Capecitabine and Celecoxib in Patients With Solid Cancers That Have Been Previously Treated With Standard Therapies

• Sponsor: University of Chicago (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01705106
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 21
• Location: 1
• Arm: 1
• Actual Duration (Months): 41.4
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

This clinical trial studies capecitabine and celecoxib in treating patients with solid malignancies that are metastatic or cannot be removed by surgery. Drugs used in chemotherapy, such as capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Celecoxib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving capecitabine and celecoxib together may be an effective treatment for solid malignancies.

Condition or Disease	Intervention/Treatment	Phase
Unspecified Adult Solid Tumor, Protocol Specific	Drug: capecitabine; Drug: celecoxib; Other: pharmacological study; Other: laboratory biomarker analysis; Other: pharmacogenomic studies	Phase 1

Detailed Description

PRIMARY OBJECTIVES:

1. To compare steady state pharmacokinetics (PK) (primarily minimum concentration [Cmin], maximum concentration [Cmax], and area under the curve [AUC]) of celecoxib on day 7 of monotherapy versus on day 14 of concomitant administration with capecitabine.

SECONDARY OBJECTIVES:

1. To develop a celecoxib PK drug interaction model using longitudinal data and determine whether the results are concordant with results from the primary objective.

2. To assess the impact of known cytochrome P450 2C9 (CYP2C9) pharmacogenetic variants with reduced enzyme activity (CYP2C9*2 and *3) on the between subject variability in celecoxib PK.

3. To assess tumor response by the Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1) and explore whether there is any correlation between celecoxib PK and response.

4. To assess toxicity by the Common Terminology Criteria for Adverse Events (CTCAE, version 4.0) and explore whether there is any correlation between celecoxib PK and toxicities related to either celecoxib or capecitabine.

OUTLINE:

Patients receive celecoxib orally (PO) twice daily (BID) for 7 days (course 0) and then on days 1-21 of course 1 and all subsequent courses. Patients also receive capecitabine PO BID on days 1-14 beginning in course 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Study Design

• Study Type: Interventional
• Actual Enrollment: 21 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Drug-drug Interaction Study of Capecitabine and Celecoxib in Patients With Advanced Solid Malignancies
• Actual Study Start Date: Aug 29, 2012
• Actual Primary Completion Date: Feb 10, 2016
• Actual Study Completion Date: Feb 10, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (capecitabine, celecoxib) Patients receive celecoxib PO BID for 7 days (course 0) and then on days 1-21 of course 1 and all subsequent courses. Patients also receive capecitabine PO BID on days 1-14 beginning in course 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Drug: capecitabine; Given PO; Other Names: CAPE Ro 09-1978/000 Xeloda ; Drug: celecoxib; Given PO; Other Names: Celebrex SC-58635 ; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies ; Other: laboratory biomarker analysis; Correlative studies; Other: pharmacogenomic studies; Correlative studies; Other Names: Pharmacogenomic Study

Outcome Measures

Primary Outcome Measures

1. AUC of Celecoxib on Combination Therapy (Day 14) and AUC of Celecoxib on Celecoxib Monotherapy(Day 7) [Day 7 and 14 post treatment]

   These parameters will be estimated for each subject under each treatment condition. The mean ratios (combination therapy/celecoxib monotherapy) will then be estimated together with 90% confidence intervals (CI).

Secondary Outcome Measures

1. CYP2C9 Genotype [one week]

   Polymorphisms *2 and *3 will be genotyped and analyzed for their impact on celecoxib AUC using analysis of variance (ANOVA), controlling for gender, age, and other covariates.

2. Response Rate [Up to 2 years]

   Logistic regression analysis will be performed to describe the relationship (if any) between celecoxib AUC and response rate.

3. Drug-related Toxicities [Up to six months]

   Ordinal logistic regression modeling will be used to explore the relationship between celecoxib AUC and toxicity.

4. PK Drug Interaction Model [4 weeks]

   NONMEM software will be used to develop a model describing the drug interaction between capecitabine and celecoxib using PK data collected during the first four weeks of the study.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically or cytologically confirmed solid tumor that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective

OR

Histologically or cytologically confirmed solid tumor for which single agent capecitabine is an appropriate treatment option.

