Presentation on theme: "A phase I study of CHR-2797, an orally active aminopeptidase inhibitor, in elderly and/or treatment refractory patients with acute myeloid leukemia or."— Presentation transcript:
A phase I study of CHR-2797, an orally active aminopeptidase inhibitor, in elderly and/or treatment refractory patients with acute myeloid leukemia or multiple myeloma F.E. Davies 1, G.J. Ossenkoppele 2, P. Zachée 3, R.M. Noppeney 4, A.K. Burnett 5, M. Delforge 6, P. Sonneveld 7, G.J. Morgan 1, S. Zweegman 2, D.A. Breems 3, L.W. Hooftman 8, B. Löwenberg 7 1 Royal Marsden Hospital, London; 2 Vrije Universiteit MC, Amsterdam; 3 ZNA Antwerpen; 4 University Hospital, Essen; 5 Cardiff University Hospital; 6 UZ Gasthuisberg, Leuven; 7 Erasmus MC, Rotterdam; 8 Chroma Therapeutics Ltd, Oxford
Disclosures for Dr Faith Davies Presentation includes discussion of the following off-label use of a drug or medical device: Investigational: Aminopeptidase inhibitor CHR-2797 in acute myeloid leukemia or multiple myeloma Research Support/P.I. No relevant conflicts of interest to declare Employee Consultant Major Stockholder No relevant conflicts of interest to declare Speakers Bureau No relevant conflicts of interest to declare Honoraria Scientific Advisory Board No relevant conflicts of interest to declare In compliance with ACCME policy, ASH requires the following disclosures to the session audience: 49 th ASH Annual Meeting Atlanta, Georgia
CHR-2797: an aminopeptidase inhibitor CHR-2797 is a first-in-class aminopeptidase inhibitor Anti-tumor activity of CHR-2797 established in animal models CHR-2797 is an orally available compound with a pharmacokinetic profile that justifies once-daily dosing* CHR-2797 leads to signs of amino acid deprivation in sensitive cells** by targeting intracellular members of the M1/17 family of aminopeptidases, such as: – puromycin-sensitive aminopeptidase (PuSA) – leucine aminopeptidase (LAP) – leukotriene A 4 hydrolase (LTA 4 hydrolase) CHR-79888 is the active metabolite of CHR-2797 *Protheroe et al. J Clin Oncol 2007; 25 (18 June 20 Suppl): 3537; **Krige et al. AACR 2007;
Effect of CHR-2797 on protein recycling Cellular proteins Ubiquitylated cellular proteins Proteasomal degradation Ubiquitin ligase(s) Aminopeptidases Amino acids C-terminally truncated peptides Protein synthesis CHR-2797 Insufficient amino acids
Synergy between CHR-2797 and cytotoxic agents in AML blast proliferation assays Jenkins et al. Blood 2007; 110 (11): Abstract #1608.
Rationale - AML and MM AML, MDS and MM are diseases of the elderly Intensive induction chemotherapy is the only potentially curative treatment, however, it is not appropriate for many patients Prognosis is generally poor and few therapeutic advances have been made for this patient group in the last 20 years New treatments approaches are needed In-vivo studies have demonstrated: –CHR-2797 has profound cytoreductive properties in AML – possibly due to CD13/aminopeptidase N* –CHR-2797 induces apoptosis in MM, even in the presence of the protective effect of the bone marrow stroma** *Jenkins et al. Blood 2007; 110 (11): Abstract #1608; **Davies et al. Blood 2007; 110 (11): Abstract #2505.
