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Cyclin-Dependent Kinase Inhibitor Proteins

Protein Kinase Inhibitors

Enzyme Inhibitors

Patients receive onalespib 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.

CDK Inhibitor AT7519

Laboratory Biomarker Analysis

Onalespib

Pharmacological Study

Khanh T Do

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.

Onalespib and CDKI AT7519 in Treating Patients With Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery

A Phase 1 Trial of the Combination of the Heat Shock Protein-90 (HSP90) Inhibitor Onalespib (AT13387) and the Cyclin-Dependent Kinase (CDK) Inhibitor AT7519M in Patients With Advanced Solid Tumors

Scored using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

Assessed using the NCI CTCAE version 5.0.

Defined as =\< 1 out of 6 patients experiencing dose limiting toxicity.

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.

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.

Measured by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v.1.1).

Spots Global Cancer Trial Database for cdk inhibitor at7519