Akt Inhibitor MK2206 or Everolimus in Treating Patients With Refractory Kidney Cancer

PRIMARY OBJECTIVES:

I. To assess progression free survival (PFS) of vascular endothelial growth factor (VEGF)
therapy refractory renal cell carcinoma (RCC) patients who receive either MK-2206 (Akt
inhibitor MK-2206) or everolimus.

II. To assess safety of MK-2206 in patients with VEGF therapy refractory RCC.

SECONDARY OBJECTIVES:

I. To assess overall response rate (ORR) and overall survival (OS). (Clinical) II. To assess
time to treatment failure (TTF). (Clinical) III. To determine whether baseline AKT
activation is predictive for clinical benefit after treatment with MK-2206 or everolimus.
(Pre-clinical/exploratory) IV. To determine whether circulating cytokines and angiogenic
factors predict for clinical benefit after treatment with MK-2206 or everolimus.
(Pre-clinical/exploratory) V. To assess impact of karyotype on outcome in patients treated
with MK-2206 or everolimus. (Pre-clinical/exploratory)

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive Akt inhibitor MK2206 orally (PO) on days 1, 8, 15, and 22. Courses
repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
Patients who are progression free after 1 year may receive a 12 week study drug supply of
Akt inhibitor MK2206.

ARM II: Patients receive everolimus PO once daily (QD) on days 1-28. Courses repeat every 4
weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed metastatic or
unresectable RCC; all histologies are permitted; patient should have undergone
nephrectomy

- Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded for
non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional
techniques or as >= 10 mm with spiral computed tomography (CT) scan

- Patients must have received, and progressed on an anti-VEGF therapy, including
bevacizumab, sorafenib, sunitinib or pazopanib

- Eastern Cooperative Oncology Group (ECOG) performance status =< 1

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Total 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

- Serum creatinine =< 1.5 x upper limit of normal (ULN)

- International normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.5 x
ULN; therapeutic anticoagulation with warfarin is allowed if target INR =< 3 on a
stable dose of warfarin or on a stable dose of low molecular weight (LMW) heparin for
> 2 weeks at time of randomization

- Women of childbearing potential and men must use two forms of contraception (hormonal
or barrier method of birth control; abstinence) prior to study entry, for the
duration of study participation and for 8 weeks after the last dose of study drug;
should a woman become pregnant or suspect she is pregnant while she or her partner is
participating in this study, the patient should inform the treating physician
immediately

- Ability to understand and the willingness to sign a written informed consent document

- Serum pregnancy test in female patients of childbearing potential must be negative
within 24 hours of enrolling on this study

Exclusion Criteria:

- Patients who received oral tyrosine-kinase inhibitors (TKIs) (sorafenib, sunitinib,
or pazopanib) within 2 weeks prior to entering the study, radiotherapy, immunotherapy
or chemotherapy within 4 weeks prior to entering the study, bevacizumab within 4
weeks prior to entering the study, or those who have not recovered from adverse
events due to agents administered more than 4 weeks earlier (recovered to =< grade 1)

- Patients may not be receiving any other investigational agents; patients may not have
received an mammalian target of rapamycin (mTOR) inhibitor

- Patients with known brain metastases should be excluded from this clinical trial

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to MK-2206 or other agents used in the study

- Patients receiving any medications or substances that are strong inhibitors or
inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP4503A4) are
ineligible

- Patient should have a hemoglobin A1C value of < 8%; preclinical studies demonstrated
the potential of MK-2206 for induction of hyperglycemia in all preclinical species
tested; studies also demonstrate a risk of hyperglycemia, hyperlipidemia and
hypertriglyceridemia associated with everolimus therapy; patients with diabetes or in
risk for hyperglycemia, hyperlipidemia and/or hypertriglyceridemia should not be
excluded from trials with MK-2206 or everolimus, but the patient should be well
controlled on oral agents (recent [i.e. within 3 months] hemoglobin [Hb]A1C =< 7.0)
before the patient enters the trial

- Baseline corrected Fridericia QT interval (QTcF) > 450 msec (male) or QTcF > 470 msec
(female) will exclude patients from entry on study

- 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

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with MK-2206 or everolimus

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

- Individuals who are diagnosed with an intercurrent cancer are excluded, with the
exception of non-melanoma skin cancers, and other cancers where curative treatment
was completed at least two years ago