Chemotherapeutic Agent Toxicity, Colorectal Cancer, Diarrhea
Conditions
Keywords
diarrhea, chemotherapeutic agent toxicity, recurrent colon cancer, recurrent rectal cancer, stage IV colon cancer, stage IV rectal cancer
Brief summary
RATIONALE: Calcium aluminosilicate anti-diarrheal (CASAD) may help treat and prevent diarrhea caused by irinotecan. It is not yet known whether CASAD is more effective than a placebo in treating and preventing diarrhea in patients receiving irinotecan. PURPOSE: This randomized phase II trial is studying CASAD to see how well it works compared with a placebo in treating and preventing diarrhea in patients with metastatic colorectal cancer receiving irinotecan.
Detailed description
OBJECTIVES: Primary * To compare the efficacy of calcium aluminosilicate anti-diarrheal (CASAD) versus placebo in reducing the incidence of grade 3 or 4 diarrhea in patients with metastatic colorectal cancer receiving an irinotecan-based chemotherapy regimen. Secondary * To compare stools per day in patients treated with these drugs. * To compare chemotherapy dose reductions and delays due to diarrhea in patients treated with these drugs. * To compare quality of life of patients treated with these drugs. * To compare the safety of these drugs in these patients. * To compare the incidence of grade 3 or 4 diarrhea in patients treated with these drugs. OUTLINE: This is a multicenter study. Patients are stratified according to chemotherapy regimen (irinotecan hydrochloride in combination with fluorouracil and/or biologic therapy vs irinotecan hydrochloride alone). Patients are randomized to 1 of 2 treatment arms. * Arm I: Patients receive oral calcium aluminosilicate anti-diarrheal (CASAD) 4 times daily for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients who develop grade 3 or 4 diarrhea and are removed from the study may receive CASAD for an additional 6 weeks. * Arm II: Patients receive oral placebo 4 times daily for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients who develop grade 3 or 4 diarrhea and are removed from the study may then receive CASAD for 6 weeks. Patients undergo quality-of-life assessment at baseline and at weeks 3, 5, and 6. After completion of study treatment, patients are followed for 30 days.
Interventions
DRUGcalcium aluminosilicate anti-diarrheal
Given orally
OTHERplacebo
Given orally
Sponsors
National Cancer Institute (NCI)
M.D. Anderson Cancer Center
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
SUPPORTIVE_CARE
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Diagnosis of colorectal cancer * Metastatic disease * Scheduled to receive irinotecan hydrochloride alone or in combination with fluorouracil, cetuximab, leucovorin calcium, or other biological therapy (including bevacizumab) * No uncontrolled brain metastasis * Previously treated brain metastasis allowed PATIENT CHARACTERISTICS: * Eastern Cooperative Oncology Group (ECOG) performance status 0-2 * Absolute neutrophil count (ANC) \> 1,000/mm³ * Platelet count \> 100,000/mm³ * Total bilirubin \< 1.5 times upper limit of normal (ULN) * Aspartate aminotransferase (AST or SGOT) and/or alanine aminotransferase (ALT or SGPT) \< 2.5 times ULN (\< 5 times ULN if liver metastasis is present) * Alkaline phosphatase \< 2.5 times ULN * Creatinine clearance \> 35 mL/min * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * No known UDP-glucuronosyltransferase 1A1 (UGT1A1) deficiency with homozygotes. * No known history of Gilbert's disease * No diarrhea \> grade 1 * No serious illness or medical condition, including any of the following: * Uncontrolled congestive heart failure * Uncontrolled hypertension (i.e., blood pressure \> 150/100 mm Hg) * Uncontrolled arrhythmia * Active angina pectoris * Symptomatic heart disease according to New York Heart Association(NYHA) class II-IV * No serious uncontrolled active infection * No existing colostomy or ileostomy * Not able to take and document oral study medications * No history of allergies to irinotecan hydrochloride * No history of significant neurological or psychiatric disorders that would preclude giving consent or participating in study treatment or follow up PRIOR CONCURRENT THERAPY: * See Disease Characteristics * Prior treatment for metastatic disease allowed * At least 4 weeks since prior irinotecan * More than 2 weeks since prior chemotherapy * Irinotecan alone or in combination with other chemotherapy or biologic agents allowed * More than 4 weeks since prior radiotherapy * No concurrent radiotherapy * No concurrent medication schedule that does not permit a 2-hour window between administration of calcium aluminosilicate anti-diarrheal (CASAD) and other medications
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Grade 3/4 Diarrhea | First 6 weeks from baseline in initial intervention with CASAD or PLACEBO | One hundred patients were randomized equally between CASAD and placebo arms in order to assess whether CASAD was efficacious in preventing grade 3/4 diarrhea within 6 weeks for each arm compared. Bayesian futility monitoring in the study with a recommendation to stop the trial for futility if it became clear that CASAD was not better than placebo. |
Countries
United States
Participant flow
Recruitment details
Recruitment Period: February 04, 2009 to May 3, 2012. All recruitment done at the University of Texas (UT) MD Anderson Cancer Center.
