Novel Oncology Therapies in Combination With Adjuvant Chemo in High-risk MSS-CRC

A Phase 2, Open-label, Randomized, Multicenter, Platform Study of Novel Oncology Therapies in Combination With Adjuvant Chemotherapy in High-risk, Microsatellite-stable Colorectal Cancer (COLUMBIA-2)

Columbia 2 is a Phase 2 platform study to evaluate the safety and efficacy of standard of care (FOLFOX) alone and in combination with novel oncology therapies in adjuvant high-risk microsatellite-stable colorectal cancer

Study Overview

• Status: Withdrawn
• Conditions: Microsatellite-stable Colorectal Cancer
• Intervention / Treatment: Drug: Standard of Care - mFOLFOX6; Drug: E1 - mFOLFOX and durvalumab; Drug: E2 - mFOLFOX6, durvalumab and oleclumab; Drug: E3 - mFOLFOX6, durvalumab and monalizumab

Detailed Description

Columbia 2 is a Phase 2, open-label, randomized, multicenter, platform study of novel oncology therapies in combination with adjuvant chemotherapy in patients with high-risk microsatellite-stable colorectal cancer.

• Study Type: Interventional
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

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

Description

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. Histologically proven Stage II or Stage III CRC

   Subjects must also meet the following criteria:

   1. Eligible for 6 months of mFOLFOX6 adjuvant chemotherapy within 8 weeks after surgery
   2. Must NOT have received prior systemic chemotherapy, immunotherapy, or radiotherapy for treatment of CRC.
   3. Must NOT have defective DNA mismatch repair (MSI) as documented by testing
5. Margin-negative (R0; defined as >1 mm clearance) surgical resection
6. Postoperative ctDNA-positive status defined by the presence of ctDNA derived from plasma; determined using a validated assay per protocol
7. Subjects must have adequate organ function
8. Body weight > 35 kg
9. Adequate method of contraception per protocol

Exclusion Criteria:

1. Any condition that, in the opinion of the investigator, would interfere with evaluation of the investigational product or interpretation of subject safety or study results.
2. Evidence of metastatic disease (including presence of tumor cells in ascites or peritoneal carcinomatosis resected "en bloc").
3. History of allogeneic organ transplantation.
4. Active or prior documented autoimmune disorders within the past 5 years as noted in the protocol.

