Randomized Phase II Clinical Trial of Cisplatin/Carboplatin and Etoposide (CE) Alone or in Combination With Nivolumab as Frontline Therapy for Extensive Stage Small Cell Lung Cancer (ED-SCLC)
Overview
- Phase
- Phase 2
- Intervention
- Carboplatin
- Conditions
- Extensive Stage Lung Small Cell Carcinoma
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 160
- Locations
- 776
- Primary Endpoint
- Progression-free Survival (PFS)
- Status
- Completed
- Last Updated
- 10 months ago
Overview
Brief Summary
This randomized phase II clinical trial studies whether the addition of nivolumab to cisplatin (or carboplatin) and etoposide will improve outcomes when treating patients with extensive stage small cell lung cancer. Chemotherapy drugs, such as cisplatin, carboplatin, and etoposide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving cisplatin/carboplatin and etoposide together with nivolumab may work better in treating patients with extensive stage small cell lung cancer.
Detailed Description
PRIMARY OBJECTIVE: I. To evaluate the progression-free survival (PFS) of patients with extensive stage small cell lung cancer (ED-SCLC) treated with cisplatin/carboplatin and etoposide (CE) or CE with nivolumab (CEN) as front-line treatment. SECONDARY OBJECTIVES: I. To estimate overall survival of patients with ED-SCLC treated with cisplatin/carboplatin and etoposide (CE) or CE with nivolumab (CEN) as front-line treatment. II. To assess best overall response rate after treatment with CE with or without nivolumab as first line treatment. III. To evaluate the toxicity profile of nivolumab with CE. EXPLORATORY OBJECTIVES: I. To evaluate immune biomarkers and biomarkers correlatives. II. To evaluate serial circulating tumor deoxyribonucleic acid (DNA) and explore whether clinical outcome is associated with fluctuations in DNA levels following the administration of therapy. OUTLINE: Patients are randomized to 1 of 2 arms. ARM A: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1, carboplatin IV over 30-60 minutes on day 1 or cisplatin IV over 60-120 minutes on day 1, and etoposide IV over 60-120 minutes on days 1-3. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients continue to receive nivolumab IV over 30 minutes every 2 weeks for up to 2 years. ARM B: Patients receive carboplatin IV over 30-60 minutes on day 1 or cisplatin IV over 60-120 minutes on day 1, and etoposide IV over 60-120 minutes on days 1-3. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months if the patient is less than 2 years from registration, every 6 months if the patient is 2-3 years from registration, and yearly for up to 5 years from study enrollment.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients must have histologically or cytologically confirmed extensive stage small cell lung cancer and must be a candidate for systemic therapy; NOTE: The extensive disease SCLC classification for this protocol includes all patients with disease sites not defined as limited stage; limited stage disease category includes patients with disease restricted to one hemithorax with regional lymph node metastases, including hilar, ipsilateral and contralateral mediastinal, and/or ipsilateral supraclavicular nodes; extensive disease patients are defined as those patients with extrathoracic metastatic disease, malignant pleural effusion, bilateral or contralateral supraclavicular adenopathy; patients with locally recurrent SCLC who are not eligible for curative intent chemoradiation are eligible
- •Patients must have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
- •Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
- •Absolute neutrophil count \>= 1,500/mm\^3 (must be obtained =\< 7 days prior to protocol registration)
- •Platelets \>= 100,000/mm\^3 (must be obtained =\< 7 days prior to protocol registration)
- •Leukocytes \>= 3000/mm\^3 (must be obtained =\< 7 days prior to protocol registration)
- •Hemoglobin \>= 9 g/dL (must be obtained =\< 7 days prior to protocol registration)
- •Total bilirubin =\< 1.5 x institutional upper limit of normal (ULN) (except subjects with Gilbert syndrome, who can have total bilirubin \< 3 mg/dL) (must be obtained =\< 7 days prior to protocol registration)
- •Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) =\< 3 X institutional upper limit of normal (ULN) (=\< 5 X if liver function test \[LFT\] elevations due to known liver metastases) (must be obtained =\< 7 days prior to protocol registration)
- •Serum creatinine =\< 1.5 x ULN or calculated creatinine clearance \> 50 mL/min (using the Cockcroft-Gault formula) (must be obtained =\< 7 days prior to protocol registration)
Exclusion Criteria
- •Patients must not have history of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab or other agents used in the study
- •Women must not be pregnant or breast-feeding; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with the agents used in this study, breastfeeding must be discontinued or the subject is not eligible for the study; all females of childbearing potential must have a blood test or urine study, with a minimum sensitivity 50 mlU/L or equivalent units of human chorionic gonadotropin (HCG), within 14 days prior to registration to rule out pregnancy; a female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e. has had menses at any time in the preceding 24 consecutive months)
- •Patient must not have leptomeningeal disease
- •Patients must NOT have uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
- •Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
- •Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection, patients are excluded
- •Patients are ineligible if they received a live, attenuated vaccine within 4 weeks before randomization
Arms & Interventions
Arm A (nivolumab, CE)
Patients receive nivolumab IV over 30 minutes on day 1, carboplatin IV over 30-60 minutes on day 1 or cisplatin IV over 60-120 minutes on day 1, and etoposide IV over 60-120 minutes on days 1-3. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients continue to receive nivolumab IV over 30 minutes every 2 weeks for up to 2 years.
