Clinical trial NCT01239342: Akt Inhibitor MK2206 or Everolimus in Treating Patients With Refractory Kidney Cancer
Official title: A Randomized Phase 2 Study of MK-2206 in Comparison With Everolimus in Refractory Renal Cell Carcinoma
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Metastatic Kidney Carcinoma
Recurrent Renal Cell Carcinoma
Stage III Renal Cell Cancer AJCC v7
Stage IV Renal Cell Cancer AJCC v7
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2010-11-11
Enrollment: 43
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This randomized phase II trial studies the side effects and how well Akt inhibitor MK2206 or everolimus works in treating patients with kidney cancer that does not respond to treatment. Akt inhibitor MK2206 and everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Everolimus may also stop the growth of kidney cancer by blocking blood flow to the tumor. It is not yet known whether Akt inhibitor MK2206 or everolimus is more effective in treating kidney cancer.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Median Progression Free Survival (PFS) in Months
timeFrame: Time interval between date of treatment and date of disease progression, date of death or last follow-up date, whichever occurs first, assessed up to 5 years
Secondary outcomes:
measure: Clinical Benefit Defined as Number of Participants With Complete Response (CR) + Partial Response (PR) + Stable Disease (SD)
timeFrame: Up to 5 years
measure: Summary of Selected Toxicities Grade 3 or Greater Toxicity Based on the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0
timeFrame: Up to 5 years
measure: Overall Response Rate (ORR) Defined as Complete Response (CR) + Partial Response (PR)
timeFrame: Up to 5 years
measure: Median Overall Survival (OS) in Months
timeFrame: Time interval between the date of treatment and the date of death or last follow-up, assessed up to 5 years
measure: Time to Failure (TTF)
timeFrame: Time interval between the date of treatment and the date of disease progression, date of death, date of treatment discontinuation due to severe toxicity or last follow-up date, assessed up to 5 years
Other outcomes:
Locations:
city: Beverly Hills
country: United States
facility: Tower Cancer Research Foundation
state: California
city: Duarte
country: United States
facility: City of Hope Comprehensive Cancer Center
state: California
city: Los Angeles
country: United States
facility: USC / Norris Comprehensive Cancer Center
state: California
city: Sacramento
country: United States
facility: University of California Davis Comprehensive Cancer Center
state: California
city: South Pasadena
country: United States
facility: City of Hope South Pasadena
state: California
city: Hershey
country: United States
facility: Penn State Milton S Hershey Medical Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Cancer Institute (UPCI)
state: Pennsylvania
city: Houston
country: United States
facility: M D Anderson Cancer Center
state: Texas
Study officials:
affiliation: M.D. Anderson Cancer Center
name: Eric Jonasch
role: PRINCIPAL_INVESTIGATOR
References: