Akt Inhibitor MK2206 in Combination With Lapatinib Ditosylate in Patients With Advanced or Metastatic Solid Tumors or Breast Cancer

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01245205
First received: November 19, 2010
Last updated: March 20, 2014
Last verified: September 2013
  Purpose

This phase I clinical trial is studying the side effects and the best dose of giving Akt inhibitor MK2206 (MK2206) together with lapatinib ditosylate (lapatinib) in treating patients with advanced or metastatic solid tumors or breast cancer. MK2206 and lapatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.


Condition Intervention Phase
HER2-positive Breast Cancer
Male Breast Cancer
Recurrent Breast Cancer
Stage IIIB Breast Cancer
Stage IIIC Breast Cancer
Stage IV Breast Cancer
Unspecified Adult Solid Tumor, Protocol Specific
Drug: Akt inhibitor MK2206
Drug: lapatinib ditosylate
Other: pharmacological study
Other: laboratory biomarker analysis
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Study of MK-2206 in Combination With Lapatinib in Refractory Solid Tumors Followed by Dose-expansion in Advanced HER2+ Breast Cancer

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Maximum-tolerated dose (MTD) defined as the dose level at which less than one-third of patients experience a dose-limiting toxicity (DLT) using NCI CTCAE v.4 (Part I) [ Time Frame: 35 days ] [ Designated as safety issue: Yes ]
  • Adverse reactions to Akt inhibitor MK2206 and lapatinib ditosylate in patients with advanced and unresectable or metastatic HER2+ breast cancer previously treated with trastuzumab as assessed by NCI CTCAE v. 4 (Part II) [ Time Frame: Up to 3 months ] [ Designated as safety issue: Yes ]
    Possible adverse events will be reported in tabular format.


Secondary Outcome Measures:
  • Response rate (complete or partial response or stable disease) measured by RECIST (Part I) [ Time Frame: Up to 4 weeks ] [ Designated as safety issue: No ]
    Two-sided 95% confidence intervals for the proportions of subjects with a confirmed anti-tumor response will be computed.

  • DLTs assessed by NCI CTCAE v. 4 (Part I) [ Time Frame: Up to 4 weeks ] [ Designated as safety issue: Yes ]
    The toxicities observed will be summarized by type and severity using the most recent version of the NCI CTCAE v.4 terminology. Both the number and severity of toxicity and adverse events will be analyzed in descriptive manner and presented in tabular format.

  • Safety of Akt inhibitor MK2206 and lapatinib ditosylate assessed by NCI CTCAE v. 4 (Part I) [ Time Frame: Up to 4 weeks ] [ Designated as safety issue: Yes ]
    Data analyses will be performed using SAS version 9.2 or greater. All demographic variables (e.g., gender, age, weight, etc.) will be summarized by standard descriptive statistics: means, standard deviations, medians, and ranges for variables on a continuous scale, and frequency tables for variables on a categorical scale.

  • Response rates using RECIST guidelines (Part II) [ Time Frame: Up to 3 months ] [ Designated as safety issue: No ]
    Responses will be summarized by means of descriptive statistics and frequency tables. Confidence intervals for the proportions of subjects with a confirmed anti-tumor response will be computed in the expansion cohort.

  • Disease progression using RECIST guidelines (Part II) [ Time Frame: Up to 3 months ] [ Designated as safety issue: No ]
  • Progression-free survival rates (Part II) [ Time Frame: Up to 3 months ] [ Designated as safety issue: No ]
    PFS times will be presented in a tabular format. Given the reduced sample size, statistical inference might not be possible. However, if enough events will be observed, a Kaplan-Meier curve will be displayed.

  • Pharmacokinetic (PK) parameters (Part II) [ Time Frame: Pre-dose, 0 and 30 minutes, 1, 2, 4, 6, 8, 12, and 24 hours ] [ Designated as safety issue: No ]
    All PK parameters will be summarized by using means, standard deviations and ranges. PK parameters of patients with severe toxicities (grade >= 3) will be compared to PK parameters of patients with no severe toxicities using Wilcoxon's Rank Sum test. Given the exploratory nature of these analyses, no multiplicity adjustments will be made.

  • Mechanisms of lapatinib ditosylate resistance (Part II) [ Time Frame: Up to 3 months ] [ Designated as safety issue: No ]
    Expressions will all be presented descriptively (mean, standard deviation, median, range) in tabular format and correlated with response or clinical benefit using regression models.


Estimated Enrollment: 52
Study Start Date: November 2010
Estimated Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (Akt inhibitor MK2206 and lapatinib tosylate)

Patients receive Akt inhibitor MK2206 PO QD, QOD for 28 days (35 days for course 1) and lapatinib tosylate PO QD or BID on days 1-28 (days 9-35 for course 1). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Once the maximum-tolerated dose is determined, a cohort of patients with breast cancer receive Akt inhibitor MK2206 PO QD, QOD for 28 days and lapatinib tosylate PO QD or BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Akt inhibitor MK2206
Given PO
Other Name: MK2206
Drug: lapatinib ditosylate
Given PO
Other Names:
  • GSK572016
  • GW-572016
  • GW2016
  • Lapatinib
  • Tykerb
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Other: laboratory biomarker analysis
Correlative studies

