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 myelomaF.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. Löwenberg71Royal 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 declareEmployeeConsultantMajor StockholderSpeakers BureauHonorariaScientific Advisory Board49th ASH Annual Meeting ♦ Atlanta, GeorgiaPresentation 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 inhibitorAnti-tumor activity of CHR-2797 established in animal modelsCHR-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 proteinsUbiquitin ligase(s)Protein synthesisInsufficientamino acidsUbiquitylated cellular proteinsAmino acidsCHR-2797Proteasomal degradationAminopeptidasesC-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 patientsPrognosis is generally poor and few therapeutic advances have been made for this patient group in the last 20 yearsNew treatments approaches are neededIn-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 objectivesSafetyTolerabilityDose-limiting toxicity (DLT) and maximum tolerated dose (MTD)Secondary objectivesPharmacokinetic parameters for CHR-2797 when administered orally at increasing dose levelsPreliminary assessment of anti-tumor activity of CHR-2797 in patients with AML, MDS, or MM
8 CHR : study schemaOpen-label, non-randomized, multicenter phase I-II studyCohort of 3 patientsRecommended dose leveldetermined in phase I administered to maximumof 40 patients for 84 daysCHR mg once daily, oral doseCohort of 3 patientsCHR mg once daily, oral doseCohort of 3 patientsIf one observed DLT, 3 additionalpatients added to original cohortCHR mg once daily, oral doseFirst 28 days are dose-finding/DLT phaseCohort of 3 patientsCHR mg once daily oral dose285684PHASE ITime (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 chemotherapyPS < 2 (ECOG scale)Estimated life expectancy greater than 3 monthsSerum creatinine 1.5 x ULNTotal bilirubin 1.5 X ULN, AST/ALT 2.5 x ULN
10 Definitions: DLT & MTD DLT Drug-related, non-hematologic grade III-IV toxicityexcept 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 toxicityMTDDose 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:female13:3DiagnosisNo. (%)AML13 (81.3)MDS1 (6.3)MM2 (12.5)ECOG at baseline8 (50.0)16 (37.5)2
12 Patient characteristics (cont) Time from diagnosis, years (range)3.1 ( )Previous treatmentde novo4previous therapy12median no. previous cytotoxic chemotherapy2 (range 0-8)
14 Treatment summary: duration of treatment DoseNo. of patients (n=16)Median duration of therapy including extended treatment, days (range)*60 mg3144 (119 – 196)90 mg448.5 ( )130 mg674.5 (48 – 407)180 mg21 (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 termPatients reporting (%)Total # patients reportingMost severe grade reported per patientGr 1Gr 2Gr 3Gr 4Thrombocytopenia31.35Diarrhea18.8321Dyspepsia12.5Abdominal pain6.3ALT increasedAlopeciaAnorexiaAtrial fibrillation1*Right bundle branch blockDizziness* same patient
16 Dose-limiting toxicity DLTDoseNo. of patientsNo. of occurrencesALT elevation (Grade III)130 mg1Thrombocytopenia (Grade IV)180 mg2
17 Results: tolerability 13/16 patients finished dose-finding phase (28 days)6/16 patients continued for at least 84 daysCHR-2797 was well toleratedNo grade III/IV drug-related non-hematologic toxicity during first 28 days’ treatment, except for 1 patient with Grade III ALT elevationCHR-2797 had no effect on hemoglobin or neutrophils
19 Results: response data 3/13 AML patients had CR, one of which was also a cytogenetic responseAfter 1-3 months of CHR-2797 therapy (60 and 130 mg)All > 65 years of ageResponse was independent of number of lines of previous therapy or AML category1 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 AMLAs an orally bioavailable agent, CHR-2797 has a pharmacokinetic profile that supports once-daily dosingElderly 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 response3/13 patients had bone marrow CR: there was one cytogenetic response, and one patient was in remission for 4 monthsCHR-2797 is the only aminopeptidase inhibitor in clinical development for both solid and hematologic tumorsMechanism-based combinations of CHR-2797 with other agents are planned based on favorable synergy patternsPhase 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 hospitalsRoyal Marsden Hospital, LondonCardiff University Hospital, CardiffErasmus MC/Daniel Den Hoed, RotterdamVrije Universiteit, AmsterdamUniversity Hospital, LeuvenAntwerp Hospital Network (ZNA), AntwerpUniversität Gesamthochschule, EssenUniversitätsklinikum, MünsterNexus Oncology LtdChroma Therapeutics Ltd