RAndomized Phase II/III Trial of Consolidation Radiation + Immunotherapy for ES-SCLC: RAPTOR Trial
Overview
- Phase
- Phase 2
- Intervention
- Biospecimen Collection
- Conditions
- Extensive Stage Lung Small Cell Carcinoma
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 138
- Locations
- 819
- Primary Endpoint
- Progression-free survival (PFS) (Phase II)
- Status
- Recruiting
- Last Updated
- 10 days ago
Overview
Brief Summary
This phase II/III trial compares the effect of adding radiation therapy to the usual maintenance therapy with atezolizumab versus atezolizumab alone in patients who have already received atezolizumab plus chemotherapy for the treatment of small cell lung cancer that has spread outside of the lung or to other parts of the body (extensive stage). Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving radiation therapy in addition to atezolizumab may extend the time without extensive small cell lung cancer growing or spreading compared to atezolizumab alone.
Detailed Description
PRIMARY OBJECTIVES: I. To compare investigator-assessed progression free survival (PFS) between atezolizumab plus radiotherapy and atezolizumab alone. (Phase II) II. To compare overall survival (OS) between atezolizumab plus radiotherapy and atezolizumab alone. (Phase III) SECONDARY OBJECTIVES: I. To assess the toxicity between the atezolizumab plus radiotherapy arm and the atezolizumab arm. II. To assess the impact of adding radiotherapy on PFS and OS in patients with 1-3 visible tumors and \> 3 visible tumors. III. To assess the impact of adding radiotherapy on PFS and OS in patients receiving consolidation radiotherapy to all visible disease ("complete consolidation") and patients who do not receive consolidation radiation to all visible disease ("incomplete consolidation"). EXPLORATORY OBJECTIVE: I. To assess the association between pre-treatment tumor burden (determined by central radiographic assessment, using both tumor number and tumor volume), and PFS and OS benefit. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive atezolizumab intravenously (IV) over 30 minutes +/- 10 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive atezolizumab IV over 30 minutes +/- 10 minutes. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo radiation therapy once daily (QD) on days 1-5 during weeks 1-5 only. Patients undergo positron emission tomography and computed tomography (PET/CT) scan, computed tomography (CT), and magnetic resonance imaging (MRI) throughout the trial. Patients also undergo blood and tissue collection throughout the trial. After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Any confirmation (cytologic, histologic, or pathologic) of extensive stage small cell lung cancer at any site, either primary or metastases
- •Partial response (PR) or stable disease (SD) after 4-6 cycles of etoposide/platinum (E/P) doublet plus atezolizumab by re-staging scans (positron emission tomography \[PET\]/computed tomography \[CT\] scan, diagnostic CT scan, magnetic resonance imaging \[MRI\] optional per treating physician); atezolizumab should continue through randomization. Patients must be randomized within 9 weeks of last dose of etoposide/platinum (if not receiving PCI) or 6 weeks from completion of prophylactic cranial irradiation (PCI)
- •NOTE: Patients must have at least 3 cycles of E/P plus atezolizumab. They can have one cycle of induction E/P without concurrent atezolizumab if unable to receive concurrent E/P combined with atezolizumab for all cycles of induction therapy
- •Patients must have measurable disease (per Response Evaluation Criteria in Solid Tumors \[RECIST\]) and 3 or fewer observable liver metastases and no evidence of progressive disease (per RECIST) at time of enrollment
- •At time of enrollment after induction E/P chemotherapy and atezolizumab, if there is a pleural effusion, patients will be eligible if thoracentesis is cytologically negative or if pleural fluid is too small a volume to effectively sample by thoracentesis and does not show increased metabolic activity on CT/PET imaging
- •Appropriate stage for study entry based on the following diagnostic workup:
- •History/physical examination within 14 days prior to registration;
- •Imaging within 42 days prior to registration to include:
- •MRI brain with contrast or CT brain with contrast
- •CT chest, abdomen and pelvis or whole body PET/CT scan any time after the fourth cycle of chemotherapy and prior to registration
Exclusion Criteria
- •Metastatic disease invading the liver (\> 3 metastases), heart or \> 10 metastatic sites detectable after induction systemic therapy. Each visible bone metastasis on radiographic scan counts as one site
- •Patients with a concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen with atezolizumab or radiation
- •Prior radiotherapy in the thorax that would result in overlapping RT fields, unless the overlapping fields meet acceptable dose constraints for normal tissue
- •Active autoimmune disease, including, but not limited to: systemic lupus erythematosus; rheumatoid arthritis; inflammatory bowel disease (e.g. Crohn's, ulcerative colitis); vascular thrombosis associated with antiphospholipid syndrome; Wegener's granulomatosis; Sjogren's syndrome; Guillain-Barre syndrome; multiple sclerosis; vasculitis; or glomerulonephritis.
- •If the autoimmune disease is not active for over 3 years and the patient is not receiving immunosuppressive treatment such as methotrexate or steroids above a dose equivalent to 10 mg prednisone daily, the patient is eligible.
- •Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone are eligible
- •Patients with controlled type 1 diabetes mellitus on a stable insulin regimen are eligible
- •Patients with eczema, psoriasis, lichen simplex chronicus or vitiligo with dermatologic manifestations are excluded only if they have active disease with acute exacerbation and on immunosuppressive medications within the 12 months prior to enrollment. They are eligible otherwise.
