a study of a patient-specific neoantigen vaccine in combination with immune checkpoint blockade for patients with metastatic colorectal cancer

Conditions: Colorectal Neoplasms

Summary: the primary objective of the phase 2 portion of the study is to characterize the clinical activity of maintenance therapy with grt-c901/grt-r902 (patient-specific vaccines) in combination with checkpoint inhibitors in addition to fluoropyrimidine/bevacizumab versus a fluoropyrimidine/bevacizumab alone as assessed by molecular response which is based on changes in circulating tumor (ct)dna. the primary objective of the phase 3 portion is to demonstrate clinical efficacy of the regimen as assessed by progression-free survival.

tumors harboring non-synonymous deoxyribonucleic acid (dna) mutations can present peptides containing these mutations as non-self antigens in the context of human leukocyte antigens (hlas) on the tumor cell surface. a fraction of mutated peptides result in neoantigens capable of generating t-cell responses that exclusively target tumor cells. sensitive detection of these mutations allows for the identification of neoantigens unique to each patient's tumor to be included in a patient-specific cancer vaccine that targets these neoantigens. this vaccine regimen uses two vaccine vectors as a heterologous prime/boost approach (grt-c901 first followed by grt-r902) to stimulate an immune response. this study will explore the anti-tumor activity of this patient-specific immunotherapy in combination with checkpoint inhibitors in addition to fluoropyrimidine/bevacizumab.

Eligibility criteria:
inclusion criteria: * patients with histologically confirmed metastatic colorectal cancer (crc) who are planned for, or have received \<30 days of first-line treatment in the metastatic setting with folfox/bev, capeox/bev, folfoxiri/bev, or capoxiri/bev per soc * measurable and unresectable metastatic disease according to recist v1.1 * availability of formalin-fixed paraffin-embedded (ffpe) tumor specimens. * eastern cooperative oncology group (ecog) performance status of 0 or 1 * patient has adequate organ function per defined criteria * if women of childbearing potential (wcbp), must be willing to undergo pregnancy testing and agrees to the use at least 1 highly effective contraceptive method during the study treatment period and for 150 days after last investigational study treatment. exclusion criteria: * patients with deficient mismatch repair (dmmr) or microsatellite instability (msi-h) phenotype * patient has a known tumor mutation burden \<1 non-synonymous mutations/megabase * known dna polymerase epsilon mutations * patients with known brafv600e mutations * bleeding disorder or history of significant bruising or bleeding following im injections or blood draws * immunosuppression anticipated at time of study treatment * history of allogeneic tissue/solid organ transplant * active or history of autoimmune disease or immune deficiency * patient with symptomatic or actively progressing central nervous system (cns) metastases, carcinomatous meningitis, or has been treated with whole brain radiation * history of other cancer within 2 years with the exception of neoplasm that has undergone potentially curative therapy * any severe concurrent non-cancer disease that, in the judgment of the investigator, would make the patient inappropriate for the current study * active tuberculosis or recent (\<2 weeks) clinically significant infection, evidence of active hepatitis b or hepatitis c, or known history of positive test for hiv * history of pneumonitis requiring systemic steroids for treatment (with the exception of prior resolved in-field radiation pneumonitis) * myocardial infarction within previous 3 months, unstable angina, serious uncontrolled cardiac arrhythmia, history of myocarditis, or congestive heart failure (class iii or iv). * pregnant, planning to become pregnant, or nursing.

Keywords: colorectal cancer vaccine mcrc colon rectum crc rectal immunotherapy mss-crc personal cancer vaccine personalized cancer vaccine individualized cancer vaccine