Determine the efficacy of combination gemcitabine and docetaxel chemotherapy in the treatment of metastatic colorectal cancer with CHFR and/or MSI phenotype
ID
Source
Brief title
Condition
- Malignant and unspecified neoplasms gastrointestinal NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Objectives
Determine the response rate of gemcitabine and docetaxel combination therapy
for treatment of relapsed or refractory metastatic colorectal adenocarcinoma
with methylation of CHFR and/or microsatellite instability
Secondary outcome
Secondary Objectives
Determine the progression free survival with gemcitabine and docetaxel
combination therapy in the selected patient population
Determine the overall survival with gemcitabine and docetaxel combination
therapy in the selected patient population
Assess CHFR methylation in circulating tumor DNA and compare to CHFR
methylation observed in tumor tissue
Assess changes in CHFR methylation in circulating tumor DNA over the time of
therapy to determine if CHFR demethylation occurs as a predictor of progression
Analyze tumor tissue using a global methylation approach to develop a more
robust predictive signature of treatment response
Evaluate changes in quality of life for patients treated with this regimen by
serial measurements using the QLQ-C30 and QLQ-CR29 questionnaire.
Background summary
*CHFR is a checkpoint protein which causes cell cycle arrest and associated
chemotherapy resistance when exposed to microtubule inhibitors
*Epigenetic silencing of CHFR expression via CpG promoter methylation has been
shown to increase sensitivity to microtubule inhibitors
*Microsatellite instability (MSI-H) colorectal cancer is associated with
sensitivity to gemcitabine
*Methylation of CHFR and/or microsatellite instability is/are present in
approximately 25-40% of all colorectal adenocarcinoma tumors, with significant
overlap of CHFR methylation with MSI-H
*Gemcitabine and docetaxel have been safely combined in the treatment of
non-small cell lung cancer and breast cancer
*Gemcitabine and docetaxel combination therapy has demonstrated significant
preclinical activity in colorectal cancer cell lines with CHFR and/or MSI
phenotype
Study objective
Determine the efficacy of combination gemcitabine and docetaxel chemotherapy in
the treatment of metastatic colorectal cancer with CHFR and/or MSI phenotype
Study design
Patients metastatic colorectal carcinoma who are either intolerant or
refractory to one or more standard lines of chemotherapy will be asked to
participate. After informed consent archival tumor tissue will be tested for
MSI and CHFR promoter methylation. If tested positive for one of these tumor
characteristics, and all othere eligibility criteria are met, study treatment
will be commenced.
Patients will receive intravenous gemcitabine 500mg/m2 on days 1 and 8 and
docetaxel 70mg/m2 on day 8 of each 21 day cycle
Patients will receive filgrastim (G-CSF) on days 9 through 15 or pegfilgrastim
6mg on day 9 or 10 of each cycle
Patients will be evaluated for toxicity prior to receiving each cycle and every
6 weeks for response using RECIST criteria 1.0
A minimum of 10 and a maximum of 40 patients will be enrolled
Intervention
Patients will receive intravenous gemcitabine 500mg/m2 on days 1 and 8 and
docetaxel 70mg/m2 on day 8 of each 21 day cycle
Patients will receive filgrastim (G-CSF) on days 9 through 15 or pegfilgrastim
6mg on day 9 or 10 of each cycle
Study burden and risks
The study treatment is an approved chemotherapeutic regime for other types of
cancer and deemed safe.
Side effects of systemic therapy can occur and patients can experience side
effects or complications of the blood sampling . The risks of participating in
the study are limited, and if successful, study treatment may benefit the
subject as well. The information that we learn from this study has the
potential to improve therapy for patients with refractory colorectal cancer,
and may benefit individuals who are diagnosed with this disease in the future.
De Boelelaan 1117
Amsterdam 1081 HV
NL
De Boelelaan 1117
Amsterdam 1081 HV
NL
Listed location countries
Age
Inclusion criteria
histologically or cytologically confirmed metastastic or unresectable colorectal adenocarcioma measurable disease
intolerant or refractory to one or more standard lines of chemotherapy
age>18
ECOG 0-1
life expectancy of greater than 12 weeks
normal organ and marrow function
MSI phenotype of archival tissue biopsy determined by PCR and IHC
CHFR gene promoter methylation in archival tissue biopsy
ability to understand and willingness to sign a written informed consent document
Exclusion criteria
chemotherapy or radiotherapy within 4 weeks prior to entering study, or not being recovered from adverse events.
receiving any other investigational agents
known brain metastases
history of allergic reactions attributed to cmpounds of simiar chemical or biological composition to gemcitabine or docetaxel.
receiving any medications or substances thtat are inhibitors or inducers of CYP3A4
uncontrolled intercurrent illness
pregnant women
HIV positive patients
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2013-005086-40-NL |
| ClinicalTrials.gov | NCT01639131 |
| CCMO | NL47205.029.14 |