MK2206 or Everolimus in Treating Patients With Refractory Kidney Cancer

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01239342
First received: November 10, 2010
Last updated: December 6, 2013
Last verified: December 2013
  Purpose

This randomized phase II trial is studying the side effects and how well MK2206 or everolimus works in treating patients with refractory kidney cancer. 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 MK2206 or everolimus is more effective in treating kidney cancer.


Condition Intervention Phase
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
Drug: Akt inhibitor MK2206
Drug: everolimus
Other: laboratory biomarker analysis
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Randomized Phase 2 Study of MK-2206 in Comparison With Everolimus in Refractory Renal Cell Carcinoma

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Progression-free survival (PFS) [ 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 ] [ Designated as safety issue: No ]
    Estimated using the Kaplan-Meier method and will be compared between the two treatment arms using stratified log-rank test.


Secondary Outcome Measures:
  • Grade 3 or greater toxicity that requires treatment discontinuation based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0 [ Time Frame: Up to 4 years ] [ Designated as safety issue: Yes ]
    The method of Thall, Simon and Estey (1995, 1996) will be used.

  • Overall survival (OS) [ Time Frame: Time interval between the date of treatment and the date of death or last follow-up, assessed up to 4 years ] [ Designated as safety issue: No ]
    The Kaplan-Meier method will be used, and stratified log-rank test will be used to compare between the two treatment arms.

  • Overall response rate (ORR) [ Time Frame: Up to 4 years ] [ Designated as safety issue: No ]
    Logistic regression model will be fit to assess the effect of treatment on the rate of overall response.

  • Time to failure (TTF) [ Time Frame: 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 4 years ] [ Designated as safety issue: No ]
    The Kaplan-Meier method will be used, and stratified log-rank test will be used to compare between the two treatment arms.

  • Clinical benefit of treatment, AKT activation, circulating cytokines and angiogenic factors, and karyotype [ Time Frame: Up to 4 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 105
Study Start Date: January 2011
Estimated Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I

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.

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

Drug: Akt inhibitor MK2206
Given PO
Other Name: MK2206
Other: laboratory biomarker analysis
Optional correlative studies
Experimental: 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.

Drug: everolimus
Given PO
Other Names:
  • 42-O-(2-hydroxy)ethyl rapamycin
  • Afinitor
  • RAD001

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 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). 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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-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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01239342

Locations
United States, California
UC Davis Comprehensive Cancer Center
Sacramento, California, United States, 95817
United States, Texas
M D Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
Investigators
Principal Investigator: Eric Jonasch M.D. Anderson Cancer Center
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01239342     History of Changes
Other Study ID Numbers: NCI-2010-02270, NCI-2010-02270, CDR0000688457, MDA-2010-0247, 2010-0247, 8727, N01CM00039, N01CM00038
Study First Received: November 10, 2010
Last Updated: December 6, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Carcinoma
Carcinoma, Renal Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Kidney Diseases
Urologic Diseases
Everolimus
Sirolimus
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Antifungal Agents
Anti-Infective Agents
Anti-Bacterial Agents

ClinicalTrials.gov processed this record on April 16, 2014