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

• ClinicalTrials.gov Identifier: NCT05141721
• Recruitment Status: Active, not recruiting
• First Posted: December 2, 2021
• Last Update Posted: December 22, 2023
• Sponsor: Gritstone bio, Inc.
• Information provided by (Responsible Party): Gritstone bio, Inc.

Tracking Information

• First Submitted Date: November 19, 2021
• First Posted Date: December 2, 2021
• Last Update Posted Date: December 22, 2023
• Actual Study Start Date: February 12, 2022
• Estimated Primary Completion Date: March 2027 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 14, 2023)

• Phase 2: Molecular response defined as ≥ 30% decrease from baseline in circulating tumor DNA (ctDNA) [ Time Frame: 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) [ Time Frame: Up to 60 months ]
  defined by time from randomization until disease progression as per iRECIST or death from any cause

Original Primary Outcome Measures (submitted: November 19, 2021)

• Phase 2: Antitumor activity of maintenance therapy combining GRT-C901/GRT-R902 with checkpoint inhibitors and fluoropyrimidine/bevacizumab [ Time Frame: Baseline and up to 27 months ]
  Antitumor activity measured by number of patients with ≥50% decrease from baseline in circulating tumor DNA (ctDNA).
• Phase 3: Progression-free Survival per Immune-based Response Evaluation Criteria in Solid Tumors (iRECIST) as assessed by blinded independent review committee (IRC) [ Time Frame: From time of randomization until disease progression or death from any cause (up to 60 months) ]

Current Secondary Outcome Measures (submitted: June 14, 2023)

• 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Up to 60 months ]
• Phase 2 and 3: Overall Survival as time from randomization to death from any cause [ Time Frame: Phase 2 up to 27 months, Phase 3 up to 60 months ]
• Phase 2 and 3: Overall Response Rate [ Time Frame: Phase 2 up to 27 months, Phase 3 up to 60 months ]
  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 and 3: Duration of response (DOR) defined by time from the first objective response of PR or PR until disease progression or death [ Time Frame: 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. [ Time Frame: 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 [ Time Frame: Phase 2 up to 27 months, Phase 3 up to 60 months ]
  VPS = Vaccine Production Stage; STS = Study Treatment Stage
• 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. [ Time Frame: Study Treatment Screening visit (up to 28 days before Day 1 of study drug administration) ]

Original Secondary Outcome Measures (submitted: November 19, 2021)

• Phase 2 and 3: Incidence of adverse events (AEs), 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 [ Time Frame: 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 [ Time Frame: From time of randomization until disease progression or death from any cause (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 [ Time Frame: From time of randomization until disease progression or death from any cause (up to 60 months) ]
• Phase 2 and 3: Overall Survival [ Time Frame: Phase 2 up to 27 months, Phase 3 up to 60 months ]
• Phase 2 and 3: Overall Response Rate [ Time Frame: Phase 2 up to 27 months, Phase 3 up to 60 months ]
  Response measured by number of patients with best response of Partial Response (PR), immune-base PR (iPR), Complete Response (CR), or iCR.
• Phase 2 and 3: Duration of Response [ Time Frame: From time of first response until disease progression (Phase 2 up to 27 months, Phase 3 up to 60 months) ]
• Phase 2 and 3: Clinical Benefit Rate (CBR) [ Time Frame: Phase 2 up to 27 months, Phase 3 up to 60 months ]
  CBR measured by number of patients who have achieved Stable Disease (SD), iSD, PR, iPR, CR, or iCR.
• Phase 2 and 3: Deepening of Response [ Time Frame: From time of first response (SD or PR) until conversion to PR or CR (Phase 2 up to 27 months, Phase 3 up to 60 months) ]
  Deepening of response measured by number of patients with SD or better response to routine therapy who convert from SD to PR or from PR to CR.
• Phase 2 and 3: Success of Vaccine Manufacture [ Time Frame: Study Treatment Screening visit (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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of a Patient-Specific Neoantigen Vaccine in Combination With Immune Checkpoint Blockade for Patients With Metastatic Colorectal Cancer
• Official Title: 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
• Brief 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.
• Detailed Description: 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.
• Study Type: Interventional
• Study Phase: Phase 2; Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Colorectal Neoplasms

Intervention

• Drug: GRT-C901
  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.
• Drug: GRT-R902
  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.
• Drug: Atezolizumab
  Atezolizumab will be administered via intravenous (IV) infusion at a dose of 1680 mg once every 4 weeks.
  Other Name: Tecentriq
• Drug: Ipilimumab
  Ipilimumab will be administered via subcutaneous (SC) injection at a dose of 30 mg with the first dose of GRT-C901 and GRT-R902.
  Other Name: Yervoy
• Drug: Fluoropyrimidine plus leucovorin
  Fluoropyrimidine (infusional 5-FU or capecitabine) and leucovorin administered as maintenance therapy per standard of care.
  Other Name: Xeloda
• Drug: Bevacizumab
  Bevacizumab administered as maintenance therapy per standard of care.
  Other Name: Avastin

Study Arms

• Experimental: Vaccine Arm
  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.
  Interventions:

  • Drug: GRT-C901
  • Drug: GRT-R902
  • Drug: Atezolizumab
  • Drug: Ipilimumab
  • Drug: Fluoropyrimidine plus leucovorin
  • Drug: Bevacizumab
• Active Comparator: Control Arm
  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.
  Interventions:

  • Drug: Fluoropyrimidine plus leucovorin
  • Drug: Bevacizumab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: June 14, 2023): 700
• Original Estimated Enrollment (submitted: November 19, 2021): 665
• Estimated Study Completion Date: March 2027
• Estimated Primary Completion Date: March 2027 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT05141721
• Other Study ID Numbers: GO-010
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Gritstone bio, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Gritstone bio, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Gritstone bio, Inc.
• Verification Date: April 2023