A Phase 1 interventional study of Temozolomide in Rectal Cancer, sponsored by Asan Medical Center. Completed at 1 site in Korea, Republic of. Open to participants aged 20 Years and older. Per ClinicalTrials.gov, last updated 2021-02-04.
Sponsored by Asan Medical Center · Phase 1, Interventional, and Treatment
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.
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.
1,762 studies on the registry are indexed under Rectal Neoplasms; 518 are open to participants now.
This study's enrollment of 22 is below the median of 65 across 1,298 interventional studies indexed under Rectal Neoplasms.
Browse Rectal Neoplasms studies →Asan Medical Center is the lead sponsor of 562 studies on the registry; 71 are open to participants now.
Counted across the registry records on this site, refreshed daily.
Exclusion Criteria:
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.
Also known as: Capecitabine, preoperative radiotherapy
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%.
Time frame: 5-6 weeks during study treatment
Recommended Dose (RD)
RD will be defined as one level below the MTD.
Time frame: 5-6 weeks after CRT
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.
Time frame: at the time of surgery (6-8 weeks after study treatment)
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 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.
Time frame: 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.
Time frame: after surgery (6-8 weeks after study treatment)
Disease-free Survival
Time frame: 3-year or 5-year after surgery
Participants were enrolled from 14 May 2013 through 8 May 2014
| Milestone | 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 |
|---|---|---|---|
| Started | 2 | 2 | 18 |
| Completed | 2 | 2 | 18 |
| Not completed | 0 | 0 | 0 |
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%.
| mg/m^2 | Dose Level 1 | Dose Level 2 | Dose Level 3/Recommended Dose |
|---|---|---|---|
| Maximum Tolerated Dose (MTD) | 0 | 0 | 0 |
RD will be defined as one level below the MTD.
| mg/m^2 | Dose Level 1 | Dose Level 2 | Dose Level 3/Recommended Dose |
|---|---|---|---|
| Recommended Dose (RD) | 0 | 0 | 75 |
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.
| participants | Unmethylated MGMT | Hypermethylated MGMT |
|---|---|---|
| Pathological Complete Response | 1 | 6 |
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.
| events | Dose Level 1 | Dose Level 2 | Dose Level 3/Recommended Dose |
|---|---|---|---|
| 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 |
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.
Results for this outcome have not been posted.
Results for this outcome have not been posted.
Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Dose Level 1 | — | 0/2 (0%) | 2/2 (100%) |
| Dose Level 2 | — | 0/2 (0%) | 2/2 (100%) |
| Dose Level 3/Recommended Dose | — | 0/18 (0%) | 18/18 (100%) |
| Event | Dose Level 1 | Dose Level 2 | Dose Level 3/Recommended Dose |
|---|---|---|---|
| AnemiaBlood and lymphatic system disorders | 2/2 | 1/2 | 10/18 |
| LeukopeniaBlood and lymphatic system disorders | 2/2 | 0/2 | 13/18 |
| NeutropeniaBlood and lymphatic system disorders | 2/2 | 0/2 | 7/18 |
| NauseaGastrointestinal disorders | 1/2 | 2/2 | 14/18 |
| FatigueGeneral disorders | 1/2 | 2/2 | 3/18 |
| AnorexiaGastrointestinal disorders | 1/2 | 1/2 | 3/18 |
| ConstipationGastrointestinal disorders | 0/2 | 1/2 | 6/18 |
| DiarrheaGastrointestinal disorders | 0/2 | 1/2 | 3/18 |
| VomitingGastrointestinal disorders | 0/2 | 1/2 | 5/18 |
| ALT abnormalitiesHepatobiliary disorders | 0/2 | 0/2 | 7/18 |
| Age, Continuous(years) | Capecitabine, Temozolomide, Radiotherapy |
|---|---|
| Median | 54 (41 to 77) |
| Sex: Female, Male(Participants) | Capecitabine, Temozolomide, Radiotherapy |
|---|---|
| Female | 7 |
| Male | 15 |
| Region of Enrollment(participants) | Capecitabine, Temozolomide, Radiotherapy |
|---|---|
| Korea, Republic of | 22 |
Plan to share: No
This study is completed, as verified in Jan 2021. You cannot join it, but the record below documents what was studied.
Get an email when the registry record changes — status, dates, results — or when someone posts here.
Sign in to followQuestions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.
Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.
Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.
Asan Medical Center