BAY 43-9006 Plus Cetuximab to Treat Colorectal Cancer

Completed · Phase 2

Conditions studied: Metastatic Colorectal Cancer

In brief

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.

Key facts

Study ID: NCT00326495
Run by: National Cancer Institute (NCI)
People needed: 51
Starts: 2006-05-10
Expected to finish: 2014-11-07
Last updated by the study team: 2017-07-24

Who can join

Age: 18 and older. Sex: any. Healthy volunteers: not accepted.

You may not qualify if…

Patients who have had chemotherapy, biologic therapy, or radiotherapy within 4 weeks prior to entering the study or those who have not recovered to at least eligibility levels from adverse events due to agents administered more than 4 weeks earlier. Patients must be greater than or equal to 2 weeks since any investigational agent administered as part of a Phase 0 study (also referred to as an early Phase I study or pre-Phase I study where a sub-therapeutic dose of drug is administered) at the PIs (principal investigator's) discretion, and should have recovered to eligibility levels from any toxicities
Patients who have received any other investigational agents within 4 weeks prior to entering the study or those who have not recovered to at least eligibility levels from adverse events due to agents administered more than 4 weeks earlier.
Patients with known brain metastases would be excluded from this clinical trial, with the exception of patients whose brain metastatic disease status remains stable for greater than or equal to 6 months after treatment of the brain metastases without steroids or anti seizure medications. These patients may be enrolled at the discretion of the principal investigator.
History of allergic reactions attributed to compounds of similar chemical or biologic composition to BAY 43-9006 (for example, other multi-targeted kinase inhibitors, such as sunitinib) or cetuximab (for example, other drugs containing murine proteins, such as bevacizumab) used in the study.
Prior therapy with cetuximab or BAY 43-9006.
Patients on therapeutic anticoagulation are excluded. Prophylactic anticoagulation (i.e. low dose warfarin) of venous or arterial access devices is allowed provided that the requirements for PT, INR (International normalized ratio) or PTT are met.
Evidence of bleeding diathesis.
Uncontrolled intercurrent illness including, but not limited to, ongoing or active serious infection, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, uncontrolled hypertension, or psychiatric illness/social situations that would limit compliance with study requirements.
Pregnant women are excluded from this study because BAY 43-9006 is a kinase inhibitor agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with BAY 43-9006, breastfeeding should be discontinued if the mother is treated with BAY 43-9006.
Human immunodeficiency virus (HIV)-positive patients receiving anti-retroviral therapy are excluded from this study due to the possibility of pharmacokinetic interactions between anti-retroviral medications and BAY 43-9006. HIV positive patients not receiving antiretroviral therapy are excluded due to the possibility that BAY 43-9006 may worsen their condition and the likelihood that the underlying condition may obscure the attribution of adverse events with respect to BAY 43-9006.
History of another malignancy within the past 5 years, apart from adequately treated non-melanoma skin cancers, superficial bladder cancer or in situ cervical cancer.
Patients with conditions that would impair their ability to swallow tablets are excluded.
Use of the following medications will be not be allowed within 4 weeks prior to enrollment on the study and during the study: ketoconazole, itraconazole, ritonavir, cyclosporine, carbamazepine, phenytoin, phenobarbital, rifampin, St. Johns Wort, and prophylactic use of filgrastim and sargramostim. Products containing grapefruit juice will not be allowed while on study. BAY 43-9006 tosylate is metabolized by the P450 CYP3A enzyme; therefore, it is possible that BAY 43-9006 tosylate may interact with the above medications. Efforts should be made to switch patients who are taking enzyme-inducing anticonvulsant agents to other medications.
Patients in whom resection is indicated and can be performed safely (unless surgery is declined by the patient for other reasons).
For the optional PET/CT imaging with (89)Zr-panitumumab correlative study, participants with severe claustrophobia not relieved by oral anxiolytic medication or patients weighing > 136 kg (weight limit for scanner table).
Inclusion of Women and Minorities:
Both men and women and members of all races and ethnic groups are eligible for this trial.

Where it is running

National Institutes of Health Clinical Center, 9000 Rockville Pike — Bethesda, Maryland, United States

Full record on ClinicalTrials.gov

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