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

• Sponsor: Washington University School of Medicine (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02299141
• Collaborator: National Comprehensive Cancer Network (Other)
• Enrollment: 20
• Location: 1
• Arm: 1
• Anticipated Duration (Months): 88.2
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Carcinoma, Non-Small-Cell Lung; Non-Small Cell Lung Cancer; Nonsmall Cell Lung Cancer	Drug: Nintedanib	Phase 2

Study Design

• Study Type: Interventional
• 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: Jan 9, 2020
• Anticipated Study Completion Date: Sep 13, 2022

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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

2. Response Rate by Mutation Type [At the time of response (approximately day 56)]

3. 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

4. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Washington University School of Medicine	Saint Louis	Missouri	United States	63110

Sponsors and Collaborators

• Washington University School of Medicine
• National Comprehensive Cancer Network

Investigators

• Principal Investigator: Ramaswamy Govindan, M.D., Washington University School of Medicine

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Sep 4, 2019

More Information

Additional Information:

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Publications

• Waqar SN, Rawat U, Morgensztern D, et al.; A pilot study of nintedanib in molecularly selected patients with advanced non-small cell lung cancer (NSCLC) (NCT02299141). J. Clin. Oncol. 38:15_suppl, e21694-e21694; (2020) URL: https://ascopubs.org/doi/abs/10.1200/JCO.2020.38.15_suppl.e21694

• Responsible Party: Washington University School of Medicine
• ClinicalTrials.gov Identifier: NCT02299141
• Other Study ID Numbers: 201412116
• First Posted: Nov 24, 2014
• Last Update Posted: Nov 2, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• 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: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Nintedanib

Study Results

Participant Flow

Arm/Group Title	Nintedanib
Arm/Group Description	-Nintedanib will be administered orally at a dose of 200 mg twice daily during each 28 day cycle
Period Title: Overall Study
STARTED	20
COMPLETED	20
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Nintedanib
Arm/Group Description	-Nintedanib will be administered orally at a dose of 200 mg twice daily during each 28 day cycle
Overall Participants	20
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	66
Sex: Female, Male (Count of Participants)
Female	15 75%
Male	5 25%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	20 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	2 10%
White	18 90%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	20 100%

Outcome Measures

1. Primary Outcome

Title	Response Rate (RR)
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
Time Frame	After 2 cycles of therapy (approximately Day 56)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Nintedanib
Arm/Group Description	-Nintedanib will be administered orally at a dose of 200 mg twice daily during each 28 day cycle
Measure Participants	20
Count of Participants [Participants]	3 15%

2. Secondary Outcome

Title	Median Progression-free Survival (PFS)
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
Time Frame	12 months follow-up minimum

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Nintedanib
Arm/Group Description	-Nintedanib will be administered orally at a dose of 200 mg twice daily during each 28 day cycle
Measure Participants	20
Median (95% Confidence Interval) [weeks]	18

3. Secondary Outcome

Title	Response Rate by Mutation Type
Time Frame	At the time of response (approximately day 56)

Outcome Measure Data

Analysis Population Description

Only 3 participants had a response to treatment and are evaluable for this outcome measure

Arm/Group Title	Nintedanib
Arm/Group Description	-Nintedanib will be administered orally at a dose of 200 mg twice daily during each 28 day cycle
Measure Participants	3
TP53 mutation	3 15%
PDGFR-A mutation	0 0%
PDGFR-B mutation	0 0%
FGFR1-3 mutation	1 5%
VEGFR1-3 mutation	0 0%
RET alteration	0 0%

4. Secondary Outcome

Title	Unique Genetic Variations Associated With Extreme Responders (Both Non-responders and Responders)
Description	Correlate baseline genetic mutations with treatment response and progression of disease
Time Frame	Baseline and at the time of response (approximately Day 56)

Outcome Measure Data

Analysis Population Description

Only 7 participants are evaluable for this outcome measure as they were considered extreme responders.

Arm/Group Title	Responder A	Responder B	Responder C	Progressive Disease A	Progressive Disease B	Progressive Disease C	Progressive Disease D
Arm/Group Description	-Includes the mutations associated with Responder A	-Includes the mutations associated with Responder B	-Includes the mutations associated with Responder C	-Includes the mutations associated with participant Progressive Disease A	-Includes the mutations associated with participant Progressive Disease B	-Includes the mutations associated with participant Progressive Disease C	-Includes the mutations associated with participant Progressive Disease D
Measure Participants	1	1	1	1	1	1	1
TP53 C242F	1	0	0	0	0	0	0
TP53 A159V	0	1	0	0	0	0	0
TP53 A27V	0	1	0	0	0	0	0
TP53 P72R	0	1	0	0	0	0	0
TP53 M160_A161del	0	0	1	0	0	0	0
TP53 D281E	0	0	0	1	0	0	0
TP53 R342P	0	0	0	0	1	0	0
TP53 D207fs	0	0	0	0	1	0	0
TP53 Tyr234*	0	0	0	0	0	1	0
FGFR3 S249C	1	0	0	0	0	0	0
FGFR1 amplification	0	0	0	0	0	0	1
PDGFRA G166E	0	0	0	1	0	0	0

5. Secondary Outcome

Title	Genetic Mechanisms of Secondary Resistance
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.
Time Frame	At the time of progression (estimated to be 8 months)

Outcome Measure Data

Analysis Population Description

-Samples are available for 2 patients (1 patient with stable disease and 1 with partial response) but sample quantity not sufficient for genomic analysis.

Arm/Group Title	Nintedanib
Arm/Group Description	-Nintedanib will be administered orally at a dose of 200 mg twice daily during each 28 day cycle
Measure Participants	0

Adverse Events

Time Frame	-Adverse events are collected from start of treatment until 30 days following the last day of study treatment.
Adverse Event Reporting Description	-As of first submission of results, there are still two subjects receiving treatment so all-cause mortality, serious adverse events, and other adverse events will be updated as more results are submitted.
Arm/Group Title	Nintedanib
Arm/Group Description	-Nintedanib will be administered orally at a dose of 200 mg twice daily during each 28 day cycle
All Cause Mortality
	Nintedanib
	Affected / at Risk (%)	# Events
Total	8/20 (40%)
Serious Adverse Events
	Nintedanib
	Affected / at Risk (%)	# Events
Total	12/20 (60%)
Cardiac disorders
Atrial fibrillation	1/20 (5%)
Cardiac arrest	1/20 (5%)
Gastrointestinal disorders
Esophagitis	1/20 (5%)
Gastric ulcer	1/20 (5%)
General disorders
Chills	1/20 (5%)
Fever	1/20 (5%)
Infections and infestations
Lung infection	2/20 (10%)
Skin infection	1/20 (5%)
Injury, poisoning and procedural complications
Fall	1/20 (5%)
Investigations
Alanine aminotransferase increased	2/20 (10%)
Aspartate aminotransferase increased	2/20 (10%)
Blood bilirubin increased	1/20 (5%)
Musculoskeletal and connective tissue disorders
Back pain	1/20 (5%)
Nervous system disorders
Confusion	1/20 (5%)
Edema cerebral	1/20 (5%)
Encephalopathy	1/20 (5%)
Seizure	2/20 (10%)
Stroke	1/20 (5%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion	2/20 (10%)
Pneumonia	1/20 (5%)
Pulmonary embolism	1/20 (5%)
Respiratory failure	1/20 (5%)
Vascular disorders
Thromboembolic event	1/20 (5%)
Other (Not Including Serious) Adverse Events
	Nintedanib
	Affected / at Risk (%)	# Events
Total	20/20 (100%)
Blood and lymphatic system disorders
Anemia	1/20 (5%)
Cardiac disorders
Heart failure	1/20 (5%)
Eye disorders
Blurred vision	1/20 (5%)
Cataract	1/20 (5%)
Gastrointestinal disorders
Abdominal pain	3/20 (15%)
Constipation	4/20 (20%)
Diarrhea	6/20 (30%)
Dyspepsia	7/20 (35%)
Dysphagia	2/20 (10%)
Flatulence	2/20 (10%)
Nausea	9/20 (45%)
Dysesthesia-oral	1/20 (5%)
Stomatitis	5/20 (25%)
Vomiting	8/20 (40%)
Blood in stool	1/20 (5%)
General disorders
Edema limbs	5/20 (25%)
Facial pain	1/20 (5%)
Fatigue	8/20 (40%)
Pain	4/20 (20%)
Non-cardiac chest pain	1/20 (5%)
Infections and infestations
Sinusitis	1/20 (5%)
Upper respiratory infection	1/20 (5%)
Bronchial infection	1/20 (5%)
Pneumonia	1/20 (5%)
Injury, poisoning and procedural complications
Drug induced liver injury	1/20 (5%)
Investigations
Weight loss	1/20 (5%)
Alkaline phosphatase increased	1/20 (5%)
Metabolism and nutrition disorders
Anorexia	9/20 (45%)
Hypoglycemia	1/20 (5%)
Hypokalemia	4/20 (20%)
Hyponatremia	3/20 (15%)
Musculoskeletal and connective tissue disorders
Arthralgia	4/20 (20%)
Back pain	4/20 (20%)
Hip pain	1/20 (5%)
Myalgia	3/20 (15%)
Pain in extremity	4/20 (20%)
Nervous system disorders
Dizziness	6/20 (30%)
Headache	4/20 (20%)
Peripheral sensory neuropathy	4/20 (20%)
Peripheral motor neuropathy	1/20 (5%)
Tremor	1/20 (5%)
Psychiatric disorders
Anxiety	7/20 (35%)
Depression	2/20 (10%)
Insomnia	9/20 (45%)
Renal and urinary disorders
Urinary frequency	1/20 (5%)
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	1/20 (5%)
Cough	10/20 (50%)
Dyspnea	6/20 (30%)
Epistaxis	1/20 (5%)
Postnasal drip	1/20 (5%)
Skin and subcutaneous tissue disorders
Dry skin	2/20 (10%)
Hyperpigmentation	1/20 (5%)
Nail discoloration	1/20 (5%)
Skin nodules	1/20 (5%)
Alopecia	2/20 (10%)
Vascular disorders
Hot flashes	2/20 (10%)
Hypertension	5/20 (25%)
Sweating	2/20 (10%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.