Multicenter Phase 2 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: CEBBRA study.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Asociacion Grupo Tratamiento De Tumores Digestivos

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Digestive System Diseases [C06], Diseases [C] - Neoplasms [C04]

Trial duration

22 Jan 2024 → ongoing

Decision date (initial)

2023-10-30

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To assess the efficacy of cetuximab in combination with encorafenib plus binimetinib (EBC) as induction therapy for the treatment of BRAF-V600E mutated MSS aCRC in terms of being able to perform radical treatment of the primary and/or metastases by surgery and/or any other therapeutic procedure with curative intent (radical treatment)

Secondary objectives 3

1. To evaluate clinical outcomes in terms of objective response rate (ORR), tumor regression grade (TRG), progression-free survival (PFS), overall survival (OS), and disease-free survival (DFS), in BRAF-V600E-mutated MSS aCRC patients treated with EBC.
2. To assess the safety and tolerability of EBC tratment
3. To assess complications related to surgery or any other procedure for radical treatment

Conditions and MedDRA coding

BRAF V600E mutated and microsatellite stable (MSS) advanced colorectal cancer (aCRC) initially resectable or potentially resectable

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Male or female participant 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 test, lifestyle considerations, and other study procedures.
4. Participants with histologically or cytologically confirmed colorectal adenocarcinoma.
5. Presence of a BRAF V600E mutation confirmed as per standard of care according to international guidelines at any time prior to Screening.
6. Microsatellite stable (MSS) or Mismatch-Repair proficient (pMMR) disease confirmation assessed by local PCR or immunohistochemistry (ICH)
7. Participants with CRC who have one of these criteria: a. Locally advanced colorectal cancer with initially unresectable but potentially resectable disease according to the local Multidisciplinary Tumour Board (MTB). b. 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. c. Stage II-IV colorectal cancer relapsed after previous R0 or R1 resection and neoadjuvant and/or adjuvant chemotherapy, if the shorter time from the resection or from the end of the adjuvant chemotherapy to the initiation of the treatment of the study is longer than 28 days. This relapse (locoregional and/or systemic) should be initially resectable or initially unresectable but potentially resectable 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 v 1.1
10. Adequate bone marrow function characterired by the following at screening: a. ANC ≥1.5 x 10^9/L. b. Platelets ≥ 100 x 10^9/L. c. Hemoglobin ≥ 9.0 g/dL (with or without blood transfusions).
11. Adequate hepatic and renal function characterized by the following at screening: a. 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. b. ALT and AST ≤2.5 x ULN, or ≤5 x ULN in the presence of liver metastases. c. Adequate renal function defined by an estimated creatinine clearance ≥50 mL/min according to the Cockcroft Gault formula or by 24-hour urine collection for creatinine clearance, or according to local institutional standar method.
12. Able to swallow, retain, and absorb oral medications.