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have a histologically or cytologically confirmed advanced or metastatic solid tumor for which no standard curative measure exists (dose escalation) OR patients must have histologically or cytologically documented locally advanced and unresectable OR metastatic breast cancer (dose expansion)
  • Patients must have either evaluable or 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 CT scan
  • Patients must have HER2-positive (HER2+) cancer as defined by either: (a) 3+ for HER2 by immunohistochemistry (IHC), or (b) fluorescent in situ hybridization (FISH) or in situ hybridization (ISH) mean locus-to-centromeric ratio greater than or equal to 2.2; these analyses must be determined on an invasive component of the cancer at either the primary site or the metastatic site (dose expansion)
  • Patients may have previously had disease progression on lapatinib, but should not have demonstrated prior serious or life-threatening intolerance to doses of lapatinib exceeding 1000 mg per day
  • Life expectancy of greater than 12 weeks
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (or Karnofsky >= 60%)
  • Leukocytes >= 3,000/mcL
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Total bilirubin =< upper limit of normal (ULN); in the case of a patient with known Gilbert's disease, s/he will be eligible as long as total serum bilirubin is less than 1.5 x ULN
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 times upper limit of normal
  • Creatinine =< ULN OR creatinine clearance >= 60 mL/min/1.73^2 by Cockcroft-Gault for patients with creatinine levels above institutional normal
  • Patients must have previously received trastuzumab, either in the adjuvant or metastatic setting (dose expansion)
  • Women of childbearing potential and men should use contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation AS WELL AS for one month after stopping use of the study agents

    • 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
  • All patients in this cohort must have archived primary or metastatic tissue blocks available (dose expansion)
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • Patients who have had chemotherapy, therapy with trastuzumab, bevacizumab or other targeted therapy, or radiotherapy within 4 weeks (6 weeks for regimens including carmustine [BCNU], nitrosoureas or mitomycin C) prior to entering the study; the following will apply with regards to endocrine therapy:

    • Patients receiving an aromatase inhibitor (AI) are eligible as long as they stop the AI one day prior to beginning study agents
    • Given the longer half-life, patients receiving tamoxifen or fulvestrant should have received their last dose at least 2 weeks prior to beginning study agents
  • Patients who have not recovered (=< grade 1) from adverse events due to agents administered more than 4 weeks earlier (tolerable grade 2 adverse events may be allowed at the discretion of the investigator)
  • Patients may not be receiving any other investigational agents
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to MK-2206, lapatinib or other agents used in the study
  • Patients receiving any medications or substances that are strong or moderate inhibitors or inducers of CYP 450 3A4 are ineligible unless they can be transitioned off this medication prior to study drug initiation

    • Patients on strong or moderate inhibitors/inducers will become eligible if they discontinue all such medications at least 5 days prior to start of therapy and no further doses are anticipated for the duration of investigational therapy

      • In order to be considered a contraindicated medication, a patient must be taking the drug systemically and on a regular and scheduled basis; for example, a topical medication taken intermittently need not be stopped
    • Patients currently taking weak CYP3A4 inducers, and/or inhibitors are eligible
    • Patients currently taking sensitive substrates with narrow therapeutic indices are ineligible unless:

      • The medication can be monitored clinically in the opinion of the principal investigator (PI)/Study chair; monitoring will be performed on a schedule to be determined by the PI/study chair and treating physician (MD); for example, a substrate medication that can be clinically monitored is digoxin
      • It the medication CANNOT be monitored clinically, they discontinue all such medications at least 5 days prior to start of therapy and no further doses are anticipated for the duration of investigational therapy
  • Patients with diabetes or at risk for hyperglycemia should not be excluded from trials with MK-2206, but the hyperglycemia should be well controlled before the patient enters the trial

    • Inadequately controlled diabetes mellitus or hyperglycemia will be defined as:

      • Hemoglobin A1c > 8%
      • Fasting blood glucose over 200
      • Diabetes which requires injected insulin
  • Patients with malabsorption syndrome or other condition that would interfere with intestinal absorption; patients must be able to swallow tablets
  • 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; a baseline QTcF > 450 msec (male) or QTcF > 470 msec (female) will exclude patients from entry on study
  • Congestive heart failure (CHF) is a known but rare complication of lapatinib; therefore, patients with a left ventricular ejection function (LVEF) less than 50% or the lower limit of institutional normal are ineligible
  • 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 lapatinib 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 these drugs, breastfeeding should be discontinued if the mother is treated with either MK-2206 or lapatinib
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01245205

Locations
United States, South Dakota
Sanford Cancer Center-Oncology Clinic
Sioux Falls, South Dakota, United States, 57104
United States, Wisconsin
University of Wisconsin Hospital and Clinics
Madison, Wisconsin, United States, 53792
Sponsors and Collaborators
Investigators
Principal Investigator: Amye Tevaarwerk University of Wisconsin Hospital and Clinics
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01245205     History of Changes
Other Study ID Numbers: NCI-2011-02550, NCI-2011-02550, WCCC-CO-10904, CDR0000688912, CO10904, 8709, P30CA014520, U01CA062491
Study First Received: November 19, 2010
Last Updated: March 20, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Breast Neoplasms
Breast Neoplasms, Male
Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Lapatinib
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on April 16, 2014