Preoperative CRT With Temozolomide Plus Capecitabine in Rectal Cancer
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1 |
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 Design
Arms and Interventions
| 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:
|
Outcome Measures
Primary Outcome Measures
- Maximum Tolerated Dose (MTD) [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) [5-6 weeks after CRT]
RD will be defined as one level below the MTD.
Secondary Outcome Measures
- Pathological Complete Response [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.
Other Outcome Measures
- Toxicity(Adeverse Event) [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 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.
- Efficacy: Pathologic Major Responses [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 [3-year or 5-year after surgery]
Eligibility Criteria
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
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | 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
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- ML28381
Study Results
Participant Flow
| Recruitment Details | Participants were enrolled from 14 May 2013 through 8 May 2014 |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Capecitabine 825mg/m^2, Temozolomide 45mg/m^2, Radiotherapy | Capecitabine 825mg/m^2, Temozolomide 60mg/m^2, Radiotherapy | Capecitabine 825mg/m^2, Temozolomide 75mg/m^2, Radiotherapy |
|---|---|---|---|
| Arm/Group Description | 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). Temozolomide: Preoperative chemoradiotherapy with fixed dose of capecitabine and temozolomide, the dose of temozolomide will be escalated for finding MTD and RD. | 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). Temozolomide: Preoperative chemoradiotherapy with fixed dose of capecitabine and temozolomide, the dose of temozolomide will be escalated for finding MTD and RD. | 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). Temozolomide: Preoperative chemoradiotherapy with fixed dose of capecitabine and temozolomide, the dose of temozolomide will be escalated for finding MTD and RD. |
| Period Title: Overall Study | |||
| STARTED | 2 | 2 | 18 |
| COMPLETED | 2 | 2 | 18 |
| NOT COMPLETED | 0 | 0 | 0 |
Baseline Characteristics
| Arm/Group Title | Capecitabine, Temozolomide, Radiotherapy |
|---|---|
| Arm/Group Description | 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). Temozolomide: Preoperative chemoradiotherapy with fixed dose of capecitabine and temozolomide, the dose of temozolomide will be escalated for finding MTD and RD. |
| Overall Participants | 22 |
| Age (years) [Median (Full Range) ] | |
| Median (Full Range) [years] |
54
|
| Sex: Female, Male (Count of Participants) | |
| Female |
7
31.8%
|
| Male |
15
68.2%
|
| Region of Enrollment (participants) [Number] | |
| Korea, Republic of |
22
100%
|
Outcome Measures
| Title | Maximum Tolerated Dose (MTD) |
|---|---|
| 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%. |
| Time Frame | 5-6 weeks during study treatment |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Dose Level 1 | Dose Level 2 | Dose Level 3/Recommended Dose |
|---|---|---|---|
| Arm/Group Description | Capecitabine was given 825 mg/m^2 twice/day during radiotherapy with drug holidays (weekend breaks). Temozolomide was given 45 mg/m^2 once/day during radiotherapy with drug holidays (weekend breaks). | Capecitabine was given 825 mg/m^2 twice/day during radiotherapy with drug holidays (weekend breaks). Temozolomide was given 60 mg/m^2 once/day during radiotherapy with drug holidays (weekend breaks). | Capecitabine was given 825 mg/m^2 twice/day during radiotherapy with drug holidays (weekend breaks). Temozolomide was given 75 mg/m^2 once/day during radiotherapy with drug holidays (weekend breaks). |
| Measure Participants | 2 | 2 | 18 |
| Number [mg/m^2] |
0
|
0
|
0
|
| Title | Recommended Dose (RD) |
|---|---|
| Description | RD will be defined as one level below the MTD. |
| Time Frame | 5-6 weeks after CRT |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Dose Level 1 | Dose Level 2 | Dose Level 3/Recommended Dose |
|---|---|---|---|
| Arm/Group Description | Capecitabine was given 825 mg/m^2 twice/day during radiotherapy with drug holidays (weekend breaks). Temozolomide was given 45 mg/m^2 once/day during radiotherapy with drug holidays (weekend breaks). | Capecitabine was given 825 mg/m^2 twice/day during radiotherapy with drug holidays (weekend breaks). Temozolomide was given 60 mg/m^2 once/day during radiotherapy with drug holidays (weekend breaks). | Capecitabine was given 825 mg/m^2 twice/day during radiotherapy with drug holidays (weekend breaks). Temozolomide was given 75 mg/m^2 once/day during radiotherapy with drug holidays (weekend breaks). |
