Preoperative Chemoradiation With Capecitabine Plus Temozolomide in Patients With Locally Advanced Resectable Rectal Cancer: Phase I Study
20 Years
N/A
Both
Rectal Cancer
Trial Information
Preoperative Chemoradiation With Capecitabine Plus Temozolomide in Patients With Locally Advanced Resectable Rectal Cancer: Phase I Study
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.
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.
Type of Study:
Interventional
Study Design:
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
Maximum tolerated dose (MTD)
Outcome Description:
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%.
Outcome Time Frame:
5-6 weeks during study treatment
Safety Issue:
Yes
Principal Investigator
Tae Won Kim, Professor
Investigator Role:
Principal Investigator
Investigator Affiliation:
Asan Medical Center
Authority:
Korea: Food and Drug Administration
Study ID:
ML28381
NCT ID:
NCT01781403
Start Date:
April 2013
Completion Date:
March 2016
Related Keywords:
- Rectal Cancer
- Temozolomide
- capecitabine
- rectal cancer
- Rectal Neoplasms
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