Phase I Study of the Combination of the VEGFR Inhibitor, AZD2171, and MEK Inhibitor, AZD6244, in the Treatment of Solid Malignancies

Inclusion Criteria:

- Histologic proof of cancer that is now considered clinically unresectable and for
whom there is no standard therapy; NOTE: For the MTD expansion cohort only:
Metastatic melanoma histology is required

- Measurable and non-measurable disease are eligible

- Ability to provide informed consent

- ANC >= 1500/uL

- PLT >= 100,000/uL

- Total bilirubin =< 1.5 x upper limit of normal (ULN)

- AST =< 2.5 x ULN or =< 5 x ULN in presence of liver metastases

- Creatinine =< 1.5 x ULN

- HgB >= 9.0 gm/dL

- Alkaline phosphatase =< 2.5 x ULN

- Creatinine clearance > 50 ml/min, by either Cockcroft-Gault formula or 24-hour urine
collection analysis

- ECOG Performance Status (PS) 0, 1

- Willing to return to Mayo for follow up

- Life expectancy >= 12 weeks

- Women of childbearing potential only: Negative serum pregnancy test done =< 7 days
prior to registration, for women of childbearing potential only

- Expansion Phase only: Willing to provide blood samples and archived tumor tissue for
correlative research purposes

Exclusion Criteria:

- Known standard therapy for the patient's disease that is potentially curative or
definitely capable of extending life expectancy

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Any of the following prior therapies:

- Chemotherapy =< 28 days prior to registration

- Mitomycin C/nitrosoureas =< 42 days prior to registration

- Immunotherapy =< 28 days prior to registration

- Biologic therapy =< 28 days prior to registration

- Radiation therapy =< 28 days prior to registration

- Radiation to > 25% of bone marrow

- Failure to fully recover from acute, reversible effects of prior chemotherapy
regardless of interval since last treatment

- Cardiac conditions as follows:

- Uncontrolled hypertension (BP >= 150/95 despite optimal therapy)

- Heart failure NYHA Class II or above or Left ventricular ejection fraction < 50%

- Atrial fibrillation with heart rate >100 bpm

- Unstable ischemic heart disease (MI within 6 months prior to starting treatment,
or angina requiring use of nitrates more than once weekly)

- Patients who require concomitant agents that prolong QTc

- Known brain or CNS metastases without definitive therapy; patients who have received
definitive therapy for CNS lesions may be considered if there is no evidence of
progression on CT or MRI imaging obtained 3 months apart

- Any of the following because this study involves an investigational agent whose
genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are
unknown:

- Pregnant women

- Nursing women

- Men or women of childbearing potential who are unwilling to employ adequate
contraception

- Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy
considered investigational (utilized for a non-FDA-approved indication and in the
context of a research investigation)

- Co-morbid systemic illnesses or other severe concurrent disease which, in the
judgment of the investigator, would make the patient inappropriate for entry into
this study or interfere significantly with the proper assessment of safety and
toxicity of the prescribed regimens

- Immunocompromised patients (other than that related to the use of corticosteroids)
with the exception of patients known to be HIV positive and have a CD4 count > 400
and do not require antiretroviral therapy

- Receiving any other investigational agent which would be considered as a treatment
for the primary neoplasm

- Other active malignancy =< 3 years prior to registration; EXCEPTIONS: Nonmelanotic
skin cancer or carcinoma-in-situ of the cervix; NOTE: If there is a history or prior
malignancy, they must not be receiving other specific treatment (i.e. hormonal
therapy) for their cancer

- Greater than +1 proteinuria on two consecutive dipsticks taken no less than 1 week
apart unless urinary protein < 1.5g in a 24 hr period or urine protein/creatinine
ratio < 1.5

- History of exposure to AZD2171 (cediranib), AZD6244 hydrogen sulfate, or MEK, Ras or
Raf inhibitors (sorafenib); Note: prior therapy with bevacizumab, sunitinib,
pazopanib or aflivercept (VEGF Trap) are allowed

- Surgery within two weeks prior to registration

- Significant hemorrhage (> 30mL bleeding/episode in previous 3 months) or hemoptysis
(> 5mL fresh blood in previous 4 weeks)

- Mean QTc interval with Bazetts correction > 480msec (CTC Grade 1) in screening ECG or
history of familial long QT syndrome

- Patients who are unable to swallow tablets and capsules