Metastatic Microsatellite-stable Colorectal Cancer
Conditions
Keywords
Microsatellite, colorectal, MSS-CRC, colon cancer
Brief summary
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).
Detailed description
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.
Interventions
DRUGDurvalumab
Participants will receive IV infusion of durvalumab as stated in arm description.
DRUGOleclumab
Participants will receive IV infusion of oleclumab as stated in arm description.
DRUGFOLFOX
Participants will receive IV infusion of FOLFOX (5-FU, oxaliplatin, and folinic acid) as stated in arm description.
DRUGBevacizumab
Participants will receive IV infusion of bevacizumab as stated in arm description.
Sponsors
MedImmune LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
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. The treatment regimens evaluated in Part 2 will depend on the evaluation of safety outcomes in Part 1. Following a screening period of up to 28 days, participants will be centrally assigned (Part 1) or randomized (Part 2) to one of the open study arms. In both study parts, study treatment may be administered until disease progression or any discontinuation criteria are met. In Part 2, experimental arms may be closed early based on futility from results of a planned interim analysis for each study arm. In both parts, new experimental arms consisting of FOLFOX and bevacizumab plus novel agent(s) may be added based on emerging nonclinical and clinical data via protocol amendment.
Eligibility
Sex/Gender
ALL
Age
18 Years to 101 Years
Healthy volunteers
No
Inclusion criteria
1. Written informed consent and any locally required authorization obtained from the participant/legal representative prior to performing any protocol-related procedures, including screening evaluations. 2. Age ≥ 18 years at the time of screening. 3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 4. 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). 5. Participants must have at least one lesion that is measurable by RECIST v1.1 (Eisenhauer et al, 2009). 6. Participants must have adequate organ function. 7. 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. 8. Body weight \>35 kg. 9. Adequate method of contraception per protocol.
Exclusion criteria
1. History of allogeneic organ transplantation. 2. Active or prior documented autoimmune disorders within the past 5 years. 3. History of venous thrombosis within the past 3 months. 4. 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. 5. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥ 470 ms. 6. No significant history of bleeding events or gastrointestinal perforation. 7. Uncontrolled intercurrent illness. 8. 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. 9. History of active primary immunodeficiency. 10. Active infection including tuberculosis, hepatitis B, hepatitis C, or human immunodeficiency virus. 11. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients. 12. Any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade \> 1 from previous anticancer therapy. 13. History of leptomeningeal disease or cord compression. 14. Untreated central nervous system (CNS) metastases. 15. Lack of physical integrity of the upper gastrointestinal tract, malabsorption syndrome, or inability to take oral medication. 16. Known dihydropyrimidine dehydrogenase (DPD) deficiency. 17. Prior immunotherapy or anti-angiogenics. 18. Receipt of live attenuated vaccine within the past 30 days. 19. Major surgical procedure, open biopsy, or significant traumatic injury within the past 28 days. 20. Current or prior use of immunosuppressive medication within the past 14 days, with exceptions per protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 1 | 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 Abnormal Vital Signs Reported as TEAEs in Part 1 | 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). |
| Percentage of Participants With Objective Response (OR) Per Response Evaluation Criteria in Solid Tumours Version 1.1 (RECIST v1.1) in Part 2 | 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. |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) in Part 1 | 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 | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 oleclumab collected over time in Part 1 (S1) and Part 2 (E1) are reported. The LLOQ for oleclumab was considered to be 1 µg/mL. |
| Serum Concentrations of Bevacizumab in Part 1 (S1) | Pre-dose on Day 1 of Cycle 1, 2, 7, 13, and 27 | Serum concentrations of bevacizumab collected over time in Part 1 (S1) are reported. The LLOQ for bevacizumab was considered to be 500 ng/mL. |
| 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) | Number of participants with positive ADA to durvalumab in Part 1 (S1) and Part 2 (E1) are reported. |
| 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) | Number of participants with positive ADA to oleclumab in Part 1 (S1) and Part 2 (E1) are reported. |
| 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) | Number of participants with positive ADA to bevacizumab in Part 1 (S1) are reported. |
| Percentage of Participants With OR Per RECIST v1.1 in Part 1 | First dose (Day 1) through end of study (approximately 2.8 years) | The OR is defined as BOR of confirmed CR or confirmed PR based on RECIST v1.1 criteria. The CR is defined as disappearance of all TLs and 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 lesions. The PR is defined as at least a 30% decrease in the 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. |
| Best Overall Response (BOR) Per RECIST v1.1 in Part 1 | First dose (Day 1) through end of study (approximately 2.8 years) | BOR: best response including CR, PR, stable disease (SD), progressive disease (PD), and non-evaluable (NE) among all overall responses based on application of RECIST v1.1 to investigator assessments. CR: disappearance of all TLs and 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 lesions. PR: at least 30% decrease in the SoD of TL (compared to baseline) and no new NTL. Confirmation of CR and PR is required after 4 weeks. PD: at least a 20% increase in the SoDs of TLs, taking as reference the smallest sum on study, and an absolute increase of at least 5mm, or unequivocal progression of existing NTL, or new lesions. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD in at least 8 weeks from first dose of study drug. NE: either when no or only a subset of lesion measurements are made at an assessment. Number of participants with BOR are reported. |
| Duration of Response (DoR) Per RECIST v1.1 in Part 1 | First dose (Day 1) through end of study (approximately 2.8 years) | The DoR is defined as the time from the first documentation of a confirmed response (CR or PR) until the first documentation of PD or death due to any cause, whichever occurs first. The CR is defined as disappearance of all TLs and 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 lesions. The PR is defined as at least a 30% decrease in the SoD of TLs (compared to baseline) and no new lesion. Confirmation of CR and PR is required by a repeat, consecutive assessment no less than 4 weeks from the date of first documentation. The PD is defined as at least a 20% increase in the SoDs of TLs, taking as reference the smallest sum on study, and an absolute increase of at least 5 mm, or unequivocal progression of existing NTL, or new lesions. The DoR was analyzed using Kaplan-Meier method. |
| 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) | The DC is defined as BOR of confirmed CR, confirmed PR, or stable disease (SD; maintained for ≥ 16 weeks) per RECIST v1.1. The CR is defined as disappearance of all TLs and 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 lesions. The PR is defined as at least a 30% decrease in the SoD of TLs (compared to baseline) and no new lesion. Confirmation of CR and PR is required by a repeat, consecutive assessment no less than 4 weeks from the date of first documentation. The SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Participants with SD will be included in the DC if they maintain SD for \>= 16 weeks from start of treatment. |
