Gemcitabine and Docetaxel in Patients With Relapsed or Refractory Metastatic Colorectal Adenocarcinoma

Study Overview
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Brief Summary
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The primary goal of the trail was to determine the efficacy of combining Gemcitabine and Docetaxel in treatment of metastatic colorectal cancer with CHFR and/or Microsatellite Instability (MSI) phenotype.

Detailed Description
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This was an open-label, multicenter, trial. Enrolled patients received an intravenous combination of gemcitabine 800 mg/m2 on days 1 and 8 and docetaxel 70 mg/m2 on day 8 of each 21-day cycle. Patients received filgrastim (granulocyte colony-stimulating factor [G-CSF]) on days 9 through 15 or pegfilgrastim 6 mg on day 9 or 10 of each cycle. Patients were treated until disease progression or unacceptable adverse events (AEs), or withdrawn of the consent. Patients underwent safety evaluations and monitoring for adverse events for each cycle. Disease assessments (computed tomography or magnetic resonance imaging) were performed at baseline and then every 6 weeks. Response was evaluated according to the RECIST version1.1. Patients who discontinue treatment will be monitored for overall survival.

Official Title
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A Multi-institutional Open Label, Trial Evaluating the Efficacy of Gemcitabine and Docetaxel in Patients With Relapsed or Refractory Metastatic Colorectal Adenocarcinoma With Methylated CHFR and/or Microsatellite Instability Phenotype

Conditions
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Metastatic Colorectal Adenocarcinoma

Intervention / Treatment
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* Drug: Gemcitabine
* Drug: Docetaxel
* Drug: Filgrastim or Pegfilgrastim


Participation Criteria
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Eligibility Criteria
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Inclusion: Patients must have histologically or cytologically confirmed metastatic or unresectable adenocarcinoma of the colon or rectum. Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >20 mm with conventional techniques or as >10 mm with spiral CT scan, MRI, or calipers by clinical exam. See Section 11 for the evaluation of measurable disease. Patients must be either intolerant or refractory to one or more standard line(s) of chemotherapy treatment prior to enrollment. Toxicity from prior regimens must be resolved to less than or equal to grade 1 prior to enrollment. Patients with grade 2 neurotoxicity may be enrolled on a case by case basis at the discretion of the principle investigator. Patients should be off all treatment for at least 4 weeks prior to trial enrollment. Age >18 years. Because no dosing or adverse event data are currently available on the use of gemcitabine in combination with docetaxel in patients <18 years of age with colorectal adenocarcinoma, children are excluded from this study, but will be eligible for future pediatric trials. ECOG performance status 0 or 1 (Karnofsky >70%, see Appendix A). Life expectancy of greater than 12 weeks. Patients must have normal organ and marrow function. Additional eligibility criteria: Microsatellite instability phenotype of archival tissue biopsy determined by treating institution by PCR and IHC assay Methylation CHFR gene promoter in archival tissue biopsy As gemcitabine and docetaxel are known to be teratogenic, 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. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of treatment. Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier. Patients who are receiving any other investigational agents. Patients with known brain metastases should 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. History of allergic reactions attributed to compounds of similar chemical or biologic composition to gemcitabine or docetaxel. Patients receiving any medications or substances that are inhibitors or inducers of CYP 3A4 are ineligible. Lists including medications and substances known or with the potential to interact with the cytochrome 450 3A4 isoenzyme are provided in appendix C. 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. Pregnant women are excluded from this study because of the potential for teratogenic or abortifacient effects of study medications. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with gemcitabine and docetaxel breastfeeding should be discontinued if the mother is treated. These potential risks may also apply to other agents used in this study including supportive medications. HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with gemcitabine and docetaxel. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gemcitabine and Docetaxel<br>Patients were treated with gemcitabine 800 mg/m2 on days 1 and 8 and docetaxel 70 mg/m2 on day 8 of each 21-day cycle. Patients received filgrastim (granulocyte colony-stimulating factor [G-CSF]) on days 9 through 15 or pegfilgrastim 6 mg on day 9 or 10 of each cycle. Patients were treated until disease progression or unacceptable adverse events (AEs), or withdrawn of the consent. | Drug: Gemcitabine<br>* intravenous gemcitabine 800mg/m2 on days 1 and 8<br>Drug: Docetaxel<br>* intravenous docetaxel 70mg/m2 on day 8 of each 21 day cycle<br>Drug: Filgrastim or Pegfilgrastim<br>* filgrastim (granulocyte colony-stimulating factor [G-CSF]) on days 9 through 15 or pegfilgrastim 6 mg on day 9 or 10 of each cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate | The Response Rate is defined as the number of patients achieving a complete response (CR) or partial response (PR) based on the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). CR = disappearance of all target lesions, PR is =>30% decrease in sum of diameters of target lesions, progressive disease (PD) is >20% increase in sum of diameters of target lesions, stable disease (SD) is <30% decrease or <20% increase in sum of diameters of target lesions. | 9 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | Progression-free survival is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. PFS is defined as the number of months from the date of first dose of study drug to disease progression (progressive disease [PD] or relapse from complete response [CR] as assessed using RECIST 1.1 criteria) or death due to any cause. Per RECIST 1.1 criteria, CR = disappearance of all target lesions, Partial Response (PR) is =>30% decrease in sum of diameters of target lesions, Progressive Disease (PD) is >20% increase in sum of diameters of target lesions, Stable Disease (SD) is <30% decrease or <20% increase in sum of diameters of target lesions. Estimation based on the Kaplan-Meier curve. | 9 months | 
| Overall Survival With Gemcitabine and Docetaxel Combination Therapy | Overall survival is the time from the start of first dose of study drug to death. OS will be measured from date of first dose of a study drug until death or end of follow-up (OS will be censored on the date the subject was last known to be alive for subjects without documentation of death at the time of analysis). Estimation based on the Kaplan-Meier curve. | 62 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gemcitabine, Docetaxel, Filgrastim, Pegfilgrastim, Colorectal Adenocarcinoma