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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Metastatic Kidney Carcinoma, Recurrent Renal Cell Carcinoma, Stage III Renal Cell Cancer AJCC v7, Stage IV Renal Cell Cancer AJCC v7

Intervention / Treatment
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* Drug: Akt Inhibitor MK2206
* Drug: Everolimus
* Other: Laboratory Biomarker Analysis


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (Akt inhibitor MK2206)<br>Patients receive Akt inhibitor MK2206 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. | Drug: Akt Inhibitor MK2206<br>* Given PO<br>* Other names: MK2206;Other: Laboratory Biomarker Analysis<br>* Optional correlative studies<br>|
| Experimental: Arm II (everolimus)<br>Patients receive everolimus PO QD on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. | Drug: Everolimus<br>* Given PO<br>* Other names: Zortress;Other: Laboratory Biomarker Analysis<br>* Optional correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Progression Free Survival (PFS) in Months | PFS defined as Time interval between date of treatment and date of disease progression, date of death or last follow-up date, whichever occurs first. Progression defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a nontarget lesion, or the appearance of new lesions. | 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Benefit Defined as Number of Participants With Complete Response (CR) + Partial Response (PR) + Stable Disease (SD) | Clinical benefit defined as participants' with CR+PR+SD assessed using Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. Repeat radiologic studies to evaluate disease progression or response (in accordance with restaging of disease) every 8 weeks. Complete Response (CR): Disappearance all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): >30% decrease in sum diameters of target lesions, reference baseline sum diameters. Progressive Disease (PD): >20% increase in sum diameters of target lesions, reference smallest sum on study (includes baseline sum if is smallest on study). In addition to relative increase of 20%, sum must demonstrate absolute increase >5 mm. (Note: appearance 1/+ new lesions considered progressions). Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, reference smallest sum diameters. | Up to 5 years | 
| Summary of Selected Toxicities Grade 3 or Greater Toxicity Based on the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 | Adverse Events (AEs) list of reported events with associated intervention agent in a uniform presentation of events. The method of Thall, Simon and Estey (1995, 1996) was used to collect study participants' safety data summarized by treatment arm, category, severity and relevance. Comprehensive listing of AEs collected on study can be found in Adverse Event section separated by severity, Serious and Other AEs and represented by treatment arm, organ system-category within defined severity. | Up to 5 years | 
| Overall Response Rate (ORR) Defined as Complete Response (CR) + Partial Response (PR) | Response for CR + PR defined by RECIST version 1.1. Repeat radiologic studies to evaluate disease progression or response (in accordance with restaging of disease) every 8 weeks. Complete Response (CR): Disappearance all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): >30% decrease in sum diameters of target lesions, reference baseline sum diameters. Progressive Disease (PD): >20% increase in sum diameters of target lesions, reference smallest sum on study (includes baseline sum if is smallest on study). In addition to relative increase of 20%, sum must demonstrate absolute increase >5 mm. (Note: appearance 1/+ new lesions considered progressions). Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, reference smallest sum diameters. | Up to 5 years | 
| Median Overall Survival (OS) in Months | Overall survival reported in months as time interval between the date of treatment and the date of death or last follow-up. | Time interval between the date of treatment and the date of death or last follow-up, assessed up to 5 years | 
| Time to Failure (TTF) | TTF defined as 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. | 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 |