This phase I trial studies the side effects and best dose of onalespib and CDKI AT7519 in treating patients with solid tumors that have spread from the primary site (place where they started) to other places in the body (metastatic) or cannot be removed by surgery. Onalespib and CDKI AT7519 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
PRIMARY OBJECTIVES: I. To establish the safety, tolerability, and the maximum tolerated dose of the combination of onalespib and AT7519M (CDKI AT7519). SECONDARY OBJECTIVES: I. To determine the pharmacokinetics of the combination of onalespib and AT7519M. II. To assess the pharmacodynamic effect of the combination of onalespib and AT7519M on HSP70 expression and modulation of HSP90 client proteins in peripheral blood mononuclear cells (PBMCs), plasma, and tumor biopsies. III. To observe and record anti-tumor activity. OUTLINE: This is a dose-escalation study. Patients receive onalespib intravenously (IV) over 1 hour on days 1 and 4 (cycle 0 only). Patients then receive onalespib IV over 1 hour and CDKI AT7519 IV over 1 hour on days 1, 4, 8, and 11 (cycle 1 and subsequent cycles thereafter). Cycles repeat every 21 days (7 days for course 0 only) in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 30 days.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
29
MedStar Georgetown University Hospital
Washington D.C., District of Columbia, United States
National Cancer Institute Developmental Therapeutics Clinic
Bethesda, Maryland, United States
National Institutes of Health Clinical Center
Bethesda, Maryland, United States
Massachusetts General Hospital Cancer Center
Boston, Massachusetts, United States
Dana-Farber Cancer Institute
Boston, Massachusetts, United States
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, United States
Incidence of adverse events of onalespib and CDKI AT7519
Scored using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Time frame: Up to 30 days after the last dose of study drug
Tolerability of onalespib and CDKI AT7519
Assessed using the NCI CTCAE version 5.0.
Time frame: Up to 30 days after the last dose of study drug
Maximum tolerated dose of onalespib and CDKI AT7519
Defined as =\< 1 out of 6 patients experiencing dose limiting toxicity.
Time frame: 21 days
Pharmacokinetic parameters of onalespib and CDKI AT7519
Individual patient plasma concentration-time curves will be analyzed by noncompartmental methods using routines supplied in the WinNonlin Professional Version 4.0.1 software package. Pharmacokinetic parameters and variables will be calculated according to standard equations. Mean values of the pharmacokinetic parameters will be statistically compared using the paired two-tailed t-test of the log-transformed data.
Time frame: Before infusion, at 30 and 59 minutes of infusion, and at 1.5, 2, 4, 6, 8, and 24 hours at end of infusion on day 1 of course 0 and days 1 and 11 of course 1
Pharmacodynamic (PD) parameters of onalespib and CDKI AT7519
PD effect of the combination of onalespib and CDKI AT7519 on Hsp70 expression and modulation of Hsp90 client proteins in peripheral blood mononuclear cells (PBMCs) will be assessed. All PD evaluations and comparisons will be done with exploratory intent, using primarily descriptive and non-parametric techniques.
Time frame: Prior to onalespib administration during course 0, 2-4 hours after completion of onalespib on day 4 of course 0, and 2-4 hours after completion of CDKI AT7519 on day 11 of course 1
Antitumor activity of the combination
Measured by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v.1.1).
Time frame: Up to 30 days after the last dose of study drug
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