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1Royal Marsden Hospital, London; 2Vrije Universiteit MC,

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Presentation on theme: "1Royal Marsden Hospital, London; 2Vrije Universiteit MC,"— Presentation transcript:

1 1Royal Marsden Hospital, London; 2Vrije Universiteit MC,
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. Davies1, G.J. Ossenkoppele2, P. Zachée3, R.M. Noppeney4, A.K. Burnett5, M. Delforge6, P. Sonneveld7, G.J. Morgan1, S. Zweegman2, D.A. Breems3, L.W. Hooftman8, B. Löwenberg7 1Royal Marsden Hospital, London; 2Vrije Universiteit MC, Amsterdam; 3ZNA Antwerpen; 4University Hospital, Essen; 5Cardiff University Hospital; 6UZ Gasthuisberg, Leuven; 7Erasmus MC, Rotterdam; 8Chroma Therapeutics Ltd, Oxford

2 Disclosures for Dr Faith Davies
In compliance with ACCME policy, ASH requires the following disclosures to the session audience: Research Support/P.I. No relevant conflicts of interest to declare Employee Consultant Major Stockholder Speakers Bureau Honoraria Scientific Advisory Board 49th ASH Annual Meeting ♦ Atlanta, Georgia 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

3 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 A4 hydrolase (LTA4 hydrolase) CHR 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;

4 Effect of CHR-2797 on protein recycling
Cellular proteins Ubiquitin ligase(s) Protein synthesis Insufficient amino acids Ubiquitylated cellular proteins Amino acids CHR-2797 Proteasomal degradation Aminopeptidases C-terminally truncated peptides

5 Synergy between CHR-2797 and cytotoxic agents in AML blast proliferation assays
Jenkins et al. Blood 2007; 110 (11): Abstract #1608.

6 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 .

7 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

8 CHR : study schema Open-label, non-randomized, multicenter phase I-II study Cohort of 3 patients Recommended dose level determined in phase I administered to maximum of 40 patients for 84 days CHR mg once daily, oral dose Cohort of 3 patients CHR mg once daily, oral dose Cohort of 3 patients If one observed DLT, 3 additional patients added to original cohort CHR mg once daily, oral dose First 28 days are dose-finding/DLT phase Cohort of 3 patients CHR mg once daily oral dose 28 56 84 PHASE I Time (days) PHASE II

9 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

10 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

11 Patient characteristics (n = 16 patients)
Average age, years (range) 68.4 (45-84) Male:female 13:3 Diagnosis No. (%) AML 13 (81.3) MDS 1 (6.3) MM 2 (12.5) ECOG at baseline 8 (50.0) 1 6 (37.5) 2

12 Patient characteristics (cont)
Time from diagnosis, years (range) 3.1 ( ) Previous treatment de novo 4 previous therapy 12 median no. previous cytotoxic chemotherapy 2 (range 0-8)

13 Patient characteristics (cont)
Cytogenetics (AML patients only) (n=13) Favorable t(15;17) 1 Intermediate normal karyotype 8 all others 2 Unfavorable complex karyotype

14 Treatment summary: duration of treatment
Dose No. of patients (n=16) Median duration of therapy including extended treatment, days (range)* 60 mg 3 144 (119 – 196) 90 mg 4 48.5 ( ) 130 mg 6 74.5 (48 – 407) 180 mg 21 (9 – 77) *Patients with at least SD at 28 days were allowed to continue therapy at the discretion of the treating clinician

15 Most commonly reported potentially related adverse events
Adverse reaction by preferred term Patients reporting (%) Total # patients reporting Most severe grade reported per patient Gr 1 Gr 2 Gr 3 Gr 4 Thrombocytopenia 31.3 5 Diarrhea 18.8 3 2 1 Dyspepsia 12.5 Abdominal pain 6.3 ALT increased Alopecia Anorexia Atrial fibrillation 1* Right bundle branch block Dizziness * same patient

16 Dose-limiting toxicity
DLT Dose No. of patients No. of occurrences ALT elevation (Grade III) 130 mg 1 Thrombocytopenia (Grade IV) 180 mg 2

17 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

18 PK profiles in man 130 mg cohort (n = 4)

19 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)

20 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

21 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.

22 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

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