Colorectal Neoplasms
Conditions
Brief summary
This randomized phase II trial studies how giving a drug called levocetirizine to patients with colorectal cancer affects their tumor response to capecitabine and bevacizumab. Capecitabine is a chemotherapy drug that blocks tumor growth by disrupting DNA and RNA synthesis and repair (cell division and survival). Bevacizumab is a monoclonal antibody that blocks the ability of tumors to grow and spread by inhibiting the growth of blood vessels that feed them. Patients with colorectal cancer can develop a resistance to the effects of bevacizumab. Levocetirizine may decrease tumor resistance to bevacizumab. Giving bevacizumab, capecitabine, and levocetirizine dihydrochloride together may be an effective treatment for refractory colorectal cancer.
Interventions
DRUGBevacizumab
DRUGCapecitabine
DRUGLevocetirizine
Sponsors
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patient must have histologically or cytologically confirmed refractory colorectal cancer (CRC). * Patient must have measurable disease defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥10 mm with CT scan, as ≥20 mm by chest x-ray, or ≥10 mm with calipers by clinical exam. * Patient must have documented progressive disease within 3 months of his/her most recent cycle of chemotherapy. * Patient must be refractory to or intolerant of prior therapy with a fluoropyrimidine, oxaliplatin, irinotecan, and/or anti-angiogenic therapy. Patients with K-RAS wild type tumors must have received an epidermal growth factor receptor (EGFR) inhibitor such as cetuximab or panitumumab. * Patient must be ≥ 18 years of age. * Patient must have an ECOG performance status ≤ 2 * Patient must have normal bone marrow and organ function as defined below: * Absolute neutrophil count ≥ 1,500/mcl * Platelets ≥ 100,000/mcl * Total bilirubin ≤ 2.0 x IULN * AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN * Patients must have adequate renal function prior to chemotherapy defined as serum creatinine ≤ 2.0 mg/dl OR Creatinine clearance ≥ 60 mL/min/1.73 m2 for patients with creatinine levels above 2.0 * Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. * Patient must be able to understand and willing to sign an IRB approved written informed consent document.
Exclusion criteria
* Patient must not have a history of other malignancy ≤ 3 years previous with the exception of basal cell or squamous cell carcinoma of the skin which were treated with local resection only or carcinoma in situ of the cervix. * Patient must not be receiving any other investigational agents. * Patient must not have known active brain metastases. Patients with previously treated brain metastases are eligible. Patients with known brain active metastases must be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. * Patient must not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to levocetirizine, capecitabine, bevacizumab, or other agents used in the study. * Patient must not have known dihydropyrimidine dehydrogenase (DPD) deficiency or severe renal impairment (creatinine clearance below 30 mL/min by Cockcroft and Gault formula) as this would prelude use of capecitabine. * Patient must not have known proteinuria ≥ 500mg/24 hours. * Patient must not have an uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. * Patient must not be pregnant and/or breastfeeding. Patient must have a negative urine pregnancy test within seven days of study entry. * Patient must not be known to be HIV-positive on combination antiretroviral because of the potential for pharmacokinetic interactions with levocetirizine, capecitabine, and bevacizumab. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (Arm A) | Until progressive disease (PD) (estimated to be 92 days) | * Time from start of treatment to the time of progression or death, whichever occurs first * Progressive disease (target lesions): at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. * Progressive disease (non-target lesions): appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase. |
| Progression Free Survival (Arm B) | Until progressive disease (PD) (up to 60 days) | * Time from start of treatment to the time of progression or death, whichever occurs first * Progressive disease (target lesions): at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. * Progressive disease (non-target lesions): appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence and Severity of Adverse Events as Measured by Number of Participants Who Experience Grade 3 and Higher Adverse Events | Up to 6 months | NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 |
Countries
United States
Participant flow
Recruitment details
The study opened to patient enrollment on 04/26/2013 and closed to patient enrollment on 07/15/2015.
Participants by arm
| Arm | Count |
|---|---|
| Arm A: (Start Levocetirizine After Bevacizumab/Capecitabine) Bevacizumab IV 5 mg/kg on Days 1 each 2-week cycle.
Capecitabine PO 850 mg/m2 twice a day on Days 1-7 of each 2 week cycle.
Levocetirizine PO 5 mg daily before bed starting on Day 8 of Cycle 1. 5 mg daily before bed Days 1-4 of each cycle starting with cycle 2. | 23 |
| Arm B: (Start Levocetirizine Before Bevacizumab/Capecitabine) Bevacizumab IV 5 mg/kg on Days 1 each 2-week cycle.
Capecitabine PO 850 mg/m2 twice a day on Days 1-7 of each 2 week cycle.
Levocetirizine PO 5 mg daily starting 7 days prior to initiation of bevacizumab and capecitabine therapy. 5 mg daily Days 1-14 starting with cycle 2. | 24 |
| Total | 47 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Found ineligible | 1 | 0 |
| Overall Study | Insurance denial post enrollment | 0 | 1 |
| Overall Study | Noncompliance | 0 | 1 |
| Overall Study | Unrelated to study adverse event | 2 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Arm A: (Start Levocetirizine After Bevacizumab/Capecitabine) | Arm B: (Start Levocetirizine Before Bevacizumab/Capecitabine) | Total |
|---|---|---|---|
| Age, Continuous | 62 years | 57.5 years | 60 years |
| Region of Enrollment United States | 23 participants | 24 participants | 47 participants |
| Sex: Female, Male Female | 9 Participants | 9 Participants | 18 Participants |
| Sex: Female, Male Male | 14 Participants | 15 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 19 / 19 | 23 / 23 |
| serious Total, serious adverse events | 5 / 19 | 6 / 23 |
Outcome results
Primary
Progression Free Survival (Arm A)
* Time from start of treatment to the time of progression or death, whichever occurs first * Progressive disease (target lesions): at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. * Progressive disease (non-target lesions): appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.
Time frame: Until progressive disease (PD) (estimated to be 92 days)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A: (Start Levocetirizine After Bevacizumab/Capecitabine) | Progression Free Survival (Arm A) | PFS Days = 29 | 0.946 proportion of patients with PFS |
| Arm A: (Start Levocetirizine After Bevacizumab/Capecitabine) | Progression Free Survival (Arm A) | PFS Days = 36 | 0.892 proportion of patients with PFS |
| Arm A: (Start Levocetirizine After Bevacizumab/Capecitabine) | Progression Free Survival (Arm A) | PFS Days = 43 | 0.739 proportion of patients with PFS |
| Arm A: (Start Levocetirizine After Bevacizumab/Capecitabine) | Progression Free Survival (Arm A) | PFS Days = 46 | 0.685 proportion of patients with PFS |
| Arm A: (Start Levocetirizine After Bevacizumab/Capecitabine) | Progression Free Survival (Arm A) | PFS Days = 50 | 0.630 proportion of patients with PFS |
| Arm A: (Start Levocetirizine After Bevacizumab/Capecitabine) | Progression Free Survival (Arm A) | PFS Days = 92 | 0.575 proportion of patients with PFS |
Primary
Progression Free Survival (Arm B)
* Time from start of treatment to the time of progression or death, whichever occurs first * Progressive disease (target lesions): at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. * Progressive disease (non-target lesions): appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.