5. Cardiac and vascular criteria:

   1. History of venous thrombosis within the past 3 months prior to the scheduled first dose of study treatment.
   2. 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 prior to the scheduled first dose of study treatment.
   3. New York Heart Association (NYHA) Class II or greater congestive heart failure, serious cardiac arrhythmia requiring medication, or uncontrolled hypertension.
   4. History of hypertensive crisis/hypertensive encephalopathy within the past 6 months prior to the scheduled first dose of study treatment.
   5. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥ 470 ms
6. Uncontrolled intercurrent illness, see the protocol for details.
7. History of another primary malignancy except for: (a) Malignancy treated with curative intent and with no known active disease ≥ 5 years prior to the scheduled first dose of study treatment and of low potential risk for recurrence
8. History of active primary immunodeficiency.
9. Active infection including tuberculosis, hepatitis B, hepatitis C, or human immunodeficiency virus.
10. Known allergy or hypersensitivity to any of the investigational product or noninvestigational product formulations.
11. Any condition that, in the opinion of the investigator, would prevent the initiation of 6 months adjuvant therapy within 8 weeks of surgery
12. Any concurrent chemotherapy, investigational product, biologic, or hormonal therapy for cancer treatment.
13. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to the scheduled first dose of study treatment, or anticipation of the need for major surgical procedure during the course of the study.
14. Current or prior use of immunosuppressive medication within 14 days prior to the scheduled first dose of study treatment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Control Arm (mFOLFOX6); Parts of mFOLFOX6 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) 400 mg/m2 IV bolus on Day 1 then 2,400 mg/m2 over 46 to 48 hours IV infusion Q2W (Day 1-2 of every 14-day cycle).	Drug: Standard of Care - mFOLFOX6; Parts of mFOLFOX6 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) 400 mg/m2 IV bolus on Day 1 then 2,400 mg/m2 over 46 to 48 hours IV infusion Q2W (Day 1-2 of every 14-day cycle).; Other Names: FOLFOX (Oxaliplatin, Folinic acid (leucovorin), Fluorouracil (5-FU)); Drug: E1 - mFOLFOX and durvalumab; Parts of mFOLFOX6 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) 400 mg/m2 IV bolus on Day 1 then 2,400 mg/m2 over 46 to 48 hours IV infusion Q2W (Day 1-2 of every 14-day cycle). Durvalumab 1500 mg IV, Q4W (Day 1 of every other 14-day cycle); Other Names: Durvalumab (MEDI-4736); Drug: E2 - mFOLFOX6, durvalumab and oleclumab; Parts of mFOLFOX6 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) 400 mg/m2 IV bolus on Day 1 then 2,400 mg/m2 over 46 to 48 hours IV infusion Q2W (Day 1-2 of every 14-day cycle). Durvalumab 1500 mg IV, Q4W (Day 1 of every other 14-day cycle) Oleclumab 3,000 mg IV Q2W x5 then Q4W (Day 1 of every 14-day cycle through cycle 4 then Day 1 of every other 14-day cycle); Other Names: Durvalumab (MEDI-4736) + Oleclumab (MEDI-9447); Drug: E3 - mFOLFOX6, durvalumab and monalizumab; Parts of mFOLFOX6 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) 400 mg/m2 IV bolus on Day 1 then 2,400 mg/m2 over 46 to 48 hours IV infusion Q2W (Day 1-2 of every 14-day cycle). Durvalumab 1500 mg IV, Q4W (Day 1 of every other 14-day cycle) Monalizumab 750 mg IV, Q2W (Day 1 of every 14-day cycle); Other Names: Durvalumab (MEDI-4736) + Monalizumab (IPH2201)
Experimental: Durvalumab; Durvalumab 1500 mg IV, Q4W (Day 1 of every other 14-day cycle)	Drug: E1 - mFOLFOX and durvalumab; Parts of mFOLFOX6 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) 400 mg/m2 IV bolus on Day 1 then 2,400 mg/m2 over 46 to 48 hours IV infusion Q2W (Day 1-2 of every 14-day cycle). Durvalumab 1500 mg IV, Q4W (Day 1 of every other 14-day cycle); Other Names: Durvalumab (MEDI-4736); Drug: E2 - mFOLFOX6, durvalumab and oleclumab; Parts of mFOLFOX6 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) 400 mg/m2 IV bolus on Day 1 then 2,400 mg/m2 over 46 to 48 hours IV infusion Q2W (Day 1-2 of every 14-day cycle). Durvalumab 1500 mg IV, Q4W (Day 1 of every other 14-day cycle) Oleclumab 3,000 mg IV Q2W x5 then Q4W (Day 1 of every 14-day cycle through cycle 4 then Day 1 of every other 14-day cycle); Other Names: Durvalumab (MEDI-4736) + Oleclumab (MEDI-9447); Drug: E3 - mFOLFOX6, durvalumab and monalizumab; Parts of mFOLFOX6 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) 400 mg/m2 IV bolus on Day 1 then 2,400 mg/m2 over 46 to 48 hours IV infusion Q2W (Day 1-2 of every 14-day cycle). Durvalumab 1500 mg IV, Q4W (Day 1 of every other 14-day cycle) Monalizumab 750 mg IV, Q2W (Day 1 of every 14-day cycle); Other Names: Durvalumab (MEDI-4736) + Monalizumab (IPH2201)
Experimental: Oleclumab; Oleclumab 3,000 mg IV Q2W x5 then Q4W (Day 1 of every 14-day cycle through cycle 4 then Day 1 of every other 14-day cycle)	Drug: E2 - mFOLFOX6, durvalumab and oleclumab; Parts of mFOLFOX6 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) 400 mg/m2 IV bolus on Day 1 then 2,400 mg/m2 over 46 to 48 hours IV infusion Q2W (Day 1-2 of every 14-day cycle). Durvalumab 1500 mg IV, Q4W (Day 1 of every other 14-day cycle) Oleclumab 3,000 mg IV Q2W x5 then Q4W (Day 1 of every 14-day cycle through cycle 4 then Day 1 of every other 14-day cycle); Other Names: Durvalumab (MEDI-4736) + Oleclumab (MEDI-9447)
Experimental: Monalizumab; Monalizumab 750 mg IV, Q2W (Day 1 of every 14-day cycle)	Drug: E3 - mFOLFOX6, durvalumab and monalizumab; Parts of mFOLFOX6 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) 400 mg/m2 IV bolus on Day 1 then 2,400 mg/m2 over 46 to 48 hours IV infusion Q2W (Day 1-2 of every 14-day cycle). Durvalumab 1500 mg IV, Q4W (Day 1 of every other 14-day cycle) Monalizumab 750 mg IV, Q2W (Day 1 of every 14-day cycle); Other Names: Durvalumab (MEDI-4736) + Monalizumab (IPH2201)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ctDNA clearance	ctDNA clearance is defined as the change from ctDNA positive status at baseline to ctDNA negative post baseline (6 months)	From the time of first dose to 6 months post treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of adverse events	The secondary endpoint of safety as assessed by the number of subjects with adverse events and serious adverse events	From time of first dose to 90 days post last dose
Disease free survival	From randomization until time of first documented incidence of disease recurrence, secondary cancer, or death due to any cause, whichever occurs first	From time of first dose till end of study (5 years)
Disease free survival at 12 months	Percentage of subject who are disease free at 12 months post first dose of treatment	From time of first dose till end of study (5 years)
overall survival	From randomization until death due to any cause	From time of first dose till end of study (5 years)
Serum conenctration levels of novel agents in combination with mFOLFOX6	Pharmacokinetics of novel agents in combination with FOLFOX	From Day 1 up to 90 days post last dose
Number of subjects with detectable anti-drug antibody (ADA) to novel agents in combination with mFOLFOX6	Immunogenicity of novel agents in combination with mFOLFOX6	From Day 1 up to 90 days post last dose

Collaborators and Investigators

• Sponsor: MedImmune LLC

Study record dates

Study Major Dates

• Study Start (Anticipated): October 1, 2020
• Primary Completion (Anticipated): March 19, 2024
• Study Completion (Anticipated): March 19, 2024

Study Registration Dates

• First Submitted: October 16, 2019
• First Submitted That Met QC Criteria: October 29, 2019
• First Posted (Actual): October 30, 2019

Study Record Updates

• Last Update Posted (Actual): September 21, 2020
• Last Update Submitted That Met QC Criteria: September 17, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Keywords: colorectal cancer; adjuvant; Colon Cancer; Microsatellite stable; MSS-CRC
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Antineoplastic Agents, Immunological; Micronutrients; Vitamins; Antidotes; Vitamin B Complex; Fluorouracil; Oxaliplatin; Durvalumab; Leucovorin; Antibodies, Monoclonal
• Other Study ID Numbers: D910CC00002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

IPD 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

IPD Sharing 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.

IPD Sharing 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.

• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No