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Split Course Adaptive Radiation Therapy with Pembrolizumab and with or without Chemotherapy for the Treatment of Stage IV Lung Cancer, SiCARIO Study

This phase I/II trial tests the safety and efficacy of split-course adaptive radiation therapy in combination with pembrolizumab and with or without chemotherapy for the treatment of patients with stage IV lung cancer. Radiation therapy is a standard cancer treatment that uses high energy rays to kill cancer cells and shrink tumors. Split-course adaptive radiation therapy uses patient disease response to alter the intensity of the radiation therapy. Immunotherapy with monoclonal antibodies such as pembrolizumab may help the body's immune system attack the 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.
Lung, Non Small Cell, Phase I
Phase I/II
Chemotherapy - cytotoxic, Mol. targeted/Immunotherapy/Biologics, Radiotherapy
Carboplatin, Cisplatin, Ipilimumab, MK-3475, Nab-Paclitaxel, Paclitaxel, Pembrolizumab (MK-3475), Pemetrexed
Osmundson, Evan
Vanderbilt University


18 Years
Inclusion Criteria:

Age >= 18 years at time of informed consent

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

Available tumor material (
Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

Absolute neutrophil count (ANC) >= 1.5 x 10^9/L

Platelet count >= 100 x 10^9/L

Hemoglobin >= 9 g/dL

Total bilirubin =
Aspartate aminotransferase (AST) =
Alanine aminotransferase (ALT) =
Alkaline phosphatase =
Creatinine == 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

International normalized ratio (INR) or prothrombin time (PT) =
Activate partial thromboplastin time (aPTT) =
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)

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

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
Eligible for immunotherapy-based systemic regimens per judgment of patients 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 treating physician (i.e. mEGFR, ALK, KRAS G12C or ROS1 mutations). Testing not required for enrollment

Greater than 5 brain metastases on required screening brain magnetic resonance imaging (MRI) within 21 days of day 1 of study treatment

Symptomatic ascites or malignant pleural effusion (sampling not required)

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 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)

Prior radiotherapy that would preclude delivery of protocol- based radiotherapy to normal organ tolerance per patients 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

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trials, call 615-936-8422.