Exclusion criteria 24

1. Any medical or psychiatric condition including recent (within the past year) or current suicidal ideation/behaviour or laboratory abnormality that may increase the risk of study participation or, in the investigator´s judgment, make the participant inappropiate for the study.
2. Leptomeningeal disease or brain metastases.
3. History of chronic inflammatory bowel disease requiring medical intervention (immunomodulatory or immunosuppressive medication or surgery) ≤ 12 months prior to the start of study treatment.
4. Known RAS-mutant colorectal adenocarcinoma.
5. Impaired gastrointestinal function (e.g., uncontrolled nausea, vomiting or diarrhea malabsorption syndrome, small bowel resection) or disease wich may significantly alter the absorption of oral study intervention or recent changes in bowel function suggesting current or impending bowel obstruction.
6. Clinically significant cardiovascular diseases, including any of the following: a. 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 Congetive heart failure requiring treatment (New York Heart Association Grade ≥2). b. History or presence of clinically significant cardiac arrhythmias (including uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventicular tachycardia). c. History of thromboembolic or cerebrovascular events ≤12 weeks prior to the start of the study treatment. Examples include transient ischemic attacks, cerebrovascular accidents, hemodynamically significant (i.e., massive or sub-massive) deepd 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 al least 4 weeks. Note 2: Participants with thromboembolic events related to indwelling catheters (including PCC lines) or other procedures may be enrolled. d. Triplicate average QTcF interval ≥480 ms or a history of prolonged QT syndrome. e. Congenital LQTS.
7. Evidence of active non-infectious pneumonitis.
8. Prior systemic regimen in first line treatment for metastatic CRC in patients with the following exceptions: Patients with resected (R0 or R1 resections) metastasis of CRC treated with or without adjuvant or neoadjuvant chemotherapy (+/- antiEGFR or bevacizumab) that relapsed, would be eligible if the time from the last dose of chemotherapy or the surgery (the later) to the initiation of the treatment of the study were longer than 28 days.
9. Prior chemotherapy for stage II/III CRC, with the following exceptions: Patients with previous adjuvant or neoadjuvant chemotherapy for resected St II/III CRC that relapsed, would be eligible if the time from the last dose of chemotherapy or the surgery (the later) to the initiation of the treatment of the study were longer than 28 days.
10. Previous administration with an investigational drug within 28 days (or as determined by the local requirement) or 5 half-lives preceding the first dose of study intervention used in this study (wichever is longer).
11. Known contraindication to receiving cetuximab including hypersensitivity or toxicity that would suggest an inability to tolerate maximun cetuximab dose of 500 mg/m^2.
12. 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 os study treatment.
13. Known sensitivity or contraindication to any component of study intervention or their excipients al the planned doses.
14. Pregnant, or is breastfeeding (lactating).
15. Male or female of childbearing age who do not agree with taking highly effective contraceptive precautions, (for definition, please refer to Appendix 15) or abstinence during the course of the study and for 6 months after the last administration os study drug for women and men.
16. Full dose radiotherapy <28 days prior to the start of study treatment. Short course radiotherapy for local control of primary tumor or other palliative indication is allowed.
17. Participants with known positive for HIV are ineligible unless they meet all of the folllowing: a. A stable regimen of highly active anti-retroviral therapy that is not contraindicated. b. No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections. c. A CD4 count ≥250 cells/mcL. and an undetectable HIV viral load on standard PCR-based tests.
18. Residual CTCAE≥ Grade 2 toxicity from any prior anticancer therapy, with the exception of Grade 2 alopecia or Grade 2 neuropathy.
19. Previous treatment with any selective BRAF inhibitor (e.g., encorafenib, dabrafenib, vemurafenib, XL281/BMS-908662) and/or any selective MEK inhibitor prior to screening.
20. Use of any prohibited medication (including herbal medication), supplement or food that is a moderate or strong inhibitor or inducer of CYP3A4/5 ≤1 week prior to the start of study intervention.
21. Major surgery (e.g., inpatient procedure with regional or general anesthesia) or completion of radiation therapy ≤4 weeks prior to the start of study treatment.
22. Know active hepatitis B or hepatitis C infection a. Active HBV is defined as any of the following: i. HBsAg (+), HBV DNA >200 IU/ml (105 copies/mL); ii. HBsAg (+), HBV DNA ≤200 IU/mL and persistent or intermittent elevation of ALT/AST and/or liver biopsy showing chronic hepatitis with moderate or severe necroinflammation. Note: Participants who are HBsAg (-), HBcAb (+) are elegible and should be monitored/treated as per local standard of care. b. Active HCV is defined as: i. HCV antibody positive; AND. ii. Presence of HCV RNA.
23. Concurrent or previous other malignancy within 3 years of study entry, except curatively treated basal or squamous cell skin cancer, prostate intraepithelial neoplasm, carcinoma in-situ of the cervix. Bowen´s disease or prostate cancer with a Gleason score ≤6. Participants with other curatively treated malignancies with low risk of recurrence not listed may also be considered eligible after review and approval by the medical monitor.
24. Patients with known ulcerative keratitis.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. 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).
2. In case of patients undergoing surgery, the proportion of patients achieving R0 (microscopically margin-negative resection) or R1 (microscopic residual margin affected) will be assessed. For the rest of procedures, the achievement of complete tumor removal/destruction will be considered.
3. The eligibility of each individual patient for radical treatment will be evaluated at 12 or 24 weeks after the first dose of study treatment by the MTB. If a patient is eligible, radical treatment will be performed al least 2 weeks after the end of EBC treatment and at the lasest, 10 weeks after the lastest CT evaluation.

Secondary endpoints 6

1. Overall response rate (ORR), defined as the number of patients achieving complete response (CR) or partial response (PR) as best response according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, divided by the total number of patients.
2. Tumor regression grade (TRG), after any surgical treatment of the primary tumor and/or distant metastases defined as five histological categories as follows: TRG1, no residual tumor; TRG2, microscopic residual tumor; TRG3, moderate response; TRG4, minor response; and TRG5, no response.
3. Progression-free-survival (PFS), defined as the time in months from first dose of study treatment to disease progression or death (due to any cause). Patients lost to follow-up progression free and alive at the end of the study, will be censored, in K-M analysis, at the date last known to be alive and progression free.
4. Overall survival (OS), defined as the time in months from first dose of study treatment to death due to any cause. Patients lost to follow-up or alive at the end of the study, will be censured, in K-M analysis, at the date known to be alive.
5. Disease free survival (DFS), defined as the time in months from first dose of study treatment to cancer recurrence, second cancer, or death from any cause in resected patients. Patients lost to follow-up or disease free and alive at the end of the study, will be censores, in K-M analysis, at the date last known to be alive and disease free.
6. Complications related to surgery and/or any other therapeutic procedure for radical treatment ocurring within 60 days after surgery (i.e. perioperative mortality, transfusions, hemorrhage, infections, wound healing, general or local complications). Incidence and severity of adverse events (AEs) graded according to the NCI CTCAE v4.03 and changes in clinical laboratory parameters and vital signs.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Asociacion Grupo Tratamiento De Tumores Digestivos

Sponsor organisation

Asociacion Grupo Tratamiento De Tumores Digestivos

Address

Calle Tellez 30 Planta 1 Oficina 4

City

Madrid

Postcode

28007

Country

Spain

Scientific contact point

Organisation

Asociacion Grupo Tratamiento De Tumores Digestivos

Contact name

Inmaculada Ruiz de Mena

Public contact point

Organisation

Asociacion Grupo Tratamiento De Tumores Digestivos

Contact name

Inmaculada Ruiz de Mena

Third parties 3

Locations

1 EU/EEA country · 15 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 11 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications