BAY 43-9006 Plus Cetuximab to Treat Colorectal Cancer
Condition: Metastatic Colorectal Cancer
MeSH terms: Colorectal Neoplasms
Intervention: Cetuximab; BAY 43-9006
Intervention description: 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.; Is a potent inhibitor of proto-oncogene c-Raf (c-raf), and wild-type and mutant proto-oncogene b-Raf (b-raf) in vitro
Intervention MeSH terms: Cetuximab; Sorafenib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 51.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Sorafenib; Cetuximab; Advanced Cancer; Phase II; Colorectal Cancer; Colon Cancer; Rectal Cancer; CRC; Metastatic Colorectal Cancer

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 treating physician immediately.

          -  Ability to understand and the willingness to sign a written informed consent document
             and the ability to comply with daily oral self administration schedule.

          -  Patients must have systolic blood pressure less than or equal to 150 mm Hg and
             diastolic blood pressure less than or equal to 90 mmHg. Concomitant antihypertensive
             medications to achieve control of blood pressure are allowed.

        EXCLUSION CRITERIA:

          -  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.