AZD6244 With Cetuximab for Solid Tumors and Colorectal Cancer
Condition: Colonic Neoplasms; Cancer of the Colon; Colon Cancer; Colon Neoplasms; Colonic Cancer
MeSH terms: Neoplasms; Colonic Neoplasms
Study type: Interventional
Phase: Phase 1

Summary: 
      Background:

      - The experimental cancer treatment drug AZD6244 has been shown to block signals that tell
      cancer cells to grow. Cetuximab, a drug approved to treat cancer of the head, neck, colon,
      and rectum, also blocks signals that tell cancer cells to grow. Researchers are investigating
      the highest safe dose of AZD6244 to give with cetuximab, and will also investigate the
      effectiveness of this drug combination in individuals who have colorectal cancer that
      involves a particular protein known as the K-RAS protein. Cetuximab is not used to treat
      colorectal cancer with K-RAS tumors because it has not been shown to be effective, but
      researchers believe that adding AZD6244 to cetuximab may improve how well cetuximab works,
      even in people with K-RAS tumors.

      Objectives:

        -  To evaluate the safety and effectiveness of AZD6244 in combination with cetuximab for
           solid tumors that have not responded to standard treatment.

        -  To evaluate the safety and effectiveness of AZD6244 in combination with cetuximab for
           colorectal cancer that involves the K-RAS protein and has not responded to standard
           treatment.

      Eligibility:

        -  Individuals at least 18 years of age who have been diagnosed with solid tumors that have
           not responded to standard treatment.

        -  Individuals at least 18 years of age who have been diagnosed with colorectal cancer that
           has not responded to standard treatment.

      Design:

        -  This protocol will involve two separate studies: an initial study to establish the
           highest safe and effective dose of AZD6244 and cetuximab in individuals with solid
           tumors, and an expansion study of AZD6244 and cetuximab in individuals with colorectal
           cancer involving the K-RAS protein.

        -  Participants will be screened with a full medical history and physical examination,
           blood samples, imaging studies, and other tests as required by the researchers.

        -  AZD6244 is a capsule to be swallowed once or twice a day, every day, with water on an
           empty stomach. Cetuximab will be given intravenously once a week, over 2 hours for the
           first dose and over an hour for every following dose. This combination of daily AZD6244
           and weekly cetuximab will be repeated in 28-day cycles of treatment. Participants will
           keep a diary to record the time of taking AZD6244 each day, as well as any side effects.

        -  Participants will have frequent blood tests and other exams during the first cycle of
           treatment, up to five visits to the National Institutes of Health (NIH) and other visits
           to their local doctor to in the first 28-day cycle.

        -  During subsequent cycles, participants will have four visits to NIH and four visits to
           your local doctor for examinations, blood tests, and imaging studies.

        -  Participants may continue to receive the AZD6244 with cetuximab for up to 6 cycles,
           until the tumor grows, unacceptable side effects development, or the participant or
           participant's doctor decides to stop participation. There will be a final study visit
           that repeats the procedures performed during the screening visit....
    

Detailed description: 
      Background:

        -  AZD6244 is an oral highly selective and potent uncompetitive inhibitor of
           mitogen-activated protein kinase 1/2 (MEK1/2).

        -  The presence of KRAS mutations predict resistance to EGFR-directed antibody therapy of
           metastatic colorectal cancer. This appears secondary to KRAS activation of signaling
           cascades downstream of the EGFR receptor, including the RAF/MEK/ERK pathway.

        -  Our hypothesis is that EGFR inhibition by cetuximab would be augmented in patients with
           KRAS mutations if activation of the RAF/MEK/ERK cascade were to be inhibited.

      Objectives:

        -  To determine the dose limiting toxicities and the maximum tolerated dose of AZD6244 in
           combination with cetuximab in advanced, refractory solid tumors.

        -  To assess for evidence of anti-tumor activity with this combination, per tumor
           measurements using RECIST criteria.

        -  To evaluate the pharmacokinetics of AZD6244 and cetuximab when administered
           concomitantly.

        -  To evaluate the safety and tolerability of the combination of AZD6244 and cetuximab in
           patients with K-RAS mutated metastatic colorectal cancer.

        -  To assess the inhibition of the RAF/MEK/ERK pathway in peripheral blood mononuclear
           cells secondary to treatment with AZD6244.

        -  To evaluate the pharmacokinetics of AZD6244 in combination with cetuximab and the
           relation to treatment side effects.

      Eligibility:

        -  Patients must have histologically confirmed malignancy that is metastatic or
           unresectable and for which standard curative or palliative measures do not exist or are
           no longer effective. In the MTD expansion cohort: Patients must have biopsy proven K-RAS
           mutant, metastatic colorectal cancer.

        -  Age greater than or equal to 18

        -  ECOG performance status less than or equal to 2

      Study Design:

        -  This is a phase 1 dose escalation study of AZD6244 in combination with fixed-dose
           cetuximab with an expanded cohort in K-RAS mutated metastatic colorectal cancer.

        -  Patients will be treated with AZD6244 orally twice daily continuously, and cetuximab
           will be administered at standard doses on days 1, 8, 15 and 22. Dose escalations are
           outlined per the schema in the parent protocol.

        -  The dose of AZD6244 will be escalated using a 3-patient cohort design based on first
           cycle toxicities until dose limiting toxicities (DLT) and maximum tolerated dose (MTD)
           are defined. Once the MTD/RP2D has been identified, an additional 12 patients with K-RAS
           mutant colorectal cancer will be enrolled at that dose level, in an effort to more fully
           characterize pharmacokinetic characteristics of this combination. If at least an 8%
           response rate is observed in the expanded cohort, the combination will be recommended
           for future analysis.
    

Intervention name(s): Cetuximab; AZD6244
Intervention type(s): Drug; Drug
Intervention description(s): Day 1 administer cetuximab 400 mg/m2 IV loading dose over 120 minutes. On days 8, 15 and 22 administer cetuximab 250 mg/m2 IV loading dose over 60 minutes; Given orally once or twice a day depending on dose level.On days 1, 8, 15 and 22. Repeat every 28 days
Intervention MeSH terms: Cetuximab
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Antibodies; Pharmacokinetics; Kinase Inhibitors; Colon Cancer; K-Ras; Colorectal Cancer; Solid Tumor