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

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Completed

CT.gov ID

NCT00526045

Collaborator

(none)

117

Enrollment

Locations

Arms

Duration (Months)

11.7

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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 or Disease	Intervention/Treatment	Phase
Breast Cancer Hematologic Neoplasms	Drug: AUY922 2 mg/m2	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

117 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Masking:

None (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.

Study Start Date :

Jul 1, 2007

Actual Primary Completion Date :

Apr 1, 2012

Actual Study Completion Date :

Apr 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Escalation	Drug: AUY922 2 mg/m2
Experimental: HER2 Positive	Drug: AUY922 2 mg/m2
Experimental: ER+ breast cancer	Drug: AUY922 2 mg/m2

Arm

Intervention/Treatment

Experimental: Escalation

Drug: AUY922 2 mg/m2

Experimental: HER2 Positive

Drug: AUY922 2 mg/m2

Experimental: ER+ breast cancer

Drug: AUY922 2 mg/m2

Outcome Measures

Primary Outcome Measures

The safe dose of AUY922 when administered once a week [54 weeks (MTD determination)]

Secondary Outcome Measures

Efficacy of AUY922 administered once a week [Baseline, and every 2 cycles (time to document tumor progression)]
Pharmacokinetics of AUY922 and Pharmacodynamics by PET response, blood and tumor biomarkers at baseline and post-AUY922 [Baseline and every 2 cycles]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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:

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.

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.
All patients must have at least one measurable lesion as defined by RECIST. Irradiated lesions are only evaluable for disease progression.
All patients must have progressive disease before entering the study
Age ≥ 18 years.
World Health Organization (WHO) Performance Status of ≤ 2.
Life expectancy of ≥ 12 weeks.
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:

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

Prior treatment with any HSP90 or HDAC inhibitor compound.
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)

Patients who have not recovered from side effects of previous systemic anticancer therapy to less than grade 2 CTCAE prior to the first dose.
Pregnant or lactating women.
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

Known diagnosis of HIV infection (HIV testing is not mandatory).
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.
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

Locations

	Site	City	State	Country	Postal Code
1	UCLA/ University of California Los Angeles UCLA	Los Angeles	California	United States	90095
2	Georgia Health Sciences University Med College of GA	Augusta	Georgia	United States	30912
3	Dana Farber Cancer Institute StudyCoordinator:CAUY922A2101	Boston	Massachusetts	United States	02115
4	Washington University School Of Medicine-Siteman Cancer Ctr Dept. of Siteman Cancer Ctr.	Saint Louis	Missouri	United States	63110
5	Nevada Cancer Institute Clinical Trials Office	Las Vegas	Nevada	United States	89135
6	MD Anderson Cancer Center/University of Texas Thoractic Head/Neck Med.Onc(2)	Houston	Texas	United States	77030-4009
7	Cancer Therapy & Research Center / UT Health Science Center InstituteForDrugDevelopment(3)	San Antonio	Texas	United States	78229
8	Novartis Investigative Site	Groningen		Netherlands	9713 GZ
9	Novartis Investigative Site	Bellinzona		Switzerland	6500
10	Novartis Investigative Site	Sutton		United Kingdom	SM2 5PT