| Measure Participants | 2 | 2 | 18 |
| Number [mg/m^2] |
0
|
0
|
75
|
| Title | Pathological Complete Response |
|---|---|
| Description | 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. |
| Time Frame | at the time of surgery (6-8 weeks after study treatment) |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Unmethylated MGMT | Hypermethylated MGMT |
|---|---|---|
| Arm/Group Description | MGMT methylation specific PCR: unmethlyated | MGMT methylation specific PCR: hypermethylated |
| Measure Participants | 6 | 16 |
| Number [participants] |
1
4.5%
|
6
NaN
|
| Title | Toxicity(Adeverse Event) |
|---|---|
| Description | 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. |
| Time Frame | 5-6 weeks during study treatment |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Dose Level 1 | Dose Level 2 | Dose Level 3/Recommended Dose |
|---|---|---|---|
| Arm/Group Description | Capecitabine was given 825 mg/m^2 twice/day during radiotherapy with drug holidays (weekend breaks). Temozolomide was given 45 mg/m^2 once/day during radiotherapy with drug holidays (weekend breaks). | Capecitabine was given 825 mg/m^2 twice/day during radiotherapy with drug holidays (weekend breaks). Temozolomide was given 60 mg/m^2 once/day during radiotherapy with drug holidays (weekend breaks). | Capecitabine was given 825 mg/m^2 twice/day during radiotherapy with drug holidays (weekend breaks). Temozolomide was given 75 mg/m^2 once/day during radiotherapy with drug holidays (weekend breaks). |
| Measure Participants | 2 | 2 | 18 |
| Any grade 1 adverse event |
6
|
8
|
60
|
| Any grade 2 adverse event |
2
|
2
|
17
|
| Any grade 3 adverse event |
1
|
0
|
3
|
| Any grade 4 adverse event |
0
|
0
|
0
|
| Title | Efficacy: Pathologic Major Responses |
|---|---|
| Description | 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. |
| Time Frame | after surgery (6-8 weeks after study treatment) |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
| Title | Disease-free Survival |
|---|---|
| Description | |
| Time Frame | 3-year or 5-year after surgery |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
Adverse Events
| Time Frame | ||||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | ||||||
| Arm/Group Title | Dose Level 1 | Dose Level 2 | Dose Level 3/Recommended Dose | |||
| Arm/Group Description | Capecitabine was given 825 mg/m^2 twice/day during radiotherapy with drug holidays (weekend breaks). Temozolomide was given 45 mg/m^2 once/day during radiotherapy with drug holidays (weekend breaks). | Capecitabine was given 825 mg/m^2 twice/day during radiotherapy with drug holidays (weekend breaks). Temozolomide was given 60 mg/m^2 once/day during radiotherapy with drug holidays (weekend breaks). | Capecitabine was given 825 mg/m^2 twice/day during radiotherapy with drug holidays (weekend breaks). Temozolomide was given 75 mg/m^2 once/day during radiotherapy with drug holidays (weekend breaks). | |||
All Cause Mortality |
||||||
| Dose Level 1 | Dose Level 2 | Dose Level 3/Recommended Dose | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | / (NaN) | |||
Serious Adverse Events |
||||||
| Dose Level 1 | Dose Level 2 | Dose Level 3/Recommended Dose | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/2 (0%) | 0/2 (0%) | 0/18 (0%) | |||
Other (Not Including Serious) Adverse Events |
||||||
| Dose Level 1 | Dose Level 2 | Dose Level 3/Recommended Dose | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 2/2 (100%) | 2/2 (100%) | 18/18 (100%) | |||
| Blood and lymphatic system disorders | ||||||
| Anemia | 2/2 (100%) | 2 | 1/2 (50%) | 1 | 10/18 (55.6%) | 10 |
| Febrile neutropenia | 0/2 (0%) | 0 | 0/2 (0%) | 0 | 0/18 (0%) | 0 |
| Leukopenia | 2/2 (100%) | 2 | 0/2 (0%) | 0 | 13/18 (72.2%) | 13 |
| Neutropenia | 2/2 (100%) | 2 | 0/2 (0%) | 0 | 7/18 (38.9%) | 7 |
| Thrombocytopenia | 0/2 (0%) | 0 | 0/2 (0%) | 0 | 4/18 (22.2%) | 4 |
| Gastrointestinal disorders | ||||||
| Anorexia | 1/2 (50%) | 1 | 1/2 (50%) | 1 | 3/18 (16.7%) | 3 |
| Constipation | 0/2 (0%) | 0 | 1/2 (50%) | 1 | 6/18 (33.3%) | 6 |
| Diarrhea | 0/2 (0%) | 0 | 1/2 (50%) | 1 | 3/18 (16.7%) | 3 |
| Nausea | 1/2 (50%) | 1 | 2/2 (100%) | 2 | 14/18 (77.8%) | 14 |
| Vomiting | 0/2 (0%) | 0 | 1/2 (50%) | 1 | 5/18 (27.8%) | 5 |
| General disorders | ||||||
| Fatigue | 1/2 (50%) | 1 | 2/2 (100%) | 2 | 3/18 (16.7%) | 3 |
| Hand-foot syndrome | 0/2 (0%) | 0 | 0/2 (0%) | 0 | 0/18 (0%) | 0 |
| Hepatobiliary disorders | ||||||
| ALT abnormalities | 0/2 (0%) | 0 | 0/2 (0%) | 0 | 7/18 (38.9%) | 7 |
| AST abnormalities | 0/2 (0%) | 0 | 0/2 (0%) | 0 | 5/18 (27.8%) | 5 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
Results Point of Contact
| Name/Title | Dr. Tae Won Kim |
|---|---|
| Organization | Asan Medical Center |
| Phone | +82-2-3010-3910 |
| twkimmd@amc.seoul.kr |
- ML28381