MK2206 in Treating Younger Patients With Recurrent or Refractory Solid Tumors or Leukemia

A Phase I Study of MK-2206, an AKT Inhibitor, in Pediatric Patients With Recurrent or Refractory Solid Tumors or Leukemia

This phase I trial is studying the side effects, best way to give, and best dose of Akt inhibitor MK2206 (MK2206) in treating patients with recurrent or refractory solid tumors or leukemia. MK2206 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Study Overview

• Status: Completed
• Conditions: Unspecified Childhood Solid Tumor, Protocol Specific; Chronic Myelomonocytic Leukemia; Juvenile Myelomonocytic Leukemia; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Splenic Marginal Zone Lymphoma; Waldenström Macroglobulinemia; Secondary Acute Myeloid Leukemia; Accelerated Phase Chronic Myelogenous Leukemia; Childhood Chronic Myelogenous Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Intraocular Lymphoma; Post-transplant Lymphoproliferative Disorder; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Relapsing Chronic Myelogenous Leukemia; Small Intestine Lymphoma; Blastic Plasmacytoid Dendritic Cell Neoplasm; Prolymphocytic Leukemia; Refractory Chronic Lymphocytic Leukemia; Chronic Neutrophilic Leukemia; Refractory Hairy Cell Leukemia; Acute Undifferentiated Leukemia; Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Mast Cell Leukemia; Primary Central Nervous System Non-Hodgkin Lymphoma; Acute Leukemias of Ambiguous Lineage; Childhood Diffuse Large Cell Lymphoma; Childhood Grade III Lymphomatoid Granulomatosis; Childhood Immunoblastic Large Cell Lymphoma; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Progressive Hairy Cell Leukemia, Initial Treatment; Childhood Burkitt Lymphoma; Blastic Phase Chronic Myelogenous Leukemia; Noncutaneous Extranodal Lymphoma; Chronic Eosinophilic Leukemia; Aggressive NK-cell Leukemia; Myeloid/NK-cell Acute Leukemia; Primary Central Nervous System Hodgkin Lymphoma; Acute Myeloid Leukemia/Transient Myeloproliferative Disorder
• Intervention / Treatment: Other: pharmacological study; Drug: Akt inhibitor MK2206; Other: diagnostic laboratory biomarker analysis

Detailed Description

PRIMARY OBJECTIVES:

l. To estimate the maximum-tolerated dose (MTD) and/or recommended phase 2 dose of MK-2206 (Akt inhibitor MK2206) administered orally every other day (schedule 1) or once weekly (schedule 2) to children with refractory or recurrent solid malignancies, including central nervous system (CNS) tumors or lymphomas.

II. To define and describe the toxicities of MK-2206 in children with refractory solid malignancies administered on this schedule.

III. To assess the tolerability of MK-2206 at the solid tumor MTD in patients with recurrent or refractory leukemia.

IV. To characterize the pharmacokinetics of MK-2206 in children with recurrent or refractory cancer. (exploratory)

SECONDARY OBJECTIVES:

I. To preliminarily define the antitumor activity of MK-2206 within the confines of a phase 1 study.(exploratory) II. To evaluate biological activity of MK-2206 by measuring phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling in tumor and peripheral blood mononuclear cells and measure the expression of biomarkers related to AKT activation phenotypes. (exploratory)

OUTLINE: This is a dose-escalation study (part A) followed by treatment at the maximum-tolerated dose (part B).

Patients receive Akt inhibitor MK2206 orally (PO) every other day (schedule 1) OR once weekly (schedule 2) on days 1-28. Treatment repeats every 28 days for up 12 courses (1 year) in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

• Study Type: Interventional
• Enrollment (Actual): 45
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Hospital for Sick Children
  • Quebec
    • Montreal, Quebec, Canada, H3T 1C5
      • Centre Hospitalier Universitaire Sainte-Justine
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
  • California
    • Orange, California, United States, 92868-3874
      • Childrens Hospital of Orange County
    • San Francisco, California, United States, 94143
      • University of California San Francisco Medical Center-Parnassus
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Children's Healthcare of Atlanta - Egleston
  • Illinois
    • Chicago, Illinois, United States, 60614
      • Lurie Children's Hospital-Chicago
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Medical Center
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital for Children
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • Mark O Hatfield-Warren Grant Magnuson Clinical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber Cancer Institute
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • C S Mott Children's Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota Medical Center-Fairview
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh of UPMC
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • St. Jude Children's Research Hospital
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Midwest Children's Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 21 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients must have a body surface area > 0.5 m^2 when enrolling on dose levels 0 or 1 of the every other day schedule; no body surface area (BSA) restrictions apply to patients enrolling on higher dose levels; no BSA restrictions apply to patients enrolling on any dose level of the weekly schedule.