Pre-assignment details
Of the original 100 patients enrolled and randomized to the 6 week intervention period, 39 patients would go on to take open label CASAD; 22 patients from the CASAD arm and 17 patients from the placebo arm. These patients were added as a Milestone on the Participant Flow sheet. 8 patients received open label for \<21 days; 31 patients received open label CASAD for \>21 days.
Participants by arm
| Arm | Count |
|---|---|
| Arm I: Calcium Aluminosilicate Anti-Diarrheal (CASAD) Oral calcium aluminosilicate anti-diarrheal (CASAD) 4 times daily for 6 weeks in the absence of disease progression or unacceptable toxicity. Participants who develop grade 3 or 4 diarrhea may receive CASAD for an additional 6 weeks. | 50 |
| Arm II: Placebo Oral placebo 4 times daily for 6 weeks in the absence of disease progression or unacceptable toxicity. Participants who develop grade 3 or 4 diarrhea may then receive CASAD for 6 weeks. | 50 |
| Total | 100 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 5 |
| Overall Study | Change in patient condition | 0 | 3 |
| Overall Study | Non-compliant | 0 | 2 |
| Overall Study | Treatment change | 2 | 1 |
| Overall Study | Withdrawal by Subject | 7 | 7 |
Baseline characteristics
| Characteristic | Arm I: Calcium Aluminosilicate Anti-Diarrheal (CASAD) | Arm II: Placebo | Total |
|---|---|---|---|
| Age, Continuous | 57 Years | 56 Years | 56.5 Years |
| Baseline Bowel Assessment (BBA) 1/2 Full | 1 Participants | 1 Participants | 2 Participants |
| Baseline Bowel Assessment (BBA) 1/3 Full (recommended) | 4 Participants | 1 Participants | 5 Participants |
| Baseline Bowel Assessment (BBA) < 1 -3 Per Day | 7 Participants | 3 Participants | 10 Participants |
| Baseline Bowel Assessment (BBA) 1/4 Full | 0 Participants | 1 Participants | 1 Participants |
| Baseline Bowel Assessment (BBA) < 1 Per Day | 7 Participants | 6 Participants | 13 Participants |
| Baseline Bowel Assessment (BBA) < >3 Per Day | 27 Participants | 34 Participants | 61 Participants |
| Baseline Bowel Assessment (BBA) Hard difficult to pass | 8 Participants | 9 Participants | 17 Participants |
| Baseline Bowel Assessment (BBA) Loose | 25 Participants | 29 Participants | 54 Participants |
| Baseline Bowel Assessment (BBA) No | 7 Participants | 6 Participants | 13 Participants |
| Baseline Bowel Assessment (BBA) Not answered | 0 Participants | 3 Participants | 2 Participants |
| Baseline Bowel Assessment (BBA) Other | 1 Participants | 3 Participants | 1 Participants |
| Baseline Bowel Assessment (BBA) Very loose and watery | 7 Participants | 6 Participants | 13 Participants |
| Baseline Bowel Assessment (BBA) Well-formed, easy to pass | 4 Participants | 2 Participants | 6 Participants |
| Baseline Bowel Assessment (BBA) Yes, significant | 11 Participants | 8 Participants | 19 Participants |
| Baseline Bowel Assessment (BBA) Yes, some | 24 Participants | 32 Participants | 56 Participants |
| Baseline Ostomy Bowel Assessment (BOBA) >1000 ml/day | 0 Participants | 0 Participants | 0 Participants |
| Baseline Ostomy Bowel Assessment (BOBA) 200-600 ml/day (typical) | 0 Participants | 0 Participants | 0 Participants |
| Baseline Ostomy Bowel Assessment (BOBA) <200 ml/day | 0 Participants | 0 Participants | 0 Participants |
| Baseline Ostomy Bowel Assessment (BOBA) 2-3 times | 3 Participants | 3 Participants | 6 Participants |
