A Pilot Preoperative Trial of Ganetespib With Paclitaxel for Triple-Negative Breast Cancer

Based on preclinical data implicating GR, AR, and JAK/STAT activation as potent mechanisms of breast cancer cell survival despite chemotherapy administration (i.e. chemotherapy resistance), the study will test a novel approach for improving chemotherapy effectiveness by adding Hsp90 inhibition to antagonize the anti-apoptotic signaling pathways that are initiated via GR, AR, and JAK/STAT activation.

Study Overview

• Status: Withdrawn
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: Cyclophosphamide; Drug: Doxorubicin; Drug: Paclitaxel; Drug: Ganetespib

Detailed Description

STUDY OBJECTIVES

Primary:

• To determine tumor GR, AR, JAK and other Hsp90 client protein expression before and after two weeks of ganetespib monotherapy

Secondary:

• To determine the pathological Complete Response (pCR) rate associated with weekly treatment of ganetespib plus paclitaxel followed by the combination treatment of doxorubicin plus cyclophosphamide
• To characterize the toxicity of study treatment

• Study Type: Interventional
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Invasive carcinoma of the breast
• ER negative and PR negative tumors defined as < 1% of tumor nuclei that are immunoreactive for ER and PR
• HER2 non-overexpressing status documented as:
• FISH ratio of less than 2.0, OR
• IHC staining of 0 or 1+
• No evidence of distant metastatic disease. Patients with regional lymph node involvement are eligible.
• >18 years old
• Female
• No prior treatment for the disease under study
• No prior treatment within 5 years for any other cancer including chemotherapy, surgery (except for diagnostic biopsy), radiotherapy, hormonal therapy, or investigational agents, unless curative treatment of non-melanoma skin-cancer or in-situ cancer
• Able to understand and sign an informed consent (or have a legal representative who is able to do so)
• Clinically or radiologically measureable disease in the breast after diagnostic biopsy, defined as longest diameter greater than or equal to 2cm
• Willing to undergo three mandatory core biopsies after diagnosis to obtain tissue for biologic expression profiling.
• An Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1
• Adequate bone marrow reserves as evidenced by:
• Leukocytes > 3,000/μL
• Absolute neutrophil count (ANC) > 1,500/μL without the use of hematopoietic growth factors,
• Platelet count > 100,000/μL, and
• Hemoglobin > 9 g/dL
• Adequate hepatic function as evidenced by:
• Serum total bilirubin within institutional normal limits
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase less than or equal to 2.5 × ULN
• Adequate renal function as evidenced by a serum creatinine within ULN or creatinine clearance > 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal
• Eligible for treatment with paclitaxel, doxorubicin and cyclophosphamide
• If of childbearing potential, are willing to abstain from sexual intercourse or to use an effective form of contraception (e.g., a double-barrier method) during the study and for 90 days following the last dose of ganetespib

Exclusion Criteria:

• • Patients may not be receiving any other investigational agents.

  • Patients may not have a known hypersensitivity to any of the components of ganetespib
  • Patients may not have a history of severe allergic reactions to paclitaxel or other drugs formulated in Cremaphor® EL.
  • Patients with a QTc > 470 ms, a family history of long QT Syndrome, and those on medications known to cause Torsades de Pointes will be excluded from the study.
  • Patients may not have an 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.
  • Patients may not have New York Heart Association (NYHA) Class III or IV congestive heart failure or left ventricular ejection fraction (LVEF) < 50%.
  • As patients with immune deficiency are at increased risk of lethal infections when treated with marrow-suppressive therapy, HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study.
  • Patients may not have a need for chronic systemic steroid therapy
  • Patients may not be pregnant or breastfeeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Therapy; Patients will receive ganetespib monotherapy for two weeks followed by twelve weeks of ganetespib/paclitaxel therapy followed by 4 bi-weekly doses of doxorubicin/cyclophosphamide therapy followed by surgery.	Drug: Cyclophosphamide; Drug: Doxorubicin; Drug: Paclitaxel; Drug: Ganetespib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change in GR protein	2 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathological Complete Response (pCR) rate	Defined as absence of invasive carcinoma in both the breast and axilla at the time of surgery	6 month
Ganetespib toxicity	Side effects related to Ganetespib as graded per Common Terminology Criteria for Adverse Events (CTCAE) version 4	14 weeks

Collaborators and Investigators

• Sponsor: University of Chicago

Study record dates

Study Major Dates

• Study Start: May 1, 2016
• Primary Completion (Anticipated): December 1, 2018
• Study Completion (Anticipated): December 1, 2018

Study Registration Dates

• First Submitted: December 17, 2015
• First Submitted That Met QC Criteria: December 17, 2015
• First Posted (Estimate): December 22, 2015

Study Record Updates

• Last Update Posted (Estimate): May 30, 2016
• Last Update Submitted That Met QC Criteria: May 26, 2016
• Last Verified: May 1, 2016

More Information

Terms related to this study

• Keywords: triple-negative breast cancer
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Triple Negative Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Cyclophosphamide; Paclitaxel; Doxorubicin
• Other Study ID Numbers: IRB15-0848