• Diagnosis:

  • Part A (both schedules): Patients must have a diagnosis of recurrent or refractory solid tumors, including central nervous system (CNS) tumors or lymphoma; patients must have had histologic verification of malignancy at original diagnosis or relapse except in patients with intrinsic brain stem tumors, optic pathway gliomas, or patients with pineal tumors and elevations of cerebrospinal fluid (CSF) or serum tumor markers including alpha-fetoprotein or beta-human chorionic gonadotropin (HCG)
  • Part B (both schedules): Patients must have a diagnosis of recurrent or refractory leukemia

• Disease status:

  • Solid tumors: Patients must have either measurable or evaluable disease
  • Leukemia: Patients must have >= 5% blasts in the bone marrow; active extramedullary disease (except for leptomeningeal disease) may also be present
• Patient's current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life
• Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age; note: neurologic deficits in patients with CNS tumors must have been relatively stable for a minimum of 1 week prior to study enrollment; patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
• Patients must have fully recovered from the acute toxic effects of all prior anti-cancer chemotherapy

• Myelosuppressive chemotherapy:

  • Solid tumors: Patients with solid tumors must not have received myelosuppressive chemotherapy within 3 weeks of enrollment onto this study (6 weeks if prior nitrosourea)

  • Leukemia:

    • Patients with leukemia who relapse while receiving standard maintenance chemotherapy will not be required to have a waiting period before enrollment onto this study
    • Patients who relapse while they are not receiving standard maintenance therapy, must have fully recovered from all acute toxic effects of prior therapy. At least 14 days must have elapsed since the completion of cytotoxic therapy, with the exception of hydroxyurea
    • Note: Cytoreduction with hydroxyurea can be initiated and continued for up to 24 hours prior to the start of MK-2206
• At least 14 days after the last dose of a long-acting growth factor (e.g. Neulasta) or 7 days for short-acting growth factor; for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur; the duration of this interval must be discussed with the study chair
• At least 7 days after the last dose of a biologic agent; for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur; the duration of this interval must be discussed with the study chair
• At least 6 weeks since the completion of any type of immunotherapy, e.g. tumor vaccines
• At least 3 half-lives of the antibody after the last dose of a monoclonal antibody
• >= 2 weeks for local palliative radiation therapy (XRT) (small port); >= 24 weeks must have elapsed if prior total body irradiation (TBI), craniospinal XRT or if >= 50% radiation of pelvis; >= 6 weeks must have elapsed if other substantial bone marrow (BM) radiation
• Stem cell infusion without TBI: No evidence of active graft vs. host disease and >= 8 weeks must have elapsed since transplant or stem cell infusion
• Bone marrow transplantation: >= 3 months prior to study enrollment
• For patients with solid tumors without known bone marrow involvement including patients who are status post stem cell transplantation:
• Peripheral absolute neutrophil count (ANC) >= 1000/mm^3
• Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions within a 7 day period prior to enrollment)
• For patients with solid tumors with known bone marrow metastatic disease:
• These patients are eligible for study provided they meet the blood count criteria and are not known to be refractory to red cell or platelet transfusions; note: these patients are not evaluable for hematologic toxicity
• For patients with leukemia (Part B):
• Blood counts are not required to be normal prior to enrollment on this trial; however, platelet count has to be >= 20,000/mm^3 (may receive platelet transfusions)

• Creatinine clearance or radioisotope GFR >= 70 ml/min/1.73 m^2 or a serum creatinine based on age/gender as follows:

  • 1 to < 2 years: 0.6 mg/dL
  • 2 to < 6 years: 0.8 mg/dL
  • 6 to < 10 years: 1 mg/dL
  • 10 to < 13 years: 1.2 mg/dL
  • 13 to < 16 years: 1.5 (male), 1.4 (female)
  • >= 16 years: 1.7 (male), 1.4 (female)

• Patients with solid tumors:

  • Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age
  • Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 110 U/L; for the purpose of this study, the ULN for SGPT is 45 U/L
  • Serum albumin >= 2 g/dL

• Patients with leukemias:

  • Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age
  • SGPT (ALT) =< 225 U/L; for the purpose of this study, the ULN for SGPT is 45 U/L
  • Serum albumin >= 2 g/dL
• Corrected QT interval (QTc) =< 450 msec
• Patients with seizure disorder may be enrolled if on non-enzyme inducing anticonvulsants and well controlled
• Nervous system disorders (Common Terminology Criteria for Adverse Events [CTCAE] v4) resulting from prior therapy must be =< grade 2
• All patients and/or their parents or legally authorized representatives must sign a written informed consent; assent, when appropriate, will be obtained according to institutional guidelines
• Slides or tissue blocks from either initial diagnosis or relapse must be available for central review; tissue blocks or slides must be sent; if tissue blocks or slides are unavailable, the study chair must be notified prior to study enrollment

Exclusion Criteria:

