FOCUS 3 - A Study to Determine the Feasibility of Molecular Selection of Therapy Using KRAS, BRAF and Topo-1 in Patients With Metastatic or Locally Advanced Colorectal Cancer
18 Years
N/A
Both
Colorectal Cancer
Trial Information
FOCUS 3 - A Study to Determine the Feasibility of Molecular Selection of Therapy Using KRAS, BRAF and Topo-1 in Patients With Metastatic or Locally Advanced Colorectal Cancer
OBJECTIVES:
Primary - Feasibility Study
- To determine the proportion of consenting patients that can provide a formalin-fixed
paraffin-embedded block containing tumor.
- To determine the feasibility of topoisomerase-1 (topo-1) IHC and K-ras, BRAF mutational
status determination being completed with 10 working days of initial consent.
- To determine reproducibility of results between reference laboratories.
- To determine the real costs of molecular testing.
- To determine the patients' ability to comprehend the study and their attitude during
the waiting period for testing.
- To assess patients' ability to fully comprehend the trial as explained to them.
Secondary - Feasibility Study
- To further identify the EGFR-responsive subset within the K-ras wildtype population.
Primary - Definitive Study
- Compare the clinical outcomes of patients with metastatic or locally advanced
colorectal cancer and low topo-1-expressing tumors treated with fluorouracil alone
versus irinotecan hydrochloride, fluorouracil, and leucovorin calcium (IrMdG).
- Compare the progression-free survival of patients with high topo-1-expressing tumors
treated with oxaliplatin and IrMdG versus IrMdG alone.
- Compare the response rate in patients with K-ras wildtype tumor treated with cetuximab
and IrMdG versus IrMdG alone.
- Compare the response rate in patients with K-ras mutant tumors who are unlikely to
respond to EGFR inhibition treated with bevacizumab and IrMdG versus IrMdG alone.
OUTLINE: This is a multicenter, 2-part study.
- Part I (feasibility study): Once consent for tissue block release has been obtained and
patient is registered, the block is requested from the Pathology Department. This
begins the 10 working-day time line. Treatment commences once the results of the
testing are known. The following evaluations are performed during this period:
- The frequency of EGFR gene amplification on FISH, PI3K gene mutation, PTEN loss by
IHC, estimation of mRNA for EGFR ligands (amphiregulin and epiregulin), and other
protein assessments.
- An evaluation of the impact on the use or further investigation of these markers
in the main study.
- Patients consenting to trial entry and (if agreeable to data collection) patients
refusing trial entry complete a questionnaire assessing patients' ability to fully
comprehend the trial as explained to them.
- Patients are interviewed before allocation of treatment about their attitudes
about the waiting period necessary for tumor testing.
- Part II (definitive study): Patients are stratified according to availability of both
lab tests (K-ras mutation [yes vs no], BRAF mutation [yes vs no], and topoisomerase-1
[topo-1] expression [low vs high]). Patients are assigned to 1 of 4 treatment groups
based on their biomarker test results.
- Group 1 (low topo-1 and both K-ras and BRAF wildtype): Patients are randomized to
1 of 3 treatment arms.
- Arm I (regimen A [IrMdG]): Patients receive irinotecan hydrochloride IV over
30 minutes, leucovorin calcium IV over 2 hours, and fluorouracil IV bolus
followed by infusion over 46 hours on day 1. Treatment repeats every 2 weeks
for at least 6 months in the absence of disease progression or unacceptable
toxicity.
- Arm II (regimen B [MdG]): Patients receive leucovorin calcium IV over 2 hours
and fluorouracil IV bolus followed by infusion over 46 hours on day 1.
Treatment repeats every 2 weeks for at least 6 months in the absence of
disease progression or unacceptable toxicity.
- Arm III (regimen D [IrMdG and cetuximab]): Patients receive cetuximab IV over
1-2 hours, irinotecan hydrochloride IV over 30 minutes, leucovorin calcium IV
over 2 hours, and fluorouracil IV bolus followed by infusion over 46 hours on
day 1. Treatment repeats every 2 weeks for at least 6 months in the absence
of disease progression or unacceptable toxicity.
- Group 2 (low topo-1 and either K-ras or BRAF mutation): Patients are randomized to
1 of 3 treatment arms.
- Arm I (regimen A [IrMdG]): Patients receive irinotecan hydrochloride,
leucovorin calcium, and fluorouracil as in group 1, arm I.
- Arm II (regimen B [MdG]): Patients receive leucovorin calcium and
fluorouracil as in group 1, arm II.
- Arm III (regimen E [IrMdG and bevacizumab]): Patients receive bevacizumab IV
over 30-90 minutes, irinotecan hydrochloride IV over 30 minutes, leucovorin
calcium IV over 2 hours, and fluorouracil IV bolus followed by infusion over
46 hours on day 1. Treatment repeats every 2 weeks for at least 6 months in
the absence of disease progression or unacceptable toxicity.
- Group 3 (high topo-1 and both K-ras and BRAF wildtype): Patients are randomized to
1 of 3 treatment arms.
- Arm I (regimen A [IrMdG]): Patients receive irinotecan hydrochloride,
leucovorin calcium, and fluorouracil as in group 1, arm I.
