Colonic Neoplasms, Colorectal Neoplasms
Conditions
Brief summary
The primary objective is to assess and characterize the antitumor activity and safety and tolerability of adjuvant treatment with an individualized neoantigen vaccine called GRT-C901/GRT-R902 (chimpanzee adenovirus \[ChAd\] and self-amplifying messenger RNA \[samRNA\] vectors), in combination with checkpoint inhibitors. Antitumor activity will be based on molecular response in patients with colon cancer who have circulating tumor deoxyribonucleic acid (ctDNA) following surgical resection.
Detailed description
Tumors harboring non-synonymous deoxyribonucleic acid (DNA) mutations 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 results 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 personalized cancer vaccine that targets these neoantigens. This vaccine regimen uses two vaccine vectors as a heterologous prime/boost approach (GRT-C901, ChAd as prime and GRT-R902, samRNA as boost) to stimulate an immune response. This study (GRANITE-ADJUVANT) will explore the anti-tumor activity of this individualized, patient specific immunotherapy in combination with checkpoint inhibitors.
Interventions
DRUGGRT-C901
An individualized neoantigen cancer vaccine using an adenovirus vector administered via intramuscular (IM) injections at Visit 1 and boost at Visit 6.
DRUGGRT-R902
An individualized neoantigen cancer vaccine using a self-amplifying mRNA (samRNA) vector administered via IM injection at Visits 2, 4, 9, and 12.
DRUGAtezolizumab
Dose of 1680 mg administered once every 4 weeks (Q4W) via intravenous (IV) infusion at Visits 1-13.
DRUGIpilimumab
Dose of 30 mg administered via subcutaneous (SC) injection only with the first dose of GRT-C901 at Visit 1 and GRTR902 at Visit 2.
DRUGAdjuvant chemotherapy
Administered according to standard of care.
Sponsors
Gritstone bio, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
For Vaccine Production Stage: * Patients with a high-risk stage II or stage III colon cancer, including high-risk stage II colon cancer defined as meeting any of the following criteria: T4 tumors, Grade ≥3, clinical presentation with bowel obstruction or perforation, histological signs of vascular or lymphatic or perineural invasions, and \<12 nodes examined * Patient has evidence of minimal residual disease (MRD) prior to initiating adjuvant chemotherapy (ACT) based on the presence of ctDNA * Patient has received approximately \<6 weeks of ACT. * Margin negative (R0) pathology on resection * Availability of formalin fixed, paraffin embedded (FFPE) tumor specimens * Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 or equivalent for patients 12 to 17 years of age * Patient has adequate organ function as defined by: peripheral white blood cell (WBC) count ≥3000/mm\^3, absolute lymphocyte count (ALC) ≥800/mm\^3, absolute neutrophils count (ANC) ≥1500/mm\^3, platelets ≥100,000/mm\^3, hemoglobin ≥9 g/dL, albumin ≥3 g/dL, calculated creatinine clearance \>50 mL/min using Cockcroft-Gault equation, alanine transaminase (ALT) and aspartate aminotransferase (AST) ≤3 × upper limit of normal (ULN), total serum bilirubin ≤1.5 × ULN OR direct bilirubin ≤1 × ULN, international normalized ratio (INR), prothrombin time (PT), or partial thromboplastin time (PTT) ≤1.5 × ULN, unless patient is receiving anti-coagulant therapy, in which case patients are eligible if PT and PTT are within therapeutic range of intended use of anti-coagulants, and carcinoembryonic antigen levels ≤1.5 × ULN. * A woman 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 5 months after last investigational study treatment For Study Treatment Stage: * Have a confirmed diagnosis of high-risk stage II or stage III micro-satellite stable (MSS)-colon cancer and have had their tumor surgically resected, have completed standard ACT and have no evidence of disease radiographically, and have evidence of MRD based on detection of ctDNA following ACT * ECOG performance status of 0 to 1 or equivalent for patients 12-17 years of age * Have adequate organ function with peripheral WBC count ≥2000/mm\^3, ALC ≥500/mm\^3, ANC ≥1000/mm\^3, platelets ≥75,000/mm\^3, hemoglobin ≥9 g/dL, albumin ≥3 g/dL, calculated creatinine clearance \>40 mL/min using Cockcroft-Gault equation, ALT and AST ≤3 × ULN, total serum bilirubin ≤1.5 × ULN OR direct bilirubin ≤1 × ULN, and INR, PT, or PTT ≤1.5 × ULN * If a 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 5 months after last investigational study treatment * If male and sexually active with a WCBP, must agree to use highly effective contraception such as latex condom plus partner use of a highly effective contraceptive method during the study treatment period and for 5 months after last investigational study treatment.
