A Phase Ib/II, Open-label, Multicenter Study of Novel Oncology Therapies in Combination With Chemotherapy and Bevacizumab as First-line Therapy in Metastatic Microsatellite-stable Colorectal Cancer (COLUMBIA-1)
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 61
- 试验地点
- 22
- 主要终点
- Number of Participants With Abnormal Vital Signs Reported as TEAEs in Part 1
研究概览
简要总结
COLUMBIA-1 is a Phase 1b/2 platform study to evaluate the safety and efficacy of standard of care (FOLFOX plus bevacizumab) alone and in combination with novel oncology therapies in first-line metastatic microsatellite-stable colorectal cancer (MSS-CRC).
详细描述
COLUMBIA-1 is a Phase 1b/2, open-label, multicenter, randomized, multidrug platform study to evaluate the safety and efficacy of standard of care (FOLFOX plus bevacizumab) in combination with novel oncology therapies in patients with first-line metastatic MSS-CRC. The study is designed to concurrently evaluate potential novel combinations with clinical promise using a 2-part approach. Part 1 is a Phase 1b study of safety, and Part 2 is a Phase 2 study of efficacy and safety.
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 101 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Written informed consent and any locally required authorization obtained from the participant/legal representative prior to performing any protocol-related procedures, including screening evaluations.
- •Age ≥ 18 years at the time of screening.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or
- •Participants must have histologic documentation of advanced or metastatic CRC and: (a) A documented mutation test during screening and confirmed tumor locations from disease assessment for enrollment. (b) Participants must NOT have defective deoxyribonucleic acid (DNA) mismatch repair (MSI) as documented by testing. (c) Participants must not have received any prior systemic therapy for recurrent/metastatic disease (prior adjuvant chemotherapy or radio-chemotherapy is acceptable so long as progression was not within 6 months of completing the adjuvant regimen).
- •Participants must have at least one lesion that is measurable by RECIST v1.1 (Eisenhauer et al, 2009).
- •Participants must have adequate organ function.
- •Participants with medical conditions requiring systemic anticoagulation (eg, atrial fibrillation) are eligible provided that both of the following criteria are met: - The participant has an in-range International Normalized Ratio (INR) on a stable dose of oral anticoagulant or be on a stable dose of low molecular weight heparin. - The participant has no active bleeding or pathological condition that carries a high risk of bleeding.
- •Body weight >35 kg.
- •Adequate method of contraception per protocol.
排除标准
- •History of allogeneic organ transplantation.
- •Active or prior documented autoimmune disorders within the past 5 years.
- •History of venous thrombosis within the past 3 months.
- •Cardiovascular criteria: (a) Presence of acute coronary syndrome including myocardial infarction or unstable angina pectoris, other arterial thrombotic event including cerebrovascular accident or transient ischemic attack or stroke within the past 6 months. (b) New York Heart Association (NYHA) class II or greater congestive heart failure, serious cardiac arrhythmia requiring medication, or uncontrolled hypertension. (c) History of hypertensive crisis/hypertensive encephalopathy within the past 6 months.
- •Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥ 470 ms.
- •No significant history of bleeding events or gastrointestinal perforation.
- •Uncontrolled intercurrent illness.
- •History of another primary malignancy except for: (a) Malignancy treated with curative intent and with no known active disease ≥ 5 years of low potential risk for recurrence. (b) Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease. (c) Adequately treated carcinoma in situ without evidence of disease.
- •History of active primary immunodeficiency.
- •Active infection including tuberculosis, hepatitis B, hepatitis C, or human immunodeficiency virus.
- •Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
- •Any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade > 1 from previous anticancer therapy.
- •History of leptomeningeal disease or cord compression.
- •Untreated central nervous system (CNS) metastases.
- •Lack of physical integrity of the upper gastrointestinal tract, malabsorption syndrome, or inability to take oral medication.
- •Known dihydropyrimidine dehydrogenase (DPD) deficiency.
- •Prior immunotherapy or anti-angiogenics.
- •Receipt of live attenuated vaccine within the past 30 days.
- •Major surgical procedure, open biopsy, or significant traumatic injury within the past 28 days.
- •Current or prior use of immunosuppressive medication within the past 14 days, with exceptions per protocol.
