1026MO - Phase Ib dose escalation study of novel immunogenic cell death (ICD) inducer PT-112 plus PD-L1 inhibitor avelumab in solid tumours

Background

Pyrophosphate-platinum conjugate PT-112 induces ICD, recruits effector T cells, promotes immune memory and synergizes with immune checkpoint inhibitors (ICI) in murine models. This pleiotropic mechanism of action, along with durable responses to PT-112 alone in ICI non-responding pts, prompted this combination study with avelumab (“PAVE”), from which we present results of dose escalation.

Methods

A 3+3 design was used to determine the recommended phase II dose (RP2D) for PT-112 (28-day cycle IV days 1, 8, 15) with avelumab 800 mg (days 1 and 15) in pts with progressing solid tumors, with no available effective therapy (Tx). Previous ICI Tx was allowed.

Results

Across five dose cohorts (150, 200, 250, 300, and 360 mg/m² PT-112) 36 pts were enrolled: 7 non-small cell lung, 6 urothelial, 4 breast, 3 castration-resistant prostate (CRPC), and 1 squamous head and neck, plus 15 supplemental CRPC pts enrolled at 200 mg/m² to enhance safety and efficacy data. PAVE was well tolerated with no dose limiting toxicity. Common treatment-related adverse events (TRAEs) were nausea (47%), fatigue (31%), thrombocytopenia (28%), and decreased appetite (28%); 44% of pts had grade 3-4 TRAEs (most frequent was thrombocytopenia: 17%). The PT-112 RP2D is 360 mg/m², as reported for PT-112 single agent. Median prior lines of systemic Tx differed for escalation pts (4) and supplemental CRPC pts (6), and modified dosing was effective in pts with limited bone-marrow reserve. Of 12 pts with measurable disease and imaging follow-up in escalation, 8 experienced stable disease (4 with prior ICI Tx). Two CRPC pts responded: one with durable improved PSA and bone metastases, PFS 11.4 months (150mg/m², MSI stable); another with confirmed RECIST partial response (66% reduction), PSA reduction (94%), bone scan improvement, and ongoing PFS 9.5 months (200 mg/m², PIK3CBmut and PTEN loss, prior ICI Tx). 4 of 18 total CRPC pts had reductions in PSA ≥50%; 15 of 18 in alkaline phosphatase.

Conclusions

PAVE combination Tx was feasible and well-tolerated in a heavily pre-treated population. Preliminary evidence of efficacy was observed across a range of PT-112 doses, and further investigation of the combination is ongoing in the phase IIa portion of the protocol.

Clinical trial identification

NCT03409458.

Editorial acknowledgement

Legal entity responsible for the study

Phosplatin Therapeutics.

Funding

Phosplatin Therapeutics.

Disclosure

T.D. Ames, J.M. Jimeno: Leadership role, Shareholder/Stockholder/Stock options, Full/Part-time employment: Phosplatin Therapeutics. All other authors have declared no conflicts of interest.