| Progression-Free Survival (PFS) Per RECIST v1.1 in Part 1 | Assignment through end of study (approximately 2.8 years) | The PFS is defined as the time from assignment until the first documentation of PD or death due to any cause, whichever occurs first, regardless of whether the participant received subsequent anticancer therapy prior to progression. The PD is defined as at least a 20% increase in the SoDs of TLs, taking as reference the smallest sum on study, and an absolute increase of at least 5 mm, or unequivocal progression of existing NTL, or new lesions. The PFS was analyzed using the Kaplan-Meier method based on application of RECIST v1.1 to investigator assessments. Assignment occurred between Day -3 and -1. |
| Percentage of Participants With PFS at 12 Months (PFS-12) Per RECIST v1.1 in Part 1 | Assignment through 12 months | The PFS is defined as the time from assignment until the first documentation of PD or death due to any cause, whichever occurs first, regardless of whether the participant received subsequent anticancer therapy prior to progression. The PD is defined as at least a 20% increase in the SoDs of TLs, taking as reference the smallest sum on study, and an absolute increase of at least 5 mm, or unequivocal progression of existing NTL, or new lesions. The PFS was analyzed using Kaplan-Meier method based on application of RECIST v1.1 to investigator assessments. The percentage of participants progression free and alive at 12 months (PFS-12) are reported. Assignment occurred between Day -3 and -1. |
| Overall Survival (OS) Per RECIST v1.1 in Part 1 | First dose (Day 1) through end of study (approximately 2.8 years) | The OS is defined as the time from first dose until death due to any cause. The overall survival was analyzed using the Kaplan-Meier method based on application of RECIST v1.1 to investigator assessments. |
| 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) | An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A 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 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) | Number of participants with at least 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 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) | 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). |
| BOR Per RECIST v1.1 in Part 2 | Randomization through end of study (approximately 2.6 years) | BOR: best response including CR, PR, SD, PD, NE among all overall responses based on application of RECIST v1.1 to investigator assessments. CR: disappearance of all TLs, NTLs, normalization of tumor marker level, any pathological lymph nodes (target, non-target) must have reduction in short axis \<10 mm, no new lesions. PR: at least 30% decrease in the SoD of TL (compared to baseline) and no new NTL. Confirmation of CR, PR is required after 4 weeks. PD: at least a 20% increase in SoDs of TLs, taking as reference smallest sum on study, and an absolute increase of at least 5 mm, or unequivocal progression of existing NTL, or new lesions. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD in at least 8 weeks from first dose of study drug. NE: either when no or only a subset of lesion measurements are made at an assessment. Number of participants with BOR are reported. In Part 2, randomization occurred between Day -8 and the same date as dosing. |
| Percentage of Participants With DC Per RECIST v1.1 in Part 2 | Randomization through end of study (approximately 2.6 years) | The DC is defined as BOR of confirmed CR, confirmed PR, or SD (maintained for ≥ 16 weeks) per RECIST v1.1. The CR is defined as disappearance of all TLs and 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 lesions. The PR is defined as at least a 30% decrease in the SoD of TLs (compared to baseline) and no new lesion. Confirmation of CR and PR is required by a repeat, consecutive assessment no less than 4 weeks from the date of first documentation. The SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Participants with SD will be included in the DC if they maintain SD for \>= 16 weeks from start of treatment. In Part 2, randomization occurred between Day -8 and the same date as dosing. |
| DoR Per RECIST v1.1 in Part 2 | Randomization through end of study (approximately 2.6 years) | The DoR is defined as the time from the first documentation of a confirmed response (CR or PR) until the first documentation of PD or death due to any cause, whichever occurs first. The CR is defined as disappearance of all TLs and 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 lesions. The PR is defined as at least a 30% decrease in the SoD of TLs (compared to baseline) and no new lesion. Confirmation of CR and PR is required by a repeat, consecutive assessment no less than 4 weeks from the date of first documentation. The PD is defined as at least a 20% increase in the SoDs of TLs, taking as reference the smallest sum on study, and an absolute increase of at least 5 mm, or unequivocal progression of existing NTL, or new lesions. The DoR was analyzed using Kaplan-Meier method. In Part 2, randomization occurred between Day -8 and the same date as dosing. |
| PFS Per RECIST v1.1 in Part 2 | Randomization through end of study (approximately 2.6 years) | The PFS is defined as the time from randomization until the first documentation of PD or death due to any cause, whichever occurs first, regardless of whether the participant received subsequent anticancer therapy prior to progression. The PD is defined as at least a 20% increase in the SoDs of TLs, taking as reference the smallest sum on study, and an absolute increase of at least 5 mm, or unequivocal progression of existing NTL, or new lesions. The PFS was analyzed using the Kaplan-Meier method based on application of RECIST v1.1 to investigator assessments. In Part 2, randomization occurred between Day -8 and the same date as dosing. |
| Percentage of Participants With PFS at 12 Months (PFS-12) Per RECIST v1.1 in Part 2 | Randomization through 12 months | The PFS is defined as the time from randomization until the first documentation of PD or death due to any cause, whichever occurs first, regardless of whether the participant received subsequent anticancer therapy prior to progression. The PD is defined as at least a 20% increase in the SoDs of TLs, taking as reference the smallest sum on study, and an absolute increase of at least 5 mm, or unequivocal progression of existing NTL, or new lesions. The PFS was analyzed using Kaplan-Meier method based on application of RECIST v1.1 to investigator assessments. The percentage of participants progression free and alive at 12 months (PFS-12) are reported. In Part 2, randomization occurred between Day -8 and the same date as dosing. |
| OS Per RECIST v1.1 in Part 2 | Randomization through end of study (approximately 2.6 years) | The OS is defined as the time from randomization until death due to any cause. The overall survival was analyzed using the Kaplan-Meier method based on application of RECIST v1.1 to investigator assessments. In Part 2, randomization occurred between Day -8 and the same date as dosing. |
| 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 | Serum concentrations of durvalumab collected over time in Part 1 (S1) and Part 2 (E1) are reported. The lower limit of quantification (LLOQ) for durvalumab was considered to be 50 ng/mL. |
Countries
Australia, Canada, France, Spain, United States
Participant flow
Pre-assignment details
A total of 61 participants were randomized in this study of which 59 participants received treatment.
