Testing the Addition of Nivolumab to Standard Treatment for Patients With Metastatic or Unresectable Colorectal Cancer That Have a BRAF Mutation

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Recruiting
• CT.gov ID: NCT05308446
• Collaborator: (none)
• Enrollment: 84
• Locations: 72
• Arms: 2
• Anticipated Duration (Months): 26.8
• Patients Per Site: 1.2
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This phase II trial tests whether adding nivolumab to the usual treatment (encorafenib and cetuximab) works better than the usual treatment alone to shrink tumors in patients with colorectal cancer that has spread to other places in the body (metastatic) or that cannot be removed by surgery (unresectable) and whose tumor has a mutation in a gene called BRAF. Encorafenib is in a class of medications called kinase inhibitors. It is used in patients whose cancer has a certain mutation (change) in the BRAF gene. It works by blocking the action of mutated BRAF that signals cancer cells to multiply. This helps to stop or slow the spread of cancer cells. Cetuximab is in a class of medications called monoclonal antibodies. It binds to a protein called EGFR, which is found on some types of cancer cells. This may help keep cancer cells from growing. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving nivolumab in combination with encorafenib and cetuximab may be more effective than encorafenib and cetuximab alone at stopping tumor growth and spreading in patients with metastatic or unresectable BRAF-mutant colorectal cancer.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Colon Adenocarcinoma; Metastatic Rectal Adenocarcinoma; Stage III Colon Cancer AJCC v8; Stage III Rectal Cancer AJCC v8; Stage IV Colon Cancer AJCC v8; Stage IV Rectal Cancer AJCC v8; Unresectable Colon Adenocarcinoma; Unresectable Rectal Adenocarcinoma	Biological: Cetuximab; Drug: Encorafenib; Biological: Nivolumab	Phase 2

Detailed Description

PRIMARY OBJECTIVE:

1. To compare progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 in patients with microsatellite stable (MSS), BRAF^V600E metastatic and/or unresectable colorectal cancer (CRC) randomized to treatment with nivolumab + encorafenib + cetuximab compared to encorafenib + cetuximab.

SECONDARY OBJECTIVES:

1. To compare overall response rate (ORR), including confirmed and unconfirmed, complete and partial response, according to RECIST 1.1 criteria between the two arms.

2. To compare overall survival (OS) between the two arms. III. To compare duration of response between the two arms. IV. To compare safety and tolerability between the two arms.

3. To assess immune-related PFS using modified response criteria adapted for immunotherapy (irRC-PFS) in patients treated with nivolumab + encorafenib + cetuximab.

BANKING OBJECTIVE:

1. To bank tissue and blood specimens for future correlative studies.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive encorafenib orally (PO) once daily (QD) on days 1-28, cetuximab intravenously (IV) on days 1 and 15, and nivolumab IV on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive encorafenib PO QD on days 1-28 and cetuximab IV on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed until death or 3 years after registration, whichever occurs first.

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 84 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Randomized Phase II Trial of Encorafenib and Cetuximab With or Without Nivolumab (NSC #748726) for Patients With Previously Treated, Microsatellite Stable, BRAFV600E Metastatic and/or Unresectable Colorectal Cancer
• Actual Study Start Date: Jun 6, 2022
• Anticipated Primary Completion Date: Aug 31, 2024
• Anticipated Study Completion Date: Aug 31, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I (encorafenib, cetuximab, nivolumab) Patients receive encorafenib PO QD on days 1-28, cetuximab IV on days 1 and 15, and nivolumab IV on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Biological: Cetuximab; Given IV; Other Names: Cetuximab Biosimilar CDP-1 Cetuximab Biosimilar CMAB009 Cetuximab Biosimilar KL 140 Chimeric Anti-EGFR Monoclonal Antibody Chimeric MoAb C225 Chimeric Monoclonal Antibody C225 Erbitux IMC-C225 ; Drug: Encorafenib; Given PO; Other Names: Braftovi LGX 818 LGX-818 LGX818 ; Biological: Nivolumab; Given IV; Other Names: BMS-936558 CMAB819 MDX-1106 NIVO Nivolumab Biosimilar CMAB819 ONO-4538 Opdivo
Active Comparator: Arm II (encorafenib, cetuximab) Patients receive encorafenib PO QD on days 1-28 and cetuximab IV on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Biological: Cetuximab; Given IV; Other Names: Cetuximab Biosimilar CDP-1 Cetuximab Biosimilar CMAB009 Cetuximab Biosimilar KL 140 Chimeric Anti-EGFR Monoclonal Antibody Chimeric MoAb C225 Chimeric Monoclonal Antibody C225 Erbitux IMC-C225 ; Drug: Encorafenib; Given PO; Other Names: Braftovi LGX 818 LGX-818 LGX818

