Preoperative CRT With Temozolomide Plus Capecitabine in Rectal Cancer

Preoperative Chemoradiation With Capecitabine Plus Temozolomide in Patients With Locally Advanced Resectable Rectal Cancer: Phase I Study

The investigators planned a phase I study of preoperative CRT with capecitabine plus temozolomide inpatients with locally advanced resectable rectal cancer: 1) the role of temozolomide as a radiosensitizer has been well established, 2) hypermethylation (or low expression) of MGMT promoter is associated with colorectal carcinogenesis, can be found in 20~40% of colorectal cancer patients, and this proportion could be adequate for validation as its role of predictive biomarker, and 3) temozolomide can be additive or synergistic because radiotherapy is now essential in the treatment of rectal cancer.

Study Overview

• Status: Completed
• Conditions: Rectal Cancer
• Intervention / Treatment: Drug: Temozolomide

Detailed Description

Preoperative chemoradiation (CRT) with fluoropyrimidine (5-fluorouracil or capecitabine) is now regarded as a standard treatment option in patients with locally advanced resectable rectal cancer, and pathologic response rates and tumor regression grades after preoperative CRT have been proved to be important prognostic factors for survival outcomes. Several studies of preoperative CRT with fluoropyrimidines plus other agents, such as oxaliplatin, irinotecan, cetuximab, and bevacizumab, have been performed to improve pathologic response rates; however, they have failed to show improved results compared to those with fluoropyrimidine alone. Thus, fluoropyrimidine alone is a standard chemotherapeutic strategy in patients with locally advanced resectable rectal cancer who will be treated with preoperative CRT at present; further studies are needed to find effective combination for improving pathologic responses other than fluoropyrimidines alone in these patient population.

Temozolomide is an oral alkylating agent, and has been proved to be effective in patients with glioblastoma or high grade anaplastic glioma when administered with concurrent radiotherapy either as adjuvant or recurrent settings, and also seemed to be effective in patients with malignant melanoma either as monotherapy or combination chemotherapy. Temozolomide has been known to deplete O6-methylguanine DNA methyltransferase (MGMT), which is one of the DNA repair enzymes, and recent studies have shown that lower expression (by immunohistochemistry) or hypermethylation (by methylation-specific PCR) of MGMT could be a predictive marker of better responses to treatment with temozolomide in patient with glioblastoma, high grade anaplastic glioma or malignant melanoma.

Silencing of MGMT by promoter hypermethylation has been known to involve colorectal carcinogenesis pathway by the association with KRAS mutation and low-CIMP (CpG island methylation phenotype), and hypermethylation of MGMT promoter could be detected in 29% to 46% of tumor tissues from sporadic colorectal cancer patients. Nagasaka et al. showed notable results that MGMT promoter methylation status was associated with microsatellite instability and hypermethylation of MGMT promoter could be a predictive factor of low recurrence in colorectal cancer patients with adjuvant oral fluoropyrimidine chemotherapy after curative surgery. In addition, Shacham-Shmueli et al. showed that temozolomide could be an additional treatment option in a small group of patients with chemotherapy-refractory metastatic colorectal cancer which had lower MGMT expressions.

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 1

Contacts and Locations

Study Locations

• Korea, Republic of
  • Songpa-gu
    • Seoul, Songpa-gu, Korea, Republic of, 138-736
      • Asan Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically confirmed adenocarcinoma of the rectum
• Tumor located within 12cm of anal verge
• Clinical stage of T3-4 or N+ by rectal MRI with or without endorectal ultrasound
• Available tumor samples before study treatment (fresh or paraffin-embedded) for immunohistochemistry (IHC) and methylation-specific PCR (MSP) to investigate MGMT expression and hypermethylation
• Male or female aged over 20 years
• Be ambulatory and have an Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
• No prior systemic treatment (chemotherapy, immunotherapy) or radiation therapy
• Adequate major organ functions as following:
• Be willing and able to comply with the protocol for the duration of the study.
• 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:

