BAY 43-9006 Plus Cetuximab to Treat Colorectal Cancer

NCT00326495 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 06016406-C-0164
• Study Type: interventional
• Target: 51
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Metastatic Colorectal Cancer

Keywords

Sorafenib; Cetuximab; Advanced Cancer; Phase II; Colorectal Cancer; Colon Cancer; Rectal Cancer; CRC; Metastatic Colorectal Cancer

Outcome Measures

Primary Outcomes (1)

• Overall Rate of Response

  Rate of response is defined as the percentage of participants with a complete response (CR) + partial response (PR) + stable disease (SD) for 4 months. Response is defined by the Response is determined by the Response Evaluation Criteria in Solid Tumors (RECIST). Partial response is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. Complete response is a disappearance of all target lesions. Stable disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD (progressive disease), taking as reference the smallest sum LD since the treatment started. Progressive disease is at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.

  4 months

Secondary Outcomes (1)

• Count of Participants With Adverse Events

  96 months, 26 days

Study Arms (1)

BAY 43-9006 & Cetuximab

EXPERIMENTAL

BAY 43-9006: Administered orally at a dose of 400 mg twice a day (BID). Cetuximab will be given intravenously (IV) at a dose of 400 mg/m\^2 initially as a loading dose on week 2, followed by 250 mg/m\^2 weekly starting on week 3

Drug: Cetuximab; Drug: BAY 43-9006

Interventions

Cetuximab DRUG

Cetuximab is a recombinant human/mouse chimeric monoclonal antibody which binds specifically to the extracellular domain of the epidermal growth factor receptor (epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 1 (HER1), c-ErbB) in normal and tumor cells, and competitively inhibits the binding of epidermal growth factor (EGF) and other ligands, such as transforming growth factor-alpha.

Also known as: Erbitux

BAY 43-9006 & Cetuximab

BAY 43-9006 DRUG

Is a potent inhibitor of proto-oncogene c-Raf (c-raf), and wild-type and mutant proto-oncogene b-Raf (b-raf) in vitro

Also known as: Sorafenib

BAY 43-9006 & Cetuximab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• creatinine clearance greater than or equal to 60 mL/min/1.73 m\^2

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).

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A, Verslype C, Chau I, Van Cutsem E. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004 Jul 22;351(4):337-45. doi: 10.1056/NEJMoa033025.

  PMID: 15269313 BACKGROUND

• Messa C, Russo F, Caruso MG, Di Leo A. EGF, TGF-alpha, and EGF-R in human colorectal adenocarcinoma. Acta Oncol. 1998;37(3):285-9. doi: 10.1080/028418698429595.

  PMID: 9677101 BACKGROUND

• Khosravi-Far R, Der CJ. The Ras signal transduction pathway. Cancer Metastasis Rev. 1994 Mar;13(1):67-89. doi: 10.1007/BF00690419.

  PMID: 8143346 BACKGROUND

• Do K, Cao L, Kang Z, Turkbey B, Lindenberg ML, Larkins E, Holkova B, Steinberg SM, Raffeld M, Peer CJ, Figg WD, Eugeni M, Jacobs P, Choyke P, Wright JJ, Doroshow JH, Kummar S. A Phase II Study of Sorafenib Combined With Cetuximab in EGFR-Expressing, KRAS-Mutated Metastatic Colorectal Cancer. Clin Colorectal Cancer. 2015 Sep;14(3):154-61. doi: 10.1016/j.clcc.2015.02.007. Epub 2015 Mar 7.

  PMID: 25861837 RESULT

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Colorectal Neoplasms; Colonic Neoplasms; Rectal Neoplasms

Interventions

Cetuximab; Sorafenib

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Phenylurea Compounds; Urea; Amides; Organic Chemicals; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Niacinamide; Nicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring

Results Point of Contact

• Title: Dr. Alice Chen
• Organization: National Cancer Institute

chenali@mail.nih.gov

240-276-6565

Study Officials

• Shivaani Kummar, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: May 16, 2006
• First Posted: May 17, 2006
• Study Start: May 10, 2006
• Primary Completion: November 5, 2014
• Study Completion: November 7, 2014
• Last Updated: July 24, 2017
• Results First Posted: August 7, 2015

Record last verified: 2017-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)