A Randomized Phase 3 Study of MRTX849 in Combination with Cetuximab Versus Chemotherapy in Patients with Advanced Colorectal Cancer with KRAS G12C Mutation with Disease Progression On or After Standard First-Line Therapy

Study ID: 48311
Short Title: KRYSTAL-10
Trust Name: UHD
Recruitment Site: Royal Bournemouth Hospital
Disease Area: Colorectal cancer
Phase: III
Expected End Date: 03/07/2023
Postcode: BH15 2JB
Contact Name: Amanda Pattie
Contact Email: studysupport1and3.crnwessex@nihr.ac.uk
Active: Yes

Inclusion criteria, exclusion criteria and study summary

Patients must meet all of the following inclusion criteria to be eligible for enrollment into the study. 1. Histologically confirmed diagnosis of colorectal carcinoma with KRAS G12C mutation in tumor tissue. 2. Prior receipt of first-line treatment in the advanced disease setting with a fluoropyrimidine-based chemotherapy regimen containing either oxaliplatin or irinotecan, and radiographically documented progression of disease on or after treatment. Notes: - Maintenance therapy given in the metastatic setting will not be considered a separate regimen. - Patients experiencing disease relapse during adjuvant treatment or within 6 months following completion of adjuvant therapy are eligible. Patients with relapse more than 6 months after completion of adjuvant therapy are not eligible. - Source documents for historical disease evaluations to allow Investigator certification of disease progression on or after first-line treatment must be available. 3. Candidacy to receive treatment with cetuximab in accordance with the local product label, with the exception that patients must have documented KRAS G12C mutation and may or may not have demonstrated tumor positivity for EGFR-expression. 4. Presence of evaluable or measurable disease per RECIST 1.1. 5. Able to provide a sufficient amount of representative tumor specimen (primary or metastatic, archival or newly obtained) for central laboratory testing of KRAS G12C mutation status (minimum of 5 slides, preferably 15 slides). 6. Age ≥ 18 years. 7. Life expectancy of at least 3 months. 8. Recovery from the adverse effects of prior therapy to baseline or Grade 1 (any grade alopecia and Grade ≤ 2 peripheral neuropathy are eligible). 9. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 10. Laboratory values within the screening period: a. Absolute neutrophil count ³1,500/mm3 (³1.5 × 109/L) b. Platelet count ³100,000/mm3 (³100 × 109/L) c. Hemoglobin ≥ 9.0 g/dL. Note: Transfusions will be allowed to achieve this provided the patient has not received more than 2 units of red blood cells in the prior 4 weeks d. Total bilirubin ≤ 1.5 × upper limit of normal (ULN); if associated with liver metastases, ≤ 3 × ULN. e. Aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase ≤ 2.5 × ULN; if associated with liver metastases, ≤ 5 × ULN. f. Creatinine clearance ≥ 60 mL/min or glomerular filtration rate ≥60 mL/min/1.73 m2 calculated using a validated prediction equation (e.g., Cockcroft-Gault, MDRD, or 24-hour urine CrCl). g. Electrolyte levels within the screening period: corrected serum calcium ≥ 8.0 mg/dL or ionized calcium ≥ 1.0 mmol/L; magnesium ≥ 1.2 mg/dL; phosphorus ≥ 1.8 mg/dL. 11. Able to take oral medications. 12. Women of child-bearing potential (WOCBP) or men whose partner is a WOCBP agrees to use contraception while participating in this study, and for a period of 6 months following termination of study treatment. 13. Completed informed consent process, including signing IRB/EC-approved informed consent form. 14. Willing to comply with clinical trial instructions and requirements.

Patients presenting with any of the following will not be included in the study: 1. Prior treatment with both an oxaliplatin- and irinotecan-based regimen for CRC in the adjuvant and/or later treatment settings. 2. Prior treatment with a therapy targeting KRAS G12C mutation (e.g., AMG 510). 3. Prior treatment with an anti-EGFR antibody (e.g., cetuximab or panitumumab). 4. Most recent prior anticancer therapy (e.g., chemotherapy, antiangiogenic therapy or radiation therapy) discontinued within 2 weeks before the date of randomization. 5. Known contraindication to receive cetuximab, 5-FU or folinic acid at the planned doses. 6. Active brain metastases or carcinomatous meningitis. Patients are eligible if brain metastases are adequately treated and patients are neurologically stable for at least 2 weeks prior to randomization without the use of corticosteroids or are on a stable or decreasing dose of ≤10 mg daily prednisone (or equivalent). 7. Known human immunodeficiency virus (HIV) infection or acute or chronic hepatitis B or C infection. Note that the following are permitted: • Patients treated for hepatitis C (HCV) with no detectable viral load; • Patients treated for HIV with no detectable viral load for at least 1 month prior to randomization while on a stable regimen of agents that are not strong inhibitors of CYP3A4; and • Patients with hepatitis B (HBV) receiving prophylaxis against reactivation of hepatitis B (either [HBsAg-positive with normal ALT and HBV DNA < 2,000 IU/mL or < 10,000 copies/mL] or [HBsAg-negative and anti-HBcpositive]). 8. Major surgery within 4 weeks prior to randomization. 9. History of intestinal disease or major gastric surgery likely to alter absorption of study treatment or inability to swallow oral medications. 10. Any of the following cardiac abnormalities: a. Unstable angina pectoris or myocardial infarction within 6 months prior to randomization. b. Symptomatic or uncontrolled atrial fibrillation within 6 months prior to randomization. c. Congestive heart failure ≥NYHA Class 3 within 6 months prior to randomization. d. Prolonged QTc interval > 480 milliseconds or family or medical history of congenital Long QT Syndrome. 11. History of stroke or transient ischemic attack within 6 months prior to randomization. 12. Ongoing need for treatment with concomitant medication known to cause prolonged QTc interval or known as strong inhibitor or inducer of CYP3A enzyme and that cannot be switched to alternative treatment prior to study entry. 13. Known or suspected presence of another malignancy that could be mistaken for the malignancy under study during disease assessments. 14. Pregnancy. WOCBP must have a negative serum or urine pregnancy test documented prior to randomization. 15. Breast-feeding or planning to breast-feed during the study or within 6 months after the last dose of study treatment. 16. Any serious illness, uncontrolled inter-current illness, psychiatric illness, active or uncontrolled infection, or other medical condition or history, including laboratory results, which, in the Investigator’s opinion, would be likely to interfere with the patient’s capacity to provide informed consent, with the patient’s participation in the study, or with the interpretation of the results.

-

Study MapList of studies

Accessibility tools

Return to header