This is a first-in-human, phase I, open-label, non-randomized dose-escalation and dose-expansion study with the primary objective to determine the safety profile of small molecule, mitochondrial-targeted Hsp90 inhibitor, gamitrinib, including identification of dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) in patients with advanced cancers. A secondary objective of the study is to determine the recommended dose and regimen(s) for a phase II study. This study is based on preclinical data demonstrating the anticancer activity, unique mechanism of action and preliminary safety of gamitrinib. In the dose-finding portion of this study, gamitrinib formulated in Lipoid S100®-based formulation will be administered as a 1-hour IV infusion once weekly for four weeks as 28-day treatment cycles. Up to 36 patients will be enrolled in the dose-escalation component of the study based on anticipated cohorts. The starting dose will be 10 mg, corresponding to allometric scaling) from the most sensitive species (rats) in the 29-day GLP toxicology and toxicokinetic studies with 14-day recovery period of gamitrinib. Dose-escalation will follow a 3+3 design. Six patients will be enrolled in the dose-expansion component of the study at MTD for the purpose of exploring pharmacodynamic effects via tumor pre and on-therapy biopsies.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
42
This is a first-in-human, phase I, open-label, non-randomized dose-escalation and dose-expansion study with the primary objective to determine the safety profile of small molecule, mitochondrial-targeted Hsp90 inhibitor, gamitrinib, including identification of dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) in patients with advanced cancers. A secondary objective of the study is to determine the recommended dose and regimen(s) for a phase II study. This study is based on preclinical data demonstrating the anticancer activity, unique mechanism of action and preliminary safety of gamitrinib.
Fox Chase Cancer Center
Philadelphia, Pennsylvania, United States
Determine the MTD and/or RP2D of gamitrinib when administered once weekly.
First cycle dose-limiting toxicities. The maximally tolerated dose (MTD) is defined as the dose level below which the absolute observed DLT rate is \> 25%. The MTD is equivalent to the anticipated recommended phase 2 dose (RP2D).
Time frame: 7 years
Evaluate the overall safety profile of intravenously administered single-agent gamitrinib
Overall, safety profile of gamitrinib as characterized by type, frequency, severity, timing and relationship to study therapy of adverse events and laboratory abnormalities according to NCI CTCAE v5.0.
Time frame: 7 years
To evaluate the peak concentration (Cmax) of gamitrinib
Blood sample will be collected for determination of gamitrinib plasma concentrations. The PK parameter to be evaluated includes peak concentration (Cmax).
Time frame: 7 years
To evaluate the area under the concentration time curve (AUC0-t) of gamitrinib
Blood sample will be collected for determination of gamitrinib plasma concentrations. PK parameter to be evaluated includes area under the concentration time curve (AUC0-t).
Time frame: 7 years
To evaluate the clearance (CL) of gamitrinib
Blood sample will be collected for determination of gamitrinib plasma concentrations. PK parameter to be evaluated includes clearance (CL).
Time frame: 7 years
To evaluate the time to maximum concentration (Tmax) of gamitrinib
Blood sample will be collected for determination of gamitrinib plasma concentrations. PK parameter to be evaluated includes time to maximum concentration (Tmax).
Time frame: 7 years
To evaluate the coefficient of variation (CV) of gamitrinib
Blood sample will be collected for determination of gamitrinib plasma concentrations. A coefficient of variation (CV) will be assessed at each dose level.
Time frame: 7 years
Assess the pharmacodynamic effects of gamitrinib
Assessment of gamitrinib effects on pharmacodynamic markers. The processed samples will be profiled for changes in the expression of 301 metabolites by Ultrahigh Performance Liquid Chromatography/Mass Spectrometry (UPLC/MS) or Gas Chromatography/Mass Spectrometry (G/MS) using the Metabolon, Inc. discovery platform
Time frame: 7 years
Document any anti-tumor activity of single agent gamitrinib
Objective tumor response, as assessed using RECIST 1.1 and RECIL 2017 criteria
Time frame: 7 years
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