Participants by arm
| Arm | Count |
|---|---|
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab Participants in Part 1 safety run-in arm (S1) received 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 was met. | 7 |
| Part 2 (C1): FOLFOX + Bevacizumab Participants in Part 2 control 1 arm (C1) received 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 was met. | 26 |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab Participants in Part 2 experimental 1 arm (E1) received 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 was met. | 26 |
| Total | 59 |
Baseline characteristics
| Characteristic | Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Part 2 (C1): FOLFOX + Bevacizumab | Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Total |
|---|---|---|---|---|
| Age, Continuous | 59.4 Years STANDARD_DEVIATION 12.4 | 55.5 Years STANDARD_DEVIATION 13.5 | 59.8 Years STANDARD_DEVIATION 12.5 | 57.9 Years STANDARD_DEVIATION 12.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 4 Participants | 1 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants | 19 Participants | 23 Participants | 49 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 3 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 4 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) White | 7 Participants | 20 Participants | 23 Participants | 50 Participants |
| Sex: Female, Male Female | 3 Participants | 7 Participants | 11 Participants | 21 Participants |
| Sex: Female, Male Male | 4 Participants | 19 Participants | 15 Participants | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 4 / 7 | 8 / 26 | 13 / 26 |
| other Total, other adverse events | 7 / 7 | 25 / 26 | 26 / 26 |
| serious Total, serious adverse events | 1 / 7 | 7 / 26 | 12 / 26 |
Outcome results
Primary
Number of Participants With Abnormal Vital Signs Reported as TEAEs in Part 1
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).
Time frame: Day 1 through 90 days after the last dose of study drug (approximately 2.8 years)
Population: As-treated population included all participants who received any study drugs and were analyzed according to the treatment they actually received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With Abnormal Vital Signs Reported as TEAEs in Part 1 | Pyrexia | 2 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With Abnormal Vital Signs Reported as TEAEs in Part 1 | Temperature intolerance | 1 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With Abnormal Vital Signs Reported as TEAEs in Part 1 | Hypertension | 3 Participants |
Primary
Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 1
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.
Time frame: Baseline (Day 1) through 90 days after the last dose of study drug (approximately 2.8 years)
Population: As-treated population included all participants who received any study drugs and were analyzed according to the treatment they actually received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 1 | Hemoglobin (Hypo) | 1 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 1 | Lymphocytes (Hypo) | 2 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 1 | Neutrophils | 4 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 1 | Leukocytes (Hypo) | 3 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 1 | Activated Partial Thromboplastin Time | 1 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 1 | Albumin | 1 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 1 | Amylase | 2 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 1 | Bilirubin | 1 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 1 | Calcium Corrected (Hypo) | 1 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 1 | Creatine Kinase | 2 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 1 | Creatinine | 1 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 1 | Gamma Glutamyl Transferase | 1 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 1 | Glucose | 1 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 1 | Lipase | 5 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 1 | Magnesium (Hyper) | 1 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 1 | Magnesium (Hypo) | 1 Participants |
Primary
Number of Participants With Dose Limiting Toxicities (DLTs) in Part 1
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).
Time frame: From Day 1 to 28 days after the first dose of novel oncology therapy (durvalumab and oleclumab)
Population: The DLT evaluable population included all participants in Part 1 safety run-in who received the full prescribed dose of durvalumab and ≥ 75% of the prescribed number of doses of FOLFOX plus bevacizumab and the other novel oncology therapy and completed the safety follow-up through the DLT evaluation period or experienced any DLT.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With Dose Limiting Toxicities (DLTs) in Part 1 | 0 Participants |
Primary
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) in Part 1
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.
Time frame: Day 1 through 90 days after the last dose of study drug (approximately 2.8 years)
Population: As-treated population included all participants who received any study drugs and were analyzed according to the treatment they actually received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) in Part 1 | Any TEAE | 7 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) in Part 1 | Any TESAE | 1 Participants |
Primary
Percentage of Participants With Objective Response (OR) Per Response Evaluation Criteria in Solid Tumours Version 1.1 (RECIST v1.1) in Part 2
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.