• Histology other than adenocarcinoma or tumor arising from inflammatory bowel disease
• Inadequate tumor sample for MGMT IHC or MSP
• Any evidence of systemic metastasis
• Unresected synchronous colon cancer
• Intestinal obstructions or impending intestinal obstruction, but bypass surgery (colostomy or ileostomy) is permitted before study treatment
• Uncontrolled or severe cardiovascular disease
• Serious concurrent infection or nonmalignant illness that is uncontrolled or whose control may be jeopardized by complications of study therapy.
• Other malignancy within the past 5 years except cured non-melanomatous skin cancer, carcinoma in situ of the cervix, or thyroid papillary carcinoma.
• Organ allografts requiring immunosuppressive therapy.
• Psychiatric disorder or uncontrolled seizure that would preclude compliance.
• Pregnant, nursing women or patients with reproductive potential without contraception.
• Patients receiving a concomitant treatment with drugs interacting with 5-FU such as flucytosine, phenytoin, or warfarin et al.
• Known dihydropyrimidine dehydrogenase (DPD) deficiency.
• Known hypersensitivity to any of the components of the study medications.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Capecitabine, Temozolomide, Radiotherapy; The total dose of radiotherapy will be 50.4 Gy, with a daily dose of 1.8 Gy administered on 5 days of each week, comprising a total of 45 Gy to the whole pelvis, followed by a 5.4 Gy boost to the primary tumor. The doses and schedules for capecitabine will be fixed, with only temozolomide being prescribed using a dose-escalation schedule. Capecitabine and temozolomide will be administered during radiotherapy with drug holidays (weekend break).

Drug: Temozolomide; Preoperative chemoradiotherapy with fixed dose of capecitabine and temozolomide, the dose of temozolomide will be escalated for finding MTD and RD.; Other Names: Capecitabine, preoperative radiotherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Tolerated Dose (MTD)	The MTD is defined as the maximum dose level in the doses of temozolomide tested with capecitabine and radiation in which the incidence proportion of DLT exceeds 30%.	5-6 weeks during study treatment
Recommended Dose (RD)	RD will be defined as one level below the MTD.	5-6 weeks after CRT

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathological Complete Response	Pathologic responses and stages were classified according to Dworak's classification and the 7th edition of the American Joint Committee on Cancer staging system, respectively. The pathologic complete response (pCR) was defined as the total regression of the primary tumor regardless of regional lymph nodal status (ypT0), with residual fibrotic mass or acellular mucin pools only, thus without detectable tumor cells.	at the time of surgery (6-8 weeks after study treatment)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Toxicity(Adeverse Event)	Toxicity will be monitored and recorded every week during study treatment (5 or 6 weeks) as following according to the NCI-CTCAE version 4.0; An interval history and physical examination with particular attention to drug-induced side effects along with documentation of the patient's weight and performance status will be performed on each visit.; CBC with differential count, blood chemistry including calcium, phosphorus, glucose, BUN, creatinine, total protein, albumin, AST, ALT, alkaline phosphatase, total bilirubin, and electrolyte will be performed before next planned treatment.; All relevant information regarding drug dosage, laboratory examinations, and treatment-related toxicities must be recorded before each treatment is given.; Summaries of the frequency and severity of adverse effects are based on the worst episodes recorded.	5-6 weeks during study treatment
Efficacy: Pathologic Major Responses	Efficacy: Pathologic major responses = total regression + near total regression. We will carefully inspect the circumferential resection margin, defining a positive margin as any residual tumor within ≤ 1 mm of the circumferential margin. Pathologic responses and stages will be classified according to Dworak's classification1 and the AJCC (American Joint Committee on Cancer) staging system, respectively. In each case, the entire tumor including mesorectal fat will be serially sliced into 4-mm-thick sections and embedded in paraffin. A pathologic complete response is defined as grade 4 tumor regression; with residual fibrotic mass or acellular mucin pools only, thus without detectable tumor cells A near total response is defined as grade 3 tumor regression; with very few tumor cells in fibrotic tissue with or without mucous substance.	after surgery (6-8 weeks after study treatment)
Disease-free Survival		3-year or 5-year after surgery

Collaborators and Investigators

• Sponsor: Asan Medical Center

Publications and helpful links

General Publications

• Jeong JH, Hong YS, Park Y, Kim J, Kim JE, Kim KP, Kim SY, Park JH, Kim JH, Park IJ, Lim SB, Yu CS, Kim JC, Kim TW. Phase 1 Study of Preoperative Chemoradiation Therapy With Temozolomide and Capecitabine in Patients With Locally Advanced Rectal Cancer. Int J Radiat Oncol Biol Phys. 2016 Oct 1;96(2):289-295. doi: 10.1016/j.ijrobp.2016.05.009. Epub 2016 May 17.

Study record dates

Study Major Dates

• Study Start (Actual): May 10, 2013
• Primary Completion (Actual): September 3, 2014
• Study Completion (Actual): May 4, 2016

Study Registration Dates

• First Submitted: January 21, 2013
• First Submitted That Met QC Criteria: January 31, 2013
• First Posted (Estimate): February 1, 2013

Study Record Updates

• Last Update Posted (Actual): February 4, 2021
• Last Update Submitted That Met QC Criteria: January 17, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: capecitabine; Temozolomide; rectal cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Rectal Neoplasms; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Temozolomide; Capecitabine
• Other Study ID Numbers: ML28381

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO