A Trial of Maintenance ADAPT Therapy With Capecitabine and Celecoxib in Patients With Metastatic Colorectal Cancer

• Sponsor: University of Washington (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01729923
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 27
• Location: 1
• Arm: 1
• Duration (Months): 42.2
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

This phase II trial studies how well capecitabine and celecoxib with or without radiation therapy works in treating patients with colorectal cancer that is newly diagnosed or has been previously treated with fluorouracil, and has spread to other parts of the body (metastatic). 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. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving capecitabine and celecoxib together with radiation therapy may kill more tumor cells.

Condition or Disease	Intervention/Treatment	Phase
Recurrent Colon Carcinoma; Recurrent Rectal Carcinoma; Stage IVA Colon Cancer; Stage IVA Rectal Cancer; Stage IVB Colon Cancer; Stage IVB Rectal Cancer	Drug: Capecitabine; Drug: Celecoxib; Radiation: Intensity-Modulated Radiation Therapy; Other: Laboratory Biomarker Analysis; Other: Quality-of-Life Assessment; Radiation: Radiation Therapy; Radiation: Stereotactic Radiosurgery; Procedure: Therapeutic Conventional Surgery	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To determine the rate of complete response 2 years following the initiation of first line 5-FU (fluorouracil) based chemotherapy in patients with initially unresected metastatic colorectal cancer who are then treated on the activating cancer stem cells (CSCs) from dormancy and priming them for subsequent targeting (ADAPT) protocol.

SECONDARY OBJECTIVES:

1. To determine overall survival, relapse free survival (if complete response [CR]) based on intent to treat (ITT) analysis.

2. To determine quality of life while on ADAPT therapy.

3. To determine the effects of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (K-ras) mutation status, resection and radiation on response to ADAPT therapy.

OUTLINE:

Patients proceed to surgery, radiation therapy with ADAPT therapy followed by maintenance ADAPT therapy, or ADAPT therapy. Eligible patients undergo surgical resection at baseline or upon achievement of resectable disease after radiation therapy.

RADIATION + ADAPT: Patients undergo radiation therapy 5 days per week and receive capecitabine orally (PO) twice daily (BID) and celecoxib PO BID 5 days per week during radiation.

ADAPT: Patients receive capecitabine PO BID on days 1-14 and celecoxib PO BID on days 1-21. Courses repeat every 21 days for up to 3 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year, every 4 months for 2 years, and then every 6 months for 2 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 27 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial of Maintenance ADAPT Therapy With Capecitabine and Celecoxib in Patients With Metastatic Colorectal Cancer
• Study Start Date: Mar 1, 2013
• Actual Primary Completion Date: Sep 6, 2016
• Actual Study Completion Date: Sep 6, 2016

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (capecitabine, celecoxib, radiation therapy) Patients proceed to surgery, radiation therapy with ADAPT therapy followed by maintenance ADAPT therapy, or ADAPT therapy. Eligible patients undergo surgical resection at baseline or upon achievement of resectable disease after radiation therapy. RADIATION + ADAPT: Patients undergo radiation therapy 5 days per week and receive capecitabine PO BID and celecoxib PO BID 5 days per week during radiation. ADAPT: Patients receive capecitabine PO BID on days 1-14 and celecoxib PO BID on days 1-21. Courses repeat every 21 days for up to 3 years in the absence of disease progression or unacceptable toxicity.

Drug: Capecitabine; Given PO; Other Names: Ro 09-1978/000 Xeloda ; Drug: Celecoxib; Given PO; Other Names: Benzenesulfonamide, 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]- Celebrex SC-58635 YM 177 ; Radiation: Intensity-Modulated Radiation Therapy; Undergo IMRT; Other Names: IMRT Intensity Modulated RT Intensity-Modulated Radiotherapy ; Other: Laboratory Biomarker Analysis; Correlative studies; Other: Quality-of-Life Assessment; Ancillary studies; Other Names: Quality of Life Assessment ; Radiation: Radiation Therapy; Undergo radiation therapy; Other Names: Cancer Radiotherapy Irradiate Irradiated Irradiation RADIATION Radiotherapeutics Radiotherapy RT Therapy, Radiation ; Radiation: Stereotactic Radiosurgery; Undergo stereotactic radiosurgery; Other Names: Stereotactic External Beam Irradiation stereotactic external-beam radiation therapy Stereotactic Radiation Therapy Stereotactic Radiotherapy stereotaxic radiation therapy stereotaxic radiosurgery ; Procedure: Therapeutic Conventional Surgery; Undergo surgical resection

Outcome Measures

Primary Outcome Measures

1. Rate of CR, Assessed According to CEA and CA 19-9 Measurements and Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 [3 years]

   Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker level in response to ADAPT therapy.