Time frame: Randomization through end of study (approximately 2.6 years)
Population: Intent-to-treat (ITT) population included participants who received any study drug and were analyzed according to the treatment group they were randomized to.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Percentage of Participants With Objective Response (OR) Per Response Evaluation Criteria in Solid Tumours Version 1.1 (RECIST v1.1) in Part 2 | 46.2 Percentage of Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Percentage of Participants With Objective Response (OR) Per Response Evaluation Criteria in Solid Tumours Version 1.1 (RECIST v1.1) in Part 2 | 61.5 Percentage of Participants |
p-value: 0.317395% CI: [0.6, 5.6]Cochran-Mantel-Haenszel
Secondary
Best Overall Response (BOR) Per RECIST v1.1 in Part 1
BOR: best response including CR, PR, stable disease (SD), progressive disease (PD), and non-evaluable (NE) among all overall responses based on application of RECIST v1.1 to investigator assessments. CR: disappearance of all TLs and 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 lesions. PR: at least 30% decrease in the SoD of TL (compared to baseline) and no new NTL. Confirmation of CR and PR is required after 4 weeks. PD: at least a 20% increase in the SoDs of TLs, taking as reference the smallest sum on study, and an absolute increase of at least 5mm, or unequivocal progression of existing NTL, or new lesions. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD in at least 8 weeks from first dose of study drug. NE: either when no or only a subset of lesion measurements are made at an assessment. Number of participants with BOR are reported.
Time frame: First dose (Day 1) through end of study (approximately 2.8 years)
Population: As-treated population included all participants who received any study drugs and were analyzed according to the treatment they actually received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Best Overall Response (BOR) Per RECIST v1.1 in Part 1 | CR | 0 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Best Overall Response (BOR) Per RECIST v1.1 in Part 1 | PR | 5 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Best Overall Response (BOR) Per RECIST v1.1 in Part 1 | SD >=8 weeks | 2 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Best Overall Response (BOR) Per RECIST v1.1 in Part 1 | PD | 0 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Best Overall Response (BOR) Per RECIST v1.1 in Part 1 | NE | 0 Participants |
Secondary
BOR Per RECIST v1.1 in Part 2
BOR: best response including CR, PR, SD, PD, NE among all overall responses based on application of RECIST v1.1 to investigator assessments. CR: disappearance of all TLs, NTLs, normalization of tumor marker level, any pathological lymph nodes (target, non-target) must have reduction in short axis \<10 mm, no new lesions. PR: at least 30% decrease in the SoD of TL (compared to baseline) and no new NTL. Confirmation of CR, PR is required after 4 weeks. PD: at least a 20% increase in SoDs of TLs, taking as reference smallest sum on study, and an absolute increase of at least 5 mm, or unequivocal progression of existing NTL, or new lesions. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD in at least 8 weeks from first dose of study drug. NE: either when no or only a subset of lesion measurements are made at an assessment. Number of participants with BOR are reported. In Part 2, randomization occurred between Day -8 and the same date as dosing.
Time frame: Randomization through end of study (approximately 2.6 years)
Population: The ITT population included participants who received any study drug and were analyzed according to the treatment group they were randomized to.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | BOR Per RECIST v1.1 in Part 2 | PR | 12 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | BOR Per RECIST v1.1 in Part 2 | PD | 1 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | BOR Per RECIST v1.1 in Part 2 | SD >=8 weeks | 11 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | BOR Per RECIST v1.1 in Part 2 | NE | 2 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | BOR Per RECIST v1.1 in Part 2 | CR | 0 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | BOR Per RECIST v1.1 in Part 2 | NE | 1 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | BOR Per RECIST v1.1 in Part 2 | CR | 1 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | BOR Per RECIST v1.1 in Part 2 | PR | 15 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | BOR Per RECIST v1.1 in Part 2 | SD >=8 weeks | 6 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | BOR Per RECIST v1.1 in Part 2 | PD | 3 Participants |
Secondary
DoR Per RECIST v1.1 in Part 2
The DoR is defined as the time from the first documentation of a confirmed response (CR or PR) until the first documentation of PD or death due to any cause, whichever occurs first. The CR is defined as disappearance of all TLs and 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 lesions. The PR is defined as at least a 30% decrease in the SoD of TLs (compared to baseline) and no new lesion. Confirmation of CR and PR is required by a repeat, consecutive assessment no less than 4 weeks from the date of first documentation. The PD is defined as at least a 20% increase in the SoDs of TLs, taking as reference the smallest sum on study, and an absolute increase of at least 5 mm, or unequivocal progression of existing NTL, or new lesions. The DoR was analyzed using Kaplan-Meier method. In Part 2, randomization occurred between Day -8 and the same date as dosing.
Time frame: Randomization through end of study (approximately 2.6 years)
Population: The ITT population included participants who received any study drug and were analyzed according to the treatment group they were randomized to. The DoR was assessed for only those participants who had OR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | DoR Per RECIST v1.1 in Part 2 | 7.7 Months |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | DoR Per RECIST v1.1 in Part 2 | 10.3 Months |
Secondary
Duration of Response (DoR) Per RECIST v1.1 in Part 1
The DoR is defined as the time from the first documentation of a confirmed response (CR or PR) until the first documentation of PD or death due to any cause, whichever occurs first. The CR is defined as disappearance of all TLs and 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 lesions. The PR is defined as at least a 30% decrease in the SoD of TLs (compared to baseline) and no new lesion. Confirmation of CR and PR is required by a repeat, consecutive assessment no less than 4 weeks from the date of first documentation. The PD is defined as at least a 20% increase in the SoDs of TLs, taking as reference the smallest sum on study, and an absolute increase of at least 5 mm, or unequivocal progression of existing NTL, or new lesions. The DoR was analyzed using Kaplan-Meier method.
Time frame: First dose (Day 1) through end of study (approximately 2.8 years)
Population: As-treated population included all participants who received any study drugs and were analyzed according to the treatment they actually received. The DoR was assessed for only those participants who had OR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Duration of Response (DoR) Per RECIST v1.1 in Part 1 | 6.0 Months |
Secondary
Number of Participants With Abnormal Vital Signs Reported as TEAEs in Part 2
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).
