e15156 Background: Conventional alkylating agents are limited by systemic toxicities and lack of selectivity. LP-184 is a novel acylfulvene pro-drug that alkylates DNA only after being metabolized by the intracellular enzyme prostaglandin reductase1 (PTGR1), which is highly expressed in many solid tumors. In preclinical studies, LP-184 exhibited up to 12-fold enhanced anti-tumor activity in tumors with compromised DNA damage repair (DDR), such as BRCA and ATM mutations. LP-184 is being developed to target solid tumors with high PTGR1 expression and DDR deficiency. Methods: The dose escalation Phase 1a study (NCT05933265) enrolled patients with relapsed or refractory advanced solid tumors. The primary objective was to evaluate the safety and tolerability of LP-184. A Bayesian optimal interval design with a 30% target toxicity rate was used to define the maximum tolerated dose (MTD). Patients received LP-184 IV over 30 minutes on days 1 and 8 of each 21-day cycle until disease progression or intolerability. PTGR1 expression was quantified by RT-qPCR using archival tissue. Gene alterations were obtained when available from patients’ most recent pre-enrollment genetic reports. Results: 63 patients were treated across 12 dose cohorts, with dose levels (DL) ranging from 0.01 to 0.61 mg/kg. Dose limiting toxicities (DLTs) occurred in 3 patients, including one case of grade 3 platelet count decrease progressing to grade 4 at 0.49 mg/kg (DL11; DLT rate = 20%) and two cases at 0.61 mg/kg (DL12; DLT rate = 40%) consisting of grade 3 alanine aminotransferase increase and acute liver injury. Dose delays due to treatment-related adverse events (TRAEs) were reported in 15 (24%) patients. Dose reduction due to TRAEs were reported in 2 patients (3%), both treated at DL11. Drug discontinuation due to TRAEs occurred in 4 patients (6%), including one each at DL07, DL08, DL11, and DL12. The most common TRAEs (≥20%) were nausea (52%), vomiting (46%), fatigue (21%), and platelet count decrease (21%). Grade ≥3 TRAEs that occurred in more than two patients included platelet count decrease (n = 6, 10%) and anemia (n = 3, 5%). The best observed response was stable disease, which occurred in 40% of evaluable patients. Durable disease control (≥ 1 year) was observed in 3 patients with DDR mutations of known interest. LP-184 had an apparent elimination half-life of ~20 minutes and achieved the projected therapeutic concentration at DL07. PTGR1 was quantifiable in 94% of assayed samples, supporting the feasibility of assessing associations between PTGR1 expression and clinical benefit in future studies. Conclusions: LP-184 demonstrates a manageable safety profile with encouraging antitumor efficacy in tumors harboring key DDR alterations. The MTD is 0.49 mg/kg IV administered on days 1 and 8 every 21 days. Clinical trial information: NCT05933265 .
Mahadevan et al. (Thu,) studied this question.