AZD6244 With Cetuximab for Solid Tumors and Colorectal Cancer
AZD6244 With Cetuximab for Solid Tumors and Colorectal Cancer
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....
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.
-  INCLUSION CRITERIA:

 -  In the dose escalation cohorts: 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. Histology can be based on either the
 primary tumor or metastases.

 -  In the MTD expansion cohort: Patients must have biopsy proven K-RAS mutant, metastatic
 colorectal cancer that has progressed on at least 2 prior standard therapies. K-RAS
 mutation status must be verified by a CLIA-certified laboratory. (NOTE: colorectal
 patients enrolled during the dose escalation portion do not need to be K-RAS mutant in
 order to be eligible).

 -  Patients must be at least 4 weeks since prior chemotherapy, 6 weeks if the last
 regimen included nitrosureas or mitomycin C. Prior radiation is allowed as long as the
 radiation was completed 4 weeks prior to study treatment and no more than 35% of
 marrow irradiated.

 -  Age greater than or equal to18 years. Because no dosing or adverse event data are
 currently available on the use of AZD6244 in combination with cetuximab in patients
 less than 18 years of age, children are excluded from this study, but will be eligible
 for future pediatric phase 1 combination trials.

 -  ECOG performance status less than or equal to 2 (Karnofsky >60%).

 -  Life expectancy of greater than 3 months.

 -  Patients must have normal organ and marrow function as defined below:

 -  Leukocytes greater than or equal to 3,000/mcL

 -  absolute neutrophil count greater than or equal to 1,500/mcL

 -  platelets greater than or equal to 100,000/mcL

 -  total bilirubin within normal institutional limits

 -  AST(SGOT)/ALT(SGPT) less than or equal to 2.5 X institutional upper limit of
 normal (AST and ALT less than or equal to 5.0 X institutional upper limit of
 normal will be permitted if liver metastases are present)

 -  creatinine less than or equal to to to1.5X institution upper limit of normal OR
 creatinine clearance greater than or equal to 45 mL/min/1.73 m2, as calculated by
 Cockroft-Gault formula, for patients with creatinine levels above institutional
 normal. May use a 24 hr. urine collection to determine creatinine clearance.

 -  Patients may have received prior cetuximab.

 -  Patients with brain metastases that have been treated and stable for 2 months will be
 eligible for this study.

 -  Subjects undergoing anti-coagulation therapy with LMWH and warfarin are eligible.
 Subjects receiving both warfarin and AZD6244 should have more frequent PT/INR
 monitoring (see section 10.0)

 EXCLUSION CRITERIA:

 -  Patients who have had chemotherapy, radiotherapy or hormonal therapy within 4 weeks (6
 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have
 not recovered (less than or equal to grade 1) from adverse events due to agents
 administered more than 4 weeks earlier.

 -  Concurrent treatment with an investigational agent other than the investigational
 agent(s) used in this study OR treatment within 4 weeks of study entry with any
 investigational agent(s) or device(s).

 -  Failure to recover fully (as judged by the investigator) from prior surgical
 procedures.

 -  History of allergic reactions attributed to compounds of similar chemical or biologic
 composition to AZD6244 or other agents used in study.

 -  Patients taking high doses (more than recommended daily dose) of vitamin E will be
 excluded. Patients can discontinue use of high dose vitamin E prior to study entry to
 be considered eligible.

 -  Any condition (e.g., gastrointestinal tract disease resulting in an inability to take
 oral medication or a requirement for IV alimentation, prior surgical procedures
 affecting absorption, or active peptic ulcer disease) that impairs their ability to
 swallow and retain AZD6244 capsules.

 -  Patients with malabsorption syndrome, disease significantly affecting gastrointestinal
 function, or resection of the stomach or small bowel are excluded. Subjects with
 ulcerative colitis, inflammatory bowel disease, or a partial or complete small bowel
 obstruction are also excluded.

 -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
 infection, symptomatic congestive heart failure, uncontrolled hypertension, prior
 cardiomyopathy, LVEF less than 50%, unstable angina pectoris, cardiac arrhythmia (i.e.
 atrial fibrillation), or psychiatric illness/social situations that would limit
 compliance with study requirements.

 -  Pregnant women are excluded from this study because AZD6244 is a small molecule kinase
 inhibitor 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 AZD6244, breastfeeding should be discontinued if the
 mother is treated with AZD6244. These potential risks may also apply to other agents
 used in this study.

 -  HIV-positive patients on combination antiretroviral therapy are ineligible because of
 the potential for pharmacokinetic interactions with AZD6244. In addition, these
 patients are at increased risk of lethal infections when treated with
 marrow-suppressive therapy. Appropriate studies will be undertaken in patients
 receiving combination antiretroviral therapy when indicated.

 -  Patients who are serologically positive for Hepatitis B or C, or have a history of
 liver disease, other forms of hepatitis or cirrhosis are ineligible.

 -  Use of strong CYP1A2 or 3A4 inducers and/or inhibitors (for example, but not limited
 to, ketoconazole, rifampacin, atazanavir, clarithromycin, indinavir, itraconazole,
 nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin (TAO),
 voriconazole, grapefruit or grapefruit juice, ifabutin, rifapentine, phenytoin,
 carbamazepine, phenobarbital and St. John's Wort) is not permitted while on study or
 within 7 days prior to study enrollment.