- Arm II (regimen C [IrOxMdG]): Patients receive irinotecan hydrochloride IV
over 30 minutes, leucovorin calcium IV over 2 hours, oxaliplatin IV over 2
hours, and fluorouracil IV bolus followed by infusion over 46 hours on day 1.
Treatment repeats every 2 weeks for at least 6 months in the absence of
disease progression or unacceptable toxicity.
- Arm III (regimen D [IrMdG and cetuximab]): Patients receive cetuximab,
irinotecan hydrochloride, leucovorin calcium, and fluorouracil IV as in group
1, arm III.
- Group 4 (high topo-1 and either K-ras or BRAF mutation): Patients are randomized
to 1 of 3 treatment arms.
- Arm I (regimen A [IrMdG]): Patients receive irinotecan hydrochloride,
leucovorin calcium, and fluorouracil as in group 1, arm I.
- Arm II (regimen C [IrOxMdG]): Patients receive irinotecan hydrochloride,
leucovorin calcium, oxaliplatin, and fluorouracil as in group 3, arm II.
- Arm III (regimen E [IrMdG and bevacizumab]): Patients receive bevacizumab,
irinotecan hydrochloride, leucovorin calcium, and fluorouracil IV as group 2,
arm III.
After completion of study therapy, patients are followed up periodically.
PROJECTED ACCRUAL: A total of 240 patients will be accrued for the feasibility study and
approximately 3,000 patients will be accrued for the definitive study.
Inclusion Criteria
DISEASE CHARACTERISTICS:
- Histologically confirmed colorectal adenocarcinoma meeting 1 of the following
criteria:
- Prior or recurrent primary adenocarcinoma of the colon or rectum with clinical
or radiological evidence of locally advanced or metastatic disease
- Metastatic adenocarcinoma with clinical and/or radiological evidence of
colorectal primary tumor
- Inoperable metastatic or locoregional disease
- Patients suitable for surgical resection of metastatic disease after response to
first-line or adjuvant chemotherapy not allowed and should be considered for the
New-EPOC trial study
- Unidimensionally measurable disease (according to RECIST criteria)
- Must have completed adjuvant chemotherapy with fluorouracil +/- leucovorin calcium
(FU +/- LC), capecitabine, or oxaliplatin combinations in the past 6 months
- QUASAR 2 patients who have continued bevacizumab for 6 months following
completion of chemotherapy are allowed immediately after completion of
bevacizumab
- Rectal chemotherapy with FU +/- LC or capecitabine for allowed if completed ≥ 1 month
ago
- Single tumor block available
- No brain metastasis
PATIENT CHARACTERISTICS:
- WHO performance status 0-2
- ANC ≥ 1,500/mm^3
- Platelet count ≥ 100,000/mm^3
- Alkaline phosphatase ≤ 5 times upper limit of normal (ULN)
- Serum bilirubin ≤ 1.25 times ULN
- AST or ALT ≤ 2.5 times ULN
- Creatinine clearance ≥ 30 mL/min OR GFR ≥ 30 mL/min
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception
- Considered fit to undergo combination chemotherapy, with none of the following
conditions:
- Severe uncontrolled concurrent medical illness likely to interfere with protocol
treatments, including any of the following:
- Poorly controlled angina
- Uncontrolled hypertension
- Myocardial infarction within the past 3 months
- History of severe peptic ulcer disease
- Any psychiatric or neurological condition that is likely to compromise the
patient's ability to give informed consent or to comply with oral medication
- Nephrotic syndrome
- Known coagulopathy
- No prior or current malignant disease that, in the judgement of the treating
investigator, is likely to interfere with FOCUS 3 treatment or assessment of response
- No known hypersensitivity reactions to any of the components of the study treatments
- No personal or family history suggestive of dihydropyrimidine dehydrogenase (DPD)
deficiency or with known DPD deficiency
- No history of uncontrolled seizures, central nervous system disorders, or psychiatric
disability judged by the investigator to be clinically significant precluding
informed consent
- Not able to attend or comply with treatment or follow-up scheduling
PRIOR CONCURRENT THERAPY:
- See Disease Characteristics
- At least 4 weeks since prior surgery
- No prior systemic chemotherapy for metastatic disease
- No ongoing therapy with cyclosporin-A
- No ongoing treatment with a contraindicated concomitant medication
Type of Study:
Interventional
Study Design:
Allocation: Randomized, Masking: Open Label, Primary Purpose: Diagnostic
Outcome Measure:
Topoisomerase-1 (topo-1) and K-ras, BRAF results obtained within 10 working days after registration
Safety Issue:
No
Principal Investigator
Timothy Maughan, MD
Investigator Role:
Principal Investigator
Investigator Affiliation:
Velindre NHS Trust
Authority:
Unspecified
Study ID:
CDR0000648235
NCT ID:
NCT00975897
Start Date:
July 2009
Completion Date:
Related Keywords:
- Colorectal Cancer
- adenocarcinoma of the colon
- recurrent colon cancer
- stage III colon cancer
- stage IV colon cancer
- adenocarcinoma of the rectum
- recurrent rectal cancer
- stage III rectal cancer
- stage IV rectal cancer
- Colorectal Neoplasms
Name | Location |
|---|