Time frame: Day 1 through 90 days after the last dose of study drug (approximately 2.6 years)
Population: As-treated population included all participants who received any study drugs and were analyzed according to the treatment they actually received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With Abnormal Vital Signs Reported as TEAEs in Part 2 | Pyrexia | 3 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With Abnormal Vital Signs Reported as TEAEs in Part 2 | Temperature intolerance | 5 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With Abnormal Vital Signs Reported as TEAEs in Part 2 | Hypertension | 4 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With Abnormal Vital Signs Reported as TEAEs in Part 2 | Hypotension | 1 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With Abnormal Vital Signs Reported as TEAEs in Part 2 | Supraventricular tachycardia | 1 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With Abnormal Vital Signs Reported as TEAEs in Part 2 | Ventricular tachycardia | 1 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With Abnormal Vital Signs Reported as TEAEs in Part 2 | Supraventricular tachycardia | 0 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With Abnormal Vital Signs Reported as TEAEs in Part 2 | Pyrexia | 5 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With Abnormal Vital Signs Reported as TEAEs in Part 2 | Hypotension | 1 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With Abnormal Vital Signs Reported as TEAEs in Part 2 | Temperature intolerance | 5 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With Abnormal Vital Signs Reported as TEAEs in Part 2 | Ventricular tachycardia | 0 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With Abnormal Vital Signs Reported as TEAEs in Part 2 | Hypertension | 4 Participants |
Secondary
Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2
Number of participants with at least 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.
Time frame: Baseline (Day 1) through 90 days after the last dose of study drug (approximately 2.6 years)
Population: As-treated population included all participants who received any study drugs and were analyzed according to the treatment they actually received. Here, number analyzed (n) denotes number of participants analyzed for the specified parameter.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2 | Aspartate Aminotransferase | 1 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2 | Activated Partial Thromboplastin Time | 5 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2 | Bilirubin | 1 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2 | Lymphocytes (Hypo) | 3 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2 | Calcium Corrected (Hypo) | 0 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2 | Albumin | 0 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2 | Creatine Kinase | 2 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2 | Platelets | 3 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2 | Creatinine | 2 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2 | Alkaline Phosphatase | 1 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2 | Gamma Glutamyl Transferase | 5 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2 | Lymphocytes (Hyper) | 0 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2 | Potassium (Hyper) | 0 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2 | Alanine Aminotransferase | 2 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2 | Potassium (Hypo) | 0 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2 | Leukocytes (Hypo) | 2 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2 | Lipase | 12 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2 | Amylase | 7 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2 | Magnesium (Hypo) | 0 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2 | Neutrophils | 7 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2 | Sodium (Hypo) | 2 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2 | Hemoglobin (Hypo) | 0 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2 | Sodium (Hypo) | 2 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2 | Hemoglobin (Hypo) | 1 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2 | Lymphocytes (Hyper) | 2 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2 | Lymphocytes (Hypo) | 6 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2 | Neutrophils | 8 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2 | Platelets | 2 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2 | Leukocytes (Hypo) | 4 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2 | Activated Partial Thromboplastin Time | 5 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2 | Albumin | 3 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2 | Alkaline Phosphatase | 1 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2 | Alanine Aminotransferase | 1 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2 | Amylase | 3 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2 | Aspartate Aminotransferase | 0 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2 | Bilirubin | 1 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2 | Calcium Corrected (Hypo) | 1 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2 | Creatine Kinase | 3 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2 | Creatinine | 2 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2 | Gamma Glutamyl Transferase | 4 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2 | Potassium (Hyper) | 2 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2 | Potassium (Hypo) | 2 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2 | Lipase | 15 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2 | Magnesium (Hypo) | 1 Participants |
Secondary
Number of Participants With Positive ADA to Bevacizumab in Part 1 (S1)
Number of participants with positive ADA to bevacizumab in Part 1 (S1) are reported.
Time frame: Pre-dose on D1 of C1 (BL), 2, 7, 13, 27, and 90 days post last dose of study drug (approximately 2.8 years)
Population: The ADA evaluable population included all participants who received at least 1 dose of any study drug, who have a non-missing baseline ADA result and at least 1 non-missing post-baseline ADA result. Here, number analyzed (n) denotes those participants who had adequate ADA sample.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With Positive ADA to Bevacizumab in Part 1 (S1) | ADA positive at Cycle 7 Day 1 | 7 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With Positive ADA to Bevacizumab in Part 1 (S1) | ADA positive at baseline | 0 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With Positive ADA to Bevacizumab in Part 1 (S1) | ADA positive at Cycle 2 Day 1 | 5 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With Positive ADA to Bevacizumab in Part 1 (S1) | ADA positive at Cycle 13 Day 1 | 5 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With Positive ADA to Bevacizumab in Part 1 (S1) | ADA positive at Cycle 27 Day 1 | 1 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With Positive ADA to Bevacizumab in Part 1 (S1) | ADA positive at 90 days post last dose | 4 Participants |
Secondary
Number of Participants With Positive ADA to Oleclumab in Part 1 (S1) and Part 2 (E1)
Number of participants with positive ADA to oleclumab in Part 1 (S1) and Part 2 (E1) are reported.
