This trial is active, not recruiting.

Conditions adult solid neoplasm, hormone-resistant prostate cancer, recurrent melanoma, recurrent prostate carcinoma, recurrent renal cell carcinoma, stage iiia skin melanoma, stage iiib skin melanoma, stage iiic skin melanoma, stage iv prostate cancer, stage iv renal cell cancer, stage iv skin melanoma
Treatments akt inhibitor mk2206, hydroxychloroquine, laboratory biomarker analysis, pharmacological study
Phase phase 1
Target AKT
Sponsor National Cancer Institute (NCI)
Start date November 2011
End date June 2016
Trial size 62 participants
Trial identifier NCT01480154, 051105, 8983, CDR0000717546, CINJ-051105, NCI-2012-00084, P30CA072720, U01CA132194, UM1CA186716


This phase I trial studies the side effects and the best dose of Akt inhibitor MK2206 together with hydroxychloroquine in treating patients with advanced solid tumors, melanoma, prostate or kidney cancer. Akt inhibitor MK2206 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as hydroxychloroquine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving Akt inhibitor MK2206 together with hydroxychloroquine may kill more tumor cells.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Endpoint classification safety study
Intervention model single group assignment
Masking open label
Primary purpose treatment
Patients receive Akt inhibitor MK2206 PO on days 1, 8, and 15. Beginning on course 2, patients also receive hydroxychloroquine PO BID on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
akt inhibitor mk2206 MK2206
Given PO
Given PO
laboratory biomarker analysis
Correlative studies
pharmacological study
Correlative studies

Primary Outcomes

Dose-limiting toxicity rate as assessed by CTCAE version 4.0
time frame: 21 days
MTD of Akt inhibitor MK-2206 as assessed by CTCAE version 4.0
time frame: 21 days

Secondary Outcomes

Change in autophagy activity induced by hydroxychloroquine as measured by the amount of autophagosomes by EM
time frame: Baseline to 4 weeks
Changes in expression pattern of markers Beclin1, LC3, and p62 by immunohistochemistry (IHC), Western blotting, and number of autophagosomes by electron microscope (EM)
time frame: Baseline to 4 weeks
Validation of Beclin1, LC3, and p62 as markers for autophagy measured by EM
time frame: Up to 4 weeks

Eligibility Criteria

Male or female participants at least 18 years old.