• Pregnant or breast-feeding women will not be entered on this study; pregnancy tests must be obtained in girls who are post-menarchal; males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method
• Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for the prior 7 days are not eligible
• Patients who are currently receiving another investigational drug are not eligible
• Patients who are currently receiving other anticancer agents are not eligible [except leukemia patients receiving hydroxyurea, which may be continued until 24 hours prior to start of protocol therapy]; patients with leukemia may receive intrathecal therapy
• Patients must not be receiving enzyme-inducing anticonvulsants
• Patients receiving insulin or growth hormone therapy are not eligible
• Patients on medications that may cause corrected QT (QTc) interval prolongation are not eligible
• Patients who are receiving cyclosporine, tacrolimus or other agents to prevent either graft-versus-host disease post bone marrow transplant or organ rejection post transplant are not eligible for this trial
• Patients must be able to swallow whole tablets; nasogastric or G tube administration is not allowed
• Patients who have an uncontrolled infection are not eligible
• Patients with known type I or type II diabetes mellitus are not eligible
• Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment (Akt inhibitor); Patients receive oral Akt inhibitor MK2206 every other day (schedule 1) OR once weekly (schedule 2) on days 1-28. Treatment repeats every 28 days for up 12 courses (1 year) in the absence of disease progression or unacceptable toxicity.	Other: pharmacological study; Correlative studies; Other Names: pharmacological studies; Drug: Akt inhibitor MK2206; Given PO; Other Names: MK2206; Other: diagnostic laboratory biomarker analysis; Correlative studies

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MTD and/or recommended phase 2 dose of Akt inhibitor MK2206 determined according to incidence of dose-limiting toxicities (DLTs) graded using CTCAE v4.0 (Part A)	The MTD will be the maximum dose at which fewer than one-third of patients experience DLT during course 1 of therapy.	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic (PK) parameters of Akt inhibitor MK-2206	Summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).	Baseline, 0.5, 1.5, 3, 6-8, 24, 48 hours day 1 course 1; pre-dose and 6-8 hours post-dose (optional) day 15 (Schedule 1); baseline, 0.5, 1.5, 3, 6-8, 24, 48 hours day 1 course 1; pre-dose days 8 and 15; 6-8 hours post-dose day 15 (optional) (Schedule 2)
Antitumor activity assessed by Response Evaluation Criteria for Solid Tumors (RECIST) 1.1		Up to 30 days
Levels of activation of downstream signaling molecules	Summarized using descriptive statistics at each timepoint. The Wilcoxon signed-rank test or Friedman's test may be used as a preliminary test of change in activity over two or more timepoints.	Up to day 15 of course 1
Mutations or amplification of upstream signaling molecules	Summarized using descriptive statistics at each timepoint. The Wilcoxon signed-rank test or Friedman's test may be used as a preliminary test of change in activity over two or more timepoints.	Baseline

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Maryam Fouladi, COG Phase I Consortium

Study record dates

Study Major Dates

• Study Start: January 1, 2011
• Primary Completion (Actual): April 1, 2013

Study Registration Dates

• First Submitted: October 29, 2010
• First Submitted That Met QC Criteria: October 29, 2010
• First Posted (Estimate): November 1, 2010

Study Record Updates

• Last Update Posted (Estimate): April 29, 2014
• Last Update Submitted That Met QC Criteria: April 28, 2014
• Last Verified: April 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Virus Diseases; Infections; Immune System Diseases; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Lymphatic Diseases; Immunoproliferative Disorders; Neoplasms by Site; Disease Attributes; Bone Marrow Diseases; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; DNA Virus Infections; Bacterial Infections and Mycoses; Neoplastic Processes; Tumor Virus Infections; Neoplasms, Plasma Cell; Precancerous Conditions; Myelodysplastic-Myeloproliferative Diseases; Leukocyte Disorders; Leukemia, Lymphoid; Epstein-Barr Virus Infections; Herpesviridae Infections; Leukemia, B-Cell; Neoplasms, Connective Tissue; Eosinophilia; Lymphoma, B-Cell; Cell Transformation, Neoplastic; Carcinogenesis; Eye Neoplasms; Lymphoma, T-Cell, Cutaneous; Lymphoma, T-Cell; Leukemia, T-Cell; Mastocytosis, Systemic; Mastocytosis; Lymphoma; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Disease; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Hodgkin Disease; Recurrence; Lymphoma, Non-Hodgkin; Leukemia, Myelomonocytic, Acute; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Mycoses; Burkitt Lymphoma; Lymphoma, Mantle-Cell; Lymphoma, B-Cell, Marginal Zone; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Lymphoma, Large-Cell, Immunoblastic; Plasmablastic Lymphoma; Waldenstrom Macroglobulinemia; Leukemia, Lymphocytic, Chronic, B-Cell; Hypereosinophilic Syndrome; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Chronic-Phase; Acute Disease; Blast Crisis; Mycosis Fungoides; Sezary Syndrome; Lymphoma, Large-Cell, Anaplastic; Lymphomatoid Granulomatosis; Leukemia, Myeloid, Accelerated Phase; Lymphoma, Extranodal NK-T-Cell; Intraocular Lymphoma; Lymphoproliferative Disorders; Myeloproliferative Disorders; Leukemia, Prolymphocytic; Leukemia, Hairy Cell; Leukemia, Large Granular Lymphocytic; Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative; Leukemia, Mast-Cell; Leukemia, Neutrophilic, Chronic
• Other Study ID Numbers: NCI-2011-02612 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); U01CA097452 (U.S. NIH Grant/Contract); CDR0000687929; COG-ADVL1013; ADVL1013 (Other Identifier: CTEP)