A first-in-human study of the novel metabolism-based anti-cancer agent SM-88 in subjects with advanced metastatic cancer

Abstract

Purpose SM-88 (D,L-alpha-metyrosine; racemetyrosine) is a novel anti-cancer agent, used with melanin, phenytoin, and sirolimus (SMK Therapy). This pilot first-inhuman study characterized the safety, tolerability, and efficacy of SMK Therapy in subjects with advanced metastatic cancer. Methods All subjects (n = 30) received SMK Therapy for an initial 6 week Cycle (5 days on, 2 off per week) and continued if well tolerated. Safety signals, clinical response, overall survival, progression free survival (PFS), and quality of life changes were assessed. Results The most common drug related adverse events were hyperpigmentation and rash. All drug related adverse events were mild to moderate in intensity. Following treatment with SMK Therapy, 4 subjects achieved complete response, 6 partial response, and 17 stable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (total clinical benefit 90%). Responses were observed within 6 weeks, and continued to improve, with 3 complete and 3 partial responders achieving best response after at least 3.2 months. Durable stable disease was observed, lasting a median duration of 11 months (range 1-31 months). Median overall survival for all subjects was 29.8 months, and median PFS was 13 months. Following 6 weeks of treatment, most (83.3%) subjects showed an improvement in Eastern Cooperative Oncology Group (ECOG) score and an improvement in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ 30) global health status (baseline 61.2 ± 25.0; end of Cycle 1 80.7 ± 14.7; n = 29; p < 0.001). Conclusions The results of this study support continued development of SM-88.

Phase II trial of SM-88, a cancer metabolism based therapy, in non-metastatic biochemical recurrent prostate cancer

“…SM-88 used with MPS as conditioning agents, exploits this phenotype to introduce oxidative stress selectively into cancer cells [2,7,8]. This specificity may explain the limited off target effects, and efficacy independent of hormonal deprivation that has now been reported in four cohorts of patients treated with SM-88.…”

“…Racemetyrosine (SM-88,) is a small molecule amino-acid analogue that has shown antitumor activity in a range of malignancies including metastatic prostate cancer [2]. The anticancer effect is unrelated to testosterone levels in blood or tumor hormone receptor status [3][4][5].…”

Clinical development of metabolic inhibitors for oncology

“…Racemetyrosine (SM-88) is a tyrosine mimetic being developed for the treatment of various cancers, including pancreatic, lung, breast, prostate, sarcoma, and lymphoma ( 123 ). Some cancer cells more avidly take up and consume tyrosine compared with normal cells.…”

“…In a mouse colon cancer xenograft model, racemetyrosine was reported to reduce HCT116 tumor growth ( 125 ). A first-in-human, open-label, pilot study of racemetyrosine was conducted in advanced metastatic cancer patients in combination with melanin, phenytoin, and sirolimus (SMK therapy) ( 123 ). In addition, a phase Ib/II, open-label, dose-escalation study of racemetyrosine was conducted in combination with methoxsalen, phenytoin, and sirolimus in patients with non-metastatic biochemically recurrent prostate cancer ( 126 ).…”

Systemic Treatment of Ewing Sarcoma: Current Options and Future Perspectives

“…With this same rationale, the dysfunctional tyrosine SM-88 (racemetyrosine) interrupts the protein synthesis in cancer cells. Tested in a Phase I study of 30 participants with advanced metastatic cancer, it achieved four complete and six partial responses [119] and is currently being evaluated in combination with rapamycin, phenytoin, and methoxsalen in a Phase II trial.…”