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A Randomized Phase 2 Study of MK-2206 in Comparison With Everolimus in Refractory Renal Cell Carcinoma

Phase 2
18 Years
Open (Enrolling)
Clear Cell Renal Cell Carcinoma, Recurrent Renal Cell Cancer, Stage III Renal Cell Cancer, Stage IV Renal Cell Cancer, Type 1 Papillary Renal Cell Carcinoma, Type 2 Papillary Renal Cell Carcinoma

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Trial Information

A Randomized Phase 2 Study of MK-2206 in Comparison With Everolimus in Refractory Renal Cell Carcinoma


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 or

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


I. To assess overall response rate (ORR) and overall survival (OS). II. To assess time to
treatment failure (TTF). III. To determine whether baseline AKT activation is predictive for
clinical benefit after treatment with MK-2206 or everolimus.

IV. To determine whether circulating cytokines and angiogenic factors predict for clinical
benefit after treatment with MK-2206 or everolimus.

V. To assess impact of karyotype on outcome in patients treated with MK-2206 or everolimus.

OUTLINE: This is a multicenter study. Patients are stratified according to MSKCC criteria
(favorable vs intermediate vs poor) and type of prior therapy. 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.

Arm II: Patients receive everolimus PO on days 1-28. Courses repeat every 4 weeks in the
absence of disease progression or unacceptable toxicity.

Tissue and blood samples may be collected periodically for correlative studies.

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

- 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-vascular endothelial growth
factor (VEGF) therapy, including bevacizumab, sorafenib, sunitinib or pazopanib; they
may have received up to two prior agents

- 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 glutamic pyruvate transaminase [SGPT])
=< 2.5 X institutional upper limit of normal

- Serum creatinine =< 1.5 x 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

- The effects of MK-2206 and/or everolimus on the developing human fetus at the
recommended therapeutic dose are unknown; for this reason, 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 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 mTOR inhibitor

- Patients with known brain metastases should be 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

- 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 CYP 450 3A4 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] HbA1C =< 7.0) before the
patient enters the trial

- Preclinical studies indicated transient changes in QTc interval during MK-2206
treatment; prolongation of QTc interval is potentially a safety concern while on
MK-2206 therapy; cardiovascular: baseline 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 because MK-2206 and/or everolimus 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 MK-2206 and/or everolimus, 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 because of the potential for pharmacokinetic interactions with
MK-2206 or everolimus; in addition, these patients are at increased risk of lethal
infections when treated with marrow-suppressive therapy

- 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

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Progression-free survival (PFS)

Outcome Description:

Estimated using the Kaplan-Meier method and will be compared between the two treatment arms using stratified log-rank test.

Outcome Time Frame:

Time interval between date of treatment and date of disease progression, date of death or last follow-up date, assessed up to 4 years

Safety Issue:


Principal Investigator

Eric Jonasch

Investigator Role:

Principal Investigator

Investigator Affiliation:

M.D. Anderson Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

January 2011

Completion Date:

Related Keywords:

  • Clear Cell Renal Cell Carcinoma
  • Recurrent Renal Cell Cancer
  • Stage III Renal Cell Cancer
  • Stage IV Renal Cell Cancer
  • Type 1 Papillary Renal Cell Carcinoma
  • Type 2 Papillary Renal Cell Carcinoma
  • Carcinoma
  • Carcinoma, Renal Cell



UC Davis Comprehensive Cancer Center Sacramento, California  95817
M D Anderson Cancer Center Houston, Texas  77030