A Study of a Patient-Specific Neoantigen Vaccine in Combination With Immune Checkpoint Blockade for Patients With Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase 2/3, Randomized, Open-Label Study of Maintenance GRT-C901/GRT-R902, A Neoantigen Vaccine, in Combination With Immune Checkpoint Blockade for Patients With Metastatic Colorectal Cancer

Conditions
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Colorectal Neoplasms

Intervention / Treatment
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* Drug: GRT-C901
* Drug: GRT-R902
* Drug: Atezolizumab
* Drug: Ipilimumab
* Drug: Fluoropyrimidine plus leucovorin
* Drug: Bevacizumab


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vaccine Arm<br>After receiving up to 24 weeks induction therapy with a fluoropyrimidine/oxaliplatin/bevacizumab (with or without irinotecan), per standard of care and after completing vaccine production screening, patients will receive a total of 6 administrations of GRT-C901/GRT-R902 plus ipilimumab co-administered only with the first dose of GRT-C901 and GRT-R902. All patients will receive atezolizumab in addition to maintenance therapy of a fluoropyrimidine and bevacizumab according to standard of care. | Drug: GRT-C901<br>* A patient-specific neoantigen cancer vaccine administered via intramuscular (IM) injection as prime and single boost at a dose of 1x10^12 viral particles 2 times over the course of the first year.<br>Drug: GRT-R902<br>* A patient-specific neoantigen cancer vaccine boost, administered via IM injection at a dose of 30ug 4 times over the course of the first year.<br>Drug: Atezolizumab<br>* Atezolizumab will be administered via intravenous (IV) infusion at a dose of 1680 mg once every 4 weeks.<br>* Other names: Tecentriq;Drug: Ipilimumab<br>* Ipilimumab will be administered via subcutaneous (SC) injection at a dose of 30 mg with the first dose of GRT-C901 and GRT-R902.<br>* Other names: Yervoy;Drug: Fluoropyrimidine plus leucovorin<br>* Fluoropyrimidine (infusional 5-FU or capecitabine) and leucovorin administered as maintenance therapy per standard of care.<br>* Other names: Xeloda;Drug: Bevacizumab<br>* Bevacizumab administered as maintenance therapy per standard of care.<br>* Other names: Avastin;|
| Active Comparator: Control Arm<br>After receiving up to 24 weeks induction therapy with a fluoropyrimidine/oxaliplatin/bevacizumab (with or without irinotecan), per standard of care and undergoing vaccine production screening, patients will receive maintenance therapy of a fluoropyrimidine and bevacizumab according to standard of care. | Drug: Fluoropyrimidine plus leucovorin<br>* Fluoropyrimidine (infusional 5-FU or capecitabine) and leucovorin administered as maintenance therapy per standard of care.<br>* Other names: Xeloda;Drug: Bevacizumab<br>* Bevacizumab administered as maintenance therapy per standard of care.<br>* Other names: Avastin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 2: Molecular response defined as ≥ 30% decrease from baseline in circulating tumor DNA (ctDNA) |  | Baseline and up to 27 months | 
| Phase 3: Progression-free survival per Immune-based Response Evaluation Criteria in Solid Tumors (iRECIST) as assessed by blinded independent review committee (IRC) | defined by time from randomization until disease progression as per iRECIST or death from any cause | Up to 60 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 2 and 3: Incidence of treatment-emergent adverse events (TEAEs), immune-related AEs, treatment-related AEs, serious AEs, AEs leading to death, AEs leading to dose delays, and AEs leading to discontinuation of study treatment |  | Phase 2 up to 27 months, Phase 3 up to 60 months | 
| Phase 2 and 3: Progression-free survival per RECIST v1.1 and iRECIST as assessed by the investigator |  | Phase 2: up to 27 months, Phase 3: up to 60 months | 
| Phase 3: Progression-free survival per RECIST v1.1 as assessed by blinded IRC |  | Up to 60 months | 
| Phase 2 and 3: Overall Survival as time from randomization to death from any cause |  | Phase 2 up to 27 months, Phase 3 up to 60 months | 
| Phase 2 and 3: Overall Response Rate | measured by the proportion of patients with best overall response (BOR) of partial response (PR) or complete response (CR) by REICST v1.1 or , immune-based PR (iPR) or immune-based by iRECIST | Phase 2 up to 27 months, Phase 3 up to 60 months | 
| Phase 2 and 3: Duration of response (DOR) defined by time from the first objective response of PR or PR until disease progression or death |  | Phase 2 up to 27 months, Phase 3 up to 60 months | 
| Phase 2 and 3: Clinical benefit rate (CBR) as defined by the proportion of patients with best overall response of stable disease (SD), PR or CR using RECIS v1.1 or immune-based SD (iSD), iPR, or iCR by iRECIST. |  | Phase 2 up to 27 months, Phase 3 up to 60 months | 
| Phase 2 and 3: Deepening of Response the proportion of patients who have a BOR of SD or PR during the VPS and who convert from SD to PR or CR, or from PR to CR after start of the study treatment and/or SOC maintenance treatment in the STS per RECIST v1.1 | VPS = Vaccine Production Stage; STS = Study Treatment Stage | Phase 2 up to 27 months, Phase 3 up to 60 months | 
| Phase 2 and 3: The feasibility of manufacturing a patient-specific vaccine defined by the proportion of patients for whom vaccine was successfully manufactured from those randomized to the vaccine arm. |  | Study Treatment Screening visit (up to 28 days before Day 1 of study drug administration) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Colorectal cancer vaccine, mCRC, colon, rectum, CRC, rectal, immunotherapy, MSS-CRC, personal cancer vaccine, personalized cancer vaccine, individualized cancer vaccine