Inclusion Criteria: - Patients with histologically or cytologically proven advanced solid cancer and have undergone treatment with at least one regimen of standard therapy, either cytotoxic chemotherapy, a molecularly targeted agent, or immunotherapy, or have a form of cancer for which no standard therapy exists; patients with prostate cancer may continue on androgen-deprivation therapy if they are currently receiving it - Patient must have recovered from toxicity of prior chemotherapy, molecularly targeted agents and/or radiotherapy; patient may not have received chemotherapy in the prior 4 weeks (6 weeks for nitrosoureas or mitomycin C); patients may have not received a molecularly targeted agent within the past 4 weeks or 5 half lives (which ever is less); patients may not have received radiotherapy in the prior 3 weeks - Patients must be willing and able to sign informed consent - Leukocytes >= 3,000/mcL - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total serum 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 - Creatinine =< grade 1 OR creatinine clearance >= 40 mL/min/1.73 m^2 for patients with creatinine (Cr) above normal institutional limits; a calculated creatinine clearance by Cockcroft-Gault Formula is acceptable in lieu of a measured value - All patients must have measurable or evaluable disease per Response Evaluation Criteria in Solid Tumors (RECIST) criteria - Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Estimated life expectancy of at least 12 weeks - Women must: have a negative serum or urine pregnancy test within 7 days prior to study entry if she is a woman of child-bearing potential (WOCBP), or be at least one year post-menopausal, OR be surgically sterile - Women of child-bearing potential and men must agree to use adequate contraception prior to study entry, for the duration of study participation and for 6 months after study participation; acceptable methods of contraception include hormonal, barrier methods, intrauterine device, tubal ligation/vasectomy or abstinence; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; acceptable methods of contraception include hormonal, barrier methods, intrauterine device, tubal ligation/vasectomy or abstinence; women should not breast feed while on treatment with MK-2206 and hydroxychloroquine - Patients must not have a history of any condition (social or medical) that, in the opinion of the investigator, might interfere with the patient's ability to comply with the protocol or pose additional or unacceptable risk to the patient - Approval for hydroxychloroquine treatment by an eye doctor, based on a screening eye exam; examples of disqualifying baseline conditions may include macular degeneration and other retinal disease such as cataracts that would interfere with required funduscopic examinations, or severe baseline visual impairment, retinopathy or visual field changes; all patients must undergo a screening eye exam prior to enrollment - Patients must be able to swallow whole tablets; nasogastric or gastrostomy (G) tube administration is not allowed; tablets must not be crushed or chewed Exclusion Criteria: - Failure to recover fully (as judged by the investigator) from prior surgical procedures, or failure to recover from adverse events (grade =< 1) due to agents administered more than 4 weeks earlier - Concurrent treatment with an investigational agent other than the investigational agent(s) used in this study OR treatment within 4 weeks of study entry with any investigational agent(s) or device(s) - Patients with corrected QT interval (QTc) prolongation greater than Common Terminology Criteria for Adverse Events (CTCAE) grade 1 (> 480 msec); in addition, patients should not be receiving non-study medications known to prolong QTc - Patients on treatment for rheumatoid arthritis or systemic lupus erythematosus - History of allergic reactions attributed to compounds of similar chemical or biologic composition to agents used in study - Patient has uncontrolled diabetes, defined as a fasting serum glucose > 150 mg/dl or glycosylated hemoglobin (hemoglobin A1c [HbA1c]) > 7% at screening - Diabetic patients requiring insulin for glucose control at the time of study entry - Patient must not have ongoing ventricular cardiac dysrhythmias of grade >= 2 as described by the Cancer Therapy Evaluation Program (CTEP) version 4.0 of the National Cancer Institute (NCI) CTCAE - Any condition (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for intravenous [IV] alimentation, prior surgical procedures affecting absorption, ulcerative colitis, inflammatory bowel disease, a partial or complete small bowel obstruction, or active peptic ulcer disease) that impairs their ability to swallow and retain MK-2206 or hydroxychloroquine tablets - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or psychiatric illness/social situations that would affect safety or limit compliance with study requirements - Pregnant and nursing women are excluded from this study - Known human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible - Because MK-2206 is metabolized primarily by the cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) liver enzyme, the eligibility of patients taking medications that are potent inducers or inhibitors of that enzyme will be determined following a review of their case by the principal investigator; every effort should be made to switch patients taking such agents or substances to other medications - Patients with active central nervous system (CNS) metastases are excluded; patients with CNS metastases that have been treated must be off steroid treatment for > 2 months and be asymptomatic; patients that have symptoms to suggest CNS metastases should have a brain magnetic resonance imaging (MRI) within 28 days of enrollment to confirm the absence of CNS metastases; contrast computed tomography (CT) is acceptable for patients who are unable to undergo a brain MRI - Must not have psoriasis or porphyria - Must not have known hypersensitivity to 4-aminoquinoline compound - Must not have retinal or visual field changes from prior 4-aminoquinoline compound use - Must not have known glucose-6-phosphate dehydrogenase (G-6PD) deficiency - Patients with liver disease such as cirrhosis, chronic active hepatitis, or chronic persistent hepatitis - Must not be taking hydroxychloroquine for treatment or prophylaxis of malaria - Current treatment on another clinical trial; participation in non-therapeutic clinical trials is permissible

Additional Information

Official title A Phase I Trial of MK-2206 and Hydroxychloroquine in Solid Tumors, Melanoma, Renal and Prostate Cancer to Examine the Role of Autophagy in Tumorigenesis
Principal investigator Mark Stein
Description PRIMARY OBJECTIVES: I. To define the maximum tolerated dose (MTD) of MK-2206 (Akt inhibitor MK2206) and hydroxychloroquine (HCQ) when used in combination. SECONDARY OBJECTIVES: I. To determine side effects and activity of MK-2206 and hydroxychloroquine when used in combination. II. To determine if hydroxychloroquine alters the pharmacokinetics of MK-2206 due to a drug-drug interaction. III. To validate biomarkers for autophagy detection. OUTLINE: This is a dose-escalation study of Akt inhibitor MK-2206. Patients receive Akt inhibitor MK2206 orally (PO) on days 1, 8, and 15. Beginning on course 2, patients also receive hydroxychloroquine PO twice daily (BID) on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 4 weeks.
Trial information was received from ClinicalTrials.gov and was last updated in February 2016.
Information provided to ClinicalTrials.gov by National Cancer Institute (NCI).