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

NCT04068610 | Active Not Recruiting Phase 1 Results FDA Drug

• 2 other identifiers: D910CC000012019-000974-44
• Study Type: interventional
• Target: 61
• Locations: 5 countries
• Sites: 21

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).

Conditions

Metastatic Microsatellite-stable Colorectal Cancer

Keywords

Microsatellite; colorectal; MSS-CRC; colon cancer

Outcome Measures

Primary Outcomes (5)

• 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.

  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).

  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.

  Baseline (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 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).

  Day 1 through 90 days after the last dose of study drug (approximately 2.8 years)

• 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.

  Randomization through end of study (approximately 2.6 years)

Secondary Outcomes (22)

• Percentage of Participants With OR Per RECIST v1.1 in Part 1

  First dose (Day 1) through end of study (approximately 2.8 years)

• Best Overall Response (BOR) Per RECIST v1.1 in Part 1

  First dose (Day 1) through end of study (approximately 2.8 years)

• Duration of Response (DoR) Per RECIST v1.1 in Part 1

  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

  First dose (Day 1) through end of study (approximately 2.8 years)

• Progression-Free Survival (PFS) Per RECIST v1.1 in Part 1

  Assignment through end of study (approximately 2.8 years)

Study Arms (3)

Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab

EXPERIMENTAL

Participants in Part 1 safety run-in arm (S1) will receive intravenous (IV) infusions of FOLFOX (5-fluorouracil \[5-FU\]: 2400 mg/m\^2 over 46-48 hours \[Day 1 and 2 of every 14-day Cycle\], oxaliplatin: 85 mg/m\^2, folinic acid: 400 mg/m\^2) and bevacizumab 5 mg/kg on Day 1 of every Cycle (14-day cycle) in combination with IV durvalumab 1500 mg every 4 weeks (Q4W) and IV oleclumab 3000 mg every 2 weeks (Q2W) till 4 doses (Cycle 4) then Q4W starting on Cycle 5 Day 1 until disease progression, unacceptable toxicity, withdrawal of participant consent, or another discontinuation criterion will be met.

Drug: Durvalumab; Drug: Oleclumab; Drug: FOLFOX; Drug: Bevacizumab

Part 2 (C1): FOLFOX + Bevacizumab

EXPERIMENTAL

Participants in Part 2 control 1 arm (C1) will receive IV infusions of FOLFOX (5-FU: 2400 mg/m\^2 over 46-48 hours \[Day 1 and 2 of every 14-day Cycle\], oxaliplatin: 85 mg/m\^2, folinic acid: 400 mg/m\^2) in combination with IV bevacizumab 5 mg/kg on Day 1 of every Cycle (14-day cycle) until disease progression, unacceptable toxicity, withdrawal of participant consent, or another discontinuation criterion will be met.

Drug: FOLFOX; Drug: Bevacizumab

Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab

EXPERIMENTAL

Participants in Part 2 experimental 1 arm (E1) will receive IV infusions of FOLFOX (5-FU: 2400 mg/m\^2 over 46-48 hours \[Day 1 and 2 of every 14-day Cycle\], oxaliplatin: 85 mg/m\^2, folinic acid: 400 mg/m\^2) and bevacizumab 5 mg/kg on Day 1 of every Cycle (14-day cycle) in combination with IV durvalumab 1500 mg Q4W and IV oleclumab 3000 mg Q2W till 4 doses (Cycle 4) then Q4W starting on Cycle 5 Day 1 until disease progression, unacceptable toxicity, withdrawal of participant consent, or another discontinuation criterion will be met.

Drug: Durvalumab; Drug: Oleclumab; Drug: FOLFOX; Drug: Bevacizumab

Interventions

Durvalumab DRUG

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

Also known as: MEDI4736

Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab; Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab

Oleclumab DRUG

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

Also known as: MEDI9447

Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab; Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab

FOLFOX DRUG

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

Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab; Part 2 (C1): FOLFOX + Bevacizumab; Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab

Bevacizumab DRUG

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

Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab; Part 2 (C1): FOLFOX + Bevacizumab; Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab

Eligibility Criteria

• Age: 18 Years - 101 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent and any locally required authorization obtained from the participant/legal representative prior to performing any protocol-related procedures, including screening evaluations.
• Age ≥ 18 years at the time of screening.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Participants must have histologic documentation of advanced or metastatic CRC and: (a) A documented mutation test during screening and confirmed tumor locations from disease assessment for enrollment. (b) Participants must NOT have defective deoxyribonucleic acid (DNA) mismatch repair (MSI) as documented by testing. (c) Participants must not have received any prior systemic therapy for recurrent/metastatic disease (prior adjuvant chemotherapy or radio-chemotherapy is acceptable so long as progression was not within 6 months of completing the adjuvant regimen).
• Participants must have at least one lesion that is measurable by RECIST v1.1 (Eisenhauer et al, 2009).
• Participants must have adequate organ function.
• Participants with medical conditions requiring systemic anticoagulation (eg, atrial fibrillation) are eligible provided that both of the following criteria are met: - The participant has an in-range International Normalized Ratio (INR) on a stable dose of oral anticoagulant or be on a stable dose of low molecular weight heparin. - The participant has no active bleeding or pathological condition that carries a high risk of bleeding.
• Body weight \>35 kg.
• Adequate method of contraception per protocol.

