Akt Inhibitor MK2206 and Hydroxychloroquine in Treating Patients With Advanced Solid Tumors, Melanoma, Prostate or Kidney Cancer

PRIMARY OBJECTIVES:

I. To define the maximum tolerated dose (MTD) of MK-2206 (Akt inhibitor MK2206) and
hydroxychloroquine (HCQ) when used in combination.

SECONDARY OBJECTIVES:

I. To determine side effects and activity of MK-2206 and hydroxychloroquine when used in
combination.

II. To determine if hydroxychloroquine alters the pharmacokinetics of MK-2206 due to a
drug-drug interaction.

III. To validate biomarkers for autophagy detection.

OUTLINE: This is a dose-escalation study of Akt inhibitor MK-2206.

Patients receive Akt inhibitor MK2206 orally (PO) on days 1, 8, and 15. Beginning on course
2, patients also receive hydroxychloroquine PO twice daily (BID) on days 1-21. Courses repeat
every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 4 weeks.

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

- 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 not have received radiotherapy in the prior 3 weeks

- Patients must be willing and able to sign informed consent

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Total serum bilirubin within normal institutional limits

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 X institutional upper limit of normal

- Creatinine =< grade 1 OR creatinine clearance >= 40 mL/min/1.73 m^2 for patients with
creatinine (Cr) above normal institutional limits; a calculated creatinine clearance
by Cockcroft-Gault Formula is acceptable in lieu of a measured value

- All patients must have measurable or evaluable disease per Response Evaluation
Criteria in Solid Tumors (RECIST) criteria

- Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status =<
1

- Estimated life expectancy of at least 12 weeks

- 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), or be at least one year
post-menopausal, OR be surgically sterile

- Women of child-bearing potential 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; acceptable methods of contraception include hormonal, barrier
methods, intrauterine device, tubal ligation/vasectomy or abstinence; should a woman
become pregnant or suspect she is pregnant while she or her partner is participating
in this study, she should inform her treating physician immediately; acceptable
methods of contraception include hormonal, barrier methods, intrauterine device, tubal
ligation/vasectomy or abstinence; women should not breast feed while on treatment with
MK-2206 and hydroxychloroquine

- 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
and other retinal disease such as cataracts that would interfere with required
funduscopic examinations, or 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 gastrostomy (G) tube
administration is not allowed; tablets must not be crushed or chewed

Exclusion Criteria:

- 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

- 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)

- Patients with corrected QT interval (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

- Patients on treatment for rheumatoid arthritis or systemic lupus erythematosus

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

- Patient has uncontrolled diabetes, defined as a fasting serum glucose > 150 mg/dl or
glycosylated hemoglobin (hemoglobin A1c [HbA1c]) > 7% at screening

- 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 Cancer Therapy Evaluation Program (CTEP) version 4.0 of the National
Cancer Institute (NCI) CTCAE

- Any condition (e.g., gastrointestinal tract disease resulting in an inability to take
oral medication or a requirement for intravenous [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 their ability to swallow and retain MK-2206 or hydroxychloroquine tablets

- 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

- Pregnant and nursing women are excluded from this study

- Known human immunodeficiency virus (HIV)-positive patients on combination
antiretroviral therapy are ineligible

- Because MK-2206 is metabolized primarily by the cytochrome P450, family 3, subfamily
A, polypeptide 4 (CYP3A4) liver enzyme, the eligibility of patients taking medications
that are potent inducers or inhibitors of that enzyme will be determined following a
review of their case by the principal investigator; every effort should be made to
switch patients taking such agents or substances to other medications

- 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 magnetic resonance imaging (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

- 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

- Patients with liver disease such as cirrhosis, chronic active hepatitis, or chronic
persistent hepatitis

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

- Current treatment on another clinical trial; participation in non-therapeutic clinical
trials is permissible