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

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.Research Support/P.I. No relevant conflicts of interest to declareNo relevant conflicts of interest to declare

EmployeeEmployee No relevant conflicts of interest to declareNo relevant conflicts of interest to declare

ConsultantConsultant No relevant conflicts of interest to declareNo relevant conflicts of interest to declare

Major StockholderMajor Stockholder No relevant conflicts of interest to declareNo relevant conflicts of interest to declare

Speakers BureauSpeakers Bureau No relevant conflicts of interest to declareNo relevant conflicts of interest to declare

HonorariaHonoraria No relevant conflicts of interest to declareNo relevant conflicts of interest to declare

Scientific Advisory BoardScientific Advisory Board No relevant conflicts of interest to declareNo relevant conflicts of interest to declare

In compliance with ACCME policy, ASH requires the following disclosures to the session audience:

49th A

SH A

nnua

l Mee

ting

♦ A

tlant

a, G

eorg

ia

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-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

Insufficientamino acids

0.01

0.1

1

10

100

Antagonism

Synergy

CHR 2797 CHR 2797 CHR 2797 + + + Bortezomib Ara-C ATRA

Median = 0.365

Median = 0.385

Median = 1.02

Combination Index

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 I PHASE II

Open-label, non-randomized, multicenter phase I-II study

Time (days)

8456280

First 28 days are dose-finding/DLT phase

Recommended dose leveldetermined 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

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 additionalpatients 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 & MTDDLT

• 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 (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 No. (%)

0 8 (50.0)

1 6 (37.5)

2 2 (12.5)

Patient characteristics (cont)

(n=16)

Time from diagnosis, years (range) 3.1 (0.1-8.8)

Previous treatment

de novo 4

previous therapy 12

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 karyotype 8

all others 2

Unfavorable

complex karyotype 2

DoseNo. of patients

(n=16)

Median duration of therapy including extended treatment,

days (range)*

60 mg 3 144 (119 – 196)

90 mg 4 48.5 (13 - 174)

130 mg 6 74.5 (48 – 407)

180 mg 3 21 (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 potentiallyrelated 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 5

Diarrhea 18.8 3 2 1

Dyspepsia 12.5 2 1 1

Abdominal pain 6.3 1 1

ALT increased 6.3 1 1

Alopecia 6.3 1 1

Anorexia 6.3 1 1

Atrial fibrillation 6.3 1* 1

Right bundle branch block

6.3 1* 1

Dizziness 6.3 1 1* same patient

Dose-limiting toxicity

DLTDose

No. of patients

No. of occurrences

ALT elevation (Grade III) 130 mg 1 1

Thrombocytopenia (Grade IV) 180 mg 2 2

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

PK profiles in man130 mg cohort (n = 4)

Packed blood cells CHR-79888: d1 vs d28

0

100

200

300

400

500

600

0 6 12 18 24

Hours

ng/ml

Day 1 packed cells79888

Day 28 packed cells79888

Plasma CHR-2797: d1 vs d28

0

100

200

300

400

500

600

700

800

0 6 12 18 24

Hours

ng/ml

Day 1 plasma 2797

Day 28 plasma 2797

Plasma CHR-79888: d1 vs d28

0

100

200

300

400

500

600

700

800

900

1000

0 6 12 18 24

Hours

ng/ml

Day 1 plasma 79888

Day 28 plasma 79888

Packed blood cells CHR-2797: d1 vs d28

0

50

100

150

200

250

0 6 12 18 24

Hours

ng/ml

Day 1 packed cells 2797

Day 28 packed cells 2797

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 for18 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