Colorectal Cancer, Non-Small Cell Lung Cancer, Pancreatic Cancer, Shared Neoantigen-Positive Solid Tumors, Solid Tumor
Conditions
Keywords
neoantigen cancer vaccine, shared neoantigen, GRT-C903, GRT-R904, immunotherapy, PD-1, CTLA-4, nivolumab, ipilimumab
Brief summary
The purpose of this study is to evaluate the dose, safety, immunogenicity and early clinical activity of GRT-C903 and GRT-R904, a neoantigen-based therapeutic cancer vaccine, in combination with immune checkpoint blockade, in patients with advanced or metastatic non-small cell lung cancer, microsatellite stable colorectal cancer, pancreatic cancer, and shared neoantigen-positive tumors. Based on the Phase 1 data, an updated vaccine candidate (SLATE-KRAS or version 2) was developed that removed 16 of the 20 mutations included in the original vaccine (version 1) and solely targets KRAS mutations.
Detailed description
Tumors harboring non-synonymous deoxyribonucleic acid (DNA) mutations can present peptides containing these mutations as non-self antigens in the context of HLA on the tumor cell surface. A fraction of mutated peptides result in neoantigens capable of generating T-cell responses that exclusively target tumor cells. Some of these tumor-specific neoantigens are known or expected to be common across a subset of patients and are called shared neoantigens. This study aims to target shared neoantigens using a heterologous prime/boost therapeutic vaccine approach (GRT-C903 first followed by GRT-R904) in combination with checkpoint blockade to stimulate an immune response. This study will explore the safety and early clinical activity of this neoantigen-based immunotherapy intended to induce T-cell responses specific for the shared neoantigens contained within the therapeutic vaccine. Phase 1 will test multiple doses and combinations with checkpoint blockade and Phase 2 will test for early signs of clinical activity using a vaccine regimen based on Phase 1 data.
Interventions
BIOLOGICALGRT-C903
a shared neoantigen cancer vaccine prime
BIOLOGICALGRT-R904
a shared neoantigen cancer vaccine boost
BIOLOGICALnivolumab
anti-PD-1 monoclonal antibody
BIOLOGICALipilimumab
anti-CTLA-4 monoclonal antibody
Sponsors
Bristol-Myers Squibb
Gritstone bio, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Provide a signed and dated informed consent form prior to initiation of study-specific procedures. * Patients with the indicated advanced or metastatic solid tumor as follows: 1. Microsatellite-stable colorectal cancer (MSS-CRC) who are currently receiving systemic treatment with a fluoropyrimidine and oxaliplatin and/or irinotecan that may include a VEGF or EGFR targeting therapy as their 1L therapy for metastatic disease OR who have experienced disease progression following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan that may include a VEGF or EGFR targeting therapy and have not received additional lines of systemic therapy in the metastatic setting. 2. Non-small cell lung cancer (NSCLC) who are currently receiving systemic treatment with an anti-PD-(L)1 antibody in combination with cytotoxic, platinum-based chemotherapy OR who have experienced disease progression following treatment with an anti-PD-(L)1 antibody in combination with cytotoxic, platinum-based chemotherapy (or anti-PD-(L)1 alone if patient refuses platinum-based chemotherapy), and have not received additional lines of systemic therapy in the metastatic setting. 3. Pancreatic ductal adenocarcinoma (PDA) who are currently receiving systemic cytotoxic chemotherapy as their 1L therapy for metastatic disease OR who have experienced disease progression on 1L systemic cytotoxic chemotherapy and have received no more than 1 prior line of therapy in the metastatic setting. 4. Any solid tumor histology where the patient has experienced disease progression with all available therapies known to confer clinical benefit * Patient's tumor possesses one of the mutations listed below, and is determined to express a HLA allele for antigen presentation of the identified tumor mutation: VERSION 1.0 of the expression cassette: BRAF\_G466V // CTNNB1\_S37F // CTNNB1\_S45F // CTNNB1\_S45P // CTNNB1\_T41A // ERBB2\_Y772\_A775dup // KRAS\_G12C or NRAS\_G12C // KRAS\_G12D or NRAS\_G12D // KRAS\_G12V // KRAS\_G13D // KRAS\_Q61H or NRAS\_Q61H // KRAS\_Q61K or NRAS\_Q61K // KRAS\_Q61L or NRAS\_Q61L // KRAS\_Q61R or NRAS\_Q61R // TP53\_K132E // TP53\_K132N // TP53\_R213L // TP53\_R249M // TP53\_S127Y VERSION 2.0 of the expression cassette: KRAS\_G12C or NRAS\_G12C // KRAS\_G12D or NRAS\_G12D // KRAS\_G12V or NRAS\_G12V // KRAS\_Q61H or NRAS\_Q61H * ECOG Performance Status 0 or 1 * Measurable disease according to RECIST v1.1 * Adequate organ function, as measured by laboratory values (criteria listed in protocol)
Exclusion criteria
* Tumors with genetic characteristics as follows: 1. For NSCLC, patients with a known genetic driver alteration in EGFR, ALK, ROS1, RET, or TRK 2. Patients with known MSI-high disease based on institutional standard * Known exposure to chimpanzee adenovirus or any history of anaphylaxis in reaction to a vaccination * Bleeding disorder (eg., factor deficiency, coagulopathy) or history of significant bruising or bleeding following IM injections or blood draws * History of allogenic/solid organ transplant * Active, known, or suspected autoimmune disease * Active tuberculosis or recent (\<2 week) clinically significant infection, or evidence of active hepatitis B or hepatitis C * Known history of positive test for human immunodeficiency (HIV) or known acquired immunodeficiency syndrome (AIDS) Complete inclusion and
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Incidence of adverse events (AEs), serious adverse events (SAEs), and dose limiting toxicities (DLTs) | Initiation of study treatment through 100 days post-last dose (up to approximately 27 months) |
| Objective Response Rate (ORR) in Phase 2 using RECIST v1.1 | Initiation of study treatment until disease progression (up to approximately 27 months) |
| Identify the recommended Phase 2 dose (RP2D) of GRT-C903 and GRT-R904 | Up to approximately 6 months |
Secondary
| Measure | Time frame |
|---|---|
| Clinical benefit rate (CBR) using RECIST v1.1 | Initiation of study treatment until disease progression (up to approximately 27 months) |
| Measure the immune response to the neoantigens encoded by GRT-C903 and GRT-R904 | Baseline to end of treatment (up to approximately 12 months) |
| Overall survival (OS) | Up to approximately 4 years |
| Progression-free survival (PFS) | Up to approximately 4 years |
| Objective Response Rate (ORR) in Phase 1 using RECIST v1.1 | Initiation of study treatment until disease progression (up to approximately 27 months) |
| Duration of response (DOR) using RECIST v1.1 | Initiation of study treatment until disease progression (up to approximately 27 months) |
Countries
United States
Outcome results
None listed