Study to Evaluate the Efficacy and Safety of Cetuximab in Combination with Encorafenib Plus Binimetinib As Induction Treatment in BRAF V600E Mutated MSS Initially Resectable or Potentially Resectable Advanced Colorectal Cancer

NCT06207656 | Recruiting Phase 2

• 1 other identifier: TTD-21-02
• Study Type: interventional
• Target: 70
• Locations: 1 country
• Sites: 1

Brief Summary

As a result of the little benefit obtained from standard treatments and the poor prognosis of these patients, the BRAF-V600E mutant MSS aCRC represents an unmet medical need requiring clinical research. The combination of encorafenib, cetuximab and binimetinib as second- or third-line treatment for mCRC resulted in significantly better outcomes than standard therapy in a phase 3 clinical trial, which also revealed treatment safety and tolerability to be acceptable. Compared to the control group (cetuximab and irinotecan or cetuximab and FOLFIRI), the triplet therapy cohort showed higher median overall survival (9.3 vs. 5.9 months) and response rates (26.8% vs. 1.8%). Grade 3 adverse events occurred in 65.8% and 64.2% of patients for triple-therapy and control groups, respectively. Based on these results, the investigators speculated that the combination of encorafenib, cetuximab and binimetinib could be used as induction therapy to improve treatment outcomes in BRAF-V600E-mutated MSS aCRC locally advanced initially unresectable but potentially resectable; initially resectable or initially unresectable but potentially resectable oligometastatic disease; and in patients with stage II-IV who have relapsed after chemotherapy (neo and/or adjuvant) or surgery, if the shorter time after resection or from treatment end to relapse is longer than 6 months.

Conditions

Colorectal Cancer

Keywords

BRAF V600E mutated; MSS; advanced colorectal cancer; Cetuximab; Encorafenib; Binimetinib

Outcome Measures

Primary Outcomes (1)

• Efficacy of cetuximab in combination with encorafenib plus binimetinib as induction therapy for the treatment of BRAF-V600E mutated MSS aCRC to perform radical treatment of the primary and/or metastases

  Radical treatment rate, defined as the number of patients radically treated for their primary tumor and/or distant metastases by surgery and/or by any other radical therapeutic procedure with curative intent (i.e. radiofrequency, cryotherapy, laserhyperthermia, stereotactic body radiotherapy or chemoembolization).

  From first dose to radical treatment (up 60 months)

Secondary Outcomes (7)

• Overall response rate (ORR)

  From first dose to radiographic evidence of best response (up 60 months)

• Tumor regression grade (TRG), after any surgical treatment of the primary tumor and/or distant metastases

  From surgery until 30 days post surgery (up 60 months)

• Progression-free-survival (PFS)

  From first dose to the earliest documented PD or death due to any cause (up 60 months)

• Overall survival (OS)

  From first dose to death due to any cause (up 60 months)

• Disease free survival (DFS)

  From first dose to radiographic evidence of cancer recurrence, second cancer, or death (up 60 months)

Other Outcomes (1)

• To determine the presence/expression level/levels of serum and tumour tissue biomarkers associated with cell and tumour growth and/or involved in the mechanisms of action of EBC

  Tumour tissue samples: at baseline and blood samples at baseline, at week12 post treatment and at progression

Study Arms (1)

cetuximab in combination with encorafenib plus binimetinib (EBC)

EXPERIMENTAL

Patients will receive the following per 28-day cycle: * Encorafenib: 300 mg (4 × 75 mg oral capsule) daily (QD) * Binimetinib: 45 mg (3 × 15 mg oral tablet) twice daily (BID) * Cetuximab: 500 mg/m2 every 2 weeks as per standard institutional practice.

Drug: EBC

Interventions

EBC DRUG

Patients will receive the following per 28-day cycle: * Encorafenib: 300 mg (4 × 75 mg oral capsule) daily (QD) * Binimetinib: 45 mg (3 × 15 mg oral tablet) twice daily (BID) * Cetuximab: 500 mg/m2 every 2 weeks as per standard institutional practice.

cetuximab in combination with encorafenib plus binimetinib (EBC)

Eligibility Criteria

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

You may qualify if:

• \. Male or female participants age ≥18 years at the time of informed consent. 2. Capable of giving signed informed consent/assent. 3. Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures.
• \. Participants with histologically or cytologically confirmed colorectal adenocarcinoma.
• \. Presence of a BRAF V600E mutation confirmed as per standard of care according to international guidelines at any time prior to Screening.
• \. Microsatellite stable (MSS) or Mismatch-Repair proficient (pMMR) disease confirmation assessed by local PCR or immunohistochemistry (IHC).
• \. Participants with CRC who have one of these criteria:
• Locally advanced colorectal cancer with initially unresectable but potentially resectable disease according to the local Multidisciplinary Tumour Board (MTB).
• Oligometastatic colorectal cancer (possible metastasis sites: liver, lung, lymph nodes and peritoneum) with:
• i. Initially resectable disease according to the local MTB or ii. Initially unresectable but potentially resectable disease according to the local MTB c. Stage II-IV colorectal cancer treated with previous neoadjuvant and/or adjuvant chemotherapy, for R0, if the shorter time from the resection or from the end of the adjuvant treatment to the relapse of colorectal cancer (possible metastasis sites: liver, lung, lymph nodes and peritoneum) is longer than 6 months. This relapse (locoregional and/or systemic) should be initially resectable or initially unresectable but potentially resectable disease according to the local MTB 8. ECOG performance status of 0 or 1. 9. Measurable or evaluable disease as assessed by investigator, according to RECIST v1.1.
• \. Adequate bone marrow function characterized by the following at screening:
• ANC ≥1.5 × 109/L
• Platelets ≥100 × 109/L
• Hemoglobin ≥9.0 g/dL (with or without blood transfusions). 11. Adequate hepatic and renal function characterized by the following at screening:
• <!-- -->
• Serum total bilirubin ≤1.5 x ULN. Note 1: Total bilirubin \>1.5 x ULN is allowed if direct (conjugated) ≤1.5 x ULN and indirect (unconjugated) bilirubin is ≤4.25 x ULN.
• Note 2: Participants with hyperbilirubinemia due to non-hepatic cause (e.g., hemolysis, hematoma) may be enrolled following discussion and agreement with the medical monitor.

You may not qualify if:

• \. Any medical or psychiatric condition including recent (within the past year) or current suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator's judgment, make the participant inappropriate for the study.
• \. Leptomeningeal disease or brain metastases. 3. History of chronic inflammatory bowel disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) ≤12 months prior to the start of study treatment.
• \. Known RAS-mutant colorectal adenocarcinoma. 5. Impaired gastrointestinal function (e.g., uncontrolled nausea, vomiting or diarrhea, malabsorption syndrome, small bowel resection) or disease which may significantly alter the absorption of oral study intervention or recent changes in bowel function suggesting current or impending bowel obstruction.
• \. Clinically significant cardiovascular diseases, including any of the following:
• History of acute myocardial infarction, acute coronary syndromes (including unstable angina, coronary artery bypass graft, coronary angioplasty or stenting) ≤6 months prior to the start of study treatment.
• Congestive heart failure requiring treatment (New York Heart Association Grade ≥2).
• History or presence of clinically significant cardiac arrhythmias (including uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular tachycardia).
• History of thromboembolic or cerebrovascular events ≤12 weeks prior to the start of study treatment. Examples include transient ischemic attacks, cerebrovascular accidents, hemodynamically significant (i.e., massive or sub-massive) deep vein thrombosis or pulmonary emboli.
• Note 1: Participants with either deep vein thrombosis or pulmonary emboli that do not result in hemodynamic instability are allowed to enroll as long as they have been on a stable dose of anticoagulants for at least 4 weeks.
• Note 2: Participants with thromboembolic events related to indwelling catheters (including PICC lines) or other procedures may be enrolled.
• Triplicate average QTcF interval ≥480 ms or a history of prolonged QT syndrome.
• Congenital LQTS. 7. Evidence of active non-infectious pneumonitis. 8. Evidence of active and uncontrolled bacterial or viral infection, with certain exceptions, as noted below, for chronic infection with HIV, hepatitis B or hepatitis C (please see below), within 2 weeks prior to start of study treatment.
• \. Participants positive for HIV are ineligible unless they meet all of the following:
• <!-- -->
• A stable regimen of highly active anti-retroviral therapy that is not contraindicated.

Sponsors & Collaborators

• Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD): lead
• Merck, S.L., Spain: collaborator
• Pierre Fabre Ibérica, S.A.: collaborator

Study Sites (1)

Spanish Cooperative Group for Gastrointestinal Tumour Therapy (TTD)

Madrid, 28046, Spain

RECRUITING

MeSH Terms

Conditions

Colorectal Neoplasms

Condition Hierarchy (Ancestors)

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

Central Study Contacts

Esther Mahillo, phD

CONTACT

+34913788275; emahillo@ttdgroup.org

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 27, 2023
• First Posted: January 17, 2024
• Study Start: April 16, 2024
• Primary Completion (Estimated): April 1, 2029
• Study Completion (Estimated): April 1, 2029
• Last Updated: October 21, 2024

Record last verified: 2024-10

Locations

ES (1)