MK2206 in Combination With Anastrozole, Fulvestrant, or Anastrozole and Fulvestrant in Treating Postmenopausal Women With Metastatic Breast Cancer

NCT01344031 | Completed Phase 1 DMC

• 7 other identifiers: NCI-2011-02586201010701WU-201010701CDR00006993948762N01CM00099P30CA091842
• Study Type: interventional
• Target: 31
• Locations: 1 country
• Sites: 1

Brief Summary

This phase I trial studies the side effects and the best dose of MK 2206 (Akt inhibitor MK2206) when given with anastrozole, fulvestrant, or anastrozole and fulvestrant in treating postmenopausal women with breast cancer that has spread to other parts of the body. Estrogen can cause the growth of breast cancer cells. Hormone therapy using anastrozole or fulvestrant may fight breast cancer by lowering the amount of estrogen the body makes. Akt inhibitor MK2206 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving Akt inhibitor MK2206 together with anastrozole, fulvestrant, or anastrozole and fulvestrant may kill more tumor cells.

Conditions

Estrogen Receptor Positive; Invasive Breast Carcinoma; Recurrent Breast Carcinoma; Stage IV Breast Cancer AJCC v6 and v7

Outcome Measures

Primary Outcomes (4)

• MTD of Akt inhibitor MK-2206 in combination with anastrozole determined according to dose-limiting toxicities (DLTs) graded using Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) (Phase IA)

  Data analysis for the study will be descriptive in nature. Demographic and clinical characteristics of the subjects, toxicity by grade, adverse events, serious adverse events and death will be listed and summarized using descriptive statistics for each dose level.

  4 weeks

• RPTD of Akt inhibitor MK-2206 in combination with anastrozole evaluated by the tolerability of prolonged administration at the MTD assessed by CTCAE v4.0 (Phase IB)

  Data analysis for the study will be descriptive in nature. Demographic and clinical characteristics of the subjects, toxicity by grade, adverse events, serious adverse events and death will be listed and summarized using descriptive statistics for each dose level.

  3 months

• RPTD of fulvestrant in combination with Akt inhibitor MK-2206 assessed by CTCAE v4.0 (ARM C)

  Data analysis for the study will be descriptive in nature. Demographic and clinical characteristics of the subjects, toxicity by grade, adverse events, serious adverse events and death will be listed and summarized using descriptive statistics for each dose level.

  3 months

• RPTD of anastrozole plus fulvestrant in combination with Akt inhibitor MK-2206 assessed by CTCAE v4.0 (ARM D)

  Data analysis for the study will be descriptive in nature. Demographic and clinical characteristics of the subjects, toxicity by grade, adverse events, serious adverse events and death will be listed and summarized using descriptive statistics for each dose level.

  3 months

Secondary Outcomes (3)

• Incidence of toxicity, assessed by CTCAE v4.0

  Up to 30 days post-treatment

• Clinical benefit rate (CR+PR+SD for more than 6 months)

  Up to 30 days post-treatment

• Serum levels of estradiol prior to and following 1 course of Akt inhibitor MK-2206 therapy

  Up to day 28

Other Outcomes (6)

• Change in PI3K pathway abnormalities

  Baseline up to 30 days post-treatment

• Tumor cell AKT signaling

  Up to 30 days post-treatment

• Tumor cell proliferation

  Up to 30 days post-treatment

Study Arms (4)

Arm A (anastrozole and Akt inhibitor MK2206)

EXPERIMENTAL

Patients receive anastrozole PO on days 1-28. Beginning in course 2, patients receive Akt inhibitor MK2206 PO on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. NOTE: As of 8/19/2015, patients no longer receive Akt inhibitor MK2206.

Drug: Akt Inhibitor MK2206; Drug: Anastrozole; Other: Laboratory Biomarker Analysis

Arm B (Akt inhibitor MK2206 and anastrozole)

EXPERIMENTAL

The RPTD of Akt inhibitor MK2206 with anastrozole is determined after 3 courses, administered as in Arm A. NOTE: As of 8/19/2015, patients no longer receive Akt inhibitor MK2206.

Drug: Akt Inhibitor MK2206; Drug: Anastrozole; Other: Laboratory Biomarker Analysis

Arm C (Akt inhibitor MK2206 and fulvestrant)

EXPERIMENTAL

Patients receive Akt inhibitor MK2206 PO on days 1, 8, 15, and 22, fulvestrant IM on day 1and day 15 of course 1 and then on day 1 of each course in each subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. NOTE: As of 8/19/2015, patients no longer receive Akt inhibitor MK2206.

Drug: Akt Inhibitor MK2206; Drug: Fulvestrant; Other: Laboratory Biomarker Analysis

Arm D (Akt inhibitor MK2206, anastrozole, fulvestrant)

EXPERIMENTAL

Patients receive Akt inhibitor MK2206 PO as in Arm A, anastrozole PO on days 1-28 and fulvestrant IM on day 1. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. NOTE: As of 8/19/2015, patients no longer receive Akt inhibitor MK2206.

