Trial Outcomes & Findings for Preoperative CRT With Temozolomide Plus Capecitabine in Rectal Cancer (NCT NCT01781403)

NCT ID: NCT01781403

Last Updated: 2021-02-04

Results Overview

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%.

• Recruitment status: COMPLETED
• Study phase: PHASE1
• Target enrollment: 22 participants
• Primary outcome timeframe: 5-6 weeks during study treatment
• Results posted on: 2021-02-04

Participant Flow

Participants were enrolled from 14 May 2013 through 8 May 2014

Participant milestones

Measure	Capecitabine 825mg/m^2, Temozolomide 45mg/m^2, 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). Temozolomide: Preoperative chemoradiotherapy with fixed dose of capecitabine and temozolomide, the dose of temozolomide will be escalated for finding MTD and RD.	Capecitabine 825mg/m^2, Temozolomide 60mg/m^2, 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). Temozolomide: Preoperative chemoradiotherapy with fixed dose of capecitabine and temozolomide, the dose of temozolomide will be escalated for finding MTD and RD.	Capecitabine 825mg/m^2, Temozolomide 75mg/m^2, 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). Temozolomide: Preoperative chemoradiotherapy with fixed dose of capecitabine and temozolomide, the dose of temozolomide will be escalated for finding MTD and RD.
Overall Study STARTED	2	2	18
Overall Study COMPLETED	2	2	18
Overall Study NOT COMPLETED	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Preoperative CRT With Temozolomide Plus Capecitabine in Rectal Cancer

Baseline characteristics by cohort

Measure	Capecitabine, Temozolomide, Radiotherapy n=22 Participants 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.
Age, Continuous	54 years n=5 Participants
Sex: Female, Male Female	7 Participants n=5 Participants
Sex: Female, Male Male	15 Participants n=5 Participants
Region of Enrollment Korea, Republic of	22 participants n=5 Participants

PRIMARY outcome

Timeframe: 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%.

Outcome measures

Measure	Dose Level 1 n=2 Participants 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).	Dose Level 2 n=2 Participants 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).	Dose Level 3/Recommended Dose n=18 Participants 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).
Maximum Tolerated Dose (MTD)	0 mg/m^2	0 mg/m^2	0 mg/m^2

PRIMARY outcome

Timeframe: 5-6 weeks after CRT

RD will be defined as one level below the MTD.

Outcome measures

Measure	Dose Level 1 n=2 Participants 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).	Dose Level 2 n=2 Participants 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).	Dose Level 3/Recommended Dose n=18 Participants 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).
Recommended Dose (RD)	0 mg/m^2	0 mg/m^2	75 mg/m^2

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Dose Level 1 n=6 Participants 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).	Dose Level 2 n=16 Participants 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).	Dose Level 3/Recommended Dose 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).
Pathological Complete Response	1 participants	6 participants	—

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

Outcome measures

Measure	Dose Level 1 n=2 Participants 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).	Dose Level 2 n=2 Participants 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).	Dose Level 3/Recommended Dose n=18 Participants 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).
Toxicity(Adeverse Event) Any grade 1 adverse event	6 events	8 events	60 events
Toxicity(Adeverse Event) Any grade 2 adverse event	2 events	2 events	17 events
Toxicity(Adeverse Event) Any grade 3 adverse event	1 events	0 events	3 events
Toxicity(Adeverse Event) Any grade 4 adverse event	0 events	0 events	0 events

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: 3-year or 5-year after surgery

Outcome measures

Outcome data not reported

Adverse Events

Dose Level 1

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Dose Level 2

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Dose Level 3/Recommended Dose

Serious events: 0 serious events

Other events: 18 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Dose Level 1 n=2 participants at risk 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).	Dose Level 2 n=2 participants at risk 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).	Dose Level 3/Recommended Dose n=18 participants at risk 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).
Blood and lymphatic system disorders Anemia	100.0% 2/2 • Number of events 2	50.0% 1/2 • Number of events 1	55.6% 10/18 • Number of events 10
Blood and lymphatic system disorders Febrile neutropenia	0.00% 0/2	0.00% 0/2	0.00% 0/18
Blood and lymphatic system disorders Leukopenia	100.0% 2/2 • Number of events 2	0.00% 0/2	72.2% 13/18 • Number of events 13
Blood and lymphatic system disorders Neutropenia	100.0% 2/2 • Number of events 2	0.00% 0/2	38.9% 7/18 • Number of events 7
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/2	0.00% 0/2	22.2% 4/18 • Number of events 4
Gastrointestinal disorders Anorexia	50.0% 1/2 • Number of events 1	50.0% 1/2 • Number of events 1	16.7% 3/18 • Number of events 3
Gastrointestinal disorders Constipation	0.00% 0/2	50.0% 1/2 • Number of events 1	33.3% 6/18 • Number of events 6
Gastrointestinal disorders Diarrhea	0.00% 0/2	50.0% 1/2 • Number of events 1	16.7% 3/18 • Number of events 3
Gastrointestinal disorders Nausea	50.0% 1/2 • Number of events 1	100.0% 2/2 • Number of events 2	77.8% 14/18 • Number of events 14
Gastrointestinal disorders Vomiting	0.00% 0/2	50.0% 1/2 • Number of events 1	27.8% 5/18 • Number of events 5
General disorders Fatigue	50.0% 1/2 • Number of events 1	100.0% 2/2 • Number of events 2	16.7% 3/18 • Number of events 3
General disorders Hand-foot syndrome	0.00% 0/2	0.00% 0/2	0.00% 0/18
Hepatobiliary disorders ALT abnormalities	0.00% 0/2	0.00% 0/2	38.9% 7/18 • Number of events 7
Hepatobiliary disorders AST abnormalities	0.00% 0/2	0.00% 0/2	27.8% 5/18 • Number of events 5

Additional Information

Dr. Tae Won Kim

Asan Medical Center

Phone: +82-2-3010-3910

Email: twkimmd@amc.seoul.kr

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place

Restriction type: OTHER