Time frame: 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)
Population: The ADA evaluable population included all participants who received at least 1 dose of any study drug, who have a non-missing baseline ADA result and at least 1 non-missing post-baseline ADA result. Number of participants analyzed (N) denotes the number of participants evaluated for this outcome measure. Number analyzed (n) denotes those participants who had adequate ADA sample.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With Positive ADA to Oleclumab in Part 1 (S1) and Part 2 (E1) | ADA positive at Cycle 13 Day 1 | 0 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With Positive ADA to Oleclumab in Part 1 (S1) and Part 2 (E1) | ADA positive at Cycle 7 Day 1 | 0 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With Positive ADA to Oleclumab in Part 1 (S1) and Part 2 (E1) | ADA positive at Cycle 2 Day 1 | 0 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With Positive ADA to Oleclumab in Part 1 (S1) and Part 2 (E1) | ADA positive at 90 days post last dose | 0 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With Positive ADA to Oleclumab in Part 1 (S1) and Part 2 (E1) | ADA positive at baseline | 0 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With Positive ADA to Oleclumab in Part 1 (S1) and Part 2 (E1) | ADA positive at Cycle 27 Day 1 | 0 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With Positive ADA to Oleclumab in Part 1 (S1) and Part 2 (E1) | ADA positive at 90 days post last dose | 0 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With Positive ADA to Oleclumab in Part 1 (S1) and Part 2 (E1) | ADA positive at baseline | 0 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With Positive ADA to Oleclumab in Part 1 (S1) and Part 2 (E1) | ADA positive at Cycle 2 Day 1 | 2 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With Positive ADA to Oleclumab in Part 1 (S1) and Part 2 (E1) | ADA positive at Cycle 7 Day 1 | 0 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With Positive ADA to Oleclumab in Part 1 (S1) and Part 2 (E1) | ADA positive at Cycle 13 Day 1 | 0 Participants |
Secondary
Number of Participants With Positive Anti-Drug Antibodies (ADA) to Durvalumab in Part 1 (S1) and Part 2 (E1)
Number of participants with positive ADA to durvalumab in Part 1 (S1) and Part 2 (E1) are reported.
Time frame: 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)
Population: The ADA evaluable population included all participants who received at least 1 dose of any study drug, who have a non-missing baseline ADA result and at least 1 non-missing post-baseline ADA result. Number of participants analyzed (N) denotes the number of participants evaluated for this outcome measure. Number analyzed (n) denotes those participants who had adequate ADA sample.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With Positive Anti-Drug Antibodies (ADA) to Durvalumab in Part 1 (S1) and Part 2 (E1) | ADA positive at Cycle 13 Day 1 | 0 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With Positive Anti-Drug Antibodies (ADA) to Durvalumab in Part 1 (S1) and Part 2 (E1) | ADA positive at Cycle 7 Day 1 | 0 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With Positive Anti-Drug Antibodies (ADA) to Durvalumab in Part 1 (S1) and Part 2 (E1) | ADA positive at Cycle 3 Day 1 | 0 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With Positive Anti-Drug Antibodies (ADA) to Durvalumab in Part 1 (S1) and Part 2 (E1) | ADA positive at 90 days post last dose | 0 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With Positive Anti-Drug Antibodies (ADA) to Durvalumab in Part 1 (S1) and Part 2 (E1) | ADA positive at baseline | 0 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With Positive Anti-Drug Antibodies (ADA) to Durvalumab in Part 1 (S1) and Part 2 (E1) | ADA positive at Cycle 27 Day 1 | 0 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With Positive Anti-Drug Antibodies (ADA) to Durvalumab in Part 1 (S1) and Part 2 (E1) | ADA positive at 90 days post last dose | 0 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With Positive Anti-Drug Antibodies (ADA) to Durvalumab in Part 1 (S1) and Part 2 (E1) | ADA positive at baseline | 2 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With Positive Anti-Drug Antibodies (ADA) to Durvalumab in Part 1 (S1) and Part 2 (E1) | ADA positive at Cycle 3 Day 1 | 1 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With Positive Anti-Drug Antibodies (ADA) to Durvalumab in Part 1 (S1) and Part 2 (E1) | ADA positive at Cycle 7 Day 1 | 0 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With Positive Anti-Drug Antibodies (ADA) to Durvalumab in Part 1 (S1) and Part 2 (E1) | ADA positive at Cycle 13 Day 1 | 0 Participants |
Secondary
Number of Participants With TEAEs and TESAEs in Part 2
An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A 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.
Time frame: Day 1 through 90 days after the last dose of study drug (approximately 2.6 years)
Population: As-treated population included all participants who received any study drugs and were analyzed according to the treatment they actually received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With TEAEs and TESAEs in Part 2 | Any TEAE | 26 Participants |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With TEAEs and TESAEs in Part 2 | Any TESAE | 7 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With TEAEs and TESAEs in Part 2 | Any TEAE | 26 Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Number of Participants With TEAEs and TESAEs in Part 2 | Any TESAE | 12 Participants |
Secondary
OS Per RECIST v1.1 in Part 2
The OS is defined as the time from randomization until death due to any cause. The overall survival was analyzed using the Kaplan-Meier method based on application of RECIST v1.1 to investigator assessments. In Part 2, randomization occurred between Day -8 and the same date as dosing.
Time frame: Randomization through end of study (approximately 2.6 years)
Population: The ITT population included participants who received any study drug and were analyzed according to the treatment group they were randomized to.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | OS Per RECIST v1.1 in Part 2 | NA Months |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | OS Per RECIST v1.1 in Part 2 | 22.4 Months |
Secondary
Overall Survival (OS) Per RECIST v1.1 in Part 1
The OS is defined as the time from first dose until death due to any cause. The overall survival was analyzed using the Kaplan-Meier method based on application of RECIST v1.1 to investigator assessments.
Time frame: First dose (Day 1) through end of study (approximately 2.8 years)
Population: As-treated population included all participants who received any study drugs and were analyzed according to the treatment they actually received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Overall Survival (OS) Per RECIST v1.1 in Part 1 | 30.1 Months |
Secondary
Percentage of Participants With DC Per RECIST v1.1 in Part 2
The DC is defined as BOR of confirmed CR, confirmed PR, or SD (maintained for ≥ 16 weeks) per RECIST v1.1. The CR is defined as disappearance of all TLs and 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 lesions. The PR is defined as at least a 30% decrease in the SoD of TLs (compared to baseline) and no new lesion. Confirmation of CR and PR is required by a repeat, consecutive assessment no less than 4 weeks from the date of first documentation. The SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Participants with SD will be included in the DC if they maintain SD for \>= 16 weeks from start of treatment. In Part 2, randomization occurred between Day -8 and the same date as dosing.