Drug: Akt Inhibitor MK2206; Drug: Anastrozole; Drug: Fulvestrant; Other: Laboratory Biomarker Analysis

Interventions

Akt Inhibitor MK2206 DRUG

Given PO

Also known as: MK2206

Arm A (anastrozole and Akt inhibitor MK2206); Arm B (Akt inhibitor MK2206 and anastrozole); Arm C (Akt inhibitor MK2206 and fulvestrant); Arm D (Akt inhibitor MK2206, anastrozole, fulvestrant)

Anastrozole DRUG

Given PO

Also known as: Anastrazole, Arimidex, ICI D1033, ICI-D1033, ZD-1033

Arm A (anastrozole and Akt inhibitor MK2206); Arm B (Akt inhibitor MK2206 and anastrozole); Arm D (Akt inhibitor MK2206, anastrozole, fulvestrant)

Fulvestrant DRUG

Given IM

Also known as: Faslodex, Faslodex(ICI 182,780), ICI 182,780, ICI 182780, ZD9238

Arm C (Akt inhibitor MK2206 and fulvestrant); Arm D (Akt inhibitor MK2206, anastrozole, fulvestrant)

Laboratory Biomarker Analysis OTHER

Correlative studies

Arm A (anastrozole and Akt inhibitor MK2206); Arm B (Akt inhibitor MK2206 and anastrozole); Arm C (Akt inhibitor MK2206 and fulvestrant); Arm D (Akt inhibitor MK2206, anastrozole, fulvestrant)

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have histologically or cytologically confirmed invasive breast cancer that is metastatic stage IV or recurrent metastatic (histologic/cytologic confirmation of recurrence preferred, but not required)
• Either the primary or the metastatic tumor must be positive for estrogen-receptor (\> 1% tumor cell staining by immunohistochemistry or an Allred score of \>= 3 by immunohistochemistry)
• Patient must have measurable or non-measurable lesions (defined by Response Evaluation Criteria in Solid Tumors \[RECIST\] 1.1 criteria)
• Note: to be eligible for the FDG PET imaging studies in Phase IA, the presence of measurable lesions of at least 1.5 cm or the presence of bone lesions is required
• Patients may have undergone any number of prior lines of chemotherapy or endocrine regimens but must not have a history of disease progression on anastrozole (Phase IA and Phase IB), fulvestrant (Arm C), or both anastrozole and fulvestrant (Arm D)
• Phase IA and IB:
• Currently being treated with anastrozole with no evidence of disease progression OR
• Currently being treated with letrozole or exemestane with no evidence of disease progression and willing to switch to anastrozole for study enrollment OR
• Considering switching to anastrozole due to disease progression from the most recent anti-cancer therapy
• Arm C:
• Currently being treated with fulvestrant with no evidence of disease progression OR
• Considering switching to fulvestrant due to disease progression from the most recent anti-cancer therapy
• Arm D:
• Currently being treated with either anastrozole or fulvestrant with no evidence of disease progression OR
• Currently being treated with letrozole or exemestane with no evidence of disease progression and willing to switch to anastrozole for study enrollment

You may not qualify if:

• Patients may not have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study; patient must have recovered from adverse events due to agents administered more than 4 weeks earlier
• Patients may not be receiving any other investigational agents
• Patients may not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to MK-2206 or other agents used in the study
• Patients receiving any medications or substances that are strong inhibitors or inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP 450 3A4) are ineligible
• Note: one week washout period is required in patients who were previously taking strong inhibitors or inducers of CYP450 3A4; patients who are currently taking moderate inhibitors or inducers of CYP450 3A4 are encouraged to switch to other medications that do not interact with CYP450 3A4
• Patients with diabetes or in risk for hyperglycemia should not be excluded from trials with MK-2206, but the hyperglycemia should be well controlled on oral agents before the patient enters the trial (i.e. HbA1c =\< 8% and fasting glucose =\< 120 mg/dL)
• Cardiovascular: baseline QT Fridericia formula (QTcF) \> 450 msec (male) or QTcF \> 470 msec (female) will exclude patients from entry on study
• Patients may not have 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 or nursing patients are excluded from the study
• Patients with known human immunodeficiency virus (HIV) positive status are excluded from this study
• Patients may not have had disease progression on anastrozole (Phase IA and Phase IB), fulvestrant (Arm C), both anastrozole and fulvestrant (Arm D) in either the neoadjuvant, adjuvant (defined as disease recurrence identified within 6 months of adjuvant discontinuation), or metastatic setting
• Patients may not have had grade 3 or intolerable grade 2 adverse events during run-in aromatase inhibitor (AI) or fulvestrant therapy prior to starting MK-2206
• Patients may not have had prior therapy with an AKT inhibitor

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

MeSH Terms

Conditions

Breast Neoplasms

Interventions

MK 2206; Anastrozole; Fulvestrant

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Study Officials

• Cynthia Ma

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 27, 2011
• First Posted: April 28, 2011
• Study Start: April 21, 2011
• Primary Completion: July 1, 2011
• Last Updated: July 23, 2018

Record last verified: 2018-05

Locations

US (1)