Results of the OPAL Study: A Phase II Study to Evaluate the Efficacy, Safety and Tolerability of Tosedostat (CHR-2797) in Elderly Subjects with Treatment Refractory or Relapsed Acute Myeloid Leukemia

Tosedostat is a novel oral inhibitor of the M1/17 family of aminopeptidases which induces an amino acid deprivation response that is selectively toxic for myeloid blasts (Leuk Res. 2011: 5:677-81) and has shown promising activity in elderly relapsed/refractory AML patients (J Clin Oncol 2010:28:4333-8).

The OPAL study was undertaken to compare the activity of tosedostat at a once-daily dose of 120 mg for 24 weeks compared to 240 mg once daily for 8 weeks followed by 120 mg once daily for a further 16 weeks., as measured by bone marrow and hematology responses at 24 weeks.

This was a phase II randomized (1:1) multi-center study. Patients were eligible if aged 60 years or older with previous CR lasting <12 months, or no CR after primary therapy, had a peripheral blast count <30,000/μl, PS<2 and adequate renal, hepatic and cardiac function. The primary analysis was performed at 24 weeks using IWG 2003 criteria.

Seventy-three patients were randomized and received tosedostat, 38 at 120 mg and 35 at 240 mg. Median age was 72 (range, 64 to 86), and 59% were male. Twenty-six patients (36%) had secondary or therapy-related AML, of which 19 (26%) had prior MDS. Median time since AML diagnosis was 211 days and 38% had received primary therapy with cytarabine/anthracyclines; 36% with a hypomethylating agent (HMA) and 23% with other cytarabine regimes. Fifty-two percent had been refractory to primary therapy, 19% had previously had a remission of up to 6 months and 29% a 6–12 month remission (mean 97 days including refractory). Twenty-three patients (32%) had no post-treatment bone marrow sample taken, predominantly due to early progression: 34% completed 12 weeks on study and 14% completed 24 weeks and were eligible to enter an extension study which is ongoing. The overall response rate was 22%; (CR/CRp/MLFS 12%; PR 10%) and an additional 29% had a best response of stable disease. The most common adverse events which occurred (total; grade 3 or worse) were diarrhea (58%; 4.1%), peripheral edema (55%; 0%), fatigue (49%; 21%), dyspnea (41%; 16%), nausea (38%; 0%), decreased appetite (37%; 3%), febrile neutropenia (36%; 29%) and hypotension (36%, 10%). Median overall survival (OS) (at 15 July 2011) was 126 days. Median OS in patients with CR/CRp/MLFS, PR and SD were 280, 195 and 162 days respectively, and 261.5 days for patients with a response of PR or better. Median OS for patients with progression of disease or who were unevaluable was 61 days. Similar responses were seen in the two dose groups. Additional non protocol-specified analyses showed that the following types of patient appeared to respond well: AML NOC vs other AML types 16% vs 29% response, median OS 75 vs 168 days; patients with poor risk cytogenetics compared to intermediate/better, median OS 159 vs 107 days; those who received prior HMA compared to others, 38% vs 13% response, median OS 171 vs 104 days; and absence of prior CR 29% vs 14% response and median OS 169 vs 103 days.

These results provide further encouraging evidence of efficacy and a favorable toxicity profile in a difficult to treat patient population. A phase III program of pivotal studies with tosedostat in AML and MDS will start in the near future.

Cortes:Chroma Therapeutics Ltd.: Consultancy, Research Funding. Feldman:Chroma Therapeutics Ltd.: Consultancy, Research Funding. Yee:Chroma Therapeutics Ltd.: Consultancy, Research Funding. Rizzieri:Chroma Therapeutics Ltd.: Consultancy, Research Funding. Advani:Chroma Therapeutics Ltd.: Consultancy, Research Funding. Charman:Chroma Therapeutics Ltd.: Employment, Equity Ownership. Toal:Chroma Therapeutics Ltd.: Employment, Equity Ownership. Kantarjian:Chroma Therapeutics Ltd.: Consultancy, Research Funding.