Outcome Measures

Primary Outcome Measures

1. Progression-free survival (PFS) [From date of registration to date of first documentation of progression or symptomatic deterioration, or death due to any cause, assessed up to 3 years]

   Conducted in all eligible participants according to the intent-to-treat principle using the stratified log rank test when a total of 66 PFS events have been observed. Estimated using the Kaplan-Meier method and compared using the stratified log rank test.

Secondary Outcome Measures

1. Overall response rate (ORR) [Up to 3 years]

   Evaluated per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (confirmed and unconfirmed, complete and partial response) and compared across treatment arms via Fisher's exact test.

2. Overall survival (OS) [From date of registration to date of death due to any cause, assessed up to 3 years]

   Estimated using the Kaplan-Meier method and compared using the stratified log rank test. The distribution of OS will be estimated using the method of Kaplan-Meier and compared using the stratified log rank test.

3. Duration of response (DoR) [From date of first documentation of confirmed response (complete response or partial response) to date of first documentation of progression or symptomatic deterioration or death due to any cause among participants who achieve a response, up to 3 years]

   Estimated using the Kaplan-Meier method and compared using the stratified log rank test. The distribution of DoR will be estimated using the method of Kaplan-Meier and compared using the stratified log rank test.

4. Immune related progression-free survival (irRC-PFS) in Arm I [From date of registration to date of initial documentation of irRC-progression that has subsequently been confirmed or symptomatic deterioration, or death due to any cause, assessed up to 3 years]

   The distribution of irRC-PFS in Arm 1 (nivolumab + encorafenib + cetuximab) will be estimated using the method of Kaplan-Meier.

5. Incidence of adverse events [Up to 3 years]

   At least 25 eligible participants in each arm are sufficient to estimate the probability of a particular toxicity within ±20% (95% confidence interval), and any toxicity occurring with at least 10% probability is likely (93% chance) to be seen at least once. At least 50 eligible participants are sufficient to estimate the probability of a particular toxicity within ±14% (95% confidence interval), and any toxicity occurring with at least 5% probability is likely (92% chance) to be seen at least once.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Participants must have a histologically or cytologically confirmed diagnosis of adenocarcinoma of the colon or rectum. The date of diagnosis will be determined according to the pathologic date of diagnosis

• Participants must have measurable disease according to RECIST1.1 criteria. Computed tomography (CT) scans or magnetic resonance imaging (MRIs) used to assess measurable disease must have been completed within 28 days prior to registration. CT scans or MRIs used to assess non-measurable disease must have been completed within 42 days prior to registration. All disease must be assessed and documented on the Baseline Tumor Assessment Form

• Participants must have documented unresectable and/or metastatic disease on CT or MRI imaging. All disease must be assessed and documented on the Baseline Tumor Assessment Form

• Participants must have BRAF^V600E mutated colorectal cancer as tested in a Clinical Laboratory Improvement Act (CLIA)-certified laboratory

• Participants must have proficient mismatch repair (pMMR) or microsatellite stable (MSS) status as tested in a CLIA-certified laboratory and documented by the treating clinician. Proficient mismatch repair status can be determined by intact expression by immunohistochemistry of all 4 mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2). Microsatellite instability can be determined by polymerase chain reaction (PCR)

• Participants with brain metastases must have completed surgery or radiation therapy >= 28 days prior to registration. These participants must have a CT or MRI of the brain showing no new or enlarging lesions within 42 days prior to registration. These participants must also be neurologically asymptomatic and without corticosteroid treatment for at least 7 days prior to registration. Metastatic brain parenchymal disease must have been treated and participant must be off steroids for 7 days prior to registration. The presence of leptomeningeal disease (LMD) is not considered stable disease, and participants with LMD are not eligible for this study

