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
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 700
- 试验地点
- 43
- 主要终点
- Phase 3: Progression-free survival per Immune-based Response Evaluation Criteria in Solid Tumors (iRECIST) as assessed by blinded independent review committee (IRC)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
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.
干预措施: GRT-C901 (Drug)
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.
干预措施: GRT-R902 (Drug)
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.
干预措施: Atezolizumab (Drug)
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.
干预措施: Ipilimumab (Drug)
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.
干预措施: Fluoropyrimidine plus leucovorin (Drug)
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.
干预措施: Bevacizumab (Drug)
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.
干预措施: Fluoropyrimidine plus leucovorin (Drug)
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.
干预措施: Bevacizumab (Drug)
结局指标
主要结局
Phase 3: Progression-free survival per Immune-based Response Evaluation Criteria in Solid Tumors (iRECIST) as assessed by blinded independent review committee (IRC)
时间窗: Up to 60 months
defined by time from randomization until disease progression as per iRECIST or death from any cause
Phase 2: Molecular response defined as ≥ 30% decrease from baseline in circulating tumor DNA (ctDNA)
时间窗: Baseline and up to 27 months
次要结局
- Phase 3: Progression-free survival per RECIST v1.1 as assessed by blinded IRC(Up to 60 months)
- 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: 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: 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 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: 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(Phase 2 up to 27 months, Phase 3 up to 60 months)
- Phase 2 and 3: Overall Response Rate(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: 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))