Date: 2015-06-15
Type of information: Presentation of results at a congress
phase: 2
Announcement: presentation of results at the 20th Congress of the European Hematology Association, in Vienna, Austria
Company: CTI BioPharma - previously known as Cell Therapeutics (USA) National Cancer Research Institute (UK)
Product: tosedostat
Action
mechanism: enzyme inhibitor/aminopeptidase inhibitor. 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: acute myeloid leukemia high risk myelodysplastic syndrome
Therapeutic area: Cancer - Oncology
Country: UK
Trial
details: The Phase 2 multicenter clinical trial was designed to assess tosedostat (orally once-daily) in combination with intermittent LDAC (twice daily) in 33 elderly patients (median age = 75 years) with either primary AML or secondary AML after MDS. Courses of LDAC were repeated every four weeks for up to eight cycles in the absence of disease progression or unacceptable toxicity. The primary objective was to exceed the upper limit of institutional expected CR rates (P0=10%, P1= 25%, α=0.05, 1-β=80%); secondary objectives include safety and toxicity, stable disease, overall survival, and progression-free survival as well as the identification of a possible biomarker associated with sensitivity and/or disease resistance through global gene expression profiling.
Latest
news: * On June 15, 2015, CTI BioPharma announced findings from an investigator-sponsored Phase 2 trial in patients with either primary (de novo) acute myeloid leukemia (AML) or AML that has evolved from myelodysplastic syndrome (MDS). Results showed the combination of tosedostat with low dose cytarabine/Ara-C (LDAC) resulted in an overall response rate (ORR) of 54 percent in elderly patients with AML – with 45 percent of patients achieving durable complete responses (CR). These final results were presented by Dr. Giuseppe Visani, Director of Hematology and Stem Cell Transplant Center at AORMN, Pesaro, Italy in a poster session (abstract #P564) during the 20th Congress of the European Hematology Association (EHA), June 11-14, 2015 in Vienna, Austria. * On June 12, 2014, CTI BioPharma (previously known as Cell Therapeutics) announced the initiation of an international cooperative group Phase 2 clinical trial of tosedostat in combination with low-dose cytarabine in older patients with acute myeloid leukemia or high risk myelodysplastic syndrome. The trial is being conducted by the National Cancer Research Institute Haematological Oncology Study Group under the sponsorship of Cardiff University. The trial management group is led by Professor Alan K. Burnett, Head of Haematology in the Department of Medical Genetics, Haematology and Pathology at the School of Medicine at Cardiff University. Chroma Therapeutics Ltd., from whom CTI licensed tosedostat, is facilitating drug supply for the trial. In this Phase 2/3 trial, referred to as the AML Less Intensive (LI-1) trial, patients will be randomized to standard treatment, low dose cytarabine, versus one of five novel investigational treatments, one of which is tosedostat, each in combination with low dose cytarabine. The trial will utilize a \"Pick a Winner\" trial design.1 Under such a design, the Phase 2 portion of the trial is expected to initially enroll 50 patients per arm, and, if the complete response rate of cytarabine plus novel therapy appears satisfactory, an additional 50 patients per arm would be enrolled in the Phase 2 portion. Based on an interim analysis of complete response results, the trial management group may determine to move the applicable trial into the Phase 3 portion, which would then undertake to enroll 100 additional patients (for a total of 200 patients per arm). Overall survival will serve as the primary endpoint of the trial.
Final results presented at EHA show that responding patients had a significant improvement in overall survival based on response rates compared to non-responding patients (p=0.018). In the intent-to-treat population (ITT), the ORR was 54 percent – with CR observed in 45 percent of patients (n=15/33). In the responding patients, the median time for achieving best response was 74 days (range:22-145 days) and 55 percent (n=10/18) were still in remission after a median follow-up of 319 days. Safety analysis show that tosedostat in combination with LDAC was generally well tolerated. The primary adverse events observed were pneumonitis (12 percent), cardiac (6 percent), brain hemorrhage (3 percent), and asthenia (3 percent).
One of the secondary endpoints was to identify possible biomarkers associated with sensitivity and/or drug resistance. A gene expression profile (GEP) was performed on purified AML cells obtained from 29 patients. Analysis of these patient cells identified a molecular signature associated with clinical response (CR vs. no CR). Based on the differentially expressed genes (n=212), samples were divided according to either CR or no CR. Results showed that these differentially expressed genes were associated with relevant biological functions and pathways – including B-catenin (beta-catenin), TNFA-NFkB, ERB2, inflammatory response, and epithelial-mesenchimal transition – and showed that the achievement of a CR could be efficiently predicted by GEP.
"The results observed with tosedostat in acute myeloid leukemia add to a growing body of data showing the anti-tumor activity of this aminopeptidase inhibitor and the potential of using this approach to treat blood-related cancers," Alan K. Burnett, M.D., Global Lead for Myeloid Diseases at CTI BioPharma. "Based on the clinical data observed to date, we are advancing the development for tosedostat including the potential for a Phase 3 registrational study for primary acute myeloid leukemia or acute myeloid leukemia that evolves from myelodysplastic syndrome." (Abstract #P564 – "Tosedostat plus low dose cytarabine induces a high rate of responses that can be predicted by genetic profiling in AML: Final results of a Phase II multicenter study")
