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Preoperative CRT With Temozolomide Plus Capecitabine in Rectal Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01781403
Recruitment Status : Active, not recruiting
First Posted : February 1, 2013
Results First Posted : June 23, 2016
Last Update Posted : February 2, 2018
Information provided by (Responsible Party):
Tae Won Kim, Asan Medical Center

Tracking Information
First Submitted Date  ICMJE January 21, 2013
First Posted Date  ICMJE February 1, 2013
Results First Submitted Date  ICMJE May 17, 2016
Results First Posted Date  ICMJE June 23, 2016
Last Update Posted Date February 2, 2018
Actual Study Start Date  ICMJE May 10, 2013
Actual Primary Completion Date December 31, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 31, 2013)
  • Maximum Tolerated Dose (MTD) [ Time Frame: 5-6 weeks during study treatment ]
    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 ]
    RD will be defined as one level below the MTD.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT01781403 on Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 17, 2016)
Pathological Complete Response [ Time Frame: at the time of surgery (6-8 weeks after study treatment) ]
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.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 31, 2013)
Association between MGMT expression and pathologic responses [ Time Frame: at the time of surgery (6-8 weeks after study treatment) ]
Current Other Pre-specified Outcome Measures
 (submitted: January 31, 2013)
  • Toxicity [ Time Frame: 5-6 weeks during study treatment ]
    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) ]
    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 ]
Original Other Pre-specified Outcome Measures Same as current
Descriptive Information
Brief Title  ICMJE Preoperative CRT With Temozolomide Plus Capecitabine in Rectal Cancer
Official Title  ICMJE Preoperative Chemoradiation With Capecitabine Plus Temozolomide in Patients With Locally Advanced Resectable Rectal Cancer: Phase I Study
Brief Summary 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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Rectal Cancer
Intervention  ICMJE 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
Study Arms  ICMJE 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).

Intervention: Drug: Temozolomide
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.

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: May 17, 2016)
Original Estimated Enrollment  ICMJE
 (submitted: January 31, 2013)
Estimated Study Completion Date  ICMJE December 2018
Actual Primary Completion Date December 31, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 20 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Korea, Republic of
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT01781403
Other Study ID Numbers  ICMJE ML28381
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Tae Won Kim, Asan Medical Center
Study Sponsor  ICMJE Asan Medical Center
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Tae Won Kim, Professor Asan Medical Center
PRS Account Asan Medical Center
Verification Date January 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP