| Eligibility |
Inclusion Criteria:
- 1. 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.
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 (IHC).
7. Participants with CRC who have one of these criteria:
1. Locally advanced colorectal cancer with initially unresectable but potentially
resectable disease according to the local Multidisciplinary Tumour Board (MTB).
2. 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.
10. Adequate bone marrow function characterized by the following at screening:
1. ANC =1.5 × 109/L
2. Platelets =100 × 109/L
3. Hemoglobin =9.0 g/dL (with or without blood transfusions). 11. Adequate hepatic
and renal function characterized by the following at screening:
1. 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.
2. ALT and AST =2.5 × ULN, or =5 × ULN in the presence of liver metastases.
3. 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 standard method.
12. Able to swallow, retain, and absorb oral medications.
Exclusion Criteria:
- 1. 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.
2. 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.
4. 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.
6. Clinically significant cardiovascular diseases, including any of the following:
1. 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.
2. Congestive heart failure requiring treatment (New York Heart Association Grade
=2).
3. History or presence of clinically significant cardiac arrhythmias (including
uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular
tachycardia).
4. 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.
5. Triplicate average QTcF interval =480 ms or a history of prolonged QT syndrome.
6. 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.
9. Participants positive for HIV are ineligible unless they meet all of the
following:
1. A stable regimen of highly active anti-retroviral therapy that is not
contraindicated.
2. No requirement for concurrent antibiotics or antifungal agents for the prevention
of opportunistic infections.
3. A CD4 count >250 cells/mcL, and an undetectable HIV viral load on standard
PCR-based tests.
10. Active hepatitis B or hepatitis C infection
a. Active HBV is defined as any of the following:
1. HBsAg (+), HBV DNA >200 IU/mL (105 copies/mL);
2. 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 eligible and should be
monitored/treated as per local standard of care.
b. Active HCV is defined as:
1. HCV antibody positive; AND
2. Presence of HCV RNA. 11. 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.
12. Residual CTCAE= Grade 2 toxicity from any prior anticancer therapy, with the
exception of Grade 2 alopecia or Grade 2 neuropathy.
13. Previous treatment with any selective BRAF inhibitor (e.g., encorafenib,
dabrafenib, vemurafenib, XL281/BMS-908662) and/or any selective MEK inhibitor
prior to screening.
14. 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.
15. 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.
16. Previous systemic anticancer therapy for CRC, 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) would
be includible if the time from the resection or from the end of the adjuvant
treatment (the later) to the relapse of CRC were longer than 6 months
• Patients with previous adjuvant or neoadjuvant chemotherapy for resected St
II/III CRC would be eligible if the time from the resection or from the end of
the adjuvant treatment (the later) to the relapse of CRC were longer than 6
months 17. Prior systemic regimen in first line treatment for metastatic CRC in
patients with unresectable or non-potentially resectable metastatic (M1) disease.
18. Previous administration with an investigational drug within 30 days (or as
determined by the local requirement) or 5 half-lives preceding the first dose of
study intervention used in this study (whichever is longer).
19. Known contraindication to receiving cetuximab including hypersensitivity or
toxicity that would suggest an inability to tolerate maximum cetuximab dose of
500 mg/m2.
20. Known sensitivity or contraindication to any component of study intervention
or their excipients at the planned doses.
21. Pregnant, or is breastfeeding (lactating). 22. 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 of study drug for women and
men.
23. 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.
24. Patients with ulcerative keratitis.
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