• Eastern Cooperative Oncology Group (ECOG) performance status =< 1

• Life expectancy > 3 months

• Absolute neutrophil count (ANC) >= l500/ul

• Hemoglobin >= 9g/dL

• Platelets >= 100,000/ul

• Creatinine within institutional normal limits or glomerular filtration rate >= 50 mL/min/1.73 m^2 by Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) equation

• Total bilirubin < 1.5 x upper limit of normal

• Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvate transaminase (SGPT) < 2.5 x upper limit of normal for patients without liver metastases OR SGOT and SGPT < 5 x upper limit of normal for patients with liver metastases

• Measurable or non-measurable disease will be allowed

• Women of child-bearing 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, up until 30 days after final study treatment; should a woman become pregnant or suspect that she is pregnant while participating in this study, she should inform her treating physician immediately

• Patients taking substrates of CYP2C9 should be encouraged to switch to alternative drugs whenever possible, given the potential for drug-drug interactions with the study drugs

• Signed informed consent

Exclusion Criteria:

• Prior treatment with capecitabine and/or celecoxib is allowed; however, patients with a documented history (at the time of enrollment) of >= grade 3 toxicities with capecitabine or celecoxib are excluded

• Patients taking any of the following drugs are excluded: inducers or inhibitors of CYP2C9, warfarin, aspirin, corticosteroids, or non-steroidal anti-inflammatory drugs (NSAIDs)

• History of myocardial infarction or stroke within the last 6 months, or history of uncontrolled cardiovascular or cerebrovascular disease; a 12-lead electrocardiogram (ECG) will be performed during the screening period

• History of perforation or bleeding related to peptic ulcer disease

• History of hypersensitivity or allergy to study drugs, aspirin, sulfonamides, or NSAIDs

• Known poor metabolizers of CYP2C9 substrates

• Known deficiency of dihydropyrimidine dehydrogenase (DPD)

• Patients who have had chemotherapy, immunotherapy, or investigational anti-cancer therapy within 4 weeks of starting study drug, or radiotherapy within 14 days of starting study drug, or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier

• Patients may not be receiving any other investigational agents or any concomitant antineoplastic therapy, with the exception of androgen ablating agents (for patients with prior prostate cancer)

• Serious underlying medical or psychiatric illnesses that would, in the opinion of the treating physician, substantially increase the risk for complications related to treatment; similarly, any unstable medical condition that in the opinion of the treating physician or study investigators, would interfere with determination of the study objectives

• Pregnancy or breastfeeding

• Major surgery within 4 weeks

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Chicago Comprehensive Cancer Center	Chicago	Illinois	United States	60637-1470

Sponsors and Collaborators

• University of Chicago
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Manish R. Sharma, M.D., University of Chicago Comprehensive Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of Chicago
• ClinicalTrials.gov Identifier: NCT01705106
• Other Study ID Numbers: 12-1318; NCI-2012-01704
• First Posted: Oct 12, 2012
• Last Update Posted: May 30, 2018
• Last Verified: Apr 1, 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Additional relevant MeSH terms: Celecoxib; Capecitabine

Study Results

Participant Flow

Arm/Group Title	Treatment (Capecitabine, Celecoxib)
Arm/Group Description	Patients receive celecoxib PO BID for 7 days (course 0) and then on days 1-21 of course 1 and all subsequent courses. Patients also receive capecitabine PO BID on days 1-14 beginning in course 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. capecitabine: Given PO celecoxib: Given PO pharmacological study: Correlative studies laboratory biomarker analysis: Correlative studies pharmacogenomic studies: Correlative studies
Period Title: Overall Study
STARTED	21
COMPLETED	21
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Treatment (Capecitabine, Celecoxib)
Arm/Group Description	Patients receive celecoxib PO BID for 7 days (course 0) and then on days 1-21 of course 1 and all subsequent courses. Patients also receive capecitabine PO BID on days 1-14 beginning in course 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. capecitabine: Given PO celecoxib: Given PO pharmacological study: Correlative studies laboratory biomarker analysis: Correlative studies pharmacogenomic studies: Correlative studies
Overall Participants	21
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	57.5
Sex: Female, Male (Count of Participants)
Female	5 23.8%
Male	16 76.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 4.8%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 4.8%
White	19 90.5%
More than one race	0 0%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	AUC of Celecoxib on Combination Therapy (Day 14) and AUC of Celecoxib on Celecoxib Monotherapy(Day 7)
Description	These parameters will be estimated for each subject under each treatment condition. The mean ratios (combination therapy/celecoxib monotherapy) will then be estimated together with 90% confidence intervals (CI).
Time Frame	Day 7 and 14 post treatment

Outcome Measure Data

Analysis Population Description

The study was terminated early due to slow accrual, thus none of participants was analyzed. Data were not collected.

Arm/Group Title	Treatment (Capecitabine, Celecoxib)
Arm/Group Description	Patients receive celecoxib PO BID for 7 days (course 0) and then on days 1-21 of course 1 and all subsequent courses. Patients also receive capecitabine PO BID on days 1-14 beginning in course 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. capecitabine: Given PO celecoxib: Given PO pharmacological study: Correlative studies laboratory biomarker analysis: Correlative studies pharmacogenomic studies: Correlative studies
Measure Participants	0

2. Secondary Outcome

Title	CYP2C9 Genotype
Description	Polymorphisms *2 and *3 will be genotyped and analyzed for their impact on celecoxib AUC using analysis of variance (ANOVA), controlling for gender, age, and other covariates.
Time Frame	one week

Outcome Measure Data

Analysis Population Description

The study was terminated early due to slow accrual, thus none of participants was analyzed. Data were not collected.