You may not qualify if:

• History of allogeneic organ transplantation.
• Active or prior documented autoimmune disorders within the past 5 years.
• History of venous thrombosis within the past 3 months.
• Cardiovascular criteria: (a) Presence of acute coronary syndrome including myocardial infarction or unstable angina pectoris, other arterial thrombotic event including cerebrovascular accident or transient ischemic attack or stroke within the past 6 months. (b) New York Heart Association (NYHA) class II or greater congestive heart failure, serious cardiac arrhythmia requiring medication, or uncontrolled hypertension. (c) History of hypertensive crisis/hypertensive encephalopathy within the past 6 months.
• Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥ 470 ms.
• No significant history of bleeding events or gastrointestinal perforation.
• Uncontrolled intercurrent illness.
• History of another primary malignancy except for: (a) Malignancy treated with curative intent and with no known active disease ≥ 5 years of low potential risk for recurrence. (b) Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease. (c) Adequately treated carcinoma in situ without evidence of disease.
• History of active primary immunodeficiency.
• Active infection including tuberculosis, hepatitis B, hepatitis C, or human immunodeficiency virus.
• Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
• Any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade \> 1 from previous anticancer therapy.
• History of leptomeningeal disease or cord compression.
• Untreated central nervous system (CNS) metastases.
• Lack of physical integrity of the upper gastrointestinal tract, malabsorption syndrome, or inability to take oral medication.

Sponsors & Collaborators

• MedImmune LLC: lead

Study Sites (21)

Research Site

Los Angeles, California, 90095, United States

Location

Research Site

Sacramento, California, 95817, United States

Location

Research Site

Ann Arbor, Michigan, 48109, United States

Location

Research Site

Las Vegas, Nevada, 89169, United States

Location

Research Site

New York, New York, 10065, United States

Location

Research Site

Canton, Ohio, 44718, United States

Location

Research Site

Providence, Rhode Island, 02903, United States

Location

Research Site

Chattanooga, Tennessee, 37404, United States

Location

Research Site

Nashville, Tennessee, 37203, United States

Location

Research Site

Houston, Texas, 77030, United States

Location

Research Site

Charlottesville, Virginia, 22908, United States

Location

Research Site

Clayton, 3168, Australia

Location

Research Site

Heidelberg, 3084, Australia

Location

Research Site

Melbourne, 3000, Australia

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Research Site

Toronto, Ontario, M5G 1X6, Canada

Location

Research Site

Nantes, 44000, France

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Research Site

Villejuif, 94805, France

Location

Research Site

Barcelona, 08035, Spain

Location

Research Site

Barcelona, 08916, Spain

Location

Research Site

Madrid, 28027, Spain

Location

Research Site

Madrid, 28046, Spain

Location

Related Publications (1)

• Segal NH, Tie J, Kopetz S, Ducreux M, Chen E, Dienstmann R, Hollebecque A, Reilley MJ, Elez E, Cosaert J, Cain J, Soo-Hoo Y, Hewson N, Cooper ZA, Kumar R, Tabernero J. COLUMBIA-1: a randomised study of durvalumab plus oleclumab in combination with chemotherapy and bevacizumab in metastatic microsatellite-stable colorectal cancer. Br J Cancer. 2024 Oct;131(6):1005-1013. doi: 10.1038/s41416-024-02796-3. Epub 2024 Jul 25.

  PMID: 39048638 DERIVED

Related Links

• CSP redacted
• SAP redacted
• CSR redacted

MeSH Terms

Conditions

Colonic Neoplasms

Interventions

durvalumab; Folfox protocol; Bevacizumab

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Limitations and Caveats

The data cut-off for the study was October 2022. The decision was made to end recruitment for the study because superior efficacy was not observed for the novel study drug combinations under investigation. For patient that were benefiting from the treatment the study remained active for them to continue receiving treatment.

Results Point of Contact

• Title: Global Clinical Lead
• Organization: AstraZeneca Clinical study Information Center

information.center@astrazeneca.com

+1-877-240-9479

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: August 1, 2019
• First Posted: August 28, 2019
• Study Start: September 13, 2019
• Primary Completion: October 10, 2022
• Study Completion (Estimated): November 24, 2026
• Last Updated: May 15, 2026
• Results First Posted: November 15, 2023

Record last verified: 2026-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Locations

FR (2); AU (3); US (11); ES (4); CA (1)