MK2206 and Paclitaxel in Treating Patients With Locally Advanced or Metastatic Solid Tumors or Metastatic Breast Cancer

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01263145
First received: December 17, 2010
Last updated: July 15, 2014
Last verified: May 2014
  Purpose

This phase I trial studies the side effects and best dose of Akt inhibitor MK2206 (MK2206) when given together with paclitaxel and to see how well they work in treating patients with solid tumors that have spread to other places in the body and usually cannot be cured or controlled with treatment or breast cancer that has spread to other places in the body. 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 paclitaxel, 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 and paclitaxel may be a better treatment for solid tumors or breast cancer.


Condition Intervention Phase
Recurrent Breast Cancer
Stage IV Breast Cancer
Unspecified Adult Solid Tumor, Protocol Specific
Drug: Akt inhibitor MK2206
Drug: paclitaxel
Other: pharmacological study
Other: laboratory biomarker analysis
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase Ib Dose Escalation and Biomarker Study of MK-2206 in Combination With Standard Doses of Weekly Paclitaxel in Patients With Locally Advanced or Metastatic Solid Tumors With an Expansion in Advanced Breast Cancer

Resource links provided by NLM:


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

Primary Outcome Measures:
  • MTD of the combination of MK-2206 and paclitaxel defined as the dose level in which less than or equal to 1 out of 6 patients develop dose limiting toxicity assessed using Common Terminology Criteria for Adverse Events version 4 (Phase I) [ Time Frame: 21 days ] [ Designated as safety issue: Yes ]
  • Antitumor activity of the combination in metastatic breast cancer (Expansion phase) [ Time Frame: Up to 3 weeks after completion of study treatment ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Pharmacokinetic parameters of Akt inhibitor MK2206 [ Time Frame: On days 1-3, 5, 8, 16, 17, and 19 of course 1 and then on day 1 of all subsequent courses ] [ Designated as safety issue: No ]
    Standard analyses for the pharmacokinetic endpoints will be conducted, including summary of descriptive measures, e.g., tabulation of frequencies for categorical variables, numerical (mean, range, standard deviation, 95% confidence intervals) and graphical (box plots, histograms) summary of the distribution for continuous endpoints, correlation analyses (Pearson and Spearman), and linear and nonlinear regression analyses, etc.

  • Pharmacokinetic parameters of paclitaxel [ Time Frame: On days 1, 2, 15, and 16 of course 1 ] [ Designated as safety issue: No ]
    Standard analyses for the pharmacokinetic endpoints will be conducted, including summary of descriptive measures, e.g., tabulation of frequencies for categorical variables, numerical (mean, range, standard deviation, 95% confidence intervals) and graphical (box plots, histograms) summary of the distribution for continuous endpoints, correlation analyses (Pearson and Spearman), and linear and nonlinear regression analyses, etc.

  • Change in percentage of marker of proliferation Ki-67 (Ki-67) positive cells [ Time Frame: Baseline to up to 2 weeks ] [ Designated as safety issue: No ]
    Will be calculated using a two-sided one-sample t-test, at a significance level of 0.05.

  • Change in percentage of biomarkers assessed using immunohistochemistry [ Time Frame: Baseline to up to 2 weeks ] [ Designated as safety issue: No ]
  • Change in reverse phase proteomic arrays (RPPA) [ Time Frame: Baseline to up to day 8 ] [ Designated as safety issue: No ]
    Will be analyzed using the Wilcoxon rank test.

  • Change in multiplex proteomics [ Time Frame: Baseline to up to day 17 ] [ Designated as safety issue: No ]
  • Change in average number of circulating tumor cells (CTCs) [ Time Frame: Baseline to up to 2 weeks ] [ Designated as safety issue: No ]
    Will be determined by chi-square analysis or Fisher's Exact test and compared by Student t-test.


Other Outcome Measures:
  • PIK3CA mutation status [ Time Frame: Up to day 17 ] [ Designated as safety issue: No ]
    Chi-square or Fisher's exact status will be used to calculate associations between PIK3CA status and clinical parameters.

  • Prevalence of single nucleotide polymorphisms (SNPs) in PI3K pathway genes [ Time Frame: Up to day 17 ] [ Designated as safety issue: No ]
    Descriptive analysis will be performed.

  • Change in expression of plasma markers [ Time Frame: Baseline to up to day 17 ] [ Designated as safety issue: No ]
    The marker expression will be compared by Student t-test.


