Breast Cancer
Conditions
Keywords
HER2, pertuzumab, trastuzumab, docetaxel, paclitaxel, carboplatin, crofelemer, chemotherapy induced diarrhea
Brief summary
Chemotherapy induced diarrhea is seen in up to 40-80% of patients receiving this treatment for HER2 positive locally advanced or metastatic breast cancer. This diarrhea can significantly impact a patient's quality of life and ability to tolerate chemo/anti-HER2 therapy. This study will look at the efficacy of the drug crofelemer in preventing diarrhea in breast cancer patients.
Detailed description
Various anti-diarrheal agents, such as loperamide, codeine, octreotide, are available for diarrhea management, but few are used in the prophylactic setting and none provide a targeted approach for treating chemotherapy induced diarrhea (CID). Pre-clinical studies have suggested that blocking EGFR results in excess chloride secretion and thus diarrhea. Crofelemer is an extract from the blood red bark of Croton lechleri that inhibits luminal chloride efflux by blocking the calcium activated chloride channel (CaCC) and cystic fibrosis transmembrane regulator (CFTR) chloride channels. Due to its size and polarity, it acts only luminally and is not systemically absorbed. It is currently FDA approved for use in preventing diarrhea in HIV/AIDS patients on anti-retroviral therapy.
Interventions
DRUGCrofelemer
Crofelemer 125 mg BID during cycles 1-2 of THP or TCHP
Sponsors
Lombardi Comprehensive Cancer Center
Medstar Health Research Institute
Genentech, Inc.
Napo Pharmaceuticals, Inc.
Sandra Swain
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Willing and able to provide written informed consent; 2. Men and women ≥18 years of age; 3. Pathologically confirmed diagnosis of HER2 positive breast cancer of any stage (previous treatment is allowed without limits on lines of prior therapy); 4. Scheduled to receive at least 3 consecutive cycles of THP or TCHP; 5. Performance status of 0-2 according to the ECOG scale; 6. Negative pregnancy test at time of informed consent for women of childbearing potential; 7. Able to read, understand, follow the study procedure and complete crofelemer, rescue medication, and bowel movement diaries; 8. Patients may enroll simultaneously on this study and other studies, including but not limited to NSABP B52; 9. Patients with brain metastases (including concurrent steroid treatment) are allowed on this study. 10. Left Ventricular Ejection Fraction (LVEF) greater or equal to 50% at baseline as determined by either ECHO or MUGA
Exclusion criteria
1. Pregnant and/or breastfeeding; 2. Ongoing irritable bowel syndrome (IBS) or colitis (including but not limited to ulcerative colitis, Crohn's disease, microscopic colitis, etc.); 3. Use of investigational drugs within 3 weeks of signing consent or foreseen use during the study; 4. Use of chemotherapy, trastuzumab, or pertuzumab within the past 3 weeks; 5. Use of antibiotics within the past 7 days (up to 2 prophylactic doses of antibiotics for procedures including, but not limited to port placement, is permitted); 6. Any type of ostomy; 7. Total colectomy; 8. Fecal incontinence; 9. Ongoing radiation induced diarrhea or constipation or planned radiotherapy to the abdomen or pelvis while on study; 10. Active systemic infection requiring ongoing intervention, including but not limited to oral and intravenous antibiotics, anti-fungals, anti-parasites, anti-virals; 11. Abdominal or pelvic surgery without recovery of bowel function; 12. Inadequate organ function for starting THP or TCHP, which may include the following laboratory results within 28 days prior to signing consent: 1. Total bilirubin \> upper limit of normal (ULN) (unless the patient has documented Gilbert's syndrome) 2. Serum creatinine \> 2.0 mg/dL or 177 μmol/L 3. AST (SGOT) and ALT (SPGT) \> 2.5 ULN.