- •Severe, active co-morbidity defined as follows:
- •Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications;
Arms & Interventions
Arm II (atezolizumab, radiation therapy)
Patients receive atezolizumab IV over 30 minutes +/- 10 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo radiation therapy QD on days 1-5 during weeks 1-5 only. Patients undergo PET/CT scan, CT, and MRI throughout the trial. Patients also undergo blood and tissue collection throughout the trial.
Intervention: Biospecimen Collection
Arm II (atezolizumab, radiation therapy)
Patients receive atezolizumab IV over 30 minutes +/- 10 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo radiation therapy QD on days 1-5 during weeks 1-5 only. Patients undergo PET/CT scan, CT, and MRI throughout the trial. Patients also undergo blood and tissue collection throughout the trial.
Intervention: Computed Tomography
Arm II (atezolizumab, radiation therapy)
Patients receive atezolizumab IV over 30 minutes +/- 10 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo radiation therapy QD on days 1-5 during weeks 1-5 only. Patients undergo PET/CT scan, CT, and MRI throughout the trial. Patients also undergo blood and tissue collection throughout the trial.
Intervention: Radiation Therapy
Arm II (atezolizumab, radiation therapy)
Patients receive atezolizumab IV over 30 minutes +/- 10 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo radiation therapy QD on days 1-5 during weeks 1-5 only. Patients undergo PET/CT scan, CT, and MRI throughout the trial. Patients also undergo blood and tissue collection throughout the trial.
Intervention: Magnetic Resonance Imaging
Arm II (atezolizumab, radiation therapy)
Patients receive atezolizumab IV over 30 minutes +/- 10 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo radiation therapy QD on days 1-5 during weeks 1-5 only. Patients undergo PET/CT scan, CT, and MRI throughout the trial. Patients also undergo blood and tissue collection throughout the trial.
Intervention: Positron Emission Tomography
Arm I (atezolizumab)
Patients receive atezolizumab IV over 30 minutes +/- 10 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo PET/CT scan, CT, and MRI throughout the trial. Patients also undergo blood and tissue collection throughout the trial.
Intervention: Atezolizumab
Arm II (atezolizumab, radiation therapy)
Patients receive atezolizumab IV over 30 minutes +/- 10 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo radiation therapy QD on days 1-5 during weeks 1-5 only. Patients undergo PET/CT scan, CT, and MRI throughout the trial. Patients also undergo blood and tissue collection throughout the trial.
Intervention: Atezolizumab
Arm I (atezolizumab)
Patients receive atezolizumab IV over 30 minutes +/- 10 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo PET/CT scan, CT, and MRI throughout the trial. Patients also undergo blood and tissue collection throughout the trial.
Intervention: Biospecimen Collection
Arm I (atezolizumab)
Patients receive atezolizumab IV over 30 minutes +/- 10 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo PET/CT scan, CT, and MRI throughout the trial. Patients also undergo blood and tissue collection throughout the trial.
Intervention: Computed Tomography
Arm I (atezolizumab)
Patients receive atezolizumab IV over 30 minutes +/- 10 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo PET/CT scan, CT, and MRI throughout the trial. Patients also undergo blood and tissue collection throughout the trial.
Intervention: Magnetic Resonance Imaging
Arm I (atezolizumab)
Patients receive atezolizumab IV over 30 minutes +/- 10 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo PET/CT scan, CT, and MRI throughout the trial. Patients also undergo blood and tissue collection throughout the trial.
Intervention: Positron Emission Tomography
Outcomes
Primary Outcomes
Progression-free survival (PFS) (Phase II)
Time Frame: From randomization to any documented progression or death due to any cause, whichever occurs first, assessed up to 6 years
Will compare the distributions of PFS between treatment arms using a one-sided stratified log-rank test in all randomized eligible patients. The rates at various timepoints (e.g., every 6 months after randomization) and medians of PFS for each arm will be estimated using the Kaplan-Meier method. The associated 95% confidence interval (CI) will be calculated using Greenwood's formula and based on a log-log transformation applied on the survival function. Results from an unstratified analysis will also be provided.
Overall survival (OS) (Phase III)
Time Frame: From randomization to the date of death due to any cause, assessed up to 6 years
Will compare arm I to arm 2 based on OS using a stratified log-rank test. Hazard ratios will be estimated using a stratified Cox regression model. Event rates over time will be estimated within each treatment group using the Kaplan-Meier method.
Secondary Outcomes
- PFS (Phase III)(Up to 6 years)
- PFS in patients with 1-3 distinct visible tumors and > 3 distinct visible tumors(Up to 6 years)
- OS in patients with 1-3 distinct visible tumors and > 3 distinct visible tumors(Up to 6 years)
- Incidence of adverse events(Up to 6 years)
- PFS in patients receiving consolidation radiotherapy to all visible disease and patients who do not receive consolidation radiotherapy to all visible disease(Up to 6 years)
- OS in patients receiving consolidation radiotherapy to all visible disease and patients who do not receive consolidation radiotherapy to all visible disease(Up to 6 years)