研究组 & 干预措施
Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab
Participants in Part 1 safety run-in arm (S1) will receive intravenous (IV) infusions of FOLFOX (5-fluorouracil [5-FU]: 2400 mg/m^2 over 46-48 hours [Day 1 and 2 of every 14-day Cycle], oxaliplatin: 85 mg/m^2, folinic acid: 400 mg/m^2) and bevacizumab 5 mg/kg on Day 1 of every Cycle (14-day cycle) in combination with IV durvalumab 1500 mg every 4 weeks (Q4W) and IV oleclumab 3000 mg every 2 weeks (Q2W) till 4 doses (Cycle 4) then Q4W starting on Cycle 5 Day 1 until disease progression, unacceptable toxicity, withdrawal of participant consent, or another discontinuation criterion will be met.
干预措施: FOLFOX (Drug)
Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab
Participants in Part 2 experimental 1 arm (E1) will receive IV infusions of FOLFOX (5-FU: 2400 mg/m^2 over 46-48 hours [Day 1 and 2 of every 14-day Cycle], oxaliplatin: 85 mg/m^2, folinic acid: 400 mg/m^2) and bevacizumab 5 mg/kg on Day 1 of every Cycle (14-day cycle) in combination with IV durvalumab 1500 mg Q4W and IV oleclumab 3000 mg Q2W till 4 doses (Cycle 4) then Q4W starting on Cycle 5 Day 1 until disease progression, unacceptable toxicity, withdrawal of participant consent, or another discontinuation criterion will be met.
干预措施: Oleclumab (Drug)
Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab
Participants in Part 1 safety run-in arm (S1) will receive intravenous (IV) infusions of FOLFOX (5-fluorouracil [5-FU]: 2400 mg/m^2 over 46-48 hours [Day 1 and 2 of every 14-day Cycle], oxaliplatin: 85 mg/m^2, folinic acid: 400 mg/m^2) and bevacizumab 5 mg/kg on Day 1 of every Cycle (14-day cycle) in combination with IV durvalumab 1500 mg every 4 weeks (Q4W) and IV oleclumab 3000 mg every 2 weeks (Q2W) till 4 doses (Cycle 4) then Q4W starting on Cycle 5 Day 1 until disease progression, unacceptable toxicity, withdrawal of participant consent, or another discontinuation criterion will be met.
干预措施: Durvalumab (Drug)
Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab
Participants in Part 1 safety run-in arm (S1) will receive intravenous (IV) infusions of FOLFOX (5-fluorouracil [5-FU]: 2400 mg/m^2 over 46-48 hours [Day 1 and 2 of every 14-day Cycle], oxaliplatin: 85 mg/m^2, folinic acid: 400 mg/m^2) and bevacizumab 5 mg/kg on Day 1 of every Cycle (14-day cycle) in combination with IV durvalumab 1500 mg every 4 weeks (Q4W) and IV oleclumab 3000 mg every 2 weeks (Q2W) till 4 doses (Cycle 4) then Q4W starting on Cycle 5 Day 1 until disease progression, unacceptable toxicity, withdrawal of participant consent, or another discontinuation criterion will be met.
干预措施: Oleclumab (Drug)
Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab
Participants in Part 1 safety run-in arm (S1) will receive intravenous (IV) infusions of FOLFOX (5-fluorouracil [5-FU]: 2400 mg/m^2 over 46-48 hours [Day 1 and 2 of every 14-day Cycle], oxaliplatin: 85 mg/m^2, folinic acid: 400 mg/m^2) and bevacizumab 5 mg/kg on Day 1 of every Cycle (14-day cycle) in combination with IV durvalumab 1500 mg every 4 weeks (Q4W) and IV oleclumab 3000 mg every 2 weeks (Q2W) till 4 doses (Cycle 4) then Q4W starting on Cycle 5 Day 1 until disease progression, unacceptable toxicity, withdrawal of participant consent, or another discontinuation criterion will be met.
干预措施: Bevacizumab (Drug)
Part 2 (C1): FOLFOX + Bevacizumab
Participants in Part 2 control 1 arm (C1) will receive IV infusions of FOLFOX (5-FU: 2400 mg/m^2 over 46-48 hours [Day 1 and 2 of every 14-day Cycle], oxaliplatin: 85 mg/m^2, folinic acid: 400 mg/m^2) in combination with IV bevacizumab 5 mg/kg on Day 1 of every Cycle (14-day cycle) until disease progression, unacceptable toxicity, withdrawal of participant consent, or another discontinuation criterion will be met.
干预措施: Bevacizumab (Drug)
Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab
Participants in Part 2 experimental 1 arm (E1) will receive IV infusions of FOLFOX (5-FU: 2400 mg/m^2 over 46-48 hours [Day 1 and 2 of every 14-day Cycle], oxaliplatin: 85 mg/m^2, folinic acid: 400 mg/m^2) and bevacizumab 5 mg/kg on Day 1 of every Cycle (14-day cycle) in combination with IV durvalumab 1500 mg Q4W and IV oleclumab 3000 mg Q2W till 4 doses (Cycle 4) then Q4W starting on Cycle 5 Day 1 until disease progression, unacceptable toxicity, withdrawal of participant consent, or another discontinuation criterion will be met.