Enrollment: 22
Study Start Date: January 2011
Primary Completion Date: October 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (Akt inhibitor MK2206 and paclitaxel)
Patients receive paclitaxel IV over 1 hour on days 1, 8, and 15 and Akt inhibitor MK2206 PO QD on days 2, 9, and 16. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Drug: Akt inhibitor MK2206
Given PO
Other Name: MK2206
Drug: paclitaxel
Given IV
Other Names:
  • Anzatax
  • Asotax
  • TAX
  • Taxol
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of the combination of MK-2206 and weekly paclitaxel. (Dose-escalation phase) II. To determine the safety and anti-tumor activity of the combination in metastatic breast cancer. (Expansion phase)

SECONDARY OBJECTIVES:

I. To determine the pharmacokinetics of MK-2206 and weekly paclitaxel used in combination.

II. To determine the safety of MK-2206 and weekly paclitaxel used in combination.

III. To evaluate the toxicities and tolerability of the combination. IV. To document anti-tumor activity. V. To determine baseline molecular markers that may predict clinical activity. VI. To determine pharmacodynamic markers in blood and tumor tissue that may predict an increase in apoptosis (by cleaved caspase 3) and clinical activity.

VII. To determine concordance of phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) and phosphatase and tensin homolog (PTEN) status between primary tumor and distant metastasis.

VIII. To determine concordance of PIK3CA status of circulating tumor cells and distant metastasis.

OUTLINE: This is a dose-escalation study of Akt inhibitor MK2206.

Patients receive paclitaxel intravenously (IV) over 1 hour on days 1, 8, and 15 and Akt inhibitor MK2206 orally (PO) once daily (QD) on days 2, 9, and 16. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 3 weeks.

  Eligibility

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

Inclusion Criteria:

  • Patients with histologically or cytologically confirmed locally advanced or metastatic solid tumors who have received at least two lines of therapy; for the expansion phase: female patients with metastatic breast cancer who have received a maximum of three lines of therapy
  • Absolute neutrophil count (ANC) >= 1,000/uL
  • Platelets >= 100,000/uL
  • Hemoglobin (Hgb) >= 9 g/dL
  • Creatinine =< 1.5 x upper limit of normal (ULN)
  • Prothrombin time (PT) within institutional guideline for biopsy procedure
  • Total bilirubin =< 1.5 x ULN
  • Alanine aminotransferase (ALT) =< 2.5 x ULN (=< 3 x ULN for subjects with liver involvement with cancer)
  • A known diabetic patient who is taking insulin or oral anti-diabetic therapy must have a hemoglobin A1C (HBA1C) =< 8% or a fasting serum glucose =< 110% ULN
  • Patient will have a tumor suitable for fine-needle aspirates (FNA) and core biopsy for research purposes (determined by the treating physician)
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  • Measurable disease by Response Evaluation Criteria In Solid Tumors (RECIST) or evaluable disease (e.g., bone metastasis or lesions which do not fulfill RECIST criteria for metastatic disease)
  • Patients with central nervous system (CNS) metastasis who have completed a course of therapy (for treatment of CNS metastasis) would be eligible for the study provided they are clinically stable for 1 month prior to entry as defined as:

    • No evidence of new or enlarging CNS metastasis
    • Off steroids and anticonvulsants
  • Corrected QT (QTc) interval =< 450 msec (Bazett's formula)
  • Negative serum pregnancy test beta-human chorionic gonadotropin (hCG) for patients of childbearing age
  • For the dose escalation cohorts, patients must have received front-line, cytotoxic, systemic therapy (combination or single agent, with or without the addition of targeted agents) for advanced cancer
  • For the expansion cohort, patients must have received no more than three lines of cytotoxic systemic therapy (combination or single agent, with or without the addition of targeted agents) for metastatic breast cancer; patients could have received paclitaxel in the adjuvant setting, but not in the metastatic setting
  • The last line of therapy must have been administered > 21 days prior to initiation of treatment on this study
  • Women of childbearing potential and men must use two forms of contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; 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
  • Both men and women and members of all races and ethnic groups are eligible for this trial

Exclusion Criteria:

  • Patients may not be receiving any other investigational agents
  • Patients taking a potent cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inhibitor or inducer will be excluded; patients who have discontinued any of these medications must have a wash-out period of at least 5 days or at least 5 half-lives of the drug (whichever is longer) prior to the first dose MK-2206
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to MK-2206 or other agents used in the study
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, bradycardia, related to cardiac disease, bundle branch block, 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01263145

Locations
United States, Massachusetts
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02115
United States, Tennessee
Vanderbilt-Ingram Cancer Center
Nashville, Tennessee, United States, 37232
United States, Texas
M D Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
Investigators
Principal Investigator: Stacy Moulder M.D. Anderson Cancer Center
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01263145     History of Changes
Other Study ID Numbers: NCI-2011-02562, NCI-2011-02562, CDR0000690723, 2010-0245, 8739, P30CA016672, U01CA062461, U01CA062490
Study First Received: December 17, 2010
Last Updated: July 15, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Paclitaxel
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on August 26, 2014