Exclusion criteria
For Vaccine Production Stage: * Patients with micro-satellite instable (MSI)-high disease * Patients with known tumor mutational burden (TMB) \<1 non-synonymous mutations/megabase * Patients with known DNA Polymerase Epsilon mutations * Known exposure to chimpanzee adenovirus (ChAd) within the prior 6 months, plan to receive a ChAd-based vaccine in the next 6 months, and/or any history or anaphylaxis in reaction to a vaccination * Bleeding disorder or history of significant bruising or bleeding following intramuscular (IM) injections or blood draws * Immunosuppression anticipated at time of study treatment * Patient has received prior therapy consisting of anti-cytotoxic T lymphocyte-associated antigen (CTLA-4), anti-programmed cell death-1 receptor (PD-1), anti-programmed death ligand-1(PD-L1), or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways * History of allogeneic tissue/solid organ transplant * Active or history of autoimmune disease or immune deficiency * History of other cancer within 2 years * Active tuberculosis or recent (\<2 week) clinically significant infection, or evidence of active hepatitis B or hepatitis C or known history of positive test for human immunodeficiency virus (HIV) if CD4+ T-cell count is ≤200 cells/microliter. * History of pneumonitis requiring systemic steroids for treatment (with the exception of prior resolved in-field radiation pneumonitis) * Myocardial infarction within 3 months or prior to study treatment, unstable angina, serious uncontrolled cardiac arrhythmia, history of myocarditis, or congestive heart failure (New York Heart Association \[NYHA\] Grade 3 and 4) * Pregnant, planning to become pregnant, or nursing For Study Treatment Stage * Patient is receiving treatment with investigational products and/or other anti-cancer therapies. * Known exposure to ChAd within the prior 6 months, plan to receive a ChAd-based vaccine in the next 6 months, and/or any history or anaphylaxis in reaction to a vaccination * Immunosuppression from concurrent, recent (≤4 weeks) or anticipated treatment with systemic corticosteroids or other immunosuppressive medications or conditions such as hypogammaglobulinemia, or radiation exposure * Patients who have not recovered from prior cancer therapy-induced AEs * Any severe concurrent non-cancer disease * 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 if CD4+ T-cell count is ≤200 cells/microliter * History of pneumonitis requiring systemic steroids for treatment * Myocardial infarction within 6 months prior to initiating study treatment, unstable angina, serious uncontrolled cardiac arrhythmia, history of myocarditis, or congestive heart failure (NYHA Grade 3 and 4). * Pregnant, planning to become pregnant, or nursing
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients with a ≥50% Decrease from Baseline in Circulating Tumor deoxyribonucleic acid (ctDNA) | Baseline and up to ~24 months | — |
| Incidence and Severity of Adverse Events | Up to ~100 days after last study treatment (Up to 62 weeks) | The incidence and severity will be assessed for treatment-emergent adverse events (TEAEs), immune-related AEs (irAEs), treatment-related AEs, serious AEs (SAEs), AEs leading to death while patients are on treatment or up to 100 days after the last study treatment, AEs leading to dose delays or dose discontinuation, and AEs leading to discontinuation of study treatment using National Cancer Institute (NCI) Criteria for Adverse Events (CTCAE) v5.0 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From time of randomization until death due to any cause (Up to ~36 months) | — |
| Conversion of Patients with ctDNA at Baseline to Undetectable ctDNA as Assessed via a Polymerase Chain Reaction (PCR)-Based Assay | Baseline and up to ~24 months | — |
| Recurrence-free survival (RFS) per Investigator | From time of randomization until first recurrence of the same cancer, or death (Up to ~36 months) | — |
| Success of Vaccine Manufacture | Up to 28 days before Day 1 of study drug administration | Vaccine manufacture success measured by the number of patients having sufficient neoantigens identified to warrant vaccine production. |
| T-cell response using Peripheral Blood Mononuclear Cells (PBMCs) | Up to ~24 months | — |
| Longest Duration of Molecular response of ctDNA Decrease from Baseline | Baseline and up to ~24 months | — |
| Disease-free survival (DFS) per Investigator | From time of randomization until first recurrence of any cancer, or death (Up to ~36 months) | — |
Countries
United States
Outcome results
None listed