Preoperative CRT With Capecitabine ± Temozolomide in Patients With LARC

• Status: Recruiting
• Trial end date: 2023-02-01
• Target enrollment: 0
• Participant gender: All

Summary

This is a prospective biomarker-stratified, randomised phase II study of preoperative CRT with temozolomide plus capecitabine in patients with locally advanced rectal cancer.

The primary endpoint is pathologic complete response rates defined as total regression of the primary tumor.

For each cohort of MGMT hypermethylated versus MGMT unmethylated, patients will be randomised (ratio 1:1 for each arm) into preoperative CRT with capecitabine or preoperative CRT with temozolomide plus capecitabine arms. According to the prior phase I results, MGMT hypermethylated arm is estimated as 70% of total patients and the target pathologic complete response rate was assumed as 35% in this population when treated with preoperative CRT with temozolomide and capecitabine (15% in the standard treatment arm or those with unmethylated MGMT). Investigator would like to demonstrate the superiority in terms of pathologic complete responses when treated with preoperative CRT with temozolomide plus capecitabine in patients with locally advanced rectal cancer, and to validate the predictive role of MGMT status

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Asan Medical Center
• Treatments: Capecitabine; Dacarbazine; Temozolomide

Criteria

Inclusion Criteria:

• To be eligible for inclusion, each patient must fulfill each of the following criteria:

1. Histologically confirmed adenocarcinoma of the rectum

2. Tumor located within 12cm of anal verge

3. Clinical stage of cT3-4Nany (cStage II) or cTanyN1-2 (cStage III) by rectal MRI

4. Available tumor samples for methylation-specific PCR (MSP) to investigate MGMT hypermethylation

5. Male or female aged over 20 years

6. Be ambulatory and have an Eastern Cooperative Oncology Group (ECOG) performance status0-1.

7. No prior systemic treatment (chemotherapy, immunotherapy) or radiation therapy

8. Adequate major organ functions as following:

Hematopoietic function: ANC 1,500/mm3, Platelet 100,000/mm3 Hepatic function:

serum bilirubin 2.0 mg/dL, AST/ALT levels 2.5 x UNL Renal function: serum creatinine UNL or Cockroft creatinine clearance 50 ml/min

9. Be willing and able to comply with the protocol for the duration of the study.

10. Give written informed consent prior to study-specific screening procedures, with the understanding that the patient has the right to withdraw from the study at any time, without prejudice.

Exclusion Criteria:

• Patients will be exluded from the study for any of the following reasons:

1. Histology other than adenocarcinoma or tumor arising from inflammatory bowel disease

2. Inadequate tumor sample for MGMT MSP

3. Any evidence of systemic metastasis

4. Unresected synchronous colon cancer; endoscopically resected synchronous colon cancer of pTis or pT1 is permitted

5. Subjects unable to swallow oral medication because of such as current or impending intestinal obstructions, but bypass surgery (colostomy or ileostomy) is permitted before study treatment

6. Uncontrolled or severe cardiovascular disease:

• New York Heart Association class III or IV heart disease.

• Unstable angina or myocardial infarction within the past 6 months.

• History of significant ventricular arrhythmia requiring medication with antiarrhythmics or significant conduction system abnormality.

7. Serious concurrent infection or nonmalignant illness that is uncontrolled or whose control may be jeopardized by complications of study therapy.

8. Other malignancy within the past 5 years except cured non-melanomatous skin cancer, carcinoma in situ of the cervix, or thyroid papillary carcinoma.

9. Organ allografts requiring immunosuppressive therapy.

10. Psychiatric disorder or uncontrolled seizure that would preclude compliance.

11. Pregnant, nursing women or patients with reproductive potential without contraception.

12. Patients receiving a concomitant treatment with drugs interacting with 5-FU such as flucytosine, phenytoin, or warfarin et al.

13. Known dihydropyrimidine dehydrogenase (DPD) deficiency.

14. Known hypersensitivity to any of the components of the study medications.