Secondary Outcome Measures

1. Best Overall Response Rate Among All Patients Who Had RECIST Measurements at Baseline and at Least One Subsequent Occasion [Serial measures at 9 week intervals up to 5 years]

   RECIST 1.1 criteria will be used to measure changes in the size of a selected sentinel lesion for each patient. Computed tomographic images will be measured at baseline and at subsequent 9 week intervals. Changes will be measured as percentage of the baseline measure. Results will be reported as the largest negative change. For patients with no negative changes, results will be reported as the smallest positive change.

2. Best Overall Response Rate Among All Patients Who Had RECIST Measurements at Baseline and at Least One Subsequent Occasion and Did Not Have Surgery or Radiation Therapy [Serial measures at 9 week intervals up to 5 years]

   RECIST 1.1 criteria will be used to measure changes in the size of a selected sentinel lesion for each patient. Computed tomographic images will be measured at baseline and at subsequent 9 week intervals. Changes will be measured as percentage of the baseline measure. Results will be reported as the largest negative change. For patients with no negative changes, results will be reported as the smallest positive change.

3. K-ras Mutation Status [Up to 5 years]

   The relationship between K-ras mutation, resection, and radiation and response to ADAPT therapy will be evaluated using Chi-squared analysis and Cox regression analysis.

4. Overall Survival [Until death or last reported survival, up to 5 years]

   Estimated using the Kaplan-Meier method based on the ITT population starting from the time of induction chemotherapy initiation until death or last reported survival.

5. Quality of Life (QOL), Assessed Using the M.D. Anderson Symptom Inventory (MDASI) [Up to 5 years]

   Group differences in QOL will be estimated, with repeated measures used to improve precision of estimates.

6. Relapse Free Survival in Patients Achieving CR [Up to 5 years]

   Relapse-free survival estimated using the Kaplan-Meier method based on the ITT population starting from the time of induction chemotherapy initiation.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Histologically confirmed colorectal cancer

• Evaluable or measurable radiographic evidence of colorectal cancer

• Patients with unresected metastases from colorectal cancer; patients may be either untreated with chemotherapy or currently receiving first-line 5-FU based chemotherapy (folinic acid-fluorouracil-irinotecan hydrochloride [FOLFIRI], capecitabine-irinotecan hydrochloride [CAPIRI], fluorouracil-leucovorin calcium-oxaliplatin [FOLFOX], or capecitabine-oxaliplatin [CAPOX] with or without bevacizumab) within 10 months of beginning ADAPT therapy with at least stable disease radiographically; patients who received prior adjuvant chemotherapy with 5-FU, capecitabine, or FOLFOX are eligible if adjuvant therapy was completed greater than 6 months ago

• History of histological confirmation for recurrent disease, or if recurrent disease is not readily accessible to biopsy, must have two consecutive carcinoembryonic antigen (CEA) or cancer antigen (CA) 19-9 increases, or positron emission tomography (PET) avidity

• Men and women from all ethnic and racial groups

• Eastern Cooperative Oncology Group (ECOG) performance status =< 2

• Total bilirubin =< 1.5 x the institutional upper-normal limit (IUNL)

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and/or alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) =< 2.5 x IUNL

• Alkaline phosphatase =< 2.5 x IUNL

• Leukocytes >= 3,000/uL

• Absolute neutrophil count >= 1,000/uL

• Platelets >= 100,000/uL

• Women of childbearing potential and all men must agree to use adequate contraception (hormonal or barrier method of birth control) prior to beginning ADAPT therapy and for the duration of study participation

• Negative urine pregnancy test for women of childbearing potential

• Must have the ability to understand and the willingness to provide a written informed consent to participate in the study

Exclusion Criteria:

• History of allergies to sulfonamide, aspirin, any nonsteroidal anti-inflammatory drugs (NSAIDS), 5-FU or celecoxib

• Prior 5-FU-based adjuvant chemotherapy less than 6 months prior to beginning ADAPT therapy and any residual neuropathy > grade 2

