Cediranib Maleate and Selumetinib Sulfate in Treating Patients With Solid Malignancies

PRIMARY OBJECTIVES:

I. To determine the maximally tolerated dose of cediranib maleate (AZD2171 [cediranib]) in
combination with selumetinib sulfate (AZD6244 hydrogen sulfate).

II. To describe the toxicity profile associated with AZD2171 (cediranib) in combination with
AZD6244 hydrogen sulfate.

III. To describe the tumor responses and identify any activity of this AZD2171 (cediranib) in
combination with AZD6244 hydrogen sulfate.

IV. To explore, through correlative studies, the effect of AZD2171 (cediranib) with or
without AZD6244 hydrogen sulfate on serum markers of apoptosis.

V. To assess the pharmacokinetic interaction of AZD2171 (cediranib) in combination with
AZD6244 hydrogen sulfate.

VI. To study the association of clinical (toxicity and/or tumor response or activity) with
the pharmacologic (pharmacokinetic/pharmacodynamic) parameters, and/or biologic (correlative
laboratory study) results.

OUTLINE: This is a dose-escalation study followed by a dose-expansion cohort study.

Patients receive cediranib maleate orally (PO) once daily (QD) and selumetinib sulfate PO QD
or twice daily (BID) on days 1-28 (days 8-28 of cycle 1). Cycles repeat every 28 days in the
absence of disease progression or unacceptable toxicity. Cycles may be extended to 12 weeks
after 1 year of study treatment.

After completion of study therapy, patients are followed up at 3 months.

Inclusion Criteria:

- Histologic proof of cancer that is now considered clinically unresectable and for whom
there is no standard therapy; NOTE: for the maximum tolerated dose (MTD) expansion
cohort only: metastatic melanoma histology is required

- Measurable and non-measurable disease are eligible

- Ability to provide informed consent

- Absolute neutrophil count (ANC) >= 1500/uL (obtained =< 21 days prior to registration)

- Platelets (PLT) >= 100,000/uL (obtained =< 21 days prior to registration)

- Total bilirubin =< 1.5 x upper limit of normal (ULN) (obtained =< 21 days prior to
registration)

- Aspartate aminotransferase (AST) =< 2.5 x ULN or =< 5 x ULN in presence of liver
metastases (obtained =< 21 days prior to registration)

- Creatinine =< 1.5 x ULN (obtained =< 21 days prior to registration)

- Hemoglobin (HgB) >= 9.0 gm/dL (obtained =< 21 days prior to registration)

- Alkaline phosphatase =< 2.5 x ULN (obtained =< 21 days prior to registration)

- Creatinine clearance > 50 ml/min, by either Cockcroft-Gault formula or 24-hour urine
collection analysis (obtained =< 21 days prior to registration)

- Eastern Cooperative Oncology Group (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 (blood pressure [BP] >= 150/95 despite optimal therapy)

- Heart failure New York Heart Association (NYHA) class II or above or left
ventricular ejection fraction < 50%

- Atrial fibrillation with heart rate > 100 beats per minute (bpm)

- Unstable ischemic heart disease (myocardial infarction [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 corrected QT interval (QTc)

- Known brain or central nervous system (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 computed tomography (CT) or magnetic resonance
imaging (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-Food and Drug Administration
[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 human immunodeficiency virus [HIV] positive
and have a cluster of differentiation [CD]4 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: non-melanotic
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 hour (hr) period or urine
protein/creatinine ratio < 1.5

- History of exposure to AZD2171 (cediranib), AZD6244 hydrogen sulfate, or
mitogen-activated protein kinase kinase (MEK), retrovirus-associated deoxyribonucleic
acid (DNA) sequence (Ras) or v-RAF-1 murine leukemia viral oncogene homolog (Raf)
inhibitors (sorafenib); Note: prior therapy with bevacizumab, sunitinib, pazopanib or
aflibercept (vascular endothelial growth factor [VEGF] Trap) are allowed

- Surgery within two weeks prior to registration

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

- Mean QTc interval with Bazetts correction > 480 msec (Common Toxicity Criteria [CTC]
grade 1) in screening electrocardiogram (ECG) or history of familial long QT syndrome

- Patients who are unable to swallow tablets and capsules