Time frame: Until progressive disease (PD) (up to 60 days)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A: (Start Levocetirizine After Bevacizumab/Capecitabine) | Progression Free Survival (Arm B) | PFS Days = 29 | 0.946 proportion of patients with PFS |
| Arm A: (Start Levocetirizine After Bevacizumab/Capecitabine) | Progression Free Survival (Arm B) | PFS Days = 33 | 0.892 proportion of patients with PFS |
| Arm A: (Start Levocetirizine After Bevacizumab/Capecitabine) | Progression Free Survival (Arm B) | PFS Days = 44 | 0.838 proportion of patients with PFS |
| Arm A: (Start Levocetirizine After Bevacizumab/Capecitabine) | Progression Free Survival (Arm B) | PFS Days = 50 | 0.686 proportion of patients with PFS |
| Arm A: (Start Levocetirizine After Bevacizumab/Capecitabine) | Progression Free Survival (Arm B) | PFS Days = 54 | 0.631 proportion of patients with PFS |
| Arm A: (Start Levocetirizine After Bevacizumab/Capecitabine) | Progression Free Survival (Arm B) | PFS Days = 60 | 0.576 proportion of patients with PFS |
Secondary
Incidence and Severity of Adverse Events as Measured by Number of Participants Who Experience Grade 3 and Higher Adverse Events
NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
Time frame: Up to 6 months
Population: Arm A: 4 patients not evaluable for outcome measure (2 had unrelated adverse events after enrollment but prior to treatment, 1 withdrew consent after enrollment but prior to treatment, \& 1 was found ineligible after enrollment but prior to treatment). Arm B: 1 patient not evaluable because of noncompliance after enrollment but before treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A: (Start Levocetirizine After Bevacizumab/Capecitabine) | Incidence and Severity of Adverse Events as Measured by Number of Participants Who Experience Grade 3 and Higher Adverse Events | Small intestinal obstruction | 1 participants |
| Arm A: (Start Levocetirizine After Bevacizumab/Capecitabine) | Incidence and Severity of Adverse Events as Measured by Number of Participants Who Experience Grade 3 and Higher Adverse Events | Fatigue | 1 participants |
| Arm A: (Start Levocetirizine After Bevacizumab/Capecitabine) | Incidence and Severity of Adverse Events as Measured by Number of Participants Who Experience Grade 3 and Higher Adverse Events | Urinary tract infection | 1 participants |
| Arm A: (Start Levocetirizine After Bevacizumab/Capecitabine) | Incidence and Severity of Adverse Events as Measured by Number of Participants Who Experience Grade 3 and Higher Adverse Events | Blood bilirubin increased | 2 participants |
| Arm A: (Start Levocetirizine After Bevacizumab/Capecitabine) | Incidence and Severity of Adverse Events as Measured by Number of Participants Who Experience Grade 3 and Higher Adverse Events | Peripheral motor neuropathy | 1 participants |
| Arm A: (Start Levocetirizine After Bevacizumab/Capecitabine) | Incidence and Severity of Adverse Events as Measured by Number of Participants Who Experience Grade 3 and Higher Adverse Events | Peripheral sensory neuropathy | 1 participants |
| Arm A: (Start Levocetirizine After Bevacizumab/Capecitabine) | Incidence and Severity of Adverse Events as Measured by Number of Participants Who Experience Grade 3 and Higher Adverse Events | Dyspnea | 1 participants |
| Arm A: (Start Levocetirizine After Bevacizumab/Capecitabine) | Incidence and Severity of Adverse Events as Measured by Number of Participants Who Experience Grade 3 and Higher Adverse Events | Hypertension | 1 participants |
| Arm A: (Start Levocetirizine After Bevacizumab/Capecitabine) | Incidence and Severity of Adverse Events as Measured by Number of Participants Who Experience Grade 3 and Higher Adverse Events | Thromboembolic event | 1 participants |
| Arm A: (Start Levocetirizine After Bevacizumab/Capecitabine) | Incidence and Severity of Adverse Events as Measured by Number of Participants Who Experience Grade 3 and Higher Adverse Events | Anemia | 0 participants |
