Phase I-II Study to Determine the Maximum Tolerated Dose (MTD) of AUY922 in Advanced Solid Malignancies, and Efficacy in HER2+ or ER+ Locally Advanced or Metastatic Breast Cancer Patients

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00526045
First received: September 5, 2007
Last updated: May 10, 2013
Last verified: May 2013
  Purpose

This is a phase I/II, open-label, multicenter study of AUY922 administered intravenously in patients with advanced solid malignancies to determine the maximum tolerated dose. Phase II expansion arms will investigate efficacy in patients with either HER2 positive or ER positive locally advanced or metastatic breast cancer. Additional patients with advanced solid malignancies will also be investigated in a separate expansion arm. Safety, pharmacokinetics and pharmacodynamics will be assessed.


Condition Intervention Phase
Breast Cancer
Hematologic Neoplasms
Drug: AUY922
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Dose Escalation, Multi-center, Open-label Study of AUY922 Administered IV on a Once Weekly Schedule in Adult Patients With Advanced Solid Malignancies Including Phase II Expansion Arms in Patients With Either HER2 Positive or ER Positive Locally Advanced or Metastatic Breast Cancer.

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • The safe dose of AUY922 when administered once a week [ Time Frame: 54 weeks (MTD determination) ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Efficacy of AUY922 administered once a week [ Time Frame: Baseline, and every 2 cycles (time to document tumor progression) ] [ Designated as safety issue: No ]
  • Pharmacokinetics of AUY922 and Pharmacodynamics by PET response, blood and tumor biomarkers at baseline and post-AUY922 [ Time Frame: Baseline and every 2 cycles ] [ Designated as safety issue: No ]

Enrollment: 117
Study Start Date: July 2007
Study Completion Date: April 2012
Primary Completion Date: April 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Escalation Drug: AUY922
Experimental: HER2 Positive Drug: AUY922
Experimental: ER+ breast cancer Drug: AUY922

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Dose-escalation and MTD dose expansion arm: Patients with histologically confirmed, advanced malignant solid tumors whose disease has progressed on standard therapy or for whom no standard therapy exists.

    Breast cancer phase II expansion arms only:

    1. Females patients with HER2 positive non-operable locally advanced or metastatic breast cancer must have:

      • History of trastuzumab resistance, defined as either local or systemic disease progression on treatment with at least 8 weeks of a trastuzumab containing regimen.
      • Received up to 3 prior anti HER2 based regimens (i.e. trastuzumab and/or lapatinib in combination with other agents) for metastatic disease
      • Patients who develop metastases while receiving adjuvant or neo-adjuvant trastuzumab are eligible.

      HER2 positive patients, tumor/s must demonstrate HER2 over-expression based on either:

      • Immunohistochemistry (IHC) at the 3+ level, or
      • IHC 2+ confirmed by fluorescence in-situ hybridization (FISH). Tumors tested by FISH must be positive by the specific FISH assay for the amplification of HER2.
    2. Female patients with ER positive non-operable locally advanced or metastatic breast cancer patients who received standard sequence lines of endocrine therapy and whose disease has progressed on at least one and up to 3 lines of endocrine and/or cytotoxic therapy for advanced disease.
  2. All patients must have at least one measurable lesion as defined by RECIST. Irradiated lesions are only evaluable for disease progression.
  3. All patients must have progressive disease before entering the study
  4. Age ≥ 18 years.
  5. World Health Organization (WHO) Performance Status of ≤ 2.
  6. Life expectancy of ≥ 12 weeks.
  7. Absolute Neutrophil Count (ANC) 1.5 x 109/L; hemoglobin (Hgb) 9 g/dl; platelets (plt) 100 x 109/L; potassium, calcium, magnesium and phosphorus within normal limits or correctable with supplements; AST/SGOT and ALT/SGPT ≤ 2.5 x Upper Limit of Normal (ULN) or ≤ 5.0 x ULN if liver metastases are present; serum bilirubin 1.5 x ULN; serum albumin > 2.5g/dl and serum creatinine 1.5 x ULN or 24-hour clearance 50 ml/min

Exclusion criteria:

  1. Patients with CNS metastasis which are:

    • Symptomatic or
    • Require treatment for symptom control and/or
    • Growing

    Note: patients without clinical signs or symptoms of CNS involvement are not required to have a CT/MRI of the brain

  2. Prior treatment with any HSP90 or HDAC inhibitor compound.
  3. Patient who received systemic anti-cancer treatment prior to the first dose of AUY922 within the following time frames:

