A Phase I Trial of MK-2206 and Hydroxychloroquine in Solid Tumors, Melanoma, Renal and Prostate Cancer to Examine the Role of Autophagy in Tumorigenesis

Inclusion Criteria:

- Patients with histologically or cytologically proven advanced solid cancer and have
undergone treatment with at least one regimen of standard therapy, either cytotoxic
chemotherapy, a molecularly targeted agent, or immunotherapy, or have a form of
cancer for which no standard therapy exists; patients with prostate cancer may
continue on androgen-deprivation therapy if they are currently receiving it

- All patients must have measurable or evaluable disease per RECIST criteria

- Castrate-resistant metastatic prostate or renal carcinoma (expanded cohort)

- Treated with ≥ 1 VEGF-directed therapy

- Patients with active central nervous system (CNS) metastases are excluded

- Patients with CNS metastases that have been treated must be off steroid
treatment for > 2 months and be asymptomatic

- Patients that have symptoms to suggest CNS metastases should have a brain MRI
within 28 days of enrollment to confirm the absence of CNS metastases

- Contrast computed tomography (CT) is acceptable for patients who are unable
to undergo a brain MRI

- ECOG performance status ≤ 1

- Estimated life expectancy of at least 12 weeks

- Leukocytes ≥ 3,000/mcL

- Absolute neutrophil count ≥ 1,500/mcL

- Platelets ≥ 100,000/mcL

- Total serum bilirubin within normal institutional limits

- AST(SGOT)/ALT(SGPT) ≤ 2.5 times institutional upper limit of normal

- Creatinine ≤ grade 1 OR creatinine clearance ≥ 40 mL/min

- Pregnant and nursing women are excluded from this study

- Women must have a negative serum or urine pregnancy test within 7 days prior to study
entry if she is a woman of child-bearing potential (WOCBP)

- WOCBP and men must agree to use adequate contraception prior to study entry, for the
duration of study participation, and for 6 months after study participation

- Patients must not have a history of any condition (social or medical) that, in the
opinion of the investigator, might interfere with the patient's ability to comply
with the protocol or pose additional or unacceptable risk to the patient

- Approval for hydroxychloroquine treatment by an eye doctor, based on a screening eye
exam

- Examples of disqualifying baseline conditions may include:

- Macular degeneration

- Retinal disease, such as cataracts, that would interfere with required
funduscopic examinations

- Severe baseline visual impairment, retinopathy, or visual field changes

- All patients must undergo a screening eye exam prior to enrollment

- Patients must be able to swallow whole tablets; nasogastric or G-tube administration
is not allowed

- No patients with QTc prolongation greater than Common Terminology Criteria for
Adverse Events (CTCAE) grade 1 (> 480 msec); in addition, patients should not be
receiving non-study medications known to prolong QTc

- No patients on treatment for rheumatoid arthritis or systemic lupus erythematosus

- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition to agents used in study

- No patient who has uncontrolled diabetes, defined as a fasting serum glucose > 150
mg/dL or glycosylated hemoglobin (HbA1c) > 7% at screening

- No diabetic patients requiring insulin for glucose control at the time of study entry

- Patient must not have ongoing ventricular cardiac dysrhythmias of grade ≥ 2 as
described by the CTEP Version 4.0 of the National Cancer Institute (NCI) CTCAE

- No 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; ulcerative colitis, inflammatory bowel disease, a partial or
complete small bowel obstruction, or active peptic ulcer disease) that impairs
patients ability to swallow and retain MK-2206 or hydroxychloroquine tablets

- No uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, or
psychiatric illness/social situations that would affect safety or limit compliance
with study requirements

- Known HIV-positive patients on combination antiretroviral therapy are ineligible

- Must not have psoriasis or porphyria

- Must not have known hypersensitivity to 4-aminoquinoline compound

- Must not have retinal or visual field changes from prior 4-aminoquinoline compound
use

- Must not have known glucose-6-phosphate dehydrogenase (G-6PD) deficiency

- No patients with liver disease such as cirrhosis, chronic active hepatitis, or
chronic persistent hepatitis

- No current treatment on another clinical trial; participation in non-therapeutic
clinical trials is permissible

- No concurrent investigational or commercial agents to treat this malignancy except:

- Androgen-deprivation therapy for prostate cancer

- LHRH agonists for breast cancer

- Patient must have recovered from toxicity of prior chemotherapy, molecularly targeted
agents and/or radiotherapy

- Patient may not have received chemotherapy in the prior 4 weeks (6 weeks for
nitrosoureas or mitomycin C)

- Patients may have not received a molecularly targeted agent within the past 4 weeks
or 5 half lives (which ever is less)

- Patients may have not received radiotherapy in the prior 3 weeks

- No failure to recover fully (as judged by the investigator) from prior surgical
procedures, or failure to recover from adverse events (grade ≤ 1) due to agents
administered more than 4 weeks earlier

- No 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)

- Known HIV-positive patients on combination antiretroviral therapy are ineligible

- Must not be taking hydroxychloroquine for treatment or prophylaxis of malaria