Cisplatin and Etoposide Plus Radiation Followed By Nivolumab/Placebo For Locally Advanced NSCLC

• ClinicalTrials.gov Identifier: NCT02768558
• Recruitment Status: Terminated
• First Posted: May 11, 2016
• Results First Posted: February 25, 2020
• Last Update Posted: June 2, 2021
• Sponsor: RTOG Foundation, Inc.
• Collaborator: Bristol-Myers Squibb
• Information provided by (Responsible Party): RTOG Foundation, Inc.

Study Description

Brief Summary:

Patients with Stage III unresectable non-small cell lung cancer will receive thoracic radiation, cisplatin and etoposide followed by nivolumab or placebo given every 2 weeks for a year.

Condition or disease	Intervention/treatment	Phase
Non-Small Cell Lung Cancer	Radiation: Radiation Therapy (RT); Drug: Cisplatin; Drug: Etoposide; Drug: Nivolumab; Other: Placebo	Phase 3

Detailed Description:

PRIMARY OBJECTIVES:

I. To compare the Overall Survival (OS) for patients with Stage III unresectable non-small cell lung cancer treated with or without nivolumab following concurrent chemoradiation.

II. To compare Progression-Free Survival (PFS) according to RECIST 1.1 criteria for patients with Stage III unresectable non-small cell lung cancer treated with or without nivolumab following concurrent chemoradiation.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Randomized, Double Blinded Phase III Trial of Cisplatin and Etoposide Plus Thoracic Radiation Therapy Followed By Nivolumab/Placebo For Locally Advanced Non-Small Cell Lung Cancer
• Actual Study Start Date: October 17, 2016
• Actual Primary Completion Date: January 23, 2019
• Actual Study Completion Date: January 23, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Nivolumab; 60 Gy of radiation therapy given concurrently with cisplatin-etoposide chemotherapy followed by nivolumab	Radiation: Radiation Therapy (RT); 2 Gy fractions once a day, 5 days per week, for a total of 60 Gy in 30 fractions.; Other Names: 3 Dimensional Conformal Radiation Therapy (3DCRT); Intensity Modulated Radiation Therapy (IMRT); Drug: Cisplatin; Concurrently with radiation therapy, 50 mg/m2, IV, on days 1, 8, 29, and 36, to begin with day 1 of radiation therapy.; Other Name: Platinol; Drug: Etoposide; Concurrently with radiation, 40 mg/m2, IV, on days 1-5 and 29-33, to begin with day 1 of radiation therapy.; Other Name: VP-16; Drug: Nivolumab; Beginning 4-12 weeks after chemoradiation, 240 mg, IV, every 2 weeks for 16 weeks, then 480 mg, IV, for 36 weeks.; Other Name: Opdivo
Placebo Comparator: Placebo; 60 Gy of radiation therapy given concurrently with cisplatin-etoposide chemotherapy followed by placebo	Radiation: Radiation Therapy (RT); 2 Gy fractions once a day, 5 days per week, for a total of 60 Gy in 30 fractions.; Other Names: 3 Dimensional Conformal Radiation Therapy (3DCRT); Intensity Modulated Radiation Therapy (IMRT); Drug: Cisplatin; Concurrently with radiation therapy, 50 mg/m2, IV, on days 1, 8, 29, and 36, to begin with day 1 of radiation therapy.; Other Name: Platinol; Drug: Etoposide; Concurrently with radiation, 40 mg/m2, IV, on days 1-5 and 29-33, to begin with day 1 of radiation therapy.; Other Name: VP-16; Other: Placebo; Beginning 4-12 weeks after chemoradiation, 240 mg, IV, every 2 weeks for 16 weeks, then 480 mg, IV, for 36 weeks.

Outcome Measures

Primary Outcome Measures :

1. Overall Survival (OS) [ Time Frame: From registration to study termination. Maximum follow-up was 14.9 months. ]
   Survival time is defined as time from registration to date of death from any cause and was to be estimated by the Kaplan-Meier method. Given the limited follow-up due to early closure and termination of data collection, only the number of patients last reported to be alive at time of study termination is reported and no statistical testing was done.
2. Progression-Free Survival (PFS) [ Time Frame: From registration to study termination. Maximum follow-up was 14.9 months. ]

   Progression is defined using the Response Evaluation Criteria In Solid Tumors Criteria (RECIST) guideline v1.1 as a 20% increase in the sum of the longest diameter of target lesions, a measurable increase in a non-target lesion, or the appearance of new lesions at any location. Progression was to be determined by an independent radiology review committee using scans submitted to a central location.

