ERB-B4 After Treatment With HDAC Inhibitor in ER+ Tamoxifen Refractory Breast Cancer

NCT00993642 | Withdrawn Early Phase 1

• 1 other identifier: CLBH589BUS46T
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

The long-term objective of this research is to understand the molecular mechanisms of acquired endocrine resistance in breast cancer. Identifying these mechanisms is critical to the implementation of novel therapeutic strategies that can target and overcome altered gene networks involved in controlling breast cancer progression. While patients with tumors over expressing HER1, 2, or 3 have been shown to have reduced survival, patients with those tumors which overexpressed HER4 (erbB4) had increased survival (Witton 2003). This is a non-randomized, single-arm, proof of principle trial. Selected are patients with advanced-stage breast cancer whose tumors are ER+, tamoxifen refractory. Histologically proven diagnosis of recurrent or metastatic breast cancer is advanced cancer for which there is no treatment available which would have a reasonable chance of cure. Treatment failure is defined as tumor progression after chemotherapy and tamoxifen therapy. Patients will be given five 30mg doses of HDAC inhibitor (LBH) over a period of two weeks. A dose will be taken on Days 1,3,5,8 and 10. Patients will have a diagnostic tumor biopsy prior to drug administration and a diagnostic biopsy within 48 hours (2 days) of the last dose. Primary endpoints are measured by biopsy of palpable tumor with immunohistochemical staining for ERBB4. Secondary end points include the evaluation of cell death, apoptosis, with immunohistochemical staining for DNA breaks by TUNEL assay.

Conditions

Breast Cancer

Keywords

estrogen receptor positive tamoxifen resistant breast cancer

Outcome Measures

Primary Outcomes (1)

• The primary objective of the study is to compare the expression level of ERBB4 pre- and post- treatment with HDACi, Panobinostat (LBH589).

  2 week

Study Arms (1)

All Participants

EXPERIMENTAL

Drug: Panobinostat (LBH589)

Interventions

Panobinostat (LBH589) DRUG

Patients will be given five 30mg doses of HDAC inhibitor (LBH) over a period of two weeks. A dose will be taken on Days 1,3,5,8 and 10. Patients will have a diagnostic tumor biopsy prior to drug administration and a diagnostic biopsy within 48 hours (2 days) of the last dose.

All Participants

Eligibility Criteria

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

You may qualify if:

• Patient age is ≥ 18 years
• Female
• Stage IV tamoxifen-refractory breast cancer (progression of at least 25% in diameters of at least one measurable lesion while taking tamoxifen or occurrence of a new lesion while taking tamoxifen), including first occurrence of metastasis within 12 months of completing adjuvant therapy with tamoxifen
• No concurrent use of other HDAC inhibitors
• Palpable disease
• Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
• Ability to provide written informed consent obtained prior to participation in the study and any related procedures being performed
• No chemotherapy in the 14 days prior, or radiation therapy to index lesions in the thirty days prior to initiation of treatment on this study
• No other concurrent chemotherapy; surgery or radiation therapy during the treatment phase of this protocol
• No active major medical problems, including untreated or uncontrolled infections
• No known CNS involvement by tumor
• Patients must meet the following laboratory criteria:
• Hematology:
• Neutrophil count of \>1500/mm3
• Platelet count of \> 100,000/mm3L

You may not qualify if:

• Prior HDAC, DAC, HSP90 inhibitors or valproic acid for the treatment of cancer
• Patients who will need valproic acid for any medical condition during the study or within 5 days prior to first panobinostat treatment
• Impaired cardiac function including any one of the following:
• Complete left bundle branch block or use of a permanent cardiac pacemaker, congenital long QT syndrome, history or presence of ventricular tachyarrhythmias, clinically significant resting bradycardia (\<50 beats per minute), QTcF \> 450 msec on screening ECG, or right bundle branch block + left anterior hemiblock (bifascicular block)
• Presence of atrial fibrillation (ventricular heart rate \>100 bpm)
• Previous history angina pectoris or acute MI within 6 months
• Congestive heart failure (New York Heart Association functional classification III-IV) or baseline MUGA/Echo shows LVEF \< 45%
• Uncontrolled hypertension
• Concomitant use of drugs with a risk of causing torsades de pointes (See Appendix 1.-1)
• Concomitant use of CYP3A4 inhibitors (See Appendix 1.-2)
• Patients with unresolved diarrhea ≥ grade 2
• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral panobinostat (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, obstruction, or stomach and/or small bowel resection)
• Other concurrent severe and/or uncontrolled medical conditions
• Patients who have received chemotherapy, any investigational drug or undergone major surgery \< 4 weeks prior to starting study drug or who have not recovered from side effects of such therapy.
• Concomitant use of any anti-cancer therapy or radiation therapy.

Sponsors & Collaborators

• Tulane University Health Sciences Center: lead
• Novartis: collaborator
• Board of Regents, State of Louisiana: collaborator

Study Sites (1)

Tulane Cancer Center, Comprehensive Clinic, CTRC

New Orleans, Louisiana, 70112, United States

Location

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Panobinostat

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Hydroxamic Acids; Hydroxylamines; Amines; Organic Chemicals; Hydroxy Acids; Carboxylic Acids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Bridgette Collins-Burow, MD, PhD

  Tulane Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: October 9, 2009
• First Posted: October 12, 2009
• Study Start: September 1, 2009
• Primary Completion: September 1, 2010
• Study Completion: December 1, 2010
• Last Updated: March 13, 2017

Record last verified: 2017-03

Locations

US (1)