Phase 2
N=51
BAY 43-9006 Plus Cetuximab to Treat Colorectal Cancer
Metastatic Colorectal Cancer
Bottom Line
View on ClinicalTrials.gov: NCT00326495 ↗Enrolled (actual)
51
Serious AEs
44.0%
Results posted
Aug 2015
Primary outcome: Primary: Overall Rate of Response — 15 percentage of participants
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 2
- Interventions
- Cetuximab (Drug); BAY 43-9006 (Drug)
- Age
- Adult, Older Adult · 18+ yrs
- Sex
- All
- Sponsor
- National Cancer Institute (NCI)
- Primary completion
- Nov 2014
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Overall Rate of Response |
15 | — |
| SECONDARY Count of Participants With Adverse Events |
50 | — |
Summary
Background:
* Colorectal cancer (CRC) is a major public health problem in the U.S. and worldwide, and 5-year survival with widespread metastatic disease is less than 5%.
* Expression of epidermal growth factor receptor (EGFR) or up-regulation of the gene occurs in the majority of CRC cases (60-80%).
* Therapies targeting EGFR, like cetuximab, have shown activity in the treatment of solid tumors like CRC.
* Cetuximab is FDA (Food and Drug Administration) approved for the treatment of EGFR-expressing CRC, but clinical responses to cetuximab are seen in only 10% of EGFR-expressing CRC.
* One possible mechanism of resistance to cetuximab could be KRAS (Kirsten rat sarcoma) mutations.
* Another major pathway implicated in colon carcinogenesis is the vascular endothelial growth factor (VEGF) pathway, which is involved in angiogenesis and is a validated target for therapy in CRC.
* BAY 43-9006 is both a Raf kinase inhibitor and an inhibitor of VEGF receptor (VEGFR2) tyrosine kinase.
* We hypothesize that the combined inhibition of EGFR, VEGFR2, and the Ras-(rapidly accelerated fibrosarcoma) Raf pathway will demonstrate promising clinical activity in CRC. Furthermore, in patients with mutant KRAS, combination of cetuximab with a drug that inhibits Raf kinase and acts downstream of Ras mutations, could restore tumor sensitivity to cetuximab.
Objectives:
* To determine the rate of response (complete response (CR) + partial response (PR) + stable disease (SD) for 4 months) and toxicity profile of combination of BAY 43-9006 and cetuximab in previously treated EGFR-expressing metastatic CRC in patients with mutant KRAS.
* To evaluate BAY 43-9006 pharmacokinetics & pharmacogenomics (CYP3A4/5 (cytochrome P450 3A4/5)).
* To evaluate for this combination treatment pharmacodynamics, effect on tumor vascularity and effect on angiogenic cytokines.
Eligibility:
* Adults with histologically or cytologically documented, measurable, EGFR-expressing metastatic CRC, which has recurred or progressed following at least one prior 5FU (Fluorouracil)-based combination chemotherapy regimen administered for the treatment of metastatic disease.
* Patients must be KRAS mutation-positive.
Design:
* BAY 43-9006 will be administered 400 mg by mouth twice daily
* Cetuximab will be administered as 400 mg/m^2 loading dose (week 1) followed by 250 mg/m^2 IV (intravenous) weekly.
* If procedure may be performed safely, tumor biopsy will be obtained prior to treatment and after 4 weeks of treatment.
* Optional positron emission tomography (PET)/computerized tomography (CT) imaging with 89Zr-labeled, EGFR-targeting antibody panitumumab may be performed to evaluate radiation dosimetry, safety, and tumor distribution prior to and following treatment with study agents.
* Patients will be evaluated for response every 8 weeks using the RECIST (Response Evaluation Criteria in Solid Tumors) criteria.
* This trial uses a phase II optimal design targeting a response rate as defined above of 20% in patients with mutant KRAS. Up to 49 patients may be treated.
Eligibility Criteria
- INCLUSION CRITERIA:
- Patients must have histologically or cytologically documented metastatic colorectal cancer, which has recurred or progressed following at least one prior chemotherapy regimen administered for the treatment of metastatic disease. The diagnosis should be confirmed by the Laboratory of Pathology at the Clinical Center, NIH (National Institutes of Health).
- Tumor should express epidermal growth factor receptor (EGFR), defined as any membrane staining for EGFR in tumor cells by immunohistochemistry (IHC) done on archival tumor blocks or slides.
- Tumor blocks or unstained slides from archival pathological specimen suitable for the isolation of genomic DNA (deoxyribonucleic acid) must be available to determine the status of mutations in KRAS in the tumor. (For the initial 13 evaluable patients already enrolled and treated on this study, every effort will be made to re-acquire these blocks from patients or their referring physicians for evaluation of KRAS.)
- 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) as greater than or equal to 20 mm with conventional techniques or as greater than or equal to 10 mm with spiral computed tomography (CT) scan.
- Patients must have received or been offered and declined at least one prior Fluorouracil (5FU)-containing combination chemotherapy regimen for metastatic disease, unless available chemotherapy regimens were for some reason contraindicated for a particular patient. Patients who have received chemotherapy and/or biologic therapy, excluding BAY 43-9006 or cetuximab, are eligible. This therapy must have been completed greater than or equal to 4 weeks prior to enrollment on protocol, and the patient must have recovered to eligibility levels from prior toxicity. Prior radiation or surgery should have been completed greater than or equal to 4 weeks prior to study enrollment and all associated toxicities resolved to eligibility levels.
- Age greater than or equal to18 years. Colorectal cancer does not usually occur in patients less than 18 years of age.
- Life expectancy greater than 3 months.
- ECOG (Eastern Cooperative Oncology Group) performance status 0 or 1.
- Patients must have normal organ and marrow function as defined below:
- absolute neutrophil count greater than or equal to 1,500/ microliter
- platelets greater than or equal to 100,000/ microliter
- total bilirubin less than or equal to 1.5 times the institutional upper limits of normal
- AST (aspartate aminotransferase) (SGOT (serum glutamic oxaloacetic transaminase))/ALT (alanine aminotransferase) (SGPT (serum glutamic pyruvic transaminase) less than or equal to 2.5 times the institutional upper limit of normal
- creatinine less than or equal to 1.5 times the institutional upper limits of normal
OR
- creatinine clearance greater than or equal to 60 mL/min/1.73 m^2
- PT (prothrombin time)/PTT (partial thromboplastin time) less than or equal to 1.5 times the institutional upper limits of normal
- Patients must have at least one lesion amenable to biopsy, as determined by an associate investigator after discussion with a member of the interventional radiology team. This lesion should be different from target lesion(s) being followed on imaging studies to evaluate response to treatment.
- The effects of the combination of BAY 43-9006 and cetuximab on the developing human fetus at the recommended therapeutic doses are unknown. For this reason and because raf kinase inhibitor agents used in this trial 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, for the duration of study participation, and for at least 2 months following completion of study. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her tre
Data sourced from ClinicalTrials.gov (NCT00326495). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.