mutations |
| Progressive Disease A | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 A159V | 0 mutations |
| Progressive Disease A | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 A27V | 0 mutations |
| Progressive Disease A | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 P72R | 0 mutations |
| Progressive Disease A | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 M160_A161del | 0 mutations |
| Progressive Disease A | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 D281E | 1 mutations |
| Progressive Disease A | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 R342P | 0 mutations |
| Progressive Disease A | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 D207fs | 0 mutations |
| Progressive Disease A | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 Tyr234* | 0 mutations |
| Progressive Disease A | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | FGFR3 S249C | 0 mutations |
| Progressive Disease A | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | PDGFRA G166E | 1 mutations |
| Progressive Disease B | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 Tyr234* | 0 mutations |
| Progressive Disease B | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 C242F | 0 mutations |
| Progressive Disease B | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 A27V | 0 mutations |
| Progressive Disease B | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 P72R | 0 mutations |
| Progressive Disease B | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | FGFR3 S249C | 0 mutations |
| Progressive Disease B | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 D207fs | 1 mutations |
| Progressive Disease B | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 R342P | 1 mutations |
| Progressive Disease B | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | FGFR1 amplification | 0 mutations |
| Progressive Disease B | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 M160_A161del | 0 mutations |
| Progressive Disease B | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 A159V | 0 mutations |
| Progressive Disease B | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 D281E | 0 mutations |
| Progressive Disease B | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | PDGFRA G166E | 0 mutations |
| Progressive Disease C | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 R342P | 0 mutations |
| Progressive Disease C | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 M160_A161del | 0 mutations |
| Progressive Disease C | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 D207fs | 0 mutations |
| Progressive Disease C | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 P72R | 0 mutations |
| Progressive Disease C | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 Tyr234* | 1 mutations |
| Progressive Disease C | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 A27V | 0 mutations |
| Progressive Disease C | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | PDGFRA G166E | 0 mutations |
| Progressive Disease C | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | FGFR3 S249C | 0 mutations |
| Progressive Disease C | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 A159V | 0 mutations |
| Progressive Disease C | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | FGFR1 amplification | 0 mutations |
| Progressive Disease C | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 C242F | 0 mutations |
| Progressive Disease C | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 D281E | 0 mutations |
| Progressive Disease D | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 R342P | 0 mutations |
| Progressive Disease D | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 P72R | 0 mutations |
| Progressive Disease D | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 D207fs | 0 mutations |
| Progressive Disease D | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | PDGFRA G166E | 0 mutations |
| Progressive Disease D | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | FGFR1 amplification | 1 mutations |
| Progressive Disease D | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 C242F | 0 mutations |
| Progressive Disease D | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 M160_A161del | 0 mutations |
| Progressive Disease D | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 A27V | 0 mutations |
| Progressive Disease D | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 D281E | 0 mutations |
| Progressive Disease D | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | FGFR3 S249C | 0 mutations |
| Progressive Disease D | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 Tyr234* | 0 mutations |
| Progressive Disease D | Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders) | TP53 A159V | 0 mutations |