   Progression-free survival time is defined as time from registration to the date of first progression, death, or last known follow-up (censored) and was to be estimated by the Kaplan-Meier method.

Secondary Outcome Measures :

1. Number of Participants With Grade 3+ Adverse Events [ Time Frame: From registration to study termination. Maximum follow-up was 14.9 months. ]
   Adverse events (AE) are graded using the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Grade refers to the severity of the AE. The CTCAE v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE.
2. Percentage of Participants With Deterioration in Functional Assessment of Cancer Therapy - Trial Outcome Index for Lung Cancer (FACT-TOI) at 15 Months [ Time Frame: Baseline and 15 months ]
   FACT-TOI is a measure of 21 items that sum the functional well being (FWB), physical well being (PWB), and the lung cancer subscale (LCS) of the Functional Assessment of Cancer Therapy - Lung (FACT-L) QOL instrument, used for measuring QOL in patients with lung cancer. All items are rated on a 5 item (point) Likert Scale, from 0 (not at all) to 4 (very much). FACT-TOI is scored by summing the individual scale scores, with higher scores indicating better quality of life. Deterioration was defined as a decrease of 5 points or more from baseline.
3. Overall Survival by PD-L1 Status [ Time Frame: From registration to study termination. Maximum follow-up was 14.9 months. ]
4. Progression-Free Survival by PD-L1 Status [ Time Frame: From registration to study termination. Maximum follow-up was 14.9 months. ]

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Pathologically (histologically or cytologically) proven diagnosis of non-small cell lung cancer (NSCLC) with unresectable, medically inoperable disease, or patients who refuse resection stage IIIA or stage IIIB disease (AJCC 7th edition)
• History/physical examination within 30 days prior to registration
• Computed tomography (CT) scan with IV contrast (CT scan without contrast acceptable if IV contrast is medically contraindicated) of the lung and upper abdomen through the adrenal glands within 60 days prior to registration (recommended within 30 days prior to registration)
• Magnetic resonance imaging (MRI) of the brain with contrast (or CT with contrast if MRI is medically contraindicated) within 60 days prior to registration; note: the use of intravenous contrast is required for the MRI or CT (unless medically contra-indicated).
• Whole-body fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT within 60 days prior to registration; Note: patients do not need to have a separate CT of chest and upper abdomen with contrast if PET/CT imaging includes a high quality CT chest with contrast.
• Age ≥ 18 years
• The trial is open to both genders
• Zubrod Performance status of 0-1
• Forced Expiratory Volume at one second (FEV1) > 1.2 liters; Diffusion Capacity of Lung for Carbon Monoxide (DLCO) ≥ 50% predicted
• Patients must be at least 3 weeks from prior thoracotomy (if performed); if prior thoracotomy then measurable disease on imaging must be present
• Negative serum pregnancy test within three days prior to registration for women of childbearing potential
• An archived tumor block or punches instead block must be available for submission for programmed death-ligand 1 (PD-L1) analysis. If an archived tumor block sample cannot be shipped for this study, then two 3mm punches from the core needle biopsy blocks may be provided for analysis. Note: core or excisional biopsy is required for this study. Fine needle aspirates (FNA) and cytology specimens are not adequate for PD-L1 analysis.
• Agreement of women of childbearing potential to use highly effective contraception during receipt of study drug and up to 161 days (23 weeks) from the last dose of nivolumab/placebo and men receiving nivolumab/placebo who are sexually active with women of childbearing potential to use highly effective contraception during receipt of study drug for 31 weeks from the last dose of nivolumab/placebo.

