Split Course Adaptive Radiation Therapy With Pembrolizumab With/Without Chemotherapy for Treating Stage IV Lung Cancer

Study Overview
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Brief Summary
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This phase I/II trial tests the safety and efficacy of split-course, adaptive radiation therapy in combination with pembrolizumab with or without chemotherapy for the treatment of patients with stage IV lung cancer who have a limited number of metastases. Radiation therapy is a standard cancer treatment that uses highly focused, high energy x-rays to kill cancer cells and shrink tumors. In this trial, radiation therapy will be given as a split-course, with each treatment coinciding with the initiation of a cycle of standard of care immunotherapy. The radiation therapy is adaptive and individualized, meaning that its intensity and shape will be tailored to a patient's disease response while on treatment. Immunotherapy with monoclonal antibodies such as pembrolizumab may enhance how the body's immune system attacks cancer, and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs like carboplatin, pemetrexed, and nab-paclitaxel work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving split-course adaptive radiation therapy with standard treatments like immunotherapy and chemotherapy may be more effective at treating stage IV lung cancer than giving them alone.

Detailed Description
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PRIMARY OBJECTIVES: I. Evaluate the safety of adaptive split course hypo-fractionated radiation therapy (RT) with immunotherapy containing systemic regimens. II. Evaluate efficacy of the use of adaptive split course hypo-fractionated RT with immunotherapy containing systemic regimens. SECONDARY OBJECTIVES: I. Evaluate progression and survival benefit of split course adaptive radioimmunotherapy (SiCARIO) regimen. II. Identify potential functional radiomic biomarkers of response to SiCARIO regimen. III. Develop real-world clinical and treatment planning workflows for implementation of the Ethos platform for anatomic and biologically adaptive RT. OUTLINE: Patients are assigned to 1 of 4 standard treatment regimens, in combination with radiation therapy, as determined by the investigator. OPTION A: Patients receive carboplatin, pemetrexed, and pembrolizumab on day 1 of each cycle. Treatment repeats every 21 days for 4 up to cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo radiation therapy on day 1 of each cycle over 5 treatment fractions. MAINTENANCE THERAPY: Patients then receive pemetrexed and pembrolizumab on day 1 of each cycle. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity. OPTION B: Patients receive carboplatin, paclitaxel, and pembrolizumab on day 1 of each cycle. Treatment repeats every 21 days for 4 up to cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo radiation therapy on day 1 of each cycle over 5 treatment fractions. MAINTENANCE THERAPY: Patients then receive pembrolizumab on day 1 of each cycle. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity. OPTION C: Patients receive pembrolizumab on day 1 of each cycle. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo radiation therapy on day 1 of each cycle over 5 treatment fractions. OPTION D: Patients receive ipilimumab and nivolumab on day 1 of each cycle. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo radiation therapy on day 1 of each cycle over 5 treatment fractions. All patients also receive fludeoxyglucose F-18 intravenously and fluorine F 18 florilglutamic acid IV and undergo PET/ CT during screening and on study. Patients also undergo collection of blood samples, as well as CT and MRI throughout the trial. After completion of study treatment, patients are followed up at 4 weeks, 12 weeks, and then every 12 weeks for 2 years.

Official Title
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SiCARIO (Split Course Adaptive Radioimmunotherapy) for the Treatment of Oligometastatic Non-Small Cell Lung Cancer (NSCLC) Using Biologically-Adaptive Radiotherapy - A Phase I/II Study

Conditions
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Lung Non-Small Cell Carcinoma, Stage IV Lung Cancer AJCC v8, Stage III Lung Cancer

Intervention / Treatment
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* Procedure: Biospecimen Collection
* Drug: Carboplatin
* Procedure: Computed Tomography
* Other: Fludeoxyglucose F-18
* Drug: Nab-paclitaxel
* Biological: Pembrolizumab
* Drug: Pemetrexed
* Procedure: Positron Emission Tomography
* Radiation: Radiation Therapy
* Other: [18-F] (fluoropropyl)-L-glutamate (FSPG) PET scan
* Biological: Ipilimumab
* Biological: Nivolumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >= 18 years at time of informed consent • Histologically documented or cytologically confirmed diagnosis of stage IVA or IVB (M1b or M1c) or locally advanced (not eligible for standard of care [SOC] chemoradiation) non-small cell lung cancer with evaluable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 criteria Available tumor material (< 6 months old) adequate for confirmation of programmed cell death 1 ligand 1 (PD-L1) expression per local standard of care testing Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 Adequate organ function to receive therapy as determined by investigators and other treating physicians Participants with brain metastases that can be comprehensively managed with surgery and/or stereotactic radiosurgery, prior to initiation of chemo-immunotherapy are allowed. Number of brain metastases allowed is not specified at eligibility is at discretion of investigator Contraceptive use should be initiated or continued per guidance in labeling for approved chemotherapies Female patients must be non-pregnant and not breastfeeding. If woman of childbearing potential (WOCBP), must utilize highly effective contraceptive method (failure rate of < 1% per year) throughout intervention period and continued per guidance specified in labeling for approved chemotherapies. Must have negative pregnancy test (serum or urine) within 1 week prior to initiation of first cycle of therapy Eligible for immunotherapy-based systemic regimens per judgment of patient's study physician Able to submit written informed consent Exclusion Criteria: Mixed small cell histology Confirmed candidate (per study physician) for alternative systemic therapy if preferred by treating physician (i.e. mEGFR, ALK, KRAS G12C or ROS1 mutations). Testing not required for enrollment Brain metastases that would require administration of whole brain radiotherapy for management on required screening brain MRI within 21 days of day 1 of study treatment Symptomatic malignant ascites or malignant pleural effusion (sampling not required). Pleural metastases are allowed if deemed targetable with radiotherapy Major surgery (requiring general anesthesia or at discretion of study physician) within 4 weeks prior to study enrollment that would prevent treatment with SiCARIO regimen History of organ transplant requiring therapeutic immunosuppression Known clinically significant (per study physician) acute or chronic infections including human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV) or active tuberculosis (testing not required). Patients with HBV and HCV must be on stable dose of antiviral therapy on study entry Uncontrolled intercurrent illness including, but not limited to, New York Heart Association (NYHA) class III-IV congestive heart failure, uncontrolled hypertension (average systolic blood pressure greater than or equal to 140 or average diastolic blood pressure greater than or equal to 90 despite optimal medical therapy), unstable angina pectoris, cardiac arrythmia, active peptic ulcer disease, bleeding diatheses or psychiatric illness that would limit in the judgment of the study physician Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization within 30 days of day 1 of study treatment History of prior independent malignancy within 3 years of enrollment, except for adequately treated basal or squamous cell carcinoma of the skin, adequately treated carcinoma in situ (e.g. cervix or non-invasive bladder cancer) Receipt of prior >1 cycle of immune checkpoint inhibitor for current malignancy (prior cytotoxic chemotherapy is allowed) Prior radiotherapy that would preclude delivery of protocol- based radiotherapy to normal organ tolerance per patient's study physician Current or prior use of immunosuppressive medications within 28 days of enrollment with exception of intranasal or inhaled corticosteroids or systemic steroids at physiologic doses (equivalent to less than or equal to 10 mg/day of prednisone). Systemic steroids required during therapy for adverse event (AE) management and for residual neurologic complications from management of central nervous system (CNS) metastases are allowed at doses exceeding 10 mg/day of prednisone equivalents Active autoimmune disease requiring systemic treatment within past 1 year Receipt of live attenuated vaccine within 30 days of enrollment Use of prohibited concomitant drug within 30 days of enrollment Known severe (>= grade 3 Common Terminology Criteria for Adverse Events [CTCAE]) hypersensitivity to study intervention or formulation Concurrent enrollment in another clinical trial (unless observational or within follow-up period) Any condition at discretion of investigator that will preclude participation in the study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Option A (carboplatin, pemetrexed, pembrolizumab, radiation)<br>Patients receive carboplatin, pemetrexed, and pembrolizumab on day 1 of each cycle. Treatment repeats every 21 days for 4 up to cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo radiation therapy on day 1 of each cycle over 5 treatment fractions. MAINTENANCE THERAPY: Patients then receive pemetrexed and pembrolizumab on day 1 of each cycle. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity. | Procedure: Biospecimen Collection<br>* Correlative studies<br>* Other names: Specimen Collection;Drug: Carboplatin<br>* Given carboplatin<br>* Other names: Ribocarbo;Procedure: Computed Tomography<br>* Undergo PET/CT<br>* Other names: tomography;Other: Fludeoxyglucose F-18<br>* Given IV<br>* Other names: Fluorodeoxyglucose F18;Biological: Pembrolizumab<br>* Given pembrolizumab<br>* Other names: SCH 900475;Drug: Pemetrexed<br>* Given pemetrexed<br>* Other names: Pemfexy;Procedure: Positron Emission Tomography<br>* Undergo PET/CT<br>* Other names: proton magnetic resonance spectroscopic imaging;Radiation: Radiation Therapy<br>* Undergo radiation therapy<br>* Other names: Therapy, Radiation;Other: [18-F] (fluoropropyl)-L-glutamate (FSPG) PET scan<br>* Undergo PET scan<br>|
