COLUMBIA-1: Novel Oncology Therapies in Combination With Chemotherapy and Bevacizumab as First- Line Therapy in MSS-CRC

Phase 2Active Not RecruitingNCT04068610

MedImmune LLC61 enrolled

Overview

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).

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Metastatic Microsatellite-stable Colorectal Cancer

Interventions

DurvalumabDRUG

Participants will receive IV infusion of durvalumab as stated in arm description.

OleclumabDRUG

Participants will receive IV infusion of oleclumab as stated in arm description.

FOLFOXDRUG

Participants will receive IV infusion of FOLFOX (5-FU, oxaliplatin, and folinic acid) as stated in arm description.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 101 Years

Medical Language ↔ Plain English

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.

Locations (21)

Research Site

Los Angeles, California, United States

Research Site

Sacramento, California, United States

Outcomes

Primary Outcomes

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)

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)

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.

Data from ClinicalTrials.gov

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Secondary Outcomes

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)

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)

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)

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)

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)

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

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)

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)

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)

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)

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.