Exclusion Criteria:

• Definitive clinical or radiological evidence of metastatic disease
• Prior or current invasive malignancy (except non-melanomatous skin cancer, localized bladder and prostate cancer) unless disease free for a minimum of 2 years (for example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible)
• Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields. For example, patients with prior breast radiotherapy treatments would likely be excluded.
• Prior systemic treatment with and anti-programmed cell death protein 1 (PD1), anti-PD-L1, anti-PD-L2, anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) (antibody, or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways
• Known immunosuppressive disease, for example HIV infection or history of bone marrow transplant or chronic lymphocytic leukemia (CLL)
• Chronic Obstructive Pulmonary Disease (COPD) exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration. COPD requiring chronic oral steroid therapy
• Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months
• Transmural myocardial infarction within the last 6 months
• Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
• History of symptomatic or p previously established interstitial lung disease
• Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection;
• History of severe hypersensitivity reaction to any monoclonal antibody or allergy to study drug components
• As there is potential for hepatic toxicity with nivolumab, drugs with a predisposition to hepatotoxicity should be used with caution in patients treated with nivolumab-containing regimen
• Pregnancy, nursing females or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic.

Contacts and Locations

Locations

United States, California

UC San Diego Moores Cancer Center

La Jolla, California, United States, 92093

Stanford University

Stanford, California, United States, 94305

United States, Florida

University of Florida

Gainesville, Florida, United States, 32610

Mount Sinai Cancer Research Center

Miami Beach, Florida, United States, 33140

United States, Georgia

Nancy N. & J.C. Lewis Cancer & Research Pavilion at St. Joseph's/Candler Hospital

Savannah, Georgia, United States, 31405

United States, Kentucky

University of Kentucky

Lexington, Kentucky, United States, 40536

United States, Maryland

Mercy Medical Cancer Center

Baltimore, Maryland, United States, 21202

United States, Michigan

Henry Ford Health System

Detroit, Michigan, United States, 48202

United States, New York

Memorial Sloan Kettering Cancer Center

New York, New York, United States, 10065

University of Rochester

Rochester, New York, United States, 14642

United States, Ohio

Metro Health Medical Center

Cleveland, Ohio, United States, 44109

United States, Pennsylvania

Reading Hospital/McGlinn Cancer Institute

West Reading, Pennsylvania, United States, 19611

United States, Texas

University of Texas Southwestern Medical Center

Dallas, Texas, United States, 75390

United States, Virginia

Inova Fairfax Hospital

Falls Church, Virginia, United States, 22042

United States, Washington

Virginia Mason

Seattle, Washington, United States, 98101

United States, Wisconsin

University of Wisconsin Hospital and Clinics

Madison, Wisconsin, United States, 53792

Sponsors and Collaborators

RTOG Foundation, Inc.

Bristol-Myers Squibb

Investigators

• Principal Investigator: David Gerber, MD; RTOG Foundation

  Study Documents (Full-Text)

Documents provided by RTOG Foundation, Inc.:

Study Protocol and Statistical Analysis Plan  [PDF] January 30, 2017

Informed Consent Form  [PDF] January 30, 2017

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Gerber DE, Urbanic JJ, Langer C, Hu C, Chang IF, Lu B, Movsas B, Jeraj R, Curran WJ, Bradley JD. Treatment Design and Rationale for a Randomized Trial of Cisplatin and Etoposide Plus Thoracic Radiotherapy Followed by Nivolumab or Placebo for Locally Advanced Non-Small-Cell Lung Cancer (RTOG 3505). Clin Lung Cancer. 2017 May;18(3):333-339. doi: 10.1016/j.cllc.2016.10.009. Epub 2016 Oct 26.

• Responsible Party: RTOG Foundation, Inc.
• ClinicalTrials.gov Identifier: NCT02768558
• Other Study ID Numbers: RTOG 3505; RF 3505 ( Other Identifier: RTOG Foundation ); CA209-333 ( Other Identifier: Bristol-Myers Squibb )
• First Posted: May 11, 2016
• Results First Posted: February 25, 2020
• Last Update Posted: June 2, 2021
• Last Verified: October 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by RTOG Foundation, Inc.:

Lung Cancer; NSCLC; Nivolumab

Additional relevant MeSH terms:

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; Cisplatin; Nivolumab; Etoposide; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors