Vaccine Therapy, Cyclophosphamide, and Pembrolizumab in Treating Patients with Mismatch Repair-Proficient Metastatic Colorectal Cancer

Inclusion Criteria

• Pathologically confirmed, mismatch repair-proficient adenocarcinoma of colorectum, who have received at least two prior lines of therapy in the metastatic setting * Mismatch repair proficiency can be assessed for eligibility by immunohistochemistry (intact expression of MLH1, MSH2, PMS2, and MSH6) or by molecular testing in a Clinical Laboratory Improvement Act (CLIA)-certified laboratory for microsatellite instability (0 or 1 microsatellites unstable)
• Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Estimated life expectancy of greater than 3 months
• Absolute neutrophil count >= 1,500 cells/mm^3
• Hemoglobin >= 9 g/dL (transfusion allowed but must demonstrate stability after transfusion)
• Platelets >= 75 K/mm^3
• Serum creatinine =< 2.0 mg/dL
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x upper limit of normal (ULN)
• Total bilirubin =< 1.5 x ULN; subjects with Gilbert’s syndrome should have direct bilirubin within normal institutional limits
• Women of childbearing potential (WOCBP) must have a negative urine or serum pregnancy test for the patient to be eligible for trial enrollment
• WOCBP must be willing to use either two adequate barrier methods or a barrier method plus a hormonal method of contraception to prevent pregnancy, or to abstain from heterosexual activity (complete abstinence) throughout the study, starting with visit 1 through 120 days after the last dose of study therapy; approved contraceptive methods include for example; intrauterine device, diaphragm with spermicide, cervical cap with spermicide, male condoms, female condoms with spermicide, or oral contraceptives; spermicides alone are not an acceptable method of contraception; non-pregnant, non-breast-feeding women may be enrolled if they are considered highly unlikely to conceive; highly unlikely to conceive is defined as 1) surgically sterilized, or 2) postmenopausal (a woman who is >= 45 years of age and has not had menses for greater than 2 years will be considered postmenopausal), or 3) amenorrheic for < 2 years without a hysterectomy and oophorectomy and with a documented follicle stimulating hormone (FSH) value in the postmenopausal range, or 4) not heterosexually active for the duration of the study, or 5) heterosexually active and willing to use 2 methods of birth control (which is also required for the female partners of male patients) * Male patients must agree to use an adequate method of contraception, or to abstain from heterosexual activity (complete abstinence), starting with the first dose of study drug through 120 days after the last dose of study therapy
• Ability to understand and the willingness to sign a written informed consent document
• Willing to undergo tumor biopsy at baseline and during treatment (during week 6 or 7); please note that tumor biopsy is not needed in subjects where the tumor is not accessible or if tumor biopsy is considered not in patient’s best interest

Exclusion Criteria

• Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer
• Has known central nervous system (CNS) metastases and/or carcinomatous meningitis
• Patients with malignant small bowel obstruction within the last 6 months, on parenteral nutrition, clinically significant ascites (palpable on physical exam and/or causing symptoms) or ascites requiring fluid removal more than twice in the last 6 weeks
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs); replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 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
• Has an active infection requiring systemic therapy
• Has a known history of active TB (Bacillus tuberculosis)
• Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
• Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
• Has history of (non-infectious) pneumonitis that required steroids, evidence of interstitial lung disease or active, non-infectious pneumonitis
• Must not require supplemental oxygen or have a pulse oximetry < 92% on room air
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment; women of childbearing potential must have a negative urine human chorionic gonadotropin (HCG)
• Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment
• Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent * Note: subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study
• Patients who have had surgery within 4 weeks of dosing of investigational agent, excluding minor procedures (dental work, skin biopsy, etc), celiac plexus block, and biliary stent placement
• Has had a prior anti-cancer monoclonal antibody (mAb) 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 received a live vaccine within 30 days of planned start of study therapy * Note: seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed
• Has received prior therapy with any other systemic immunotherapy treatment, including but not limited to: IL-2, interferon, anti-PD-1 antibodies, anti-PD-L2 antibodies, anti-CD137 antibodies, anti-OX-40 antibodies, anti-CD40 antibodies, anti-CTLA-4 antibodies, therapeutic anticancer vaccines, cellular immunotherapies including chimeric antigen receptor–modified T cells, or bi-specific CD3 antibodies
• Patients receiving growth factors including, but not limited to, granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), erythropoietin, within 14 days of study drug administration; use of such agents while on study is also prohibited
• Hypersensitivity to pembrolizumab or any of its excipients
• Patient has a known or suspected hypersensitivity to GM-CSF, hetastarch, corn, dimethyl sulfoxide, fetal bovine serum, trypsin (porcine origin), yeast or any other component of GVAX vaccine
• Patient is unwilling or unable to follow the study schedule for any reason
• Presence of any tissue or organ allograft, regardless of need for immunosuppression, including corneal allograft; patients with a history of allogeneic hematopoietic stem cell transplant will also be excluded