Background: Thapsigargin induces apoptosis through disruption of calcium homeostasis. G-202 is a thapsigargin-based prodrug whose cytotoxic activity is blocked by a masking peptide that is cleaved by PSMA, a membrane-bound protease expressed in prostate cancer cells and the endothelium of tumor vasculature but not in most other tissues or the vasculature of normal tissue. An open-label, single-arm, dose-escalation Phase I study was performed in patients with advanced solid tumors to evaluate the safety and pharmacokinetics of G-202 and establish a Phase II dosing regimen.

Methods: 3+3 dose escalation of G-202 starting at 1.2 mg/m2 administered by intravenous infusion on Days 1, 2 and 3 of a 28-day cycle. Dose escalated in 100% increments until occurrence of at least two G-202 related equivalent Grade 2 adverse events (AEs) in the same cohort, at which time 33% dose increments were implemented. A Phase II dosing regimen was established and evaluated in an expansion cohort. PK parameters were measured in Cycle 1.

Results: In the dose escalation, 28 patients (pts) were treated at 8 dose levels (1.2 to 88 mg/m2). A protocol-defined MTD was not reached, but infusion-related reactions and creatinine elevation at 88 mg/m2 led to declaration of 66.8 mg/m2 as MTD. A modified regimen to reduce infusion-related reactions of G-202 at 40 mg/m2 on Day 1 and 66.8 mg/m2 on Days 2 and 3 was evaluated in an expansion cohort of 16 pts with a total of 48 cycles administered (avg 3/pt, range 1-12). Among the 44 pts treated on the study, there were 132 drug-related AEs, 60% of which were Grade 1. Related AEs of any grade reported in at least 4 (10%) patients were fatigue (16 pts), rash (16 pts), increased creatinine/acute kidney injury/acute renal failure (12 pts), nausea (12 pts), fever (8 pts), infusion-related reaction (8 pts), anorexia (7 pts), chills (7 pts), pruritis (7 pts), AST elevation (5 pts), heartburn (5 pts), vomiting (5 pts), and thrombocytopenia(4 pts). Prophylactic intravenous hydration on the day of infusion appeared to ameliorate creatinine elevations. G-202 has a mean half-life of 21 hours and steady state distribution volume of 4995 mL/m2, suggesting confinement to plasma. Because PSMA is highly expressed in hepatocellular carcinoma (HCC), the expansion cohort was enriched with HCC pts. Five HCC pts were enrolled and received a total of 29 cycles (avg 6/pt, range 2-12). One pt completed 12 cycles before exhibiting disease progression and one pt completed 9 cycles before being withdrawn due to an unrelated treatment delay.

Conclusions: The MTD of G-202 administered intravenously for 3 consecutive days of a 28-day cycle is 66.8 mg/m2. A dosing regimen of 40 mg/m2 on Day 1 and 66.8 mg/m2 on Days 2 and 3 appears to be well-tolerated and may have activity in HCC. G-202 is being evaluated in a Phase 2 study in patients with HCC who have progressed on sorafenib.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B244.

Citation Format: Devalingam Mahalingam, Jeremy Cetnar, George Wilding, Samuel Denmeade, John Sarantopoulos, Michael Kurman, Michael Carducci. A first-in-human phase 1 clinical study of G-202, a thapsigargin-based Prostate-Specific Membrane Antigen (PSMA) activated prodrug, in patients with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B244.