• Participants with known evidence of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral load on suppressive therapy within 28 days prior to registration

• Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. Participants with HCV infection who are currently on treatment must have an undetectable HCV viral load within 28 days prior to registration

• Participants must have had one or two prior regimens of systemic chemotherapy for metastatic or locally advanced, unresectable disease. (A maintenance regimen of 5-fluorouracil or capecitabine, with or without bevacizumab, should not be counted as a separate line of treatment. The re-introduction of an initially successful induction regimen will not be counted as one additional line of treatment). Prior treatment for metastatic disease is not required for patients who experienced disease recurrence during or within 6 months of completion of adjuvant chemotherapy

• Participants must be of age >= 18 years at the time of informed consent

• Participants must have a Zubrod performance status of 0 or 1

• Participants must have a complete medical history and physical exam within 28 days prior to registration

• Absolute neutrophil count >= 1.0 x 10^3/uL (within 28 days prior to registration)

• Hemoglobin >= 9 g/dL (within 28 days prior to registration)

• Platelets >= 75 x 10^3/uL (within 28 days prior to registration)

• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (within 28 days prior to registration)

• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x institutional ULN (within 28 days prior to registration)

• If liver metastases are present, then it is acceptable for AST level =< 5.0 x ULN, and/or an ALT level =< 5.0 x ULN (within 28 days prior to registration)

• Participants must have serum creatinine =< the IULN OR measured OR calculated creatinine clearance >= 50 mL/min using the Cockroft-Gault Formula. This specimen must have been drawn and processed within 28 days prior to registration

• Participants must be able to swallow and retain pills

• Participants must have adequate cardiac function. Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, must have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, participants must be class 2 or better

• Participants must be offered the opportunity to participate in specimen banking. With participant consent, specimens must be collected and submitted via the Southwest Oncology Group (SWOG) Specimen Tracking System

• Participants must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines.

• Note: As a part of the OPEN registration process, the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system

Exclusion Criteria:

• Participants must not have a known positive serology for human immunodeficiency virus (HIV). Encorafenib is contraindicated with concomitant use of non-nucleoside analog reverse transcriptase inhibitors like efavirenz and etravirine. In addition, it is recommended in the investigator brochure of encorafenib to avoid using encorafenib with protease inhibitors. Therefore, because all participants on this study would receive encorafenib for either randomized arm of treatment, participants with HIV who receive these components of highly active antiretroviral therapy (HAART) would be at high risk for complications of drug-drug interaction

• Participants must not have had prior treatment with a BRAF inhibitor (including, but not limited to, encorafenib, dabrafenib, or vemurafenib), MEK inhibitor (including, but not limited to, trametinib, selumetinib, or binimetinib), or ERK inhibitor (of note, regorafenib is not considered a BRAF inhibitor for the context of eligibility criteria)

• Participants must not have had prior treatment with anti-EGFR therapies

• Participants must not have had prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways

• Participants must not have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of registration. Inhaled or topical steroids and adrenal replacement doses < 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. Patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic corticosteroids are permitted, even if < 10 mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted, as long as there has been a washout period for corticosteroids of >= 7 days prior to registration

• Participants must not have received a live vaccine within 30 days prior to study registration. Seasonal flu and COVID vaccines that do not contain a live virus are permitted

• Participants must not be receiving any other investigational agents

• Participants must not have impaired gastrointestinal function or disease that may significantly alter the absorption of study drug (e.g., ulcerative diseases, uncontrolled vomiting, malabsorption syndrome, small bowel resection with decreased intestinal absorption)

• Participants must not have a history of inflammatory bowel disease, (including ulcerative colitis and Crohn's disease), symptomatic autoimmune disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [e.g., Wegener's Granulomatosis]); central nervous system (CNS) or motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre Syndrome and myasthenia gravis, multiple sclerosis).

• Note: Participants with Graves' disease will be allowed

• Participants must not have a history of pneumonitis that has required oral or intravenous (IV) steroids within the last 12 months

• Participants must not have a history of a grade 3 or 4 allergic reaction attributed to humanized or human monoclonal antibody therapy

• Participants must not have a history of a prior allogeneic tissue or solid organ transplant

• Participants must not have a history of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) within 6 months prior to study registration

• Participants must not have uncontrolled blood pressure and hypertension within 28 days prior to registration.