    • Chemotherapy within 4 weeks
    • Radiotherapy within 4 weeks
    • Palliative radiotherapy: within 2 weeks
    • Trastuzumab treatment within 4 weeks
    • Nitrosoureas, mitomycin and monoclonal antibodies (except trastuzumab): within 6 weeks
    • Any continuous-dosing (i.e. daily dosing, every-other-day dosing, Monday- Wednesday-Friday dosing, weekly etc) of systemic anticancer treatment for which the recovery period is not known, or investigational drugs (i.e. targeted agents) within a duration of ≤ 5 half lives of the agent and their active metabolites (if any)
  4. Patients who have not recovered from side effects of previous systemic anticancer therapy to less than grade 2 CTCAE prior to the first dose.
  5. Pregnant or lactating women.
  6. Cardia exclusion criteria:

    • History (or family history) of long QT syndrome.
    • Mean QTc ≥ 450 msec on screening ECG
    • History of clinically manifest ischemic heart disease including myocardial infarction, stable or unstable angina, coronary arteriography or cardiac stress testing/imaging with findings consistent with coronary occlusion or infarction, ≤ 6 months prior to study start.
    • History of heart failure or left ventricular (LV) dysfunction (LVEF ≤ 45%) by MUGA or ECHO
  7. Known diagnosis of HIV infection (HIV testing is not mandatory).
  8. Acute or chronic liver disease, acute or chronic renal disease or other concurrent severe and/or uncontrolled medical conditions (e.g. uncontrolled diabetes, active or uncontrolled infection) that could cause unacceptable safety risks or compromise compliance with the protocol.
  9. Cardiac exclusion criteria:

Mean QTc ≥ 450 msec on screening ECG and clinically significant ECG abnormalities including one or more of the following: left bundle branch block (LBBB), right bundle branch block (RBBB) with left anterior hemiblock (LAHB). ST segment elevations or depressions > 1mm, or 2nd (Mobitz II) or 3rd degree AV block; clinically significant ECG abnormalities including one or more of the following: left bundle branch block (LBBB), right bundle branch block (RBBB) with left anterior hemiblock (LAHB). ST segment elevations or depressions > 1mm, or 2nd (Mobitz II) or 3rd degree AV block.

History (or family history) of long QT syndrome, heart failure or left ventricular (LV) dysfunction (LVEF ≤ 45%) by MUGA or ECHO, history of clinically manifest ischemic heart disease including myocardial infarction, stable or unstable angina, coronary arteriography or cardiac stress testing/imaging with findings consistent with coronary occlusion or infarction, ≤ 6 months prior to study start; history or presence of atrial fibrillation, atrial flutter or ventricular arrhythmias including ventricular tachycardia or Torsades de Pointes.

Other protocol-defined inclusion/exclusion criteria may apply

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00526045

Locations
United States, California
UCLA/ University of California Los Angeles UCLA
Los Angeles, California, United States, 90095
United States, Georgia
Georgia Health Sciences University Med College of GA
Augusta, Georgia, United States, 30912
United States, Massachusetts
Dana Farber Cancer Institute StudyCoordinator:CAUY922A2101
Boston, Massachusetts, United States, 02115
United States, Missouri
Washington University School Of Medicine-Siteman Cancer Ctr Dept. of Siteman Cancer Ctr.
St. Louis, Missouri, United States, 63110
United States, Nevada
Nevada Cancer Institute Clinical Trials Office
Las Vegas, Nevada, United States, 89135
United States, Texas
MD Anderson Cancer Center/University of Texas Thoractic Head/Neck Med.Onc(2)
Houston, Texas, United States, 77030-4009
Cancer Therapy & Research Center / UT Health Science Center InstituteForDrugDevelopment(3)
San Antonio, Texas, United States, 78229
Netherlands
Novartis Investigative Site
Groningen, Netherlands, 9713 GZ
Switzerland
Novartis Investigative Site
Bellinzona, Switzerland, 6500
United Kingdom
Novartis Investigative Site
Sutton, United Kingdom, SM2 5PT
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

No publications provided

Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT00526045     History of Changes
Other Study ID Numbers: CAUY922A2101, 2006-002766-20
Study First Received: September 5, 2007
Last Updated: May 10, 2013
Health Authority: United States: Food and Drug Administration
Switzerland: Federal Office of Public Health
United Kingdom: Department of Health
The Netherlands: Independent Ethics Committee

Keywords provided by Novartis:
AUY922
Solid tumors
Breast Cancer
Phase I/II
Advanced Solid malignancies (Phase I)
Breast Cancer ( Phase II )
HER2+
ER+
HSP90

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms
Hematologic Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Hematologic Diseases

ClinicalTrials.gov processed this record on August 01, 2014