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Diarrhea for >= 2 Consecutive Days | Cycle 1, Cycle 2 (each cycle is 21 days) | Percentage of participants with any grade (based on CTCAE 4.0) diarrhea lasting 2 or more consecutive days during cycles 1 and 2 of chemotherapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Grade 3-4 Diarrhea | Cycle 1, Cycle 2 (each cycle is 21 days) | number of patients with diarrhea of grade 3 or grade 4, as measured by CTCAE v4.0, by cycle and by stratum |
| Diarrhea Onset | from baseline through Cycle 3 (21 day cycles) | Time to onset of first episode of diarrhea of any grade, overall |
| Diarrhea Duration | Cycle 1, Cycle 2 (each cycle is 21 days) | Duration (days) of any grade diarrhea, defined from day 1 to day 21, by cycle in which the episode started |
| Duration Grade 3-4 Diarrhea | End of Cycle 2 (each cycle is 21 days) | Duration (days) of grade 3-4 diarrhea during cycle 1 through the end of cycle 2, defined from cycle day 1 to cycle 2 day 21 |
| Diarrhea Any Grade | Cycle 1, Cycle 2 (each cycle is 21 days) | Incidence of diarrhea of any grade, as measured by CTCAE v4.0, by cycle |
| FACIT-D Total Score | Cycle 1, Cycle 2 (each cycle is 21 days) | Quantitative FACIT-D (FACIT-D Functional Assessment of Chronic Illness Therapy for Patients With Diarrhea) total score, collected day 1 of each cycle and at the time of study completion, cycles 1 and 2 reported; The higher the score the better the QOL; Score range 0-152. |
| FACIT-D Diarrhea Score | Cycle 1, Cycle 2 (each cycle is 21 days) | Quantitative FACIT-D (FACIT-D Functional Assessment of Chronic Illness Therapy for Patients With Diarrhea) diarrhea subscale (DS) score, by cycle; Score Range 0-44; the higher the score, the better the QOL. |
| Stool Frequency Based on Consistency (Bristol Stool Scale) | Cycle 1, Cycle 2 (each cycle is 21 days) | Frequency of stool consistency of 6-7, as measured by the Bristol Stool scale (minimum 1-separate hard lumps, maximum 7-watery, no solid pieces), by cycle; Median in watery bowel movements (Bristol Stool Form Scale 6-7). |
| Anti-diarrheal Medications | Cycle 1, Cycle 2 (each cycle is 21 days) | Use of anti-diarrheal medications (other than study drug), by cycle and arm |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment Patients on the treatment arm will take one tablet of crofelemer twice a day (each tablet is 125 mg), to be swallowed whole without chewing or crushing, during cycles 1-2 of chemotherapy with THP or TCHP. Patient will be monitored off crofelemer during cycle 3 of chemotherapy.
Crofelemer: Crofelemer 125 mg BID during cycles 1-2 of THP or TCHP | 26 |
| Control Patients on the control arm will be on the study for cycles 1-3 of THP or TCHP. Patients on the control arm will not receive crofelemer at any time on this study. | 25 |
| Total | 51 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Control | Total | Treatment |
|---|---|---|---|
| Age, Continuous | 52 years | 52.9 years | 53.9 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 15 Participants | 9 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 | 2 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) White | 17 Participants | 31 Participants | 14 Participants |
| Sex: Female, Male Female | 25 Participants | 51 Participants | 26 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 26 | 0 / 25 |
| other Total, other adverse events | 26 / 26 | 24 / 25 |
| serious Total, serious adverse events | 1 / 26 | 7 / 25 |
Outcome results
Primary
Diarrhea for >= 2 Consecutive Days
Percentage of participants with any grade (based on CTCAE 4.0) diarrhea lasting 2 or more consecutive days during cycles 1 and 2 of chemotherapy.
