A Phase II Study of Everolimus in Combination With Imatinib in Metastatic Melanoma

Inclusion Criteria:

- Patients must have histologically confirmed stage III unresectable or stage IV
metastatic melanoma. Patients must have measurable disease as defined by RECIST
criteria.

- Patients with up to 1 prior cytotoxic regimen for metastatic disease will be
eligible. There will be no prior limitation on adjuvant therapies for stage II/III
disease or for patients with stage IV disease treated after resection of all
metastatic disease. There will be no prior limitation on biological or hormonal
therapies (immune therapies, interferon, hypomethylating agents, histone deacetylase
inhibitors, etc.), however, patients previously treated with mTOR inhibitors will be
excluded. Prior treatment for metastatic disease is not required. Patients must have
recovered from the acute toxicities of prior treatment. Chronic toxicities must have
recovered to ≤ grade 1. The minimum interval between prior treatment and first day of
dosing on this trial is as follows: standard cytotoxic agents and radiation therapy,
21 days; mitomycin and nitrosoureas, 6 weeks; hormonal and immunotherapy agents, 2
weeks; minor surgery, 2 weeks, major surgery, 3 weeks; investigational agents
4-weeks.

- Age >18 years. Because no dosing or adverse event data are currently available on
the use of everolimus in combination with imatinib in patients <18 years of age,
children are excluded from this study, but will be eligible for future pediatric
phase 1 combination trials.

- ECOG performance status < 1.

- Life expectancy of greater than 3 months.

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

- Leukocytes >3,000/μL; Absolute neutrophil count >1,500/ μL; platelets
>100,000/ μL; Hemoglobin ≥ 9.0 gm/dL (may be transfused to this level); PT/PTT < 1.5x
upper limit of normal; Total bilirubin ≤ 2.0 mg/dL;AST(SGOT)/ALT(SGPT) <3X
institutional upper limit of normal; Creatinine ≤ 2.0 mg/dL or creatinine clearance
>50 mL/min/1.73m2

- The effects of everolimus and imatinib on the developing human fetus are unknown.
For this reason, women of child-bearing potential and men must agree to use adequate
contraception (barrier method of birth control; abstinence) prior to study entry, for
the duration of study participation and 3 months after stopping study drug. Should a
woman (or the partner of a man participating in this trial) 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.

Exclusion Criteria:

- Patients may not be receiving any other investigational agents. Patients may not have
received prior treatment for their cancer with an mTOR inhibitor.

- Patients with known brain metastases or leptomeningeal disease are excluded from this
clinical trial because of their poor prognosis and because they often develop
progressive neurologic dysfunction that would confound the evaluation of neurologic
and other adverse events. Patients with previously treated brain metastases, who no
longer require steroids, and have no evidence of progression for at least 8 weeks
following treatment of known brain metastases, are eligible.

- Baseline diastolic blood pressure > 95 mmHg. Blood pressure medications may be used
to bring the diastolic pressure to levels acceptable for protocol enrollment.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris,
ventricular cardiac arrhythmia, myocardial infarction within the previous 6 months,
dyspnea at rest, active GI bleeding or ulcer disease, diabetes mellitus, or
psychiatric illness/social situations that would limit compliance with study
requirements.

- Pregnant women are excluded from this study because everolimus and imatinib are
agents 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 everolimus and imatinib, breastfeeding should be
discontinued if the mother is treated on this protocol. These potential risks may
also apply to other agents used in this study.

- Known HIV-positive patients, because of the potential for pharmacokinetic
interactions with everolimus and imatinib, and because the potential
immunosuppressive actions of everolimus may increase progression or infectious
complications of HIV. Appropriate studies will be undertaken in HIV-positive
patients when indicated.

- Patients receiving warfarin (see section 5.2), or chronic treatment with steroids or
another immunosuppressive agent. In addition, patients requiring the following agents
are excluded from the study, and must not take the agents while on the trial:
ketoconazole, itraconazole, erythromycin, clarithromycin, dexamethasone, phenytoin,
carbamazepine, rifampin, Phenobarbital, St. John's Wort, simvastatin, other HMG-CoA
reductase inhibitors (if metabolized by CYP3A4), cyclosporine, pimozide,
triazolo-benzodiazepines, dihydropyridine calcium channel blockers, and acetaminophen
or acetaminophen containing products such as Percoset or Vicodin. Patients taking
CYP3A4 interacting agents with narrow therapeutic windows will be excluded from the
trial.

- Patient is < 5 years free of another primary malignancy except: if the other primary
malignancy is not currently clinically significant nor requiring active intervention,
or if other primary malignancy is a basal cell skin cancer or a cervical carcinoma in
situ. Existence of any other malignant disease is not a allowed.