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A Phase I Dose Escalation, Single Center, Open-Label Study of AUY922 Administered IV on a Once-Weekly Schedule in Adult Patients 75 Years of Age or Older With Advanced Solid Malignancies

Phase 1
75 Years
Not Enrolling
Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

A Phase I Dose Escalation, Single Center, Open-Label Study of AUY922 Administered IV on a Once-Weekly Schedule in Adult Patients 75 Years of Age or Older With Advanced Solid Malignancies


I. The primary objective is to determine the maximally tolerated dose (MTD) of AUY922 (Hsp90
inhibitor AUY922) as a single agent when administered intravenously (IV) on a once-weekly
schedule to adult patients 75 years of age or older with advanced solid tumors whose disease
has progressed despite standard therapy or for whom no standard therapy exists.


I. To characterize the safety and tolerability of treatment with AUY922. II. To characterize
the pharmacokinetic profiles of AUY922, including the parent drug and any potential

III. To determine the efficacy of AUY922 in elderly patients with measurable disease.

IV. To evaluate of effect of geriatric-focused assessment of comorbidity and functional
status on the toxicity and response to AUY922.

V. To assess the ethical constraints to enrollment of elderly patients in phase I trials.


I. Determine the effect of therapy with AUY922 on the number of circulating tumor cells

II. To assess changes HSP70 induction as a measure of pharmacodynamic effect in pre- and
post-AUY922 samples in peripheral blood mononuclear cell (PBMCs) to explore age-related
differences in HSP90 inhibition by AUY922 compared with the previous phase I trial.

III. To assess changes in cellular response markers of apoptosis in pre- and post-AUY922
dosing in peripheral blood including measurement of M30 and M65 to explore age-related
differences in pharmacodynamics compared to patients enrolled in the previous phase I trial.

IV. To determine associations between pharmacokinetic (PK) and pharmacodynamic (PD)

V. To determine the relationship between geriatric-focused assessment of comorbidity and
functional ability and toxicity and response.

OUTLINE: This is a dose-escalation study.

Patients receive Hsp90 inhibitor AUY922 IV over 1 hour on days 1, 8, 15, and 22. Courses
repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 28 days.

Inclusion Criteria:

- Patients must have a histologically proven solid tumor malignancy which is refractory
to standard therapy and for which no curative therapy is available

- Patients must have at least one measurable lesion as defined by Response Evaluation
Criteria in Solid Tumors (RECIST); irradiated lesions are only evaluable for disease

- Eastern Cooperative Oncology Group (ECOG) Performance Status of =< 1

- Life expectancy of >= 12 weeks

- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L

- Hemoglobin (Hgb) >= 9 g/dl

- Platelets (plt) >= 100 x 10^9/L

- Potassium within normal limits or correctable with supplements

- Total calcium (corrected for serum albumin) and phosphorus within normal limits

- Magnesium above lower limit of normal (LLN) or correctable with supplements

- Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and
alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) =< 2.5 x
upper limit of normal (ULN) if no liver metastases are present

- AST/SGOT and ALT/SGPT =< 5 x ULN if liver metastases are present

- Serum bilirubin =< 1.5 x ULN

- Serum creatinine =< 1.5 x ULN or 24-hour clearance >= 50 ml/min

- Patients must be able to understand and voluntarily sign written informed consent

Male participants with partners who are of child bearing potential must:

- Agree to use double barrier method of birth control 28 days prior to study entry,
during course of study and for 28 days following the last dose of AUY922

- OR have history of a vasectomy

Exclusion Criteria:

Patients with central nervous system (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 computed tomography (CT)/magnetic resonance imaging (MRI) of the

- Prior treatment with any heat shock protein (HSP)90 or histone deacetylase (HDAC)
inhibitor compounds

Patients who received systemic anti-cancer treatment prior to the first dose of AUY922
within the following time frames:

- Radiotherapy or conventional chemotherapy: within 4 weeks

- Palliative radiotherapy: within 2 weeks

- Nitrosoureas, mitomycin, or monoclonal antibodies, such as trastuzumab, within 6

- Any systemic anti-cancer treatment for which the elimination 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)

- Treatment with therapeutic doses of coumadin-type anticoagulants (maximum daily dose
of 2 mg, for line patency permitted)

- Unresolved diarrhea >= Common Terminology Criteria for Adverse Events (CTCAE) grade
1, despite treatment with antidiarrheal agents

- Patients with malignant ascites that require invasive treatment

- Male patients whose partners are women of child-bearing potential (WCBP) not using
double-barrier methods of contraception

- Acute or chronic liver or renal disease

- Other concurrent severe and/or uncontrolled medical conditions that could cause
unacceptable safety risks or compromise compliance with the protocol

- Major surgery =< 2 weeks prior to Cycle 1, Day 1 or who have not recovered from such
therapy; (placement of a venous access device within 2 weeks is permitted)

Impaired cardiac function, including any one of the following:

- History (or family history) of long QT syndrome

- Mean corrected QT interval (QTc) >= 450 msec on baseline electrocardiogram (ECG)

- History of clinically manifested ischemic heart disease =< 6 months prior to study

- History of heart failure or left ventricular (LV) dysfunction (left ventricular
ejection fraction [LVEF] =< 45%) by multigated acquisition scan (MUGA) or
echocardiogram (ECHO)

- Clinically significant ECG abnormalities including 1 or more of the following: left
bundle branch block (LBBB), right bundle branch block (RBBB) with left anterior
hemiblock (LAHB); ST segment elevation or depression > 1mm, or 2nd (Mobitz II), or
3rd degree atrioventricular (AV) block

- History or presence of atrial fibrillation, atrial flutter or ventricular arrhythmias
including ventricular tachycardia or Torsades de Pointes

- Other clinically significant heart disease (e.g. congestive heart failure,
uncontrolled hypertension, history of labile hypertension, or history of poor
compliance with an antihypertensive regimen)

- Clinically significant resting bradycardia (< 50 beats per minute)

- Patients who are currently receiving treatment with any medication which has a
relative risk of prolonging the corrected QT using Bazett's formula (QTcB) interval
or inducing Torsades de Pointes and cannot be switched or discontinued to an
alternative drug prior to commencing AUY922

- Patients who are dependent on a pacemaker due to cardiac conduction dysfunction;
known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not

- Patients with a history of another primary malignancy that is currently clinically
significant or currently requires active intervention

- Patients unwilling or unable to comply with the protocol

Type of Study:


Study Design:

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

Outcome Measure:

MTD of Hsp90 inhibitor AUY922

Outcome Description:

A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value assessed as clinically relevant, and occurs < 28 days following the first dose of AUY922. Toxicity will be measured by CTCAE criteria (Version 4.02). The MTD will be determined using a standard design.

Outcome Time Frame:

at 28 days

Safety Issue:


Principal Investigator

Dale Shepard

Investigator Role:

Principal Investigator

Investigator Affiliation:

Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

September 2011

Completion Date:

February 2012

Related Keywords:

  • Unspecified Adult Solid Tumor, Protocol Specific



Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center Cleveland, Ohio  44195