| Experimental: Option B (carboplatin, paclitaxel, pembrolizumab, radiation)<br>Patients receive carboplatin, paclitaxel, and pembrolizumab on day 1 of each cycle. Treatment repeats every 21 days for 4 up to cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo radiation therapy on day 1 of each cycle over 5 treatment fractions. MAINTENANCE THERAPY: Patients then receive pembrolizumab on day 1 of each cycle. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity. | Procedure: Biospecimen Collection<br>* Correlative studies<br>* Other names: Specimen Collection;Drug: Carboplatin<br>* Given carboplatin<br>* Other names: Ribocarbo;Procedure: Computed Tomography<br>* Undergo PET/CT<br>* Other names: tomography;Other: Fludeoxyglucose F-18<br>* Given IV<br>* Other names: Fluorodeoxyglucose F18;Drug: Nab-paclitaxel<br>* Given nab-paclitaxel<br>* Other names: Protein-bound Paclitaxel;Biological: Pembrolizumab<br>* Given pembrolizumab<br>* Other names: SCH 900475;Procedure: Positron Emission Tomography<br>* Undergo PET/CT<br>* Other names: proton magnetic resonance spectroscopic imaging;Radiation: Radiation Therapy<br>* Undergo radiation therapy<br>* Other names: Therapy, Radiation;Other: [18-F] (fluoropropyl)-L-glutamate (FSPG) PET scan<br>* Undergo PET scan<br>|
| Experimental: Option C (pembrolizumab, radiation)<br>Patients receive pembrolizumab on day 1 of each cycle. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo radiation therapy on day 1 of each cycle over 5 treatment fractions. | Procedure: Biospecimen Collection<br>* Correlative studies<br>* Other names: Specimen Collection;Procedure: Computed Tomography<br>* Undergo PET/CT<br>* Other names: tomography;Other: Fludeoxyglucose F-18<br>* Given IV<br>* Other names: Fluorodeoxyglucose F18;Biological: Pembrolizumab<br>* Given pembrolizumab<br>* Other names: SCH 900475;Procedure: Positron Emission Tomography<br>* Undergo PET/CT<br>* Other names: proton magnetic resonance spectroscopic imaging;Radiation: Radiation Therapy<br>* Undergo radiation therapy<br>* Other names: Therapy, Radiation;Other: [18-F] (fluoropropyl)-L-glutamate (FSPG) PET scan<br>* Undergo PET scan<br>|
| Experimental: Option D (ipilimumab, nivolumab, radiation)<br>Patients receive ipilimumab and nivolumab on day 1 of each cycle. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo radiation therapy on day 1 of each cycle over 5 treatment fractions. | Procedure: Biospecimen Collection<br>* Correlative studies<br>* Other names: Specimen Collection;Procedure: Computed Tomography<br>* Undergo PET/CT<br>* Other names: tomography;Other: Fludeoxyglucose F-18<br>* Given IV<br>* Other names: Fluorodeoxyglucose F18;Procedure: Positron Emission Tomography<br>* Undergo PET/CT<br>* Other names: proton magnetic resonance spectroscopic imaging;Radiation: Radiation Therapy<br>* Undergo radiation therapy<br>* Other names: Therapy, Radiation;Other: [18-F] (fluoropropyl)-L-glutamate (FSPG) PET scan<br>* Undergo PET scan<br>Biological: Ipilimumab<br>* Given Ipilimumab<br>Biological: Nivolumab<br>* Given Nivolumab<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events | Safety endpoints will be tabulated using descriptive statistics, and by appropriate subgroups. The incidence of adverse events will be summarized according to organ system in terms of severity by Common Terminology Criteria for Adverse Events and relationship to treatment | Up to 2 years | 
| Best overall response rate | By Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Exact binomial test and 95% confidence interval (CI) will be used. | Within 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival (PFS) | Estimation of the treatment effect by a Cox proportional hazards model (stratified by chemotherapy regimen and PD-L1 expression, each stratum defines separate baseline hazard function); ties handled by replacing the proportional hazards model by the discrete logistic model; 95% CI for the hazard ratio will be calculated. Kaplan-Meier estimates and associated statistics (PFS rates at 6, 9, 12; median PFS) and corresponding 95% CI will be presented by treatment group. | Time from consent to the date of first documentation of objective progressive disease assessed by RECIST 1.1 or death, assessed at 6, 9, and 12 months | 
| Overall survival | Estimation of the treatment effect by a Cox proportional hazards model (stratified by chemotherapy regimen and PD-L1 expression, each stratum defines separate baseline hazard function); ties handled by replacing the proportional hazards model by the discrete logistic model; 95% CI for the hazard ratio will be calculated. Kaplan-Meier estimates and associated statistics and corresponding 95% CI will be presented by treatment group. | Time from consent to the date of death due to any cause, assessed up to 2 years | 
| New metastasis free survival | Any new lesions different from the ones present at screening are considered as new metastases. | Time from consent to the date of the first documentation of a new distant metastasis or death, assessed up to 2 years | 
| Quantitative and qualitative markers of planning and treatment resource utilization | Develop real-world clinical and treatment planning workflows for implementation of the Ethos platform for anatomic and biologically adaptive radiation therapy (RT). | Up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Oligometastasis, Adaptive Radiotherapy, Immunotherapy