Transcript No Slide Title

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
Research Support/P.I.
No relevant conflicts of interest to declare
Employee
No relevant conflicts of interest to declare
Consultant
No relevant conflicts of interest to declare
Major Stockholder
No relevant conflicts of interest to declare
Speakers Bureau
No relevant conflicts of interest to declare
Honoraria
No relevant conflicts of interest to declare
Scientific Advisory Board
No relevant conflicts of interest to declare
49th ASH Annual Meeting ♦ Atlanta, Georgia
In compliance with ACCME policy, ASH requires the following disclosures to the session audience:
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
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
Ubiquitin
ligase(s)
Cellular
proteins
Protein
synthesis
Insufficient
Amino
amino acids
acids
Ubiquitylated
cellular proteins
CHR-2797
Proteasomal
degradation
Aminopeptidases
C-terminally
truncated
peptides
Synergy between CHR-2797 and cytotoxic
agents in AML blast proliferation assays
Combination Index
100
Median = 0.365
Median = 1.02
10
Median = 0.385
Antagonism
1
Synergy
0.1
0.01
CHR 2797 CHR 2797 CHR 2797
+
+
+
Bortezomib Ara-C
ATRA
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
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-2797 60 mg once daily, oral dose
Cohort of 3 patients
CHR-2797 90 mg once daily, oral dose
Cohort of 3 patients
If one observed DLT, 3 additional
patients added to original cohort
CHR-2797 130 mg once daily, oral dose
First 28 days are
dose-finding/DLT phase
Cohort of 3 patients
CHR-2797 180 mg once daily oral dose
0
28
56
PHASE I
84
Time (days)
PHASE II
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 pretreatment)
• 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)
Male:female
Diagnosis
68.4 (45-84)
13:3
No. (%)
AML
MDS
MM
13 (81.3)
1 (6.3)
2 (12.5)
ECOG at baseline
0
1
No. (%)
8 (50.0)
6 (37.5)
2
2 (12.5)
Patient characteristics (cont)
(n=16)
Time from diagnosis, years (range)
Previous treatment
de novo
3.1 (0.1-8.8)
previous therapy
median no. previous cytotoxic
chemotherapy
12
2 (range 0-8)
4
Patient characteristics (cont)
Cytogenetics (AML patients only)
Favorable
t(15;17)
Intermediate
normal karyotype
all others
Unfavorable
complex karyotype
(n=13)
1
8
2
2
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 (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
Most commonly reported potentially
related adverse events
Most severe grade reported
per patient
Adverse reaction by
preferred term
Patients
reporting
(%)
Total #
patients
reporting
Thrombocytopenia
31.3
5
Diarrhea
18.8
3
2
1
Dyspepsia
12.5
2
1
1
Abdominal pain
6.3
1
1
ALT increased
6.3
1
Alopecia
6.3
1
Anorexia
6.3
1
Atrial fibrillation
6.3
1*
1
Right bundle branch
block
6.3
1*
1
Dizziness
6.3
1
1
* same patient
Gr 1
Gr 2
Gr 3
Gr 4
5
1
1
1
Dose-limiting toxicity
DLT
Dose
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 man
130 mg cohort (n = 4)
Packed blood cells CHR-2797: d1 vs d28
Plasma CHR-2797: d1 vs d28
250
800
700
200
ng/ml
500
Day 1 plasma 2797
400
Day 28 plasma 2797
ng/ml
600
300
200
150
Day 1 packed cells 2797
Day 28 packed cells 2797
100
50
100
0
0
0
6
12
18
0
24
6
12
18
24
Hours
Hours
Plasma CHR-79888: d1 vs d28
Packed blood cells CHR-79888: d1 vs d28
1000
800
600
700
500
600
Day 28 plasma 79888
400
300
Day 1 packed cells
79888
400
Day 1 plasma 79888
500
ng/ml
ng/ml
900
300
Day 28 packed cells
79888
200
200
100
100
0
0
0
6
12
Hours
18
24
0
6
12
Hours
18
24
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