Intervention: Carboplatin
Arm A (nivolumab, CE)
Patients receive nivolumab IV over 30 minutes on day 1, carboplatin IV over 30-60 minutes on day 1 or cisplatin IV over 60-120 minutes on day 1, and etoposide IV over 60-120 minutes on days 1-3. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients continue to receive nivolumab IV over 30 minutes every 2 weeks for up to 2 years.
Intervention: Cisplatin
Arm A (nivolumab, CE)
Patients receive nivolumab IV over 30 minutes on day 1, carboplatin IV over 30-60 minutes on day 1 or cisplatin IV over 60-120 minutes on day 1, and etoposide IV over 60-120 minutes on days 1-3. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients continue to receive nivolumab IV over 30 minutes every 2 weeks for up to 2 years.
Intervention: Etoposide
Arm A (nivolumab, CE)
Patients receive nivolumab IV over 30 minutes on day 1, carboplatin IV over 30-60 minutes on day 1 or cisplatin IV over 60-120 minutes on day 1, and etoposide IV over 60-120 minutes on days 1-3. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients continue to receive nivolumab IV over 30 minutes every 2 weeks for up to 2 years.
Intervention: Nivolumab
Arm B (CE)
Patients receive carboplatin IV over 30-60 minutes on day 1 or cisplatin IV over 60-120 minutes on day 1, and etoposide IV over 60-120 minutes on days 1-3. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
Intervention: Carboplatin
Arm B (CE)
Patients receive carboplatin IV over 30-60 minutes on day 1 or cisplatin IV over 60-120 minutes on day 1, and etoposide IV over 60-120 minutes on days 1-3. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
Intervention: Cisplatin
Arm B (CE)
Patients receive carboplatin IV over 30-60 minutes on day 1 or cisplatin IV over 60-120 minutes on day 1, and etoposide IV over 60-120 minutes on days 1-3. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
Intervention: Etoposide
Outcomes
Primary Outcomes
Progression-free Survival (PFS)
Time Frame: Every 6 weeks for 6 months, then every 8 weeks until 1 year, and then every 12 weeks until being off treatment or end of observation. Thereafter every 3 months if < 2 years from registration, every 6 months for years 2-3, and yearly up to 3 years 9 months
PFS is defined as the time from randomization to documented disease progression or death from any cause, whichever occurs first. Patients who have not experienced an event of interest by the time of analysis will be censored at the date they are last known to be alive and progression-free. Progression was evaluated using the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Progression was defined as appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions, or at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
Secondary Outcomes
- Overall Survival (OS)(Every 6 weeks for 6 months, then every 8 weeks until 1 year, and then every 12 weeks until off treatment or end of observation. Then every 3 months if < 2 years from registration, every 6 months for years 2-3, and yearly up to 3 years 9 months.)
- Response Rate(Every 6 weeks for 6 months, then every 8 weeks until 1 year, and then every 12 weeks until being off treatment or end of observation. Thereafter every 3 months if < 2 years from registration, every 6 months for years 2-3, and yearly up to 3 years 9 months)