Nintedanib Compared With Placebo in Treating Against Radiation-Induced Pneumonitis in Patients With Non-small Cell Lung Cancer That Cannot Be Removed by Surgery and Are Undergoing Chemoradiation Therapy

NCT ID: NCT02452463

Last Updated: 2020-04-06

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 8 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-06-29
• Study Completion Date: 2019-06-10

Brief Summary

This trial studies the side effects and how well nintedanib works compared to a placebo in treating against radiation-induced pneumonitis (inflammation of the lungs) in patients with non-small cell lung cancer that cannot be removed by surgery and are undergoing chemoradiation therapy. Nintedanib may help shrink or slow the growth of radiation-induced pneumonitis by blocking some of the enzymes needed for cells to grow and may prevent the growth of new blood vessels. It may also help reduce the recurrence of non-small cell lung cancer.

Detailed Description

PRIMARY OBJECTIVES:

I. To evaluate the safety of the combination of durvalumab with nintedanib in patients with unresectable Stage II/III/oligometastatic IV non-small cell lung carcinoma (NSCLC). (Phase I) II. To compare the rate of symptomatic radiation pneumonitis at 6 months after completion of chemoradiation in patients with unresectable stage II/III/ oligometastatic IV NSCLC who completed chemoradiation followed by nintedanib versus placebo. (Phase II)

SECONDARY OBJECTIVES:

I. To compare the quality of life (QOL) in patients who received nintedanib versus placebo during active treatment until 6 months after completion of treatment.

II. To compare the progression-free survival, overall survival and 1-year progression-free survival rate in patients who received nintedanib versus placebo.

III. To compare pulmonary function test (PFT) results and radiation pneumonitis (RP) score in patients who received nintedanib versus placebo.

IV. To compare the composite index (based on PFT, RP score and QOL) at the end of active treatment and 6 months after completion of treatment between patients who received nintedanib versus placebo.

EXPLORATORY OBJECTIVES:

I. To investigate blood-based biomarkers in evaluating risk of developing radiation pneumonitis as well as the efficacy of nintedanib.

OUTLINE: This is a phase I, dose-escalation study of nintedanib followed by a phase II study. Patients who are not receiving durvalumab as standard of care prior to establishment of the recommended phase II dose are randomized to 1 of 2 arms. Patients receiving durvalumab are assigned to Arm III.

ARM I: Beginning 4-8 weeks after completion of radiation therapy, patients receive nintedanib orally (PO) twice daily (BID) on days 1-28. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

ARM II: Beginning 4-8 weeks after completion of radiation therapy, patients receive placebo capsules PO BID on days 1-28. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

ARM III: Beginning 4-8 weeks after completion of radiation therapy, patients receive nintedanib PO BID on days 1-28 and standard of care durvalumab intravenously (IV) over 60 minutes on days 1 and 15. Treatment with nintedanib repeats every 28 days for up to 6 cycles and treatment with durvalumab repeats every 2 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, between 76-97 days, between 166-187 days, and then between 2.5 years.

Conditions

Lung Non-Squamous Non-Small Cell Carcinoma; Radiation-Induced Pneumonitis; Stage II Lung Non-Small Cell Cancer AJCC v7; Stage IIA Lung Non-Small Cell Carcinoma AJCC v7; Stage IIB Lung Non-Small Cell Carcinoma AJCC v7; Stage III Lung Non-Small Cell Cancer AJCC v7; Stage IIIA Lung Non-Small Cell Cancer AJCC v7; Stage IIIB Lung Non-Small Cell Cancer AJCC v7; Stage IV Lung Non-Small Cell Cancer AJCC v7

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: SUPPORTIVE_CARE
• Blinding Strategy: DOUBLE

Study Groups

Arm I (nintedanib)

Beginning 4-8 weeks after completion of radiation therapy, patients receive nintedanib PO BID on days 1-28. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

Group Type: EXPERIMENTAL

Nintedanib

Intervention Type: DRUG

Given PO

Quality-of-Life Assessment

Intervention Type: PROCEDURE

Ancillary studies

Arm II (placebo)

Beginning 4-8 weeks after completion of radiation therapy, patients receive placebo capsules PO BID on days 1-28. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

Given PO

Quality-of-Life Assessment

Intervention Type: PROCEDURE

Ancillary studies

Arm III (nintedanib, durvalumab)

Beginning 4-8 weeks after completion of radiation therapy, patients receive nintedanib PO BID on days 1-28 and standard of care durvalumab IV over 60 minutes on days 1 and 15. Treatment with nintedanib repeats every 28 days for up to 6 cycles and treatment with durvalumab repeats every 2 weeks in the absence of disease progression or unacceptable toxicity.

Group Type: EXPERIMENTAL

Durvalumab

Intervention Type: BIOLOGICAL

Given IV

Nintedanib

Intervention Type: DRUG

Given PO

Quality-of-Life Assessment

Intervention Type: PROCEDURE

Ancillary studies

Interventions

Durvalumab

Given IV

Intervention Type: BIOLOGICAL

Nintedanib

Given PO

Intervention Type: DRUG

Placebo

Given PO

Intervention Type: OTHER

Quality-of-Life Assessment

Ancillary studies

Intervention Type: PROCEDURE

Other Intervention Names

Imfinzi; Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer; MEDI-4736; MEDI4736; BIBF 1120; BIBF-1120; Intedanib; Multitargeted Tyrosine Kinase Inhibitor BIBF 1120; tyrosine kinase inhibitor BIBF 1120; Vargatef; placebo therapy; PLCB; sham therapy; Quality of Life Assessment

Eligibility Criteria

Inclusion Criteria

• Histologically or cytologically-proven non squamous cell NSCLC; mixed histology with small cell lung carcinoma (SCLC) component not allowed
• Patients with stage II ? IV non squamous cell NSCLC who received at least 54 Gy of total planned thoracic radiation dose will be eligible; patients must have received at least one cycle of chemotherapy concurrently during the course of thoracic radiation; regimens allowed are platinum combinations with either etoposide or a taxane regardless of histology subtype; platinum with pemetrexed for patients with non-squamous NSCLC only; patients with oligometastatic stage IV cancer are eligible if they have received only one line of systemic therapy for their stage IV cancer prior to the concurrent chemoradiation phase
• Patient must have had a complete response (CR)/partial response (PR)/stable disease (SD), 4-6 weeks after completing last fraction of radiation therapy
• Eastern Cooperative Oncology Group (ECOG) performance score 0-2
• Absolute neutrophil count (ANC) >= 1,500/uL
• Platelet count >= 100,000/uL
• Hemoglobin >= 9 g/dL
• Total bilirubin =< normal or for those with Gilbert?s syndrome =< 1.5 times upper limit of normal (ULN) OR direct bilirubin normal (per institute standards)
• Aspartate aminotransferase (AST) =< 1.5 x ULN; alanine aminotransferase (ALT) and AST =< 2.5 x ULN is acceptable if there is liver metastasis
• Fertile patients must use adequate contraception

Exclusion Criteria

• Whole-brain radiotherapy (WBRT) < 14 days from the anticipated start of nintedanib/placebo administration
• Squamous cell NSCLC
• Unable to start nintedanib/placebo treatment between 4-8 weeks after completing the last dose of thoracic radiation
• Active untreated brain or leptomeningeal metastases; in patients with treated central nervous system (CNS) metastases, eligible if symptoms controlled for at least 4 weeks; dexamethasone allowed if total daily dose does not exceed 2 mg
• Major injuries or surgery (e.g., craniotomy) < 28 days from the start of nintedanib/placebo administration; wound should be healed prior to starting therapy
• Second malignancies are allowed as long as the disease does not require active treatment with concomitant systemic cytotoxic chemotherapy, investigational or biologic therapy (e.g., anti-cytotoxic T-lymphocyte-associated protein 4 [CTLA4] or human epidermal growth factor receptor 2 [HER2] monoclonal antibodies); hormone-related therapies (e.g., gonadotrophin releasing hormone (LHRH) agonists, tamoxifen, etc.) are allowed
• Concurrent uncontrolled illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situation that would increase the risk associated with study participation and/or limit compliance with study requirements
• Inability to swallow study medication
• Presence of active malabsorption disorder (e.g., flare episodes documented within the preceding 3 months, presence of symptoms requiring daily medications for control) or history of extensive small bowel resection
• Known bleeding or thrombotic diathesis
• History of arterial or venous thromboembolic event within 12 months prior to study participation
• Active hemoptysis or history of clinically relevant hemoptysis as determined by the treating physician; patients who had history of transient minor hemoptysis after bronchoscopic biopsy are eligible unless deemed otherwise by the treating physician
• Common Terminology Criteria for Adverse Events (CTCAE) grade 2 or higher proteinuria
• Investigational agent administered < 28 days prior to treatment with nintedanib. Last dose of systemic chemotherapy administered < 14 days prior to treatment with nintedanib
• Known chronic active hepatitis B or hepatitis C; human immunodeficiency virus (HIV)-positive patients receiving or are candidates for antiretroviral therapy are also excluded
• Pregnancy or breast feeding; female patients with child-bearing potential must have a negative pregnancy test (beta-human chorionic gonadotropin [B-HCG] test in urine or serum) prior to commencing study treatment
• Creatinine > 1.5 x ULN or creatinine clearance levels (CrCL) < 45 mL/min
• Centrally located tumors with radiographic evidence (computed tomography [CT] or magnetic resonance imaging [MRI]) of local invasion of major blood vessels
• Therapeutic anticoagulation (except low-dose heparin and/or heparin flush as needed for maintenance of an in-dwelling intravenous devise) or anti-platelet therapy (except for low-dose therapy with acetylsalicylic acid < 325 mg per day)
• Active or previous autoimmune disease requiring treatment within the past 2 years will exclude patients from receiving immune checkpoint inhibitor in this study. Exception allowed: endocrine conditions treated with necessary hormone replacement or other supportive medication; vitiligo, alopecia

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Roswell Park Cancer Institute

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Grace K Dy

Role: PRINCIPAL_INVESTIGATOR

Roswell Park Cancer Institute

Locations

Roswell Park Cancer Institute

Buffalo, New York, United States

Countries

United States

References

Rimner A, Moore ZR, Lobaugh S, Geyer A, Gelblum DY, Abdulnour RE, Shepherd AF, Shaverdian N, Wu AJ, Cuaron J, Chaft JE, Zauderer MG, Eng J, Riely GJ, Rudin CM, Els NV, Chawla M, McCune M, Li H, Jones DR, Sopka DM, Simone CB 2nd, Mak R, Weinhouse GL, Liao Z, Gomez DR, Zhang Z, Paik PK. Randomized Phase 2 Placebo-Controlled Trial of Nintedanib for the Treatment of Radiation Pneumonitis. Int J Radiat Oncol Biol Phys. 2023 Aug 1;116(5):1091-1099. doi: 10.1016/j.ijrobp.2023.02.030. Epub 2023 Mar 7.

Reference Type: DERIVED

PMID: 36889516 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

NCI-2015-00704

Identifier Type: REGISTRY

Identifier Source: secondary_id

I 257814

Identifier Type: OTHER

Identifier Source: secondary_id

P30CA016056

Identifier Type: NIH

Identifier Source: secondary_id

View Link

I 257814

Identifier Type: -

Identifier Source: org_study_id