This phase I trial studies the side effects and best dose of Hsp90 inhibitor AUY922 in treating older patients with advanced solid malignancies. Hsp90 inhibitor AUY922 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth
PRIMARY OBJECTIVES: 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. SECONDARY OBJECTIVES: 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 metabolites. 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. TERTIARY OBJECTIVES: I. Determine the effect of therapy with AUY922 on the number of circulating tumor cells (CTC). 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) parameters. 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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
2
Given IV
Correlative studies
Correlative studies
Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center
Cleveland, Ohio, United States
MTD of Hsp90 inhibitor AUY922
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.
Time frame: at 28 days
Toxicity by CTCAE (v 4.02)
Time frame: at 28 days
Pharmacokinetic parameters, including area under the curve (AUC), clearance, volume of distribution (VD), time to the maximum concentration (Tmax), maximum plasma concentration (Cmax), and elimination half-life
Prior to 1st infusion; 30 minutes after start infusion; end infusion; 5, 30 minutes post-infusion; 1, 2, 4, 5, 24, 48 hours post-infusion course 1 days 8 (pretreatment) and 15 (pretreatment/end infusion); and course 2 day 1 (pretreatment/end infusion)
Time frame: at baseline and at 28 days (first cycle)
Tumor response will be measured by RECIST criteria (complete response [CR], partial response [PR], stable disease [SD], progressive disease [PD], overall response [OR], response rate [RR])
Imaging with CT or MRI will be obtained at baseline (within 21 days of study Day 1) and every other cycle commencing at the end of cycle 2 (beginning of cycle 3). These scans should be schedule within 7 days of the start of the cycle. Imaging will be obtained at the end of the study.
Time frame: at baseline and at end of cycle 2 (8 weeks)
Geriatric assessment will be made including Mini Mental Exam, Get up and Go, assessment of comorbidity, and Geriatric Depression Scale
This trial will incorporate geriatric assessment to determine the relationship between functional ability or comorbidity and treatment response or toxicity. Patients will be have a geriatric assessment which will included a range of assessments, such as mini mental status, up and go test, and the geriatric depression scale, at baseline and after every 2 cycles of therapy.
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Time frame: at baseline and at end of cycle 2 (8 weeks)
Evaluation of responses to a bioethics questionnaire will be used to assess patient factors influencing enrollment in this elderly-specific phase I trial
Time frame: Baseline
Number of Circulating Tumor Cells (CTC) at baseline and after treatment with Hsp90 inhibitor AUY922
Blood will be collected for measurement of CTCs on Cycle 1 Day 1 pre-infusion, Cycle 2 Day 1 pre-infusion, Cycle 3 Day 1, pre-infusion, then Day 1 of every other cycle until the end of the study.
Time frame: at baseline and end of treatment
Level of HSP70 at baseline and after treatment with Hsp90 inhibitor AUY922
Time frame: at baseline and at 28 days (first cycle)
Level of M30 and M65 at baseline and following therapy with Hsp90 inhibitor AUY922
Time frame: at baseline and at 28 days (first cycle)