Re-expression of ER in Triple Negative Breast Cancers

Breast Cancer Clinical Trial

Official title:

Phase I/II Trial of Tamoxifen Following Epigenetic Regeneration of Estrogen Receptor Using Decitabine and LBH 589 in Patients With Triple Negative Metastatic Breast Cancer

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01194908
• Other study ID #: IRB00029718
• Secondary ID: WCI1696-09
• Status: Terminated
• Phase: Phase 1/Phase 2
• First received: September 1, 2010
• Last updated: January 18, 2015
• Start date: July 2010
• Est. completion date: January 2014

Study information

• Verified date: January 2015
• Source: Emory University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review BoardUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

Patients are being asked to take part in this study because they have metastatic breast cancer that is triple negative (does not express estrogen receptor (ER), progesterone receptor (PR) or HER2). This means that agents such as trastuzumab (Herceptin®) and tamoxifen are not currently treatment options for their cancer. Another option for treating the patient's cancer at this point is with chemotherapy. The patient should discuss this and other options with their doctor prior to entering this study.

Laboratory studies have demonstrated that ER is actually present in some triple negative breast cancers but is "silenced" (does not function properly) because methyl and histone groups are attached to it and inactivate it. Special drugs called demethylating inhibitors (such as decitabine) and histone deacetylase inhibitors (such as LBH589) can remove these methyl and histone groups and reactivate ER. This reactivated ER can then be targeted with agents like tamoxifen.

The patient is being asked to join this clinical research study to find out if ER can be reactivated in their cancer using decitabine in combination with LBH589. If ER is reactivated in their cancer, we will then determine if tamoxifen can decrease the growth of the cancer.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 5
• Est. completion date: January 2014
• Est. primary completion date: January 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histologically or cytologically confirmed triple negative (ER-, PR-, HER2-) metastatic or locally advanced breast cancer

• Measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria.

• Disease that is assessable to biopsy for hormone receptor measurement

• At least one line of therapy prior to study entry (acceptable therapies include chemotherapy ± anti-angiogenic therapy). Other investigational therapies except DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors are allowed.

• Age > 18 years

• Eastern Cooperative Oncology Group (ECOG) Performance Score of 0 or 1 (Appendix A)

• Adequate bone marrow as evidenced by:

• Absolute neutrophil count > 1,500/µL

• Platelet count > 100,000/µL

• Adequate renal function as evidenced by serum creatinine < 1.5 mg/dL

• Adequate hepatic function as evidenced by:

• Serum total bilirubin < 1.5 mg/dL

• Alkaline phosphatase < 3 times the upper limit of normal (ULN) for the reference lab (< 5 times the ULN for patients with known hepatic metastases

• Serum glutamic-oxaloacetic transaminase (SGOT)/serum glutamic-pyruvic transaminase (SGPT) < 3 times the ULN for the reference lab (< 5 times the ULN for patients with known hepatic metastases

• Patients must be recovered from both the acute and late effects of any prior surgery, radiotherapy or other antineoplastic therapy

• Patients or their legal representatives must be able to read, understand and provide informed consent to participate in the trial.

• Consent to biopsy before and after therapy with decitabine and LBH589.

• Patients of childbearing potential and their partners must agree to use an effective form of contraception during the study and for 90 days following the last dose of study medication (an effective form of contraception is an oral contraceptive or a double barrier method)

Exclusion Criteria:

• Patients with an active infection or with a fever > 101.30 F within 3 days of the first scheduled day of protocol treatment

• Patients with active central nervous system (CNS) metastases. Patients with stable CNS disease, who have undergone radiotherapy at least 4 weeks prior to the planned first protocol treatment and who have been on a stable dose of corticosteroids for >3 weeks are eligible for the trial

• History of prior malignancy within the past 5 years except for curatively treated basal cell carcinoma of the skin, cervical intra-epithelial neoplasia, or localized prostate cancer with a current prostate-specific antigen (PSA) of < 1.0 mg/dL on 2 successive evaluations, at least 3 months apart, with the most recent evaluation no more than 4 weeks prior to entry

• Patients with known hypersensitivity to any of the components of decitabine or LBH589

• Patients who received radiotherapy to more than 25% of their bone marrow; or patients who received any radiotherapy within 4 weeks of entry

• Patients who are receiving concurrent investigational therapy or who have received investigational therapy within 28 days of the first scheduled day of protocol treatment (investigational therapy is defined as treatment for which there is currently no regulatory authority approved indication)

• Peripheral neuropathy >= Grade 2

• Patients who are pregnant or lactating

• Any other medical condition, including mental illness or substance abuse, deemed by the Investigator to be likely to interfere with a patient's ability to sign informed consent, cooperate and participate in the study, or interfere with the interpretation of the results.

• History of allogeneic transplant

• Known HIV or Hepatitis B or C (active, previously treated or both)

Study Design

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

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms
• Breast Tumors
• Triple Negative Breast Neoplasms

Intervention

Drug:
• Decitabine, LBH589, Tamoxifen
Dose level -1; Decitabine (IV)(D1-5): 5mg/m2; LBH589 (IV)(D1,8): 10mg/m2 Dose level 0; Decitabine (IV)(D1-5): 10mg/m2; LBH589 (IV)(D1,8): 10mg/m2 Dose level +1; Decitabine (IV)(D1-5): 10mg/m2; LBH589 (IV)(D1,8): 15mg/m2 Dose level +2; Decitabine (IV)(D1-5): 10mg/m2; LBH589 (IV)(D1,8): 20mg/m2 Dose level +3; Decitabine (IV)(D1-5): 15mg/m2; LBH589 (IV)(D1,8): 20mg/m2 Dose level +4; Decitabine (IV)(D1-5): 20mg/m2; LBH589 (IV)(D1,8): 20mg/m2

Locations

Country	Name	City	State
United States	Emory University Winship Cancer Institute	Atlanta	Georgia

Sponsors (3)

Lead Sponsor	Collaborator
Emory University	Eisai Inc., Novartis

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To Determine the Maximum Tolerated Dose of Decitabine and LBH589 Given in Combination in Patients With Metastatic or Locally Advanced Metastatic Breast Cancers		Estrogen receptor status checked 5 days after treatment. Staging is done every 8 weeks.	Yes
Secondary	To Determine the Safety of Tamoxifen in Combination With Decitabine and LBH589		Patients will undergo an evaluation for extent of disease 8 weeks from starting study drugs and every 8 weeks (2 cycles) while on study.	Yes