Imexon (AOP 99.0001) for Treatment of Relapsed or Refractory Multiple Myeloma: A Phase I/II Study

Background: Imexon (AOP 99.0001 (4-imino-1,3-diazobicyclo-(3, 1, 0)-hexan-2-one) exerts antiproliferative activity on a range of tumor cells including myeloma cells and was found to inhibit tumor development in murine models of B-cell lymphoma. The antitumor activity of Imexon is caused by a sequence of molecular events starting with

• alkylation of thiol groups,

• reduction of the intracellular antioxidative defence mechanism,

• increase of reactive oxygen species (ROS) in mitochondria, and

• mitochondrial damage and induction of apoptosis.

Methods/Patients: 36 patients with relapsed or refractory myeloma who had been pretreated with at least two lines of prior therapy were included. Imexon was applied as a 15-min infusion on 5 consecutive days for 2 weeks (d1–5 and d8–12) with a rest period of one week (1 cycle). Escalation of the dose of Imexon was started with 50 mg/m² during the phase I part of the study.

Results: The plasma half life of the parent compound and its active metabolite Imexon was found to be approximately 1.2 hrs and 2.6 hrs, respectively. The mean duration of treatment with Imexon was 6.8 weeks in a dose range between 50 and 1000 mg/m² without reaching dose limiting toxicity. Drug related grade 1–2 AEs occurring with a frequency of >10 % were fatigue, nausea, constipation, headache, anorexia, muscle/bone pain, anemia, thrombocytopenia, leucopenia and transient elevation of GGT Grade 3–4 AEs related to study drug were leucopenia (n=3), anemia (n=2), thrombocytopenia (n=4), osteonecrosis (n=1), creatinine increase (n=1). In two patients dose reductions due to AEs were required. A total of 7 SAEs occured in 4 patients. All SAEs occurred at the 400 mg/m² DL 1 SAE (increase in creatinine) was considered to be related to study drug. There was no correlation between the dose of the study drug and AEs. In addition, no mortality was encountered while patients were on treatment with Imexon.

Imexon treatment resulted in a minimal response in one patient at the DL of 500 mg/m². In addition, a significant improvement of the preexisting distal polyneuropathy was noted in this patient during these first 3 therapy cycles. After discontinuation of Imexon, reappearance of the polyneuropathy was noted within 4 months. This led to retreatment of the patient at a dose level of 600 mg/m², which resulted in a gradual and finally complete resolution of the polyneuropathy with maintenance of the MR, but without further reduction in the mIg. No other objective response was observed in this study.

Conclusion: Overall, Imexon was safe and well tolerated in the dose range investigated. Imexon demonstrated only minor clinical activity in one patient. These results do not support the further development of Imexon as single agent in multiple myeloma. Due to its unique mechanism of action and its favourable toxicity profile it may, however, qualify for use and evaluation in combination with other agents in multiple myeloma and other malignancies.