Date: 2014-12-01
Type of information: Presentation of results at a congress
phase: 2
Announcement: presentation of results at the 56th American Society of Hematology (ASH) Annual Meeting and Exposition, being held December 6-9 in San Francisco, CA
Company: Chroma Therapeutics (UK) Cell Therapeutics (USA)
Product: tosedostat
Action
mechanism: Tosedostat is an orally dosed aminopeptidase inhibitor which blocks the M1/17 family of aminopeptidases. Disrupting aminopeptidases deprives sensitive tumour cells of amino acids by blocking protein recycling, resulting in tumor cell death. Tosedostat has demonstrated significant anti-tumour responses in bloodrelated cancers and solid tumors in phase I-II clinical trials. Tosedostat is licensed by Chroma from Vernalis and is exclusively sublicensed to CTI for marketing and co-development in North, Central and South America.
Disease: relapsed or refractory acute myeloid leukemia (AML)
Therapeutic area: Cancer - Oncology
Country:
Trial
details: The Phase II study enrolled 73 patients randomized to two treatment arms:tosedostat 120 mg once-daily for six months or 240 mg once-daily for two months followed by 120 mg once-daily for four months. The median age of the patients was 72 years old. Prior primary induction therapy for AML included 58% of the patients treated with Ara-C plus anthracycline or other Ara-C regimens, 36% of the patients treated with HMAs and 7% of the patients treated with other regimens. Fifty-two percent had been refractory to primary induction therapy. (NCT00780598)
Latest
news: * On December 1, 2014, CTI BioPharma announced the upcoming presentations of data highlighting tosedostat, an oral selective inhibitor of aminopeptidases, at the 56th American Society of Hematology (ASH) Annual Meeting and Exposition, being held December 6-9 in San Francisco, CA. The presentations include analysis of a Phase 2 trial of treatment with tosedostat in combination with cytarabine or decitabine in patients with AML or myelodysplastic syndrome (MDS). A Randomized Phase II Study of Tosedostat in Combination with Either Cytarabine or Decitabine in Newly Diagnosed Older Patients with Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome. First Author: Raya Mawad, M.D., Clinical Research Division, Fred Hutchinson Cancer Research Center and University of Washington, Seattle, WA * On March 4, 2013, Cell Therapeutics and Chroma Therapeutics have announced that Lancet Oncology has published results from the OPAL Phase 2 study of tosedostat in elderly patients with relapsed or refractory acute myeloid leukemia (AML). The trial showed that once-daily oral tosedostat resulted in a disease control rate of 51%. Subset analyses suggested the greatest benefit occurred in the difficult-to-treat patients with prior myelodysplastic syndrome (MDS) or those that had received prior hypomethylating therapy (HMA). Adverse events were mild, predictable and manageable. As previously presented at the 53rd American Society of Hematology Annual Meeting, results included: * On December 13, 2011, Chroma Therapeutics and its partner for the Americas, Cell Therapeutics, announced that final results from the Phase II OPAL study of tosedostat in elderly patients with relapsed or refractory acute myeloid leukemia (AML) were presented by Jorge Cortes, M.D. of the University of Texas M.D. Anderson Cancer Center during the ‘Acute Myeloid Leukemia - Therapy, excluding Transplantation: Clinical Studies’session at the American Society of Hematology (ASH) Annual Meeting. Highlights of the study: - Elderly (median age 72 years) poor risk patient group, approximately half (52%) of whom had AML refractory to their last treatment prior to commencing treatment with tosedostat
Overall response rate (ORR) of 22% (16/73), with 10% (7/73) achieving a complete response (CR) and 29% (21/73) of patients achieving stable disease (SD) for a disease control rate of 51%.
High response rates were observed in patients who previously received HMAs or initially were diagnosed with MDS, with an ORR of 38% (10/26) and 37% (7/19), respectively.
Median overall survival (OS) for patients achieving a CR was 322 days; partial response (PR) 195 days; and SD 162 days.
Adverse events were similar between dosing groups. Tosedostat was generally well-tolerated, with the majority of adverse events of grade 1 and 2. The most common treatment-related serious adverse event was febrile neutropenia reported in 29% of patients. The publication by Dr. Cortes, et al. titled "Two dosing regimens of tosedostat in elderly patients with relapsed or refractory acute myeloid leukemia (OPAL): a randomized open-label phase 2 study," is available at http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70037-8/abstract.
- Fifty-one percent (51%) of patients experienced disease control with 22% achieving a major leukemic response: 12% of patients achieved a complete (CR) bone marrow responses
- While responses were observed across patient groups treated with all types of prior AML therapy, 36% of patients who had failed prior therapy with hypomethylating agents (HMAs) achieved a response; similarly 37% of patients with secondary AML from prior myelodysplastic syndrome (MDS) achieved a response, suggesting that this population is potentially highly sensitive to tosedostat anti-leukemic activity.
- Median overall survival for patients achieving a CR was 323 days, Partial Response (PR) 195 days, and Stable Disease (SD) 162 days
- Tosedostat was well tolerated with most frequent grade >3 side effect being diarrhea (4%), fatigue (21%), and febrile neutropenia (29%)
The results demonstrate that once-daily oral tosedostat has encouraging antileukemic activity in poor risk elderly patients that had prior MDS or had previously failed treatment with HMAs. Based on these results Chroma and CTI are currently planning a Phase III study in patients with high risk MDS or secondary AML who have failed to respond adequately to HMAs. Chroma and CTI currently expect to initiate this study in the second quarter of 2012
