Split Course Adaptive Radiation Therapy With Pembrolizumab With/Without Chemotherapy for Treating Stage IV Lung Cancer
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1/Phase 2 |
Detailed Description
PRIMARY OBJECTIVES:
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Evaluate the safety of adaptive split course hypo-fractionated radiation therapy (RT) with immunotherapy containing systemic regimens.
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Evaluate efficacy of the use of adaptive split course hypo-fractionated RT with immunotherapy containing systemic regimens.
SECONDARY OBJECTIVES:
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Evaluate progression and survival benefit of split course adaptive radioimmunotherapy (SiCARIO) regimen.
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Identify potential functional radiomic biomarkers of response to SiCARIO regimen.
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Develop real-world clinical and treatment planning workflows for implementation of the Ethos platform for anatomic and biologically adaptive RT.
OUTLINE:
Patients receive standard of care pembrolizumab with or without carboplatin and pemetrexed or carboplatin and nab-paclitaxel and undergo radiation therapy on day 1 of each cycle. Treatment repeats every 21 days for 5 cycles in the absence of disease progression or unacceptable toxicity. Patients receive the imaging tracers [F-18] fluorodeoxyglucose (FDG) intravenously (IV) and [18-F] (fluoropropyl)-L-glutamate (FSPG) and undergo positron emission tomography (PET)/computed tomography (CT) prior to any therapy and after cycle 3 of therapy. FDG- and FSPG-PET/CT scans will be done on separate days.
MAINTENANCE THERAPY: After 5 cycles, patients may continue receiving pembrolizumab every 21 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 4 weeks, 12 weeks, and then every 12 weeks for 2 years.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Treatment (pembrolizumab, chemotherapy, radiation) Patients receive standard of care pembrolizumab with or without carboplatin and pemetrexed or carboplatin and nab-paclitaxel and undergo radiation therapy on day 1 of each cycle. Treatment repeats every 21 days for 5 cycles in the absence of disease progression or unacceptable toxicity. Patients receive fludeoxyglucose F-18 IV then undergo PET/CT and [18-F] (fluoropropyl)-L-glutamate (FSPG) IV then undergo PET/CT (two independent PET/CT studies) done prior to cycle 1 (within 21 days) and after cycle 3 (but before cycle 4) of therapy. MAINTENANCE THERAPY: After 5 cycles, patients may continue receiving pembrolizumab every 21 days in the absence of disease progression or unacceptable toxicity. |
Procedure: Biospecimen Collection
Correlative studies
Other Names:
Drug: Carboplatin
Given carboplatin
Other Names:
Procedure: Computed Tomography
Undergo PET/CT
Other Names:
Other: Fludeoxyglucose F-18
Given IV
Other Names:
Drug: Nab-paclitaxel
Given nab-paclitaxel
Other Names:
Biological: Pembrolizumab
Given pembrolizumab
Other Names:
Drug: Pemetrexed
Given pemetrexed
Other Names:
Procedure: Positron Emission Tomography
Undergo PET/CT
Other Names:
Radiation: Radiation Therapy
Undergo radiation therapy
Other Names:
Other: [18-F] (fluoropropyl)-L-glutamate (FSPG) PET scan
Undergo PET scan
|
Outcome Measures
Primary Outcome Measures
- Incidence of adverse events [Up to 2 years]
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
- Best overall response rate [Within 6 months]
By Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Exact binomial test and 95% confidence interval (CI) will be used.
Secondary Outcome Measures
- Progression free survival (PFS) [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]
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.
- Overall survival [Time from consent to the date of death due to any cause, assessed up to 2 years]
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.
- New metastasis free survival [Time from consent to the date of the first documentation of a new distant metastasis or death, assessed up to 2 years]
Any new lesions different from the ones present at screening are considered as new metastases.
- Quantitative and qualitative markers of planning and treatment resource utilization [Up to 2 years]
Develop real-world clinical and treatment planning workflows for implementation of the Ethos platform for anatomic and biologically adaptive radiation therapy (RT).
Eligibility Criteria
Criteria
Inclusion Criteria:
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Age >= 18 years at time of informed consent
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Histologically documented or cytologically confirmed diagnosis of stage IVA or IVB (M1b or M1c) non-small cell lung cancer with evaluable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 criteria
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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
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Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
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Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
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Platelet count >= 100 x 10^9/L
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Hemoglobin >= 9 g/dL
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Total bilirubin =<1.5 x upper limit of normal (ULN)
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Aspartate aminotransferase (AST) =< 3.0 x ULN
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Alanine aminotransferase (ALT) =< 3.0 x ULN
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Alkaline phosphatase =< 2.5 x ULN
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Creatinine =< 1.5 x ULN or calculated creatinine clearance (CrCl) >= 50 mL/min if creatinine (Cr) > 1.5 x ULN. GFR can also be utilized. If no local calculation guidance on CrCl, should be calculated according to Cockcroft-Gault Method
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International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN
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Activate partial thromboplastin time (aPTT) =< 1.5 x ULN unless participant is receiving anticoagulation therapy
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No prior systemic therapy for advanced/metastatic non-small cell lung cancer (NSCLC) (prior adjuvant chemotherapy following complete resection of early-stage NSCLC I-II is allowed)
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Participants with 5 or fewer brain metastases are eligible if intracranial sites can be treated with surgery and/or stereotactic radiosurgery, prior to initiation of chemo-immunotherapy
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Contraceptive use should be initiated or continued per guidance in labeling for approved chemotherapies
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Female patients must be non-pregnant and not breastfeeding.
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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
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Eligible for immunotherapy-based systemic regimens per judgment of patient's study physician
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Able to submit written informed consent
Exclusion Criteria:
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Mixed small cell histology
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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
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Greater than 5 brain metastases on required screening brain magnetic resonance imaging (MRI) within 21 days of day 1 of study treatment
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Symptomatic ascites or malignant pleural effusion (sampling not required)
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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
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History of organ transplant requiring therapeutic immunosuppression
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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
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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
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Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization within 30 days of day 1 of study treatment
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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)
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Receipt of prior cytotoxic chemotherapy or anti-neoplastic biologic/immunotherapy for current malignancy (prior adjuvant therapy for completely resected early stage NSCLC that has now recurred in metastatic state is permissible)
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Prior radiotherapy that would preclude delivery of protocol- based radiotherapy to normal organ tolerance per patient's study physician
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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
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Active autoimmune disease requiring systemic treatment within past 1 year
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Receipt of live attenuated vaccine within 30 days of enrollment
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Use of prohibited concomitant drug within 30 days of enrollment
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Known severe (>= grade 3 Common Terminology Criteria for Adverse Events [CTCAE]) hypersensitivity to study intervention or formulation
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Concurrent enrollment in another clinical trial (unless observational or within follow-up period)
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Any condition at discretion of investigator that will preclude participation in the study
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Vanderbilt University/Ingram Cancer Center | Nashville | Tennessee | United States | 37232 |
Sponsors and Collaborators
- Vanderbilt-Ingram Cancer Center
- National Cancer Institute (NCI)
- Varian Medical Systems
Investigators
- Principal Investigator: Evan Osmundson, MD, PhD, Vanderbilt University/Ingram Cancer Center
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- VICCTHOP2185
- NCI-2022-05101
- VICCTHOP2185
- P30CA068485