Time frame: Cycle 1, Cycle 2 (each cycle is 21 days)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Crofelemer | Diarrhea for >= 2 Consecutive Days | Cycle 1 | 68 percentage of patients |
| Crofelemer | Diarrhea for >= 2 Consecutive Days | Cycle 2 | 65.2 percentage of patients |
| Control | Diarrhea for >= 2 Consecutive Days | Cycle 1 | 69.6 percentage of patients |
| Control | Diarrhea for >= 2 Consecutive Days | Cycle 2 | 72.2 percentage of patients |
Secondary
Anti-diarrheal Medications
Use of anti-diarrheal medications (other than study drug), by cycle and arm
Time frame: Cycle 1, Cycle 2 (each cycle is 21 days)
Population: Only cycle 1 and cycle 2 analyzed. Total amount of Loperamide, Diphenoxylate Atropine and Octreotide; No subjects in the Crofelemer arm received octreotide in either cycle 1 or 2.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Crofelemer | Anti-diarrheal Medications | Cycle 1- Loperamide | 20.69 units | Standard Deviation 36.74 |
| Crofelemer | Anti-diarrheal Medications | Cycle 2-Loperamide | 16.25 units | Standard Deviation 23.43 |
| Crofelemer | Anti-diarrheal Medications | Cycle 1-Diphenoxylate Atropine | 16.15 units | Standard Deviation 82.36 |
| Crofelemer | Anti-diarrheal Medications | Cycle 2- Diophnoxylate Atropine | 0.8333 units | Standard Deviation 3.18 |
| Crofelemer | Anti-diarrheal Medications | Cycle 1- Octreotide | 0 units | Standard Deviation 0 |
| Crofelemer | Anti-diarrheal Medications | Cycle 2- Octreotide | 0 units | Standard Deviation 0 |
| Control | Anti-diarrheal Medications | Cycle 1- Octreotide | 6.818 units | Standard Deviation 31.98 |
| Control | Anti-diarrheal Medications | Cycle 1- Loperamide | 24.73 units | Standard Deviation 41.4 |
| Control | Anti-diarrheal Medications | Cycle 2- Diophnoxylate Atropine | 5.595 units | Standard Deviation 25.64 |
| Control | Anti-diarrheal Medications | Cycle 2-Loperamide | 21.24 units | Standard Deviation 31.52 |
| Control | Anti-diarrheal Medications | Cycle 2- Octreotide | 71.43 units | Standard Deviation 327.3 |
| Control | Anti-diarrheal Medications | Cycle 1-Diphenoxylate Atropine | 2.272 units | Standard Deviation 12.79 |
Secondary
Diarrhea Any Grade
Incidence of diarrhea of any grade, as measured by CTCAE v4.0, by cycle
Time frame: Cycle 1, Cycle 2 (each cycle is 21 days)
Population: The number analyzed is different from overall number due to early treatment discontinuation.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Crofelemer | Diarrhea Any Grade | Cycle 1 (investigator-assessed) | 16 Participants |
| Crofelemer | Diarrhea Any Grade | Cycle 2 (investigator-assessed) | 15 Participants |
| Control | Diarrhea Any Grade | Cycle 1 (investigator-assessed) | 16 Participants |
| Control | Diarrhea Any Grade | Cycle 2 (investigator-assessed) | 18 Participants |
Secondary
Diarrhea Duration
Duration (days) of any grade diarrhea, defined from day 1 to day 21, by cycle in which the episode started
Time frame: Cycle 1, Cycle 2 (each cycle is 21 days)
Population: Duration of the FIRST day of diarrhea to the LAST day of diarrhea based on patient diary. Only Cycle 1 and Cycle 2 analyzed. The number analyzed is different from overall number due to missing data.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Crofelemer | Diarrhea Duration | Cycle 1 | 13 days |
| Crofelemer | Diarrhea Duration | Cycle 2 | 15 days |
| Control | Diarrhea Duration | Cycle 1 | 15 days |
| Control | Diarrhea Duration | Cycle 2 | 12 days |
Secondary
Diarrhea Onset
Time to onset of first episode of diarrhea of any grade, overall
Time frame: from baseline through Cycle 3 (21 day cycles)
Population: The number analyzed is different from overall number due to missing data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Crofelemer | Diarrhea Onset | 3 days |
| Control | Diarrhea Onset | 2 days |
Secondary
Duration Grade 3-4 Diarrhea
Duration (days) of grade 3-4 diarrhea during cycle 1 through the end of cycle 2, defined from cycle day 1 to cycle 2 day 21
Time frame: End of Cycle 2 (each cycle is 21 days)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Crofelemer | Duration Grade 3-4 Diarrhea | 18 days |
| Control | Duration Grade 3-4 Diarrhea | 6.5 days |
Secondary
FACIT-D Diarrhea Score
Quantitative FACIT-D (FACIT-D Functional Assessment of Chronic Illness Therapy for Patients With Diarrhea) diarrhea subscale (DS) score, by cycle; Score Range 0-44; the higher the score, the better the QOL.