• Uncontrolled blood pressure and hypertension is defined as systolic blood pressure (SBP) > 170 mmHg or diastolic blood pressure (DBP) > 100 mmHg within 28 days prior to registration. Participants are permitted to be receiving multiple anti-hypertensive medications (unless otherwise indicated in the study). All blood pressure measurements within the 28 days prior to registration must be SBP =< 170 and DBP =< 100. An exception can be made by a healthcare provider for a participant with a single blood pressure elevation who upon rechecking has a normal blood pressure

• Participants must not have a prior or concurrent malignancy whose natural history or treatment (in the opinion of the treating physician) has the potential to interfere with the safety or efficacy assessment of the investigational regimen or requires concurrent therapy

• Participants must not be pregnant or nursing. Individuals who are of reproductive potential must have agreed to use an effective contraceptive method with details provided as a part of the consent process. A person who has had menses at any time in the preceding 12 consecutive months or who has semen likely to contain sperm is considered to be of "reproductive potential." In addition to routine contraceptive methods, "effective contraception" also includes refraining from sexual activity that might result in pregnancy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) including hysterectomy, bilateral oophorectomy, bilateral tubal ligation/occlusion and vasectomy with testing showing no sperm in the semen

• Participants must not be planning treatment with other systemic anti-cancer agents (e.g., chemotherapy, hormonal therapy, immunotherapy) or other treatments not part of protocol-specified anti-cancer therapy including concurrent investigational agents of any type