Study objectives (phase I) Primary objectives Safety Tolerability Dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) Secondary objectives Pharmacokinetic parameters for CHR-2797 when administered orally at increasing dose levels Preliminary assessment of anti-tumor activity of CHR-2797 in patients with AML, MDS, or MM
CHR-2797-002 : study schema PHASE IPHASE II Open-label, non-randomized, multicenter phase I-II study Time (days) 8456280 First 28 days are dose-finding/DLT phase Recommended dose level determined in phase I administered to maximum of 40 patients for 84 days CHR-2797 60 mg once daily, oral dose Cohort of 3 patients CHR-2797 90 mg once daily, oral dose Cohort of 3 patients CHR-2797 130 mg once daily, oral dose Cohort of 3 patients CHR-2797 180 mg once daily oral dose If one observed DLT, 3 additional patients added to original cohort
Key eligibility criteria Patients (age >18 years) with confirmed diagnosis of AML, MDS (RAEB-1 or 2), or MM who are not candidates for chemotherapy PS < 2 (ECOG scale) Estimated life expectancy greater than 3 months Serum creatinine 1.5 x ULN Total bilirubin 1.5 X ULN, AST/ALT 2.5 x ULN
Definitions: DLT & MTD DLT Drug-related, non-hematologic grade III-IV toxicity –except fatigue, nausea and vomiting, diarrhea, alopecia, myalgia or arthralgia (unless prophylactic or therapeutic measures administered) Grade IV thrombocytopenia (reduction in platelet count of >75% compared to baseline) Grade IV anemia (reduction in Hb of >75%, compared to pre- treatment) Inability to tolerate 28 days therapy due to toxicity MTD Dose at which DLT is documented for 2 or more patients in a 6 patient cohort
Patient characteristics (cont) (n=16) Time from diagnosis, years (range)3.1 (0.1-8.8) Previous treatment de novo4 previous therapy12 median no. previous cytotoxic chemotherapy 2 (range 0-8)
Patient characteristics (cont) Cytogenetics (AML patients only)(n=13) Favorable t(15;17)1 Intermediate normal karyotype8 all others2 Unfavorable complex karyotype2
Dose No. of patients (n=16) Median duration of therapy including extended treatment, days (range)* 60 mg 3144 (119 – 196) 90 mg 448.5 (13 - 174) 130 mg 674.5 (48 – 407) 180 mg 321 (9 – 77) *Patients with at least SD at 28 days were allowed to continue therapy at the discretion of the treating clinician Treatment summary: duration of treatment
Most commonly reported potentially related adverse events Adverse reaction by preferred term Patients reporting (%) Total # patients reporting Most severe grade reported per patient Gr 1Gr 2Gr 3Gr 4 Thrombocytopenia31.355 Diarrhea18.8321 Dyspepsia12.5211 Abdominal pain6.311 ALT increased6.311 Alopecia6.311 Anorexia6.311 Atrial fibrillation6.31*1 Right bundle branch block 6.31*1 Dizziness6.311 * same patient
Dose-limiting toxicity DLT Dose No. of patients No. of occurrences ALT elevation (Grade III) 130 mg11 Thrombocytopenia (Grade IV) 180 mg22
Results: tolerability 13/16 patients finished dose-finding phase (28 days) 6/16 patients continued for at least 84 days CHR-2797 was well tolerated –No grade III/IV drug-related non-hematologic toxicity during first 28 days treatment, except for 1 patient with Grade III ALT elevation CHR-2797 had no effect on hemoglobin or neutrophils
Results: response data 3/13 AML patients had CR, one of which was also a cytogenetic response –After 1-3 months of CHR-2797 therapy (60 and 130 mg) –All > 65 years of age –Response was independent of number of lines of previous therapy or AML category 1 AML patient completely transfusion independent for 18 weeks (60 mg) 1 AML patient was in remission for 3 months (130 mg) 1 MM patient completed 6 months of therapy in SD (90 mg)
Conclusions (1) CHR-2797 is the first synthetic aminopeptidase inhibitor to demonstrate promising activity in adult AML As an orally bioavailable agent, CHR-2797 has a pharmacokinetic profile that supports once-daily dosing Elderly and/or treatment refractory patients with AML/MDS/Myeloma tolerated chronic therapy with this drug very well and were able to continue therapy for 84 days and longer
Conclusions (2) CHR-2797 has demonstrated encouraging clinical activity, in particular in elderly/refractory AML patients: –4/13 patients had meaningful clinical response –3/13 patients had bone marrow CR: there was one cytogenetic response, and one patient was in remission for 4 months CHR-2797 is the only aminopeptidase inhibitor in clinical development for both solid and hematologic tumors Mechanism-based combinations of CHR-2797 with other agents are planned based on favorable synergy patterns Phase II studies in elderly and/or treatment refractory AML patients are either ongoing or planned.
Acknowledgements Thank all of the following: Patients and staff at the participating hospitals –Royal Marsden Hospital, London –Cardiff University Hospital, Cardiff –Erasmus MC/Daniel Den Hoed, Rotterdam –Vrije Universiteit, Amsterdam – University Hospital, Leuven –Antwerp Hospital Network (ZNA), Antwerp –Universität Gesamthochschule, Essen –Universitätsklinikum, Münster Nexus Oncology Ltd Chroma Therapeutics Ltd