• Any regular use of cyclooxygenase-2 (COX-2) inhibitors as defined by 2-3 times per week

• Use of aspirin is NOT an exclusion criterion as long as the daily dose does not exceed 325 mg daily; initiation of ADAPT therapy requires patient to discontinue aspirin for 18 months

• Pregnant or lactating women

• History of significant neurologic or psychiatric disorders, including dementia or seizures that would impede consent, treatment, or follow up

• Any serious illness or medical condition that could affect participation on trial

• Any uncontrolled congestive heart failure New York Heart Association class III or IV

• Any uncontrolled hypertension, arrhythmia, or active angina pectoris

• Any history of major myocardial infarction, stroke or transient ischemic attack (TIA); minor acute myocardial infarction (AMI) and patients who have had cardiac bypass free of symptoms for at least 2 years may be eligible at the discretion of the study chair

• Serious uncontrolled active infection

• Patients with creatinine clearance: < 50 mL/min are excluded from this protocol; capecitabine is contraindicated in severe renal impairment (clearance < 40 mL/min)

• Inability to swallow oral medications or any medical conditions that may affect intestinal absorption of the study agent or inability to comply with oral medication

• History of active peptic ulcer disease or major upper gastrointestinal (GI) bleed < 12 months; history of GI bleeding from the colorectal cancer primary is not an exclusion criterion

• Use of warfarin is not allowed; patient is recommended to switch to low molecular weight heparin (LMWH) before participating in this study

• Patients with any history of brain or bone metastasis or who have developed progressive disease on first line 5-FU based therapy

• Current use of systemic steroid medication

• Patients with an obstructive synchronous colorectal tumor requiring up-front surgery or chemoradiation

• Patients with partial or complete bowel obstruction due to abdominal carcinomatosis

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Fred Hutch/University of Washington Cancer Consortium	Seattle	Washington	United States	98109

Sponsors and Collaborators

• University of Washington
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Stacey Cohen, Fred Hutch/University of Washington Cancer Consortium

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Stacey Cohen, Principal Investigator, University of Washington
• ClinicalTrials.gov Identifier: NCT01729923
• Other Study ID Numbers: 7707; NCI-2012-02137; 7707; P30CA015704
• First Posted: Nov 20, 2012
• Last Update Posted: Jan 16, 2018
• Last Verified: Dec 1, 2017

• Additional relevant MeSH terms: Carcinoma; Rectal Neoplasms; Colonic Neoplasms; Recurrence; Celecoxib; Capecitabine; Benzenesulfonamide

Study Results

Participant Flow

Recruitment Details	This study was activated on March 30, 2013 and terminated on August 12, 2016 due to lack of funding and prior to reaching its enrollment goal. A total 27 participants were accrued.

Arm/Group Title	Treatment (Capecitabine, Celecoxib, Radiation Therapy)
Arm/Group Description	Patients proceed to surgery, radiation therapy with ADAPT therapy followed by maintenance ADAPT therapy, or ADAPT therapy. Eligible patients undergo surgical resection at baseline or upon achievement of resectable disease after radiation therapy. RADIATION + ADAPT: Patients undergo radiation therapy 5 days per week and receive capecitabine PO BID and celecoxib PO BID 5 days per week during radiation. ADAPT: Patients receive capecitabine PO BID on days 1-14 and celecoxib PO BID on days 1-21. Courses repeat every 21 days for up to 3 years in the absence of disease progression or unacceptable toxicity. Capecitabine: Given PO Celecoxib: Given PO Intensity-Modulated Radiation Therapy: Undergo IMRT Laboratory Biomarker Analysis: Correlative studies Quality-of-Life Assessment: Ancillary studies Radiation Therapy: Undergo radiation therapy Stereotactic Radiosurgery: Undergo stereotactic radiosurgery Therapeutic Conventional Surgery: Undergo surgical resection
Period Title: Overall Study
STARTED	27
COMPLETED	0
NOT COMPLETED	27

