PH-139: A Phase I Safety and Pharmacokinetic Study of Gamitrinib Administered Intravenously to Patients With Advanced Cancer
Summary
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.
Arms & interventions
- DrugGamitrinib
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.
Outcome measures
Primary
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
Secondary
Evaluate the overall safety profile of intravenously administered single-agent gamitrinib
Time frame: 7 years
To evaluate the peak concentration (Cmax) of gamitrinib
Time frame: 7 years
To evaluate the area under the concentration time curve (AUC0-t) of gamitrinib
Time frame: 7 years
To evaluate the clearance (CL) of gamitrinib
Time frame: 7 years
To evaluate the time to maximum concentration (Tmax) of gamitrinib
Time frame: 7 years
To evaluate the coefficient of variation (CV) of gamitrinib
Time frame: 7 years
Assess the pharmacodynamic effects of gamitrinib
Time frame: 7 years
Document any anti-tumor activity of single agent gamitrinib
Time frame: 7 years
Eligibility criteria
Study locations (1)
Fox Chase Cancer Center
Philadelphia, Pennsylvania, 19111
References
- Hayat U, Elliott GT, Olszanski AJ, Altieri DC. Feasibility and safety of targeting mitochondria for cancer therapy - preclinical characterization of gamitrinib, a first-in-class, mitochondriaL-targeted small molecule Hsp90 inhibitor. Cancer Biol Ther. 2022 Dec 31;23(1):117-126. doi: 10.1080/15384047.2022.2029132.(PubMed)