Time frame: Randomization through end of study (approximately 2.6 years)
Population: The ITT population included participants who received any study drug and were analyzed according to the treatment group they were randomized to.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Percentage of Participants With DC Per RECIST v1.1 in Part 2 | 88.5 Percentage of Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Percentage of Participants With DC Per RECIST v1.1 in Part 2 | 84.6 Percentage of Participants |
Secondary
Percentage of Participants With Disease Control (DC) Per RECIST v1.1 in Part 1
The DC is defined as BOR of confirmed CR, confirmed PR, or stable disease (SD; maintained for ≥ 16 weeks) per RECIST v1.1. The CR is defined as disappearance of all TLs and 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 lesions. The PR is defined as at least a 30% decrease in the SoD of TLs (compared to baseline) and no new lesion. Confirmation of CR and PR is required by a repeat, consecutive assessment no less than 4 weeks from the date of first documentation. The SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Participants with SD will be included in the DC if they maintain SD for \>= 16 weeks from start of treatment.
Time frame: First dose (Day 1) through end of study (approximately 2.8 years)
Population: As-treated population included all participants who received any study drugs and were analyzed according to the treatment they actually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Percentage of Participants With Disease Control (DC) Per RECIST v1.1 in Part 1 | 100 Percentage of Participants |
Secondary
Percentage of Participants With OR Per RECIST v1.1 in Part 1
The OR is defined as BOR of confirmed CR or confirmed PR based on RECIST v1.1 criteria. The CR is defined as disappearance of all TLs and 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 lesions. The PR is defined as at least a 30% decrease in the 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.
Time frame: First dose (Day 1) through end of study (approximately 2.8 years)
Population: As-treated population included all participants who received any study drugs and were analyzed according to the treatment they actually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Percentage of Participants With OR Per RECIST v1.1 in Part 1 | 71.4 Percentage of Participants |
Secondary
Percentage of Participants With PFS at 12 Months (PFS-12) Per RECIST v1.1 in Part 1
The PFS is defined as the time from assignment until the first documentation of PD or death due to any cause, whichever occurs first, regardless of whether the participant received subsequent anticancer therapy prior to progression. The PD is defined as at least a 20% increase in the SoDs of TLs, taking as reference the smallest sum on study, and an absolute increase of at least 5 mm, or unequivocal progression of existing NTL, or new lesions. The PFS was analyzed using Kaplan-Meier method based on application of RECIST v1.1 to investigator assessments. The percentage of participants progression free and alive at 12 months (PFS-12) are reported. Assignment occurred between Day -3 and -1.
Time frame: Assignment through 12 months
Population: As-treated population included all participants who received any study drugs and were analyzed according to the treatment they actually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Percentage of Participants With PFS at 12 Months (PFS-12) Per RECIST v1.1 in Part 1 | 28.6 Percentage of Participants |
Secondary
Percentage of Participants With PFS at 12 Months (PFS-12) Per RECIST v1.1 in Part 2
The PFS is defined as the time from randomization until the first documentation of PD or death due to any cause, whichever occurs first, regardless of whether the participant received subsequent anticancer therapy prior to progression. The PD is defined as at least a 20% increase in the SoDs of TLs, taking as reference the smallest sum on study, and an absolute increase of at least 5 mm, or unequivocal progression of existing NTL, or new lesions. The PFS was analyzed using Kaplan-Meier method based on application of RECIST v1.1 to investigator assessments. The percentage of participants progression free and alive at 12 months (PFS-12) are reported. In Part 2, randomization occurred between Day -8 and the same date as dosing.
Time frame: Randomization through 12 months
Population: The ITT population included participants who received any study drug and were analyzed according to the treatment group they were randomized to.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Percentage of Participants With PFS at 12 Months (PFS-12) Per RECIST v1.1 in Part 2 | 38.6 Percentage of Participants |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Percentage of Participants With PFS at 12 Months (PFS-12) Per RECIST v1.1 in Part 2 | 36.1 Percentage of Participants |
Secondary
PFS Per RECIST v1.1 in Part 2
The PFS is defined as the time from randomization until the first documentation of PD or death due to any cause, whichever occurs first, regardless of whether the participant received subsequent anticancer therapy prior to progression. The PD is defined as at least a 20% increase in the SoDs of TLs, taking as reference the smallest sum on study, and an absolute increase of at least 5 mm, or unequivocal progression of existing NTL, or new lesions. The PFS was analyzed using the Kaplan-Meier method based on application of RECIST v1.1 to investigator assessments. In Part 2, randomization occurred between Day -8 and the same date as dosing.
Time frame: Randomization through end of study (approximately 2.6 years)
Population: The ITT population included participants who received any study drug and were analyzed according to the treatment group they were randomized to.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | PFS Per RECIST v1.1 in Part 2 | 11.1 Months |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | PFS Per RECIST v1.1 in Part 2 | 10.9 Months |
Secondary
Progression-Free Survival (PFS) Per RECIST v1.1 in Part 1
The PFS is defined as the time from assignment until the first documentation of PD or death due to any cause, whichever occurs first, regardless of whether the participant received subsequent anticancer therapy prior to progression. The PD is defined as at least a 20% increase in the SoDs of TLs, taking as reference the smallest sum on study, and an absolute increase of at least 5 mm, or unequivocal progression of existing NTL, or new lesions. The PFS was analyzed using the Kaplan-Meier method based on application of RECIST v1.1 to investigator assessments. Assignment occurred between Day -3 and -1.
Time frame: Assignment through end of study (approximately 2.8 years)
Population: As-treated population included all participants who received any study drugs and were analyzed according to the treatment they actually received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Progression-Free Survival (PFS) Per RECIST v1.1 in Part 1 | 9.5 Months |
Secondary
Serum Concentrations of Bevacizumab in Part 1 (S1)
Serum concentrations of bevacizumab collected over time in Part 1 (S1) are reported. The LLOQ for bevacizumab was considered to be 500 ng/mL.
Time frame: Pre-dose on Day 1 of Cycle 1, 2, 7, 13, and 27
Population: The PK evaluable population included participants who received at least 1 dose of any study drug with at least 1 reportable PK concentration. Here, number analyzed denotes those participants who had adequate serum samples.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Serum Concentrations of Bevacizumab in Part 1 (S1) | Cycle 1 Day 1 | NA ng/mL | — |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Serum Concentrations of Bevacizumab in Part 1 (S1) | Cycle 2 Day 1 | 36090 ng/mL | Geometric Coefficient of Variation 16.55 |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Serum Concentrations of Bevacizumab in Part 1 (S1) | Cycle 7 Day 1 | 73350 ng/mL | Geometric Coefficient of Variation 39.94 |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Serum Concentrations of Bevacizumab in Part 1 (S1) | Cycle 13 Day 1 | 70370 ng/mL | Geometric Coefficient of Variation 30.52 |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Serum Concentrations of Bevacizumab in Part 1 (S1) | Cycle 27 Day 1 | NA ng/mL | — |
Secondary
Serum Concentrations of Durvalumab in Part 1 (S1) and Part 2 (E1)
Serum concentrations of durvalumab collected over time in Part 1 (S1) and Part 2 (E1) are reported. The lower limit of quantification (LLOQ) for durvalumab was considered to be 50 ng/mL.
Time frame: 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
Population: Pharmacokinetic (PK) evaluable population included participants who received at least 1 dose of any study drug with at least 1 reportable PK concentration. Here, number of participants analyzed denotes those participants who were analyzed for this outcome measure. Number analyzed (n) denotes those participants who had adequate serum samples.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Serum Concentrations of Durvalumab in Part 1 (S1) and Part 2 (E1) | Cycle 1 Day 1 | NA ng/mL | — |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Serum Concentrations of Durvalumab in Part 1 (S1) and Part 2 (E1) | Cycle 3 Day 1 | 67980 ng/mL | Geometric Coefficient of Variation 20.31 |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Serum Concentrations of Durvalumab in Part 1 (S1) and Part 2 (E1) | Cycle 7 Day 1 | 112500 ng/mL | Geometric Coefficient of Variation 28.63 |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Serum Concentrations of Durvalumab in Part 1 (S1) and Part 2 (E1) | Cycle 13 Day 1 | 101500 ng/mL | Geometric Coefficient of Variation 30.22 |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Serum Concentrations of Durvalumab in Part 1 (S1) and Part 2 (E1) | Cycle 13 Day 1 | 147000 ng/mL | Geometric Coefficient of Variation 30.57 |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Serum Concentrations of Durvalumab in Part 1 (S1) and Part 2 (E1) | Cycle 7 Day 1 | 97610 ng/mL | Geometric Coefficient of Variation 46.56 |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Serum Concentrations of Durvalumab in Part 1 (S1) and Part 2 (E1) | Cycle 1 Day 1 | NA ng/mL | — |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Serum Concentrations of Durvalumab in Part 1 (S1) and Part 2 (E1) | Cycle 27 Day 1 | 120700 ng/mL | Geometric Coefficient of Variation 29.83 |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Serum Concentrations of Durvalumab in Part 1 (S1) and Part 2 (E1) | Cycle 3 Day 1 | 48600 ng/mL | Geometric Coefficient of Variation 39.67 |
Secondary
Serum Concentrations of Oleclumab in Part 1 (S1) and Part 2 (E1)
Serum concentrations of oleclumab collected over time in Part 1 (S1) and Part 2 (E1) are reported. The LLOQ for oleclumab was considered to be 1 µg/mL.
Time frame: 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
Population: The PK evaluable population included participants who received at least 1 dose of any study drug with at least 1 reportable PK concentration. Here, number of participants analyzed denotes those participants who were analyzed for this outcome measure. Number analyzed (n) denotes those participants who had adequate serum samples.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Serum Concentrations of Oleclumab in Part 1 (S1) and Part 2 (E1) | Cycle 1 Day 1 | NA µg/mL | — |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Serum Concentrations of Oleclumab in Part 1 (S1) and Part 2 (E1) | Cycle 2 Day 1 | 111.2 µg/mL | Geometric Coefficient of Variation 25.38 |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Serum Concentrations of Oleclumab in Part 1 (S1) and Part 2 (E1) | Cycle 7 Day 1 | 186.5 µg/mL | Geometric Coefficient of Variation 53.45 |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Serum Concentrations of Oleclumab in Part 1 (S1) and Part 2 (E1) | Cycle 13 Day 1 | 146.7 µg/mL | Geometric Coefficient of Variation 24.43 |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Serum Concentrations of Oleclumab in Part 1 (S1) and Part 2 (E1) | Cycle 13 Day 1 | 170.1 µg/mL | Geometric Coefficient of Variation 35.77 |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Serum Concentrations of Oleclumab in Part 1 (S1) and Part 2 (E1) | Cycle 7 Day 1 | 159.8 µg/mL | Geometric Coefficient of Variation 81.62 |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Serum Concentrations of Oleclumab in Part 1 (S1) and Part 2 (E1) | Cycle 1 Day 1 | NA µg/mL | — |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Serum Concentrations of Oleclumab in Part 1 (S1) and Part 2 (E1) | Cycle 27 Day 1 | 107.9 µg/mL | Geometric Coefficient of Variation 30.42 |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | Serum Concentrations of Oleclumab in Part 1 (S1) and Part 2 (E1) | Cycle 2 Day 1 | 69.81 µg/mL | Geometric Coefficient of Variation 199.1 |