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

• ClinicalTrials.gov Identifier: NCT04068610
• Recruitment Status: Active, not recruiting
• First Posted: August 28, 2019
• Last Update Posted: July 31, 2020
• Sponsor: MedImmune LLC
• Information provided by (Responsible Party): MedImmune LLC

Study Description

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).

Condition or disease	Intervention/treatment	Phase
Metastatic Microsatellite-stable Colorectal Cancer	Drug: Standard of Care; Drug: Experimental	Phase 1; Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 112 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment

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, subjects 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.

• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1b/2, Open-label, Multicenter Study of Novel Oncology Therapies in Combination With Chemotherapy and Bevacizumab as First-line Therapy in Metastatic Microsatellite-stable Colorectal Cancer (COLUMBIA-1)
• Actual Study Start Date: September 13, 2019
• Estimated Primary Completion Date: February 22, 2024
• Estimated Study Completion Date: February 22, 2024

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Control Arm (FOLFOX + Bevacuzimab); Parts of FOLFOX are: Oxaliplatin 85 mg/m2 IV infusion Q2W (Day 1 of every 14-day cycle), Folinic acid (leucovorin) 400 mg/m2 IV infusion Q2W (Day 1 of every 14-day cycle), Fluorouracil (5-FU) 2400 mg/m2 administered by continuous IV infusion over 46 to 48 hours Q2W (Day 1-2 of every 14-day cycle). Note: 5-FU will be administered as infusion only. Bevacizumab 5 mg/kg IV infusion Q2W (Day 1 of every 14-day cycle)	Drug: Standard of Care; Parts of FOLFOX are: Oxaliplatin 85 mg/m2 IV infusion Q2W (Day 1 of every 14-day cycle), Folinic acid (leucovorin) 400 mg/m2 IV infusion Q2W (Day 1 of every 14-day cycle), Fluorouracil (5-FU) 2400 mg/m2 administered by continuous IV infusion over 46 to 48 hours Q2W (Day 1-2 of every 14-day cycle). Note: 5-FU will be administered as infusion only. Bevacizumab 5 mg/kg IV infusion Q2W (Day 1 of every 14-day cycle); Other Names: FOLFOX (Oxaliplatin, Folinic acid (leucovorin), Fluorouracil (5-FU)); Bevacizumab (Avastin)
Experimental: Exp. Arm (FOLFOX + Bevacuzimab + Durvalumab + Oleclumab); Parts of FOLFOX are: Oxaliplatin 85 mg/m2 IV infusion Q2W (Day 1 of every 14-day cycle), Folinic acid (leucovorin) 400 mg/m2 IV infusion Q2W (Day 1 of every 14-day cycle), Fluorouracil (5-FU) 2400 mg/m2 administered by continuous IV infusion over 46 to 48 hours Q2W (Day 1-2 of every 14-day cycle). Note: 5-FU will be administered as infusion only. Bevacizumab 5 mg/kg IV infusion Q2W (Day 1 of every 14-day cycle) Durvalumab 1500 mg IV Q4W Oleclumab 3000mg IV Q2W x 4 then Q4W	Drug: Experimental; Parts of FOLFOX are: Oxaliplatin 85 mg/m2 IV infusion Q2W (Day 1 of every 14-day cycle), Folinic acid (leucovorin) 400 mg/m2 IV infusion Q2W (Day 1 of every 14-day cycle), Fluorouracil (5-FU) 2400 mg/m2 administered by continuous IV infusion over 46 to 48 hours Q2W (Day 1-2 of every 14-day cycle). Note: 5-FU will be administered as infusion only. Bevacizumab 5 mg/kg IV infusion Q2W (Day 1 of every 14-day cycle) Durvalumab 1500 mg IV Q4W Oleclumab 3000mg IV Q2W x 4 then Q4W; Other Names: Durvalumab (MEDI-4736); Oleclumab (MEDI-9447)

Outcome Measures

Primary Outcome Measures :