Time frame: Cycle 1, Cycle 2 (each cycle is 21 days)
Population: The number analyzed is different from overall number due to early treatment discontinuation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Crofelemer | FACIT-D Diarrhea Score | Cycle 1 | 40.5 score on a scale | Standard Deviation 6.2 |
| Crofelemer | FACIT-D Diarrhea Score | Cycle 2 | 34.9 score on a scale | Standard Deviation 6.8 |
| Control | FACIT-D Diarrhea Score | Cycle 1 | 39.8 score on a scale | Standard Deviation 6.3 |
| Control | FACIT-D Diarrhea Score | Cycle 2 | 34.1 score on a scale | Standard Deviation 7.8 |
Secondary
FACIT-D Total Score
Quantitative FACIT-D (FACIT-D Functional Assessment of Chronic Illness Therapy for Patients With Diarrhea) total score, collected day 1 of each cycle and at the time of study completion, cycles 1 and 2 reported; The higher the score the better the QOL; Score range 0-152.
Time frame: Cycle 1, Cycle 2 (each cycle is 21 days)
Population: The number analyzed is different from overall number due to early treatment discontinuation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Crofelemer | FACIT-D Total Score | Cycle 1 | 129.0 score on a scale | Standard Deviation 14.3 |
| Crofelemer | FACIT-D Total Score | Cycle 2 | 116.7 score on a scale | Standard Deviation 19.8 |
| Control | FACIT-D Total Score | Cycle 1 | 123.8 score on a scale | Standard Deviation 20.4 |
| Control | FACIT-D Total Score | Cycle 2 | 114.4 score on a scale | Standard Deviation 23.3 |
Secondary
Grade 3-4 Diarrhea
number of patients with diarrhea of grade 3 or grade 4, as measured by CTCAE v4.0, by cycle and by stratum
Time frame: Cycle 1, Cycle 2 (each cycle is 21 days)
Population: The number analyzed is different from overall number due to early treatment discontinuation.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Crofelemer | Grade 3-4 Diarrhea | Cycle 1 | 1 Participants |
| Crofelemer | Grade 3-4 Diarrhea | Cycle 2 | 0 Participants |
| Control | Grade 3-4 Diarrhea | Cycle 2 | 4 Participants |
| Control | Grade 3-4 Diarrhea | Cycle 1 | 2 Participants |
Secondary
Stool Frequency Based on Consistency (Bristol Stool Scale)
Frequency of stool consistency of 6-7, as measured by the Bristol Stool scale (minimum 1-separate hard lumps, maximum 7-watery, no solid pieces), by cycle; Median in watery bowel movements (Bristol Stool Form Scale 6-7).
Time frame: Cycle 1, Cycle 2 (each cycle is 21 days)
Population: The number analyzed is different from overall number due to early treatment discontinuation.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Crofelemer | Stool Frequency Based on Consistency (Bristol Stool Scale) | Cycle 1 | 14.5 number of bowel movements |
| Crofelemer | Stool Frequency Based on Consistency (Bristol Stool Scale) | Cycle 2 | 14.0 number of bowel movements |
| Control | Stool Frequency Based on Consistency (Bristol Stool Scale) | Cycle 1 | 19 number of bowel movements |
| Control | Stool Frequency Based on Consistency (Bristol Stool Scale) | Cycle 2 | 17.5 number of bowel movements |