III.

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.

Absolute uterine infertility affects millions of women in the United States and more throughout the world. For instance, each year in the United States about 5,000 hysterectomies are performed in women under the age of 24. In total, nearly 9 million women of reproductive age have had a hysterectomy. Based on fecundity rates, thousands of these women may be candidates for uterus transplantation. An ongoing study enrolling some of these potential recipients onto a uterus transplant "waiting list" has revealed that most of these women have Rokitansky syndrome, hysterectomy secondary to endometriosis, cervical cancer, or compelling personal accounts justifying their candidacy. Fertility restoration by uterus transplantation was derived from fertility preservation research, including the development of the radical trachelectomy, oxygenation and perfusion of the in situ uterus, and work with organ donor networks. A decade of modern animal research set the foundation for this human work. Ongoing experiments include stable, long-term large animal allografts for investigating immunosuppression regimens and other transplantation details. Each of the animal models has contributed to the current knowledge base. Recently, nonhuman primates have been used to further investigate the possibility of human uterus transplantation. Nonhuman primate anatomy is analogous to that of humans with notable exceptions. The first human uterus transplant surgery took place in 2000, but it did not result in a pregnancy. However, taken in total, the magnitude of the intervening work from multiple groups throughout the world has made uterus transplantation a topic for discussion. It may also soon be a reality.

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