RADVAX: A Stratified Phase I Trial of Pembrolizumab With Hypofractionated Radiotherapy in Patients With Advanced and Metastatic Cancers

Inclusion Criteria

• Be willing and able to provide written informed consent/assent for the trial.
• Be 18 years of age on day of signing informed consent.
• Histologically confirmed diagnosis of cancer as per the cohort specifications
• Stage IV cancer by AJCC staging criteria (except for pancreatic cancer cohort)
• Locally advanced or metastatic pancreatic cancer for the pancreatic cancer cohort
• Progression of disease while on anti-PD-1 or anti-PD-L1 therapy for melanoma and NSCLC patients. For this group, patients must met the following criteria:
• Received at least 2 doses of an anti-PD1 or anti-PD-L1 therapy
• Had progressive disease documented radiologically by RECIST v1.1 criteria.
• Progression or refractory disease to at least one regimen of therapy for metastatic disease in the breast and pancreatic cancer cohorts
• Presence of an index lesion > 1 cm amenable to hypofractionated radiotherapy
• Patients who have metastatic cancer must have at least one lesion that is outside the radiation field that measures greater than one cm that can be followed by RECIST 1.1. This lesion, if it is close to the radiated lesion, must receive no more than 10% of the dose prescribed to the target lesion.
• Have provided tissue from an archival tissue sample or newly obtained core or excisional biopsy of a tumor lesion.
• Have a performance status of 0 or 1 on the ECOG Performance Scale.
• Ability to tolerate hypofractionated radiation therapy (e.g. lie flat and hold position)
• Demonstrate adequate organ function , all screening labs should be performed within 14 days of treatment initiation.
• Adequate Organ Function Laboratory Values System Laboratory Value Hematological Absolute neutrophil count (ANC) ≥1,500 /mcL Platelets ≥100,000 / mcL Hemoglobin ≥9 g/dL or ≥5.6 mmol/L Renal Serum creatinine OR Measured or calculateda creatinine clearance (GFR can also be used in place of creatinine or CrCl)
• 1.5 X upper limit of normal (ULN) OR

≥60 mL/min for subject with creatinine levels > 1.5 X institutional ULN Hepatic Serum total bilirubin

• 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN AST (SGOT) and ALT (SGPT)
• 2.5 X ULN OR
• 5 X ULN for subjects with liver metastases Creatinine clearance should be calculated per institutional standard
• Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.
• Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.

Exclusion Criteria

• The subject must be excluded from participating in the trial if the subject:
• Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment.
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. Systemic steroids administered specifically as a premedication for chemotherapy infusion or radiotherapy are allowed.
• Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
• Has had prior chemotherapy, targeted small molecule therapy, or radiation therap