Preoperative CRT With Temozolomide Plus Capecitabine in Rectal Cancer

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Tae Won Kim, Asan Medical Center
ClinicalTrials.gov Identifier:
NCT01781403
First received: January 21, 2013
Last updated: July 17, 2014
Last verified: July 2014
  Purpose

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.


Condition Intervention Phase
Rectal Cancer
Drug: Temozolomide
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Preoperative Chemoradiation With Capecitabine Plus Temozolomide in Patients With Locally Advanced Resectable Rectal Cancer: Phase I Study

Resource links provided by NLM:


Further study details as provided by Asan Medical Center:

Primary Outcome Measures:
  • Maximum tolerated dose (MTD) [ Time Frame: 5-6 weeks during study treatment ] [ Designated as safety issue: Yes ]
    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%.

  • Recommended dose (RD) [ Time Frame: 5-6 weeks after CRT ] [ Designated as safety issue: No ]
    RD will be defined as one level below the MTD.


Secondary Outcome Measures:
  • Association between MGMT expression and pathologic responses [ Time Frame: at the time of surgery (6-8 weeks after study treatment) ] [ Designated as safety issue: No ]

Other Outcome Measures:
  • Toxicity [ Time Frame: 5-6 weeks during study treatment ] [ Designated as safety issue: Yes ]

    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

    1. 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.
    2. 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.
    3. All relevant information regarding drug dosage, laboratory examinations, and treatment-related toxicities must be recorded before each treatment is given.
    4. Summaries of the frequency and severity of adverse effects are based on the worst episodes recorded.

  • Efficacy [ Time Frame: after surgery (6-8 weeks after study treatment) ] [ Designated as safety issue: No ]

    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.


  • Disease-free survival [ Time Frame: 3-year or 5-year after surgery ] [ Designated as safety issue: No ]

Estimated Enrollment: 38
Study Start Date: May 2013
Estimated Study Completion Date: March 2016
Estimated Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: Capecitabine, preoperative radiotherapy

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.

  Eligibility

Ages Eligible for Study:   20 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01781403

Locations
Korea, Republic of
Asan Medical Center
Seoul, Songpa-gu, Korea, Republic of, 138-736
Sponsors and Collaborators
Asan Medical Center
Investigators
Principal Investigator: Tae Won Kim, Professor Asan Medical Center
  More Information

No publications provided

Responsible Party: Tae Won Kim, Professor, Asan Medical Center
ClinicalTrials.gov Identifier: NCT01781403     History of Changes
Other Study ID Numbers: ML28381
Study First Received: January 21, 2013
Last Updated: July 17, 2014
Health Authority: Korea: Food and Drug Administration

Keywords provided by Asan Medical Center:
Temozolomide
capecitabine
rectal cancer

Additional relevant MeSH terms:
Rectal Neoplasms
Colorectal Neoplasms
Digestive System Diseases
Digestive System Neoplasms
Gastrointestinal Diseases
Gastrointestinal Neoplasms
Intestinal Diseases
Intestinal Neoplasms
Neoplasms
Neoplasms by Site
Rectal Diseases
Capecitabine
Dacarbazine
Fluorouracil
Temozolomide
Alkylating Agents
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on October 23, 2014