1. Part 1 of the study: Number of participants with Dose Limiting Toxicities (DLTs) as a measure of safety. [ Time Frame: From the time of first dose through 28 days during the Part 1 of the study. ]
   The primary endpoint is safety as assessed by the presence of adverse events and serious adverse events
2. Part 2 of the study: Objective Response (OR) rate as a measure of antitumor activity of FOLFOX plus bevacizumab plus novel oncology therapy combinations versus FOLFOX plus bevacizumab. [ Time Frame: From randomization/enrollment until progression, or the last evaluable disease assessment in the absence of PD prior to the initiation of subsequent anticancer therapy or discontinuation from the study, whichever occurs first, assessed up to 5 years. ]
   Best overall response of confirmed CR or confirmed PR according to RECIST v1.1

Secondary Outcome Measures :

1. Incidence of Adverse Events as a measure of safety during the treatment period [ Time Frame: From time of informed consent through treatment period (24 months) or up to 3 months post last dose of study treatment ]
   The secondary endpoint of safety as assessed by the presence of adverse events and serious adverse events
2. Incidence of clinically significant vital sign values as a measure of safety during the treatment period [ Time Frame: From time of informed consent through treatment period (12 months) or up to 3 months post last dose of study treatment ]
   Assess the presence of clinically significant vital sign values from baseline
3. Incidence of clinically significant laboratory values as a measure of safety during the treatment period [ Time Frame: From time of informed consent through treatment period (12 months) or up to 3 months post last dose of study treatment ]
   The secondary endpoint of safety as assessed by the presence of clinically significant laboratory values
4. Duration of Response (DoR) as a measure of efficacy of FOLFOX plus bevacizumab plus novel oncology therapy combinations versus FOLFOX plus bevacizumab [ Time Frame: From time of first documented response until disease progression or up to a maximum of 5 years after randomization ]
   The duration from the first documentation of a subsequently confirmed OR to the first documentation of a disease progression according to RECIST v1.1 or death due to any cause, whichever occurs first. Only subjects who have achieved OR (confirmed CR or confirmed PR) will be evaluated for DoR
5. Disease Control Rate (DCR) as a measure of efficacy of FOLFOX plus bevacizumab plus novel oncology therapy combinations versus FOLFOX plus bevacizumab [ Time Frame: From time of randomization until disease progression or up to a maximum of 5 years ]
   confirmed CR, confirmed PR, or SD based on RECIST v1.1
6. Progression-Free Survival (PFS) as a measure of efficacy of FOLFOX plus bevacizumab plus novel oncology therapy combinations versus FOLFOX plus bevacizumab [ Time Frame: From time of randomization until disease progression or up to a maximum of 5 years ]
   From randomization until the first documentation of disease progression according to RECIST v1.1 or death due to any cause, whichever occurs first
7. Progression-Free Survival 12 month landmark rate (PFS-12) as a measure of efficacy of FOLFOX plus bevacizumab plus novel oncology therapy combinations versus FOLFOX plus bevacizumab [ Time Frame: From time of randomization until disease progression or up to a maximum of 12 months ]
   From randomization until the first documentation of disease progression according to RECIST v1.1 or death due to any cause, whichever occurs first
8. Overall Survival (OS) as a measure of efficacy of FOLFOX plus bevacizumab plus novel oncology therapy combinations versus FOLFOX plus bevacizumab [ Time Frame: From time of randomization until death ]
   From randomization until death due to any cause.
9. Serum concentration levels of novel agents in combination with FOLFOX + bevacuzimab [ Time Frame: From Day 1 up to 90 days post last dose ]
   Pharmacokinetics of novel agents in combination with FOLFOX + bevacuzimab
10. Number of subjects with detectable anti-drug antibody (ADA) to novel agents in combination with FOLFOX + bevacuzimab [ Time Frame: From Day 1 up to 90 days post last dose ]
    Immunogenicity of novel agents in combination with FOLFOX + bevacuzimab

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 101 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Written informed consent and any locally required authorization obtained from the subject/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. Subjects 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) Subjects must NOT have defective DNA mismatch repair (MSI) as documented by testing. (c) Subjects 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. Subjects must have at least one lesion that is measurable by RECIST v1.1 (Eisenhauer et al, 2009).
6. Subjects must have adequate organ function.
7. Subjects with medical conditions requiring systemic anticoagulation (eg, atrial fibrillation) are eligible provided that both of the following criteria are met: - The subject has an in-range INR on a stable dose of oral anticoagulant or be on a stable dose of low molecular weight heparin. - The subject 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 NCI 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.

Contacts and Locations

Locations

United States, California

Research Site

Los Angeles, California, United States, 90024

Research Site

Sacramento, California, United States, 95817

United States, Connecticut

Research Site

New Haven, Connecticut, United States, 06520

United States, Iowa

Research Site

Ames, Iowa, United States, 50010

United States, Michigan

Research Site

Ann Arbor, Michigan, United States, 48109

United States, Nevada

Research Site

Las Vegas, Nevada, United States, 89169

United States, New York

Research Site

New York, New York, United States, 10065

United States, North Carolina

Research Site

Chapel Hill, North Carolina, United States, 27599

United States, Ohio

Research Site

Canton, Ohio, United States, 44718

United States, Pennsylvania

Research Site

Philadelphia, Pennsylvania, United States, 19104

United States, Rhode Island

Research Site

Providence, Rhode Island, United States, 02903

United States, Tennessee

Research Site

Chattanooga, Tennessee, United States, 37404

Research Site

Nashville, Tennessee, United States, 37203

United States, Texas

Research Site

Houston, Texas, United States, 77584

United States, Utah

Research Site

Salt Lake City, Utah, United States, 84112

United States, Virginia

Research Site

Charlottesville, Virginia, United States, 22908

Australia

Research Site

Blacktown, Australia, 2148

Research Site

Clayton, Australia, 3168

Research Site

Heidelberg, Australia, 3084

Research Site

Melbourne, Australia, 3000

Research Site

Waratah, Australia, 2298

Canada, Alberta

Research Site

Calgary, Alberta, Canada, T2N 4N2

Research Site

Edmonton, Alberta, Canada, T6G 1Z2

Canada, Ontario

Research Site

Oshawa, Ontario, Canada, L1G 2B9

Research Site

Toronto, Ontario, Canada, M5G 1X6

Canada, Quebec

Research Site

Montreal, Quebec, Canada, H3T 1M5

France

Research Site

Bordeaux, France, 33000

Research Site

Lille, France, 59000

Research Site

Nantes, France, 44000

Research Site

Paris, France, 75012

Research Site

Paris, France, 75015

Research Site

Toulouse Cedex 9, France, 31059

Research Site

Villejuif, France, 94805

Spain

Research Site

Barcelona, Spain, 08035

Research Site

Barcelona, Spain, 08916

Research Site

Madrid, Spain, 28027

Research Site

Madrid, Spain, 28046

Research Site

Majadahonda, Spain, 28222

Research Site

Valencia, Spain, 46010

Sponsors and Collaborators

MedImmune LLC

More Information

• Responsible Party: MedImmune LLC
• ClinicalTrials.gov Identifier: NCT04068610
• Other Study ID Numbers: D910CC00001
• First Posted: August 28, 2019
• Last Update Posted: July 31, 2020
• Last Verified: July 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (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.
• URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by MedImmune LLC:

Microsatellite; colorectal; MSS-CRC; colon cancer

Additional relevant MeSH terms:

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Leucovorin; Bevacizumab; Durvalumab; Fluorouracil; Oxaliplatin; Antineoplastic Agents, Immunological; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Physiological Effects of Drugs; Growth Inhibitors; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Immunosuppressive Agents; Immunologic Factors; Antidotes; Protective Agents