A phase 1, first-in-human, open-label, dose-escalation and -expansion study of gamitrinib, a first-in-class, mitochondria-directed inhibitor of the molecular chaperone heat shock protein-90 (Hsp90) in patients with advanced cancer.

TPS3180 Background: Mitochondria are subcellular organelles whose signaling and bioenergetics functions are exploited in cancer. This requires tight control of intra-organelle protein folding, which is made possible by the accumulation of molecular chaperones of the Heat Shock Protein-90 (Hsp90) family in mitochondria of tumors, but not normal tissues. This provides a unique therapeutic opportunity to disable multiple tumor pathways at once, but previously developed Hsp90 inhibitors do not accumulate in mitochondria, and systemic inhibition of chaperone activity is toxic in humans. Gamitrinib is a first-in-class anticancer agent specifically designed to disrupt protein folding in mitochondria, combining the Hsp90 inhibitory backbone of 17-allylamino-geldanamycin (17-AAG) to the mitochondria-targeting moiety, triphenylphosphonium. Gamitrinib selectively accumulates in mitochondria, does not affect the function of cytosolic Hsp90, and irreversibly disrupts organelle protein folding with activation of multiple cell death pathways. In preclinical studies, Gamitrinib shows potent, cytotoxic activity against multiple cancer cell types (IC 50 0.16–29 µM), inhibits primary and metastatic tumor growth in xenograft and genetic mouse models, has slower clearance (85.6 ± 5.8 mL/min/kg) and longer half-life (12.2 ± 1.55 h) than unconjugated 17-AAG, and is well-tolerated with no alterations in clinical-chemistry parameters, organ function, or tissue histology at dose levels of up to 5 (rats)- and 12 (dogs)-fold higher than therapeutically effective doses in mice (Cancer Biol Ther 23:117). Methods: Based on preclinical activity, favorable safety, and unique mechanism of anticancer activity, a first-in-human, open-label, dose-escalation phase 1 trial of Gamitrinib in sequential cohorts of adult patients with advanced solid tumors or lymphoma, for whom no standard therapy is available, was initiated (NCT04827810). Per study protocol, Gamitrinib is administered as a 1-h weekly intravenous (IV) injection on a 28 day-cycle with a 3+3 dose-escalation design and dosing continuing until disease progression, unacceptable toxicity, or patient discontinuation for any other reason. Trial objectives include determination of MTD and/or RP2D, overall safety, PK profile, correlative studies of target engagement in paired pre- and post-treatment biopsies in a 6-patient expansion cohort at MTD and documentation of anti-tumor activity by RECIST 1.1 and RECIL 2017 criteria. As of 2026, 18 evaluable patients have been accrued over 5 escalating Gamitrinib dose levels (10-85 mg) with no DLTs as assessed by NCI CTCAE v5.0 grading. 336 plasma samples have been collected for PK analysis. The study is currently open and enrollment is ongoing. Clinical trial information: NCT04827810 .