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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


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Recurrent Breast Cancer, Stage IV Breast Cancer, Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

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


PRIMARY OBJECTIVES:

I. To determine the 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 PIK3CA and 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 multicenter, 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.

Tumor tissue and blood samples are collected periodically for pharmacodynamic and
pharmacokinetic studies.

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


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/μL

- Platelets >= 100,000/μL

- 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 (HBA)_1C =< 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

- 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 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 because the effects of MK-2206 on the
developing human fetus are unknown; also, because there is an unknown but potential
risk for adverse events in nursing infants secondary to treatment of the mother with
MK-2206 and paclitaxel, breastfeeding should be discontinued

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

MTD of the combination of MK-2206 and weekly paclitaxel determined by dose-limiting toxicities (Phase I)

Outcome Time Frame:

21 days

Safety Issue:

Yes

Principal Investigator

Ana Maria Gonzalez-Angulo

Investigator Role:

Principal Investigator

Investigator Affiliation:

M.D. Anderson Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2011-02562

NCT ID:

NCT01263145

Start Date:

January 2011

Completion Date:

Related Keywords:

  • Recurrent Breast Cancer
  • Stage IV Breast Cancer
  • Unspecified Adult Solid Tumor, Protocol Specific
  • Breast Neoplasms
  • Neoplasms

Name

Location

Dana-Farber Cancer InstituteBoston, Massachusetts  02115
M D Anderson Cancer CenterHouston, Texas  77030