| Baseline Ostomy Bowel Assessment (BOBA) 4-6 times | 2 Participants | 0 Participants | 2 Participants |
| Baseline Ostomy Bowel Assessment (BOBA) 600-1000 ml/day | 0 Participants | 0 Participants | 0 Participants |
| Baseline Ostomy Bowel Assessment (BOBA) >6 times | 0 Participants | 0 Participants | 0 Participants |
| Baseline Ostomy Bowel Assessment (BOBA) Does not measure output | 6 Participants | 4 Participants | 10 Participants |
| Baseline Ostomy Bowel Assessment (BOBA) Loose (pudding, cake batter consistency) | 2 Participants | 1 Participants | 3 Participants |
| Baseline Ostomy Bowel Assessment (BOBA) No | 4 Participants | 4 Participants | 8 Participants |
| Baseline Ostomy Bowel Assessment (BOBA) Other | 2 Participants | 1 Participants | 3 Participants |
| Baseline Ostomy Bowel Assessment (BOBA) Semi-formed (peanut butter consistency) | 1 Participants | 3 Participants | 4 Participants |
| Baseline Ostomy Bowel Assessment (BOBA) Very loose and watery | 3 Participants | 0 Participants | 3 Participants |
| Baseline Ostomy Bowel Assessment (BOBA) Well-formed, easy to pass | 0 Participants | 0 Participants | 0 Participants |
| Baseline Ostomy Bowel Assessment (BOBA) Yes, significant | 1 Participants | 0 Participants | 1 Participants |
| Baseline Ostomy Bowel Assessment (BOBA) Yes, some | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 6 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 45 Participants | 44 Participants | 89 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 9 Participants | 16 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 42 Participants | 41 Participants | 83 Participants |
| Region of Enrollment United States | 50 participants | 50 participants | 100 participants |
| Sex: Female, Male Female | 21 Participants | 25 Participants | 46 Participants |
| Sex: Female, Male Male | 29 Participants | 25 Participants | 54 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 50 | 0 / 50 |
| other Total, other adverse events | 50 / 50 | 50 / 50 |
| serious Total, serious adverse events | 4 / 50 | 9 / 50 |
Outcome results
Primary
Number of Participants With Grade 3/4 Diarrhea
One hundred patients were randomized equally between CASAD and placebo arms in order to assess whether CASAD was efficacious in preventing grade 3/4 diarrhea within 6 weeks for each arm compared. Bayesian futility monitoring in the study with a recommendation to stop the trial for futility if it became clear that CASAD was not better than placebo.
Time frame: First 6 weeks from baseline in initial intervention with CASAD or PLACEBO
Population: Patients who experienced any diarrhea during the intervention period and patients who experienced Grade 3/4 diarrhea during the intervention period.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm I: Calcium Aluminosilicate Anti-Diarrheal (CASAD) | Number of Participants With Grade 3/4 Diarrhea | Any diarrhea in first 6 weeks | 27 Participants |
| Arm I: Calcium Aluminosilicate Anti-Diarrheal (CASAD) | Number of Participants With Grade 3/4 Diarrhea | Grade 3/4 diarrhea in first 6 weeks | 7 Participants |
| Arm II: Placebo | Number of Participants With Grade 3/4 Diarrhea | Any diarrhea in first 6 weeks | 26 Participants |
| Arm II: Placebo | Number of Participants With Grade 3/4 Diarrhea | Grade 3/4 diarrhea in first 6 weeks | 3 Participants |