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Illinois CancerCare-Bloomington	Bloomington	Illinois	United States	61704
2	Illinois CancerCare-Canton	Canton	Illinois	United States	61520
3	Illinois CancerCare-Carthage	Carthage	Illinois	United States	62321
4	Carle on Vermilion	Danville	Illinois	United States	61832
5	Cancer Care Specialists of Illinois - Decatur	Decatur	Illinois	United States	62526
6	Decatur Memorial Hospital	Decatur	Illinois	United States	62526
7	Illinois CancerCare-Dixon	Dixon	Illinois	United States	61021
8	Carle Physician Group-Effingham	Effingham	Illinois	United States	62401
9	Crossroads Cancer Center	Effingham	Illinois	United States	62401
10	Illinois CancerCare-Eureka	Eureka	Illinois	United States	61530
11	Illinois CancerCare-Galesburg	Galesburg	Illinois	United States	61401
12	Illinois CancerCare-Kewanee Clinic	Kewanee	Illinois	United States	61443
13	Illinois CancerCare-Macomb	Macomb	Illinois	United States	61455
14	Carle Physician Group-Mattoon/Charleston	Mattoon	Illinois	United States	61938
15	Illinois CancerCare-Ottawa Clinic	Ottawa	Illinois	United States	61350
16	Illinois CancerCare-Pekin	Pekin	Illinois	United States	61554
17	Illinois CancerCare-Peoria	Peoria	Illinois	United States	61615
18	Illinois CancerCare-Peru	Peru	Illinois	United States	61354
19	Illinois CancerCare-Princeton	Princeton	Illinois	United States	61356
20	Southern Illinois University School of Medicine	Springfield	Illinois	United States	62702
21	Carle Cancer Center	Urbana	Illinois	United States	61801
22	Illinois CancerCare - Washington	Washington	Illinois	United States	61571
23	Mary Greeley Medical Center	Ames	Iowa	United States	50010
24	McFarland Clinic PC - Ames	Ames	Iowa	United States	50010
25	McFarland Clinic PC-Boone	Boone	Iowa	United States	50036
26	McFarland Clinic PC-Trinity Cancer Center	Fort Dodge	Iowa	United States	50501
27	McFarland Clinic PC-Jefferson	Jefferson	Iowa	United States	50129
28	McFarland Clinic PC-Marshalltown	Marshalltown	Iowa	United States	50158
29	Saint Joseph Mercy Hospital	Ann Arbor	Michigan	United States	48106
30	Saint Joseph Mercy Brighton	Brighton	Michigan	United States	48114
31	Trinity Health IHA Medical Group Hematology Oncology - Brighton	Brighton	Michigan	United States	48114
32	Saint Joseph Mercy Canton	Canton	Michigan	United States	48188
33	Trinity Health IHA Medical Group Hematology Oncology - Canton	Canton	Michigan	United States	48188
34	Saint Joseph Mercy Chelsea	Chelsea	Michigan	United States	48118
35	Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital	Chelsea	Michigan	United States	48118
36	Ascension Saint John Hospital	Detroit	Michigan	United States	48236
37	Great Lakes Cancer Management Specialists-Doctors Park	East China Township	Michigan	United States	48054
38	Academic Hematology Oncology Specialists	Grosse Pointe Woods	Michigan	United States	48236
39	Great Lakes Cancer Management Specialists-Van Elslander Cancer Center	Grosse Pointe Woods	Michigan	United States	48236
40	Trinity Health Saint Mary Mercy Livonia Hospital	Livonia	Michigan	United States	48154
41	Great Lakes Cancer Management Specialists-Macomb Medical Campus	Macomb	Michigan	United States	48044
42	Bhadresh Nayak MD PC-Sterling Heights	Sterling Heights	Michigan	United States	48312
43	Great Lakes Cancer Management Specialists-Macomb Professional Building	Warren	Michigan	United States	48093
44	Macomb Hematology Oncology PC	Warren	Michigan	United States	48093
45	Saint John Macomb-Oakland Hospital	Warren	Michigan	United States	48093
46	Huron Gastroenterology PC	Ypsilanti	Michigan	United States	48106
47	Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus	Ypsilanti	Michigan	United States	48197
48	Saint Francis Medical Center	Cape Girardeau	Missouri	United States	63703
49	Strecker Cancer Center-Belpre	Belpre	Ohio	United States	45714
50	Adena Regional Medical Center	Chillicothe	Ohio	United States	45601
51	Mount Carmel East Hospital	Columbus	Ohio	United States	43213
52	Columbus Oncology and Hematology Associates Inc	Columbus	Ohio	United States	43214
53	Riverside Methodist Hospital	Columbus	Ohio	United States	43214
54	Grant Medical Center	Columbus	Ohio	United States	43215
55	The Mark H Zangmeister Center	Columbus	Ohio	United States	43219
56	Doctors Hospital	Columbus	Ohio	United States	43228
57	Delaware Health Center-Grady Cancer Center	Delaware	Ohio	United States	43015
58	Grady Memorial Hospital	Delaware	Ohio	United States	43015
59	Columbus Oncology and Hematology Associates	Dublin	Ohio	United States	43016
60	Mount Carmel Grove City Hospital	Grove City	Ohio	United States	43123
61	Fairfield Medical Center	Lancaster	Ohio	United States	43130
62	OhioHealth Mansfield Hospital	Mansfield	Ohio	United States	44903
63	OhioHealth Marion General Hospital	Marion	Ohio	United States	43302
64	Knox Community Hospital	Mount Vernon	Ohio	United States	43050
65	Licking Memorial Hospital	Newark	Ohio	United States	43055
66	Southern Ohio Medical Center	Portsmouth	Ohio	United States	45662
67	Springfield Regional Cancer Center	Springfield	Ohio	United States	45504
68	Springfield Regional Medical Center	Springfield	Ohio	United States	45505
69	Saint Ann's Hospital	Westerville	Ohio	United States	43081
70	Genesis Healthcare System Cancer Care Center	Zanesville	Ohio	United States	43701
71	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
72	ThedaCare Regional Cancer Center	Appleton	Wisconsin	United States	54911

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Van K Morris, Southwest Oncology Group

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT05308446
• Other Study ID Numbers: NCI-2022-02494; NCI-2022-02494; S2107; S2107; U10CA180888
• First Posted: Apr 4, 2022
• Last Update Posted: Aug 24, 2022
• Last Verified: Jun 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Adenocarcinoma; Rectal Neoplasms; Colonic Neoplasms; Antineoplastic Agents, Immunological; Nivolumab; Cetuximab; Antibodies; Immunoglobulins; Antibodies, Monoclonal

Study Results

No Results Posted as of Aug 24, 2022