| Arm A: (Start Levocetirizine After Bevacizumab/Capecitabine) | Incidence and Severity of Adverse Events as Measured by Number of Participants Who Experience Grade 3 and Higher Adverse Events | Heart failure | 0 participants |
| Arm A: (Start Levocetirizine After Bevacizumab/Capecitabine) | Incidence and Severity of Adverse Events as Measured by Number of Participants Who Experience Grade 3 and Higher Adverse Events | Colonic fistula | 0 participants |
| Arm A: (Start Levocetirizine After Bevacizumab/Capecitabine) | Incidence and Severity of Adverse Events as Measured by Number of Participants Who Experience Grade 3 and Higher Adverse Events | Colonic perforation | 0 participants |
| Arm A: (Start Levocetirizine After Bevacizumab/Capecitabine) | Incidence and Severity of Adverse Events as Measured by Number of Participants Who Experience Grade 3 and Higher Adverse Events | Gram-negative bacilli infection | 0 participants |
| Arm A: (Start Levocetirizine After Bevacizumab/Capecitabine) | Incidence and Severity of Adverse Events as Measured by Number of Participants Who Experience Grade 3 and Higher Adverse Events | Clostridium bloodstream infection | 0 participants |
| Arm A: (Start Levocetirizine After Bevacizumab/Capecitabine) | Incidence and Severity of Adverse Events as Measured by Number of Participants Who Experience Grade 3 and Higher Adverse Events | Alanine aminotransferase increased | 0 participants |
| Arm A: (Start Levocetirizine After Bevacizumab/Capecitabine) | Incidence and Severity of Adverse Events as Measured by Number of Participants Who Experience Grade 3 and Higher Adverse Events | Anorexia | 0 participants |
| Arm A: (Start Levocetirizine After Bevacizumab/Capecitabine) | Incidence and Severity of Adverse Events as Measured by Number of Participants Who Experience Grade 3 and Higher Adverse Events | Bone pain | 0 participants |
| Arm A: (Start Levocetirizine After Bevacizumab/Capecitabine) | Incidence and Severity of Adverse Events as Measured by Number of Participants Who Experience Grade 3 and Higher Adverse Events | Muscle weakness lower limbs | 0 participants |
| Arm A: (Start Levocetirizine After Bevacizumab/Capecitabine) | Incidence and Severity of Adverse Events as Measured by Number of Participants Who Experience Grade 3 and Higher Adverse Events | Urinary retention | 0 participants |
| Arm A: (Start Levocetirizine After Bevacizumab/Capecitabine) | Incidence and Severity of Adverse Events as Measured by Number of Participants Who Experience Grade 3 and Higher Adverse Events | Respiratory failure | 0 participants |
| Arm A: (Start Levocetirizine After Bevacizumab/Capecitabine) | Incidence and Severity of Adverse Events as Measured by Number of Participants Who Experience Grade 3 and Higher Adverse Events | Generalized muscle weakness | 0 participants |
| Arm B: (Start Levocetirizine Before Bevacizumab/Capecitabine) | Incidence and Severity of Adverse Events as Measured by Number of Participants Who Experience Grade 3 and Higher Adverse Events | Anorexia | 1 participants |
| Arm B: (Start Levocetirizine Before Bevacizumab/Capecitabine) | Incidence and Severity of Adverse Events as Measured by Number of Participants Who Experience Grade 3 and Higher Adverse Events | Small intestinal obstruction | 0 participants |
| Arm B: (Start Levocetirizine Before Bevacizumab/Capecitabine) | Incidence and Severity of Adverse Events as Measured by Number of Participants Who Experience Grade 3 and Higher Adverse Events | Colonic fistula | 1 participants |
| Arm B: (Start Levocetirizine Before Bevacizumab/Capecitabine) | Incidence and Severity of Adverse Events as Measured by Number of Participants Who Experience Grade 3 and Higher Adverse Events | Fatigue | 1 participants |
| Arm B: (Start Levocetirizine Before Bevacizumab/Capecitabine) | Incidence and Severity of Adverse Events as Measured by Number of Participants Who Experience Grade 3 and Higher Adverse Events | Urinary retention | 1 participants |