干预措施: Bevacizumab (Drug)
Part 2 (C1): FOLFOX + Bevacizumab
Participants in Part 2 control 1 arm (C1) will receive IV infusions of FOLFOX (5-FU: 2400 mg/m^2 over 46-48 hours [Day 1 and 2 of every 14-day Cycle], oxaliplatin: 85 mg/m^2, folinic acid: 400 mg/m^2) in combination with IV bevacizumab 5 mg/kg on Day 1 of every Cycle (14-day cycle) until disease progression, unacceptable toxicity, withdrawal of participant consent, or another discontinuation criterion will be met.
干预措施: FOLFOX (Drug)
Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab
Participants in Part 2 experimental 1 arm (E1) will receive IV infusions of FOLFOX (5-FU: 2400 mg/m^2 over 46-48 hours [Day 1 and 2 of every 14-day Cycle], oxaliplatin: 85 mg/m^2, folinic acid: 400 mg/m^2) and bevacizumab 5 mg/kg on Day 1 of every Cycle (14-day cycle) in combination with IV durvalumab 1500 mg Q4W and IV oleclumab 3000 mg Q2W till 4 doses (Cycle 4) then Q4W starting on Cycle 5 Day 1 until disease progression, unacceptable toxicity, withdrawal of participant consent, or another discontinuation criterion will be met.
干预措施: FOLFOX (Drug)
Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab
Participants in Part 2 experimental 1 arm (E1) will receive IV infusions of FOLFOX (5-FU: 2400 mg/m^2 over 46-48 hours [Day 1 and 2 of every 14-day Cycle], oxaliplatin: 85 mg/m^2, folinic acid: 400 mg/m^2) and bevacizumab 5 mg/kg on Day 1 of every Cycle (14-day cycle) in combination with IV durvalumab 1500 mg Q4W and IV oleclumab 3000 mg Q2W till 4 doses (Cycle 4) then Q4W starting on Cycle 5 Day 1 until disease progression, unacceptable toxicity, withdrawal of participant consent, or another discontinuation criterion will be met.
干预措施: Durvalumab (Drug)
结局指标
主要结局
Number of Participants With Abnormal Vital Signs Reported as TEAEs in Part 1
时间窗: Day 1 through 90 days after the last dose of study drug (approximately 2.8 years)
Number of participants with abnormal vital signs reported as TEAEs are reported. Abnormal vital signs are defined as any abnormal finding in the vital sign parameters (body temperature, blood pressure, and pulse rate).
Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 1
时间窗: Baseline (Day 1) through 90 days after the last dose of study drug (approximately 2.8 years)
Number of participants with at least common terminology criteria for adverse events (CTCAE v5.0) 2-grade shift from baseline (last assessment prior to first dose) to worst toxicity grade in clinical laboratory parameters are reported. Clinical laboratory parameter analysis included hematology, clinical chemistry, coagulation, and urinalysis.
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) in Part 1
时间窗: Day 1 through 90 days after the last dose of study drug (approximately 2.8 years)
An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug.
Number of Participants With Dose Limiting Toxicities (DLTs) in Part 1
时间窗: From Day 1 to 28 days after the first dose of novel oncology therapy (durvalumab and oleclumab)
DLT: Any study drug related Grade (G)3 or higher toxicity including: any G3/G4 immune-mediated AE, any G3/4 noninfectious pneumonitis/colitis, transaminase elevation (TE) \>8x upper limit of normal (ULN) or total bilirubin (TBL) \>5xULN, increase in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \>=3xULN along with TBL \>=2xULN, isolated liver TE \>5 but =\<8xULN or isolated TBL \>3 but =\<5xULN that does not downgrade to G1 or less within 14 days of onset, G3 nausea/vomiting/diarrhea that does not resolve to G2 or less within 3 days of maximal supportive care (MSC), G3/4 febrile neutropenia, G3/4 neutropenia not associated with fever/systemic infection, G4 anemia, G3 anemia with clinical sequelae/requires \>2 units of red blood cells transfusion, thrombocytopenia (G4 \>=7 days, G3 that did not improve by at least 1 grade within 7 days, G3/4 associated with G3/higher hemorrhage).