Arm/Group Title	Treatment (Capecitabine, Celecoxib)
Arm/Group Description	Patients receive celecoxib PO BID for 7 days (course 0) and then on days 1-21 of course 1 and all subsequent courses. Patients also receive capecitabine PO BID on days 1-14 beginning in course 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. capecitabine: Given PO celecoxib: Given PO pharmacological study: Correlative studies laboratory biomarker analysis: Correlative studies pharmacogenomic studies: Correlative studies
Measure Participants	0

3. Secondary Outcome

Title	Response Rate
Description	Logistic regression analysis will be performed to describe the relationship (if any) between celecoxib AUC and response rate.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

The study was terminated early due to slow accrual, thus none of participants was analyzed. Data were not collected.

Arm/Group Title	Treatment (Capecitabine, Celecoxib)
Arm/Group Description	Patients receive celecoxib PO BID for 7 days (course 0) and then on days 1-21 of course 1 and all subsequent courses. Patients also receive capecitabine PO BID on days 1-14 beginning in course 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. capecitabine: Given PO celecoxib: Given PO pharmacological study: Correlative studies laboratory biomarker analysis: Correlative studies pharmacogenomic studies: Correlative studies
Measure Participants	0

4. Secondary Outcome

Title	Drug-related Toxicities
Description	Ordinal logistic regression modeling will be used to explore the relationship between celecoxib AUC and toxicity.
Time Frame	Up to six months

Outcome Measure Data

Analysis Population Description

The study was terminated early due to slow accrual, thus none of participants was analyzed. Data were not collected.

Arm/Group Title	Treatment (Capecitabine, Celecoxib)
Arm/Group Description	Patients receive celecoxib PO BID for 7 days (course 0) and then on days 1-21 of course 1 and all subsequent courses. Patients also receive capecitabine PO BID on days 1-14 beginning in course 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. capecitabine: Given PO celecoxib: Given PO pharmacological study: Correlative studies laboratory biomarker analysis: Correlative studies pharmacogenomic studies: Correlative studies
Measure Participants	0

5. Secondary Outcome

Title	PK Drug Interaction Model
Description	NONMEM software will be used to develop a model describing the drug interaction between capecitabine and celecoxib using PK data collected during the first four weeks of the study.
Time Frame	4 weeks

Outcome Measure Data

Analysis Population Description

The study was terminated early due to slow accrual, thus none of participants was analyzed. Data were not collected.

Arm/Group Title	Treatment (Capecitabine, Celecoxib)
Arm/Group Description	Patients receive celecoxib PO BID for 7 days (course 0) and then on days 1-21 of course 1 and all subsequent courses. Patients also receive capecitabine PO BID on days 1-14 beginning in course 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. capecitabine: Given PO celecoxib: Given PO pharmacological study: Correlative studies laboratory biomarker analysis: Correlative studies pharmacogenomic studies: Correlative studies
Measure Participants	0

