imifoplatin (PT-112)

Our data provide additional insight into mitochondrial stress and ICD in response to PT-112. PT-112 anticancer immunogenicity could have clinical applications and is currently under investigation in a Phase 2 mCRPC study.

P2, N=109, Active, not recruiting, Promontory Therapeutics Inc. | Recruiting --> Active, not recruiting | N=180 --> 109

P1/2, N=68, Completed, Promontory Therapeutics Inc. | Active, not recruiting --> Completed | Phase classification: P1b/2a --> P1/2

PT-112 substantially reduced the amount of mitochondrial CoQ10 in L929 cells, while the basal CoQ10 levels were below our detection limits in L929dt cells, suggesting a potential relationship between a low basal level of CoQ10 and PT-112 sensitivity. Finally, the expression of HIF-1α was much higher in cells sensitive to PT-112 compared to cells with an intact OXPHOS pathway, suggesting potential clinical applications.

PT-112 was broadly active in the PC cell lines tested, while sparing benign prostate cells, indicative of PT-112 cancer cell selectivity and of activity that crosses the varied malignant prostate phenotypes, including androgen receptor positive and negative cell lines. Cell death was primarily apoptotic, as shown by the inhibitory effects of Z-VAD-fmk. Consistent with prior work reported in glycolytic murine cells, in this PC cell panel PT-112 induced mtROS accumulation and mitochondrial membrane depolarization, as well as DAMP release, demonstrating that these may be fundamental and linked responses of cancer cells to PT-112.

Funding: Phosplatin Therapeutics. Clinical trial identification: NCT03409458.

PT-112 was well-tolerated with evidence of efficacy in mCRPC as mono-Tx and in combination with avelumab in heavily pre-treated pts. Bone pain improvement and nearly universal observation of ALP reduction suggest marked therapeutic activity of PT-112 in bone metastases. Serologic / RECIST responses and prolonged disease control in multiple pts substantiate further development of PT-112 in mCRPC.

PT-112 was well-tolerated with evidence of efficacy in mCRPC as mono-Tx and in combination with avelumab in heavily pre-treated pts. Bone pain improvement and nearly universal observation of ALP reduction suggest marked therapeutic activity of PT-112 in bone metastases. Serologic / RECIST responses and prolonged disease control in multiple pts substantiate further development of PT-112 in mCRPC.