Percentage of Participants With Objective Response (OR) Per Response Evaluation Criteria in Solid Tumours Version 1.1 (RECIST v1.1) in Part 2
时间窗: Randomization through end of study (approximately 2.6 years)
The OR is defined as best overall response (BOR) of confirmed complete response (CR) or confirmed partial response (PR) based on RECIST v1.1 criteria. The CR is defined as disappearance of all target lesions (TLs) and non-target lesions (NTLs), normalization of tumor marker level, any pathological lymph nodes (target and non-target) must have reduction in short axis \< 10 mm, and no new lesion. The PR is defined as at least a 30% decrease in the sum of the diameters (SoD) of TLs (compared to baseline) and no new lesions. Confirmation of CR and PR is required by a repeat, consecutive assessment no less than 4 weeks from the date of first documentation. In Part 2, randomization occurred between Day -8 and the same date as dosing.
次要结局
- Percentage of Participants With OR Per RECIST v1.1 in Part 1(First dose (Day 1) through end of study (approximately 2.8 years))
- Percentage of Participants With DC Per RECIST v1.1 in Part 2(Randomization through end of study (approximately 2.6 years))
- Percentage of Participants With PFS at 12 Months (PFS-12) Per RECIST v1.1 in Part 2(Randomization through 12 months)
- Serum Concentrations of Durvalumab in Part 1 (S1) and Part 2 (E1)(Part 1: Pre-dose on Day 1 of Cycle 1, 3, 7, 13; Part 2 (E1): Pre-dose on Day 1 of Cycle 1, 3, 7, 13, and 27)
- Number of Participants With Positive Anti-Drug Antibodies (ADA) to Durvalumab in Part 1 (S1) and Part 2 (E1)(Part 1: Pre-dose on Day(D)1 of Cycles(C)1 (baseline [BL]), 3, 7, 13, and 90 days post last dose of study drug (approximately 2.8 years); Part 2(E1):Pre-dose on D1 of C1 (BL), 3, 7, 13, 27, and 90 days post last dose of study drug (approximately 2.6 years))
- Best Overall Response (BOR) Per RECIST v1.1 in Part 1(First dose (Day 1) through end of study (approximately 2.8 years))
- Progression-Free Survival (PFS) Per RECIST v1.1 in Part 1(Assignment through end of study (approximately 2.8 years))
- Percentage of Participants With PFS at 12 Months (PFS-12) Per RECIST v1.1 in Part 1(Assignment through 12 months)
- Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2(Baseline (Day 1) through 90 days after the last dose of study drug (approximately 2.6 years))
- BOR Per RECIST v1.1 in Part 2(Randomization through end of study (approximately 2.6 years))
- Number of Participants With Abnormal Vital Signs Reported as TEAEs in Part 2(Day 1 through 90 days after the last dose of study drug (approximately 2.6 years))
- DoR Per RECIST v1.1 in Part 2(Randomization through end of study (approximately 2.6 years))
- PFS Per RECIST v1.1 in Part 2(Randomization through end of study (approximately 2.6 years))
- Duration of Response (DoR) Per RECIST v1.1 in Part 1(First dose (Day 1) through end of study (approximately 2.8 years))
- Number of Participants With TEAEs and TESAEs in Part 2(Day 1 through 90 days after the last dose of study drug (approximately 2.6 years))
- OS Per RECIST v1.1 in Part 2(Randomization through end of study (approximately 2.6 years))
- Percentage of Participants With Disease Control (DC) Per RECIST v1.1 in Part 1(First dose (Day 1) through end of study (approximately 2.8 years))
- Overall Survival (OS) Per RECIST v1.1 in Part 1(First dose (Day 1) through end of study (approximately 2.8 years))
- Number of Participants With Positive ADA to Oleclumab in Part 1 (S1) and Part 2 (E1)(Part 1: Pre-dose on D1 of C1 (BL), 2, 7, 13, and 90 days post last dose of study drug (approximately 2.8 years); Part 2 (E1): Pre-dose on D1 of C1 (BL), 2, 7, 13, 27, and 90 days post last dose of study drug (approximately 2.6 years))
- Serum Concentrations of Oleclumab in Part 1 (S1) and Part 2 (E1)(Part 1: Pre-dose on Day 1 of Cycle 1, 2, 7, and 13; Part 2 (E1): Pre-dose on Day 1 of Cycle 1, 2, 7, 13, and 27)
- Serum Concentrations of Bevacizumab in Part 1 (S1)(Pre-dose on Day 1 of Cycle 1, 2, 7, 13, and 27)
- Number of Participants With Positive ADA to Bevacizumab in Part 1 (S1)(Pre-dose on D1 of C1 (BL), 2, 7, 13, 27, and 90 days post last dose of study drug (approximately 2.8 years))