Adverse Events

Time Frame	Patients were followed for 30 days post treatment.
Arm/Group Title	Treatment (Capecitabine, Celecoxib)
Arm/Group Description	Patients receive celecoxib PO BID for 7 days (course 0) and then on days 1-21 of course 1 and all subsequent courses. Patients also receive capecitabine PO BID on days 1-14 beginning in course 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. capecitabine: Given PO celecoxib: Given PO pharmacological study: Correlative studies laboratory biomarker analysis: Correlative studies pharmacogenomic studies: Correlative studies
All Cause Mortality
	Treatment (Capecitabine, Celecoxib)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment (Capecitabine, Celecoxib)
	Affected / at Risk (%)	# Events
Total	9/21 (42.9%)
Cardiac disorders
Chest pain	1/21 (4.8%)
Gastrointestinal disorders
Diarrhea	2/21 (9.5%)
Small intestinal obstruction	2/21 (9.5%)
Musculoskeletal and connective tissue disorders
Musculoskeletal and connective tissue disorder - Other, specify	1/21 (4.8%)
Nervous system disorders
Seizure	1/21 (4.8%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	2/21 (9.5%)
Respiratory, thoracic and mediastinal disorders - Other (Pneumonia)	2/21 (9.5%)
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysesthesia syndrome	1/21 (4.8%)
Other (Not Including Serious) Adverse Events
	Treatment (Capecitabine, Celecoxib)
	Affected / at Risk (%)	# Events
Total	20/21 (95.2%)
Blood and lymphatic system disorders
Anemia	1/21 (4.8%)
Cardiac disorders
Tachycardia	1/21 (4.8%)
Eye disorders
Cataract, right eye	1/21 (4.8%)
Gastrointestinal disorders
Abdominal Pain	5/21 (23.8%)
Anal hemorrhage	1/21 (4.8%)
Constipation	2/21 (9.5%)
Diarrhea	11/21 (52.4%)
Gastrointestinal disorders - Other (Excessive saliva)	1/21 (4.8%)
Lip pain	1/21 (4.8%)
Mucositis	4/21 (19%)
Mucositis oral	2/21 (9.5%)
Nausea	8/21 (38.1%)
Oral dysesthesia, intermittent	1/21 (4.8%)
Proctitis	1/21 (4.8%)
Stomach pain	1/21 (4.8%)
Vomiting	4/21 (19%)
General disorders
Fatigue	12/21 (57.1%)
Fever	1/21 (4.8%)
Non-cardiac chest pain	1/21 (4.8%)
Pain, intermittent left sided pain	1/21 (4.8%)
Pain, left shoulder	1/21 (4.8%)
Pain, Right shoulder pain	1/21 (4.8%)
Infections and infestations
Eye infection, left eye staph infection	1/21 (4.8%)
Infections and infestations - Other (Black thrush)	1/21 (4.8%)
Infections and infestations - Other (Oral thrush)	1/21 (4.8%)
Infections and infestations - Other (Right hand laceration)	1/21 (4.8%)
Lip infection, herpes skin lesion upper lip	1/21 (4.8%)
Nail infection	1/21 (4.8%)
Papulopustular rash, hands	1/21 (4.8%)
Paronychia	1/21 (4.8%)
Urinary tract infection	1/21 (4.8%)
Injury, poisoning and procedural complications
Fall	1/21 (4.8%)
Injury, poisoning and procedural complications - Other (Pulled posterior left chest wall muscle)	1/21 (4.8%)
Investigations
Blood bilirubin increased, intermittent (Gilbert's syndrome)	1/21 (4.8%)
Creatinine increased	1/21 (4.8%)
Neutrophil count decreased	1/21 (4.8%)
Platelet count decreased	3/21 (14.3%)
Weight loss	2/21 (9.5%)
Metabolism and nutrition disorders
Anorexia	9/21 (42.9%)
Hypercalcemia	1/21 (4.8%)
Hypokalemia	1/21 (4.8%)
Musculoskeletal and connective tissue disorders
Back pain	1/21 (4.8%)
Bone pain	1/21 (4.8%)
Flank pain, right	1/21 (4.8%)
Neck pain	1/21 (4.8%)
Pain in extremity	2/21 (9.5%)
Nervous system disorders
Dizziness	2/21 (9.5%)
Dysgeusia	3/21 (14.3%)
Headache, intermittent	1/21 (4.8%)
Paresthesia, right arm	1/21 (4.8%)
Paresthesia, Right eye over cheek	1/21 (4.8%)
Peripheral sensory neuropathy	4/21 (19%)
Tremor, hands	1/21 (4.8%)
Psychiatric disorders
Agitation	1/21 (4.8%)
Insomnia	3/21 (14.3%)
Psychiatric disorders - Other (rage/altered mental status)	1/21 (4.8%)
Renal and urinary disorders
Hematuria	1/21 (4.8%)
Respiratory, thoracic and mediastinal disorders
Cough	3/21 (14.3%)
Dyspnea	7/21 (33.3%)
Hypoxia	1/21 (4.8%)
Pleural effusion	1/21 (4.8%)
Postnasal drip, intermittent	2/21 (9.5%)
Respiratory, thoracic and mediastinal disorders - Other (Pneumonia)	2/21 (9.5%)
Sore throat	1/21 (4.8%)
Skin and subcutaneous tissue disorders
Bullous dermatitis (on heels from treadmill)	1/21 (4.8%)
Dry skin, palms	1/21 (4.8%)
Palmar-plantar erythrodysesthesia syndrome	12/21 (57.1%)
Rash, back and hands	1/21 (4.8%)
Rash, forearms	1/21 (4.8%)
Rash, scrotum	1/21 (4.8%)
Skin and subcutaneous tissue disorders - Other (hypochromic lesions chest/nipples)	1/21 (4.8%)
Skin and subcutaneous tissue disorders - Other (Night sweats)	1/21 (4.8%)
"Skin and subcutaneous tissue disorders - Other (Skin lesion right shoulder)"	1/21 (4.8%)
Skin hyperpigmentation	1/21 (4.8%)
Surgical and medical procedures
Thromboembolic event (pulmonary embolism)	1/21 (4.8%)
Vascular disorders
Hot flashes	1/21 (4.8%)
Hypertension	1/21 (4.8%)
Hypotension, orthostatic	1/21 (4.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.