Baseline Characteristics

Arm/Group Title	Treatment (Capecitabine, Celecoxib, Radiation Therapy)
Arm/Group Description	Patients proceed to surgery, radiation therapy with ADAPT therapy followed by maintenance ADAPT therapy, or ADAPT therapy. Eligible patients undergo surgical resection at baseline or upon achievement of resectable disease after radiation therapy. RADIATION + ADAPT: Patients undergo radiation therapy 5 days per week and receive capecitabine PO BID and celecoxib PO BID 5 days per week during radiation. ADAPT: Patients receive capecitabine PO BID on days 1-14 and celecoxib PO BID on days 1-21. Courses repeat every 21 days for up to 3 years in the absence of disease progression or unacceptable toxicity. Capecitabine: Given PO Celecoxib: Given PO Intensity-Modulated Radiation Therapy: Undergo IMRT Laboratory Biomarker Analysis: Correlative studies Quality-of-Life Assessment: Ancillary studies Radiation Therapy: Undergo radiation therapy Stereotactic Radiosurgery: Undergo stereotactic radiosurgery Therapeutic Conventional Surgery: Undergo surgical resection
Overall Participants	27
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	24 88.9%
>=65 years	3 11.1%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	46
Sex: Female, Male (Count of Participants)
Female	12 44.4%
Male	15 55.6%
Region of Enrollment (Count of Participants)
United States	27 100%

Outcome Measures

1. Primary Outcome

Title	Rate of CR, Assessed According to CEA and CA 19-9 Measurements and Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
Description	Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker level in response to ADAPT therapy.
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Capecitabine and Celecoxib
Arm/Group Description	Patients are treated with oral capecitabine and celecoxib twice daily 7 days per week. Radiation therapy may be used for selected patients. During radiation, treatment with oral capecitabine and celecoxib will be given twice daily 5 days per week. Surgery may also be used for selected patients.
Measure Participants	27
Count of Participants [Participants]	1 3.7%

2. Secondary Outcome

Title	Best Overall Response Rate Among All Patients Who Had RECIST Measurements at Baseline and at Least One Subsequent Occasion
Description	RECIST 1.1 criteria will be used to measure changes in the size of a selected sentinel lesion for each patient. Computed tomographic images will be measured at baseline and at subsequent 9 week intervals. Changes will be measured as percentage of the baseline measure. Results will be reported as the largest negative change. For patients with no negative changes, results will be reported as the smallest positive change.
Time Frame	Serial measures at 9 week intervals up to 5 years

Outcome Measure Data

Analysis Population Description

All patients who had RECIST measures at baseline and at least one other time point.

Arm/Group Title	Capecitabine and Celecoxib
Arm/Group Description	Patients are treated with oral capecitabine and celecoxib twice daily 7 days per week. Radiation therapy may be used for selected patients. During radiation, treatment with oral capecitabine and celecoxib will be given twice daily 5 days per week. Surgery may also be used for selected patients.
Measure Participants	19
Mean (Full Range) [percentage of baseline lesion size]	-17

3. Secondary Outcome

Title	Best Overall Response Rate Among All Patients Who Had RECIST Measurements at Baseline and at Least One Subsequent Occasion and Did Not Have Surgery or Radiation Therapy
Description	RECIST 1.1 criteria will be used to measure changes in the size of a selected sentinel lesion for each patient. Computed tomographic images will be measured at baseline and at subsequent 9 week intervals. Changes will be measured as percentage of the baseline measure. Results will be reported as the largest negative change. For patients with no negative changes, results will be reported as the smallest positive change.
Time Frame	Serial measures at 9 week intervals up to 5 years

Outcome Measure Data

Analysis Population Description

Patients who had RECIST measurements at baseline and at least one subsequent occasion and did not have surgery or radiation therapy

Arm/Group Title	Capecitabine and Celecoxib
Arm/Group Description	Patients are treated with oral capecitabine and celecoxib twice daily 7 days per week. Radiation therapy may be used for selected patients. During radiation, treatment with oral capecitabine and celecoxib will be given twice daily 5 days per week. Surgery may also be used for selected patients.
Measure Participants	8
Mean (Full Range) [percentage of baseline lesion size]	11

4. Secondary Outcome

Title	K-ras Mutation Status
Description	The relationship between K-ras mutation, resection, and radiation and response to ADAPT therapy will be evaluated using Chi-squared analysis and Cox regression analysis.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

K-ras mutation status was not collected.

Arm/Group Title	Capecitabine and Celecoxib
Arm/Group Description	Patients are treated with oral capecitabine and celecoxib twice daily 7 days per week. Radiation therapy may be used for selected patients. During radiation, treatment with oral capecitabine and celecoxib will be given twice daily 5 days per week. Surgery may also be used for selected patients.
Measure Participants	0

5. Secondary Outcome

Title	Overall Survival
Description	Estimated using the Kaplan-Meier method based on the ITT population starting from the time of induction chemotherapy initiation until death or last reported survival.
Time Frame	Until death or last reported survival, up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Capecitabine and Celecoxib
Arm/Group Description	Patients are treated with oral capecitabine and celecoxib twice daily 7 days per week. Radiation therapy may be used for selected patients. During radiation, treatment with oral capecitabine and celecoxib will be given twice daily 5 days per week. Surgery may also be used for selected patients.
Measure Participants	27
Median (Full Range) [months]	15

6. Secondary Outcome

Title	Quality of Life (QOL), Assessed Using the M.D. Anderson Symptom Inventory (MDASI)
Description	Group differences in QOL will be estimated, with repeated measures used to improve precision of estimates.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

We have been unable to confirmation that the original Principal Investigator secured the appropriate permission to use this instrument. Therefore, we are unable to use the data.

Arm/Group Title	Capecitabine and Celecoxib
Arm/Group Description	Patients are treated with oral capecitabine and celecoxib twice daily 7 days per week. Radiation therapy may be used for selected patients. During radiation, treatment with oral capecitabine and celecoxib will be given twice daily 5 days per week. Surgery may also be used for selected patients.
Measure Participants	0

7. Secondary Outcome

Title	Relapse Free Survival in Patients Achieving CR
Description	Relapse-free survival estimated using the Kaplan-Meier method based on the ITT population starting from the time of induction chemotherapy initiation.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

Measure Description: Inclusive of subject still alive at time of last reporting Time Frame: Until last reported survival Study terminated; data not further analyzed

Arm/Group Title	Capecitabine and Celecoxib
Arm/Group Description	Patients are treated with oral capecitabine and celecoxib twice daily 7 days per week. Radiation therapy may be used for selected patients. During radiation, treatment with oral capecitabine and celecoxib will be given twice daily 5 days per week. Surgery may also be used for selected patients.
Measure Participants	1
Number [months]	7

Adverse Events

Time Frame	3 years
Adverse Event Reporting Description	The adverse event recording period will start on the first day of study treatment and end 30 days after last protocol required treatment is administered. Only grade 2 and higher AEs will be recorded with the exception of any AE that requires a dose reduction or treatment interruption.
Arm/Group Title	Treatment (Capecitabine, Celecoxib, Radiation Therapy)
Arm/Group Description	Patients proceed to surgery, radiation therapy with ADAPT therapy followed by maintenance ADAPT therapy, or ADAPT therapy. Eligible patients undergo surgical resection at baseline or upon achievement of resectable disease after radiation therapy. RADIATION + ADAPT: Patients undergo radiation therapy 5 days per week and receive capecitabine PO BID and celecoxib PO BID 5 days per week during radiation. ADAPT: Patients receive capecitabine PO BID on days 1-14 and celecoxib PO BID on days 1-21. Courses repeat every 21 days for up to 3 years in the absence of disease progression or unacceptable toxicity. Capecitabine: Given PO Celecoxib: Given PO Intensity-Modulated Radiation Therapy: Undergo IMRT Laboratory Biomarker Analysis: Correlative studies Quality-of-Life Assessment: Ancillary studies Radiation Therapy: Undergo radiation therapy Stereotactic Radiosurgery: Undergo stereotactic radiosurgery Therapeutic Conventional Surgery: Undergo surgical resection
All Cause Mortality
	Treatment (Capecitabine, Celecoxib, Radiation Therapy)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment (Capecitabine, Celecoxib, Radiation Therapy)
	Affected / at Risk (%)	# Events
Total	1/27 (3.7%)
Gastrointestinal disorders
Nonoliguric Renal Failure	1/27 (3.7%)	1
Other (Not Including Serious) Adverse Events
	Treatment (Capecitabine, Celecoxib, Radiation Therapy)
	Affected / at Risk (%)	# Events
Total	18/27 (66.7%)
Gastrointestinal disorders
Diarrhea	3/27 (11.1%)
Post-Operative Pain	2/27 (7.4%)
Abdominal Pain	2/27 (7.4%)
General disorders
Fatigue	4/27 (14.8%)
Immune system disorders
Lupus (autoimmune reaction)	2/27 (7.4%)
Skin and subcutaneous tissue disorders
Hand/Foot Syndrome	13/27 (48.1%)

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.