| Arm B: (Start Levocetirizine Before Bevacizumab/Capecitabine) | Incidence and Severity of Adverse Events as Measured by Number of Participants Who Experience Grade 3 and Higher Adverse Events | Urinary tract infection | 0 participants |
| Arm B: (Start Levocetirizine Before Bevacizumab/Capecitabine) | Incidence and Severity of Adverse Events as Measured by Number of Participants Who Experience Grade 3 and Higher Adverse Events | Colonic perforation | 1 participants |
| Arm B: (Start Levocetirizine Before Bevacizumab/Capecitabine) | Incidence and Severity of Adverse Events as Measured by Number of Participants Who Experience Grade 3 and Higher Adverse Events | Blood bilirubin increased | 0 participants |
| Arm B: (Start Levocetirizine Before Bevacizumab/Capecitabine) | Incidence and Severity of Adverse Events as Measured by Number of Participants Who Experience Grade 3 and Higher Adverse Events | Generalized muscle weakness | 1 participants |
| Arm B: (Start Levocetirizine Before Bevacizumab/Capecitabine) | Incidence and Severity of Adverse Events as Measured by Number of Participants Who Experience Grade 3 and Higher Adverse Events | Peripheral motor neuropathy | 0 participants |
| Arm B: (Start Levocetirizine Before Bevacizumab/Capecitabine) | Incidence and Severity of Adverse Events as Measured by Number of Participants Who Experience Grade 3 and Higher Adverse Events | Gram-negative bacilli infection | 1 participants |
| Arm B: (Start Levocetirizine Before Bevacizumab/Capecitabine) | Incidence and Severity of Adverse Events as Measured by Number of Participants Who Experience Grade 3 and Higher Adverse Events | Peripheral sensory neuropathy | 0 participants |
| Arm B: (Start Levocetirizine Before Bevacizumab/Capecitabine) | Incidence and Severity of Adverse Events as Measured by Number of Participants Who Experience Grade 3 and Higher Adverse Events | Bone pain | 1 participants |
| Arm B: (Start Levocetirizine Before Bevacizumab/Capecitabine) | Incidence and Severity of Adverse Events as Measured by Number of Participants Who Experience Grade 3 and Higher Adverse Events | Dyspnea | 2 participants |
| Arm B: (Start Levocetirizine Before Bevacizumab/Capecitabine) | Incidence and Severity of Adverse Events as Measured by Number of Participants Who Experience Grade 3 and Higher Adverse Events | Clostridium bloodstream infection | 1 participants |
| Arm B: (Start Levocetirizine Before Bevacizumab/Capecitabine) | Incidence and Severity of Adverse Events as Measured by Number of Participants Who Experience Grade 3 and Higher Adverse Events | Hypertension | 2 participants |
| Arm B: (Start Levocetirizine Before Bevacizumab/Capecitabine) | Incidence and Severity of Adverse Events as Measured by Number of Participants Who Experience Grade 3 and Higher Adverse Events | Muscle weakness lower limbs | 1 participants |
| Arm B: (Start Levocetirizine Before Bevacizumab/Capecitabine) | Incidence and Severity of Adverse Events as Measured by Number of Participants Who Experience Grade 3 and Higher Adverse Events | Thromboembolic event | 0 participants |
| Arm B: (Start Levocetirizine Before Bevacizumab/Capecitabine) | Incidence and Severity of Adverse Events as Measured by Number of Participants Who Experience Grade 3 and Higher Adverse Events | Alanine aminotransferase increased | 1 participants |
| Arm B: (Start Levocetirizine Before Bevacizumab/Capecitabine) | Incidence and Severity of Adverse Events as Measured by Number of Participants Who Experience Grade 3 and Higher Adverse Events | Anemia | 1 participants |
| Arm B: (Start Levocetirizine Before Bevacizumab/Capecitabine) | Incidence and Severity of Adverse Events as Measured by Number of Participants Who Experience Grade 3 and Higher Adverse Events | Respiratory failure | 1 participants |
| Arm B: (Start Levocetirizine Before Bevacizumab/Capecitabine) | Incidence and Severity of Adverse Events as Measured by Number of Participants Who Experience Grade 3 and Higher Adverse Events | Heart failure | 1 participants |