POSTER TITLE AND ABSTRACT NUMBER
A Phase 1 Dose Escalation Study of a Fully Human, Antagonist Anti-
CD40 Antibody, HCD122 (Formerly CHIR-12.12) in Patients with
Relapsed and Refractory Multiple Myeloma
William Bensinger1, Sundar Jagannath2, Pamela Becker1, Kenneth Anderson3, Edward
Stadtmauer4, Lea Aukerman5, Judith Fox5, Sandhya Girish5, Sanela Bilic5, Serge Guzy6,
Alan Solinger6, Sherri Dort5, Yongyu Wang5, Deborah Hurst5
1Fred Hutchinson Cancer Research Ctr., Seattle, WA; 2St.Vincent's Comprehensive Cancer
Ctr., New York, NY; 3Dana-Farber Cancer Institute, Boston, MA; 4Univ. of Pennsylvania,
Philadelphia, PA; 5Novartis Oncology, Florham Park, NJ and Emeryville, CA; 6XOMA Ltd,
Berkeley, CA
Abstract # 3575
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PANEL 1 UPDATED ABSTRACT
HCD122 is a novel, fully human, IgG1 antagonistic monoclonal antibody targeting the CD40 receptor. This
antibody blocks CD40-mediated signaling and is a potent mediator of antibody-dependent cellular
cytotoxicity (ADCC). Previous preclinical investigation confirmed expression of CD40 on myeloma cells in
the majority of patients and reported antitumor activity of HCD122 against multiple myeloma cells ex vivo
(Tai, Y et al. Cancer Res 2005; 65(13): 5898-5906). This ongoing phase 1 study will determine the
maximum tolerated dose of HCD122 in multiple myeloma patients (pts) who are relapsed or refractory
after at least one prior therapy. Planned dose levels are 1, 3 and 10 mg/kg administered IV once weekly
for 4 weeks. Each dose group will enroll 3-6 pts to evaluate safety, pharmacokinetics (PK) and clinical
response. To date, 9 pts have been treated at 2 dose levels: 3 pts at 1 mg/kg and 6 pts at 3 mg/kg.
Median patient age is 65 yrs (46-81 yrs); median number of prior therapies is 3 (2-10). No dose limiting
toxicity (DLT) occurred at the 1 mg/kg dose level. At 3 mg/kg, 1 DLT of grade 4 thrombocytopenia
occurred in 1 pt. Transient asymptomatic grade 3 amylase and/or lipase elevation occurred in 3 subjects.
No grade 3 and 4 adverse events have been reported. Infusions were well tolerated in all patients, with
easily managed grade 1-2 toxicities, primarily chills (5 pts), nausea (3 pts), pyrexia (2 pts), and arthralgia
(2 pts) mainly reported during the first infusion. Preliminary PK analysis showed more than dose
proportional - increase in Cmax and AUC at the 3 mg/kg dose level compared to the 1 mg/kg dose level.
At the 3 mg/kg dose, antibody accumulation occurred week-to-week; the mean Cmax after the fourth
infusion on Day 22 was 126.1 g/mL (range 52 - 195 ug/mL) and HCD122 levels were measurable up to
Day 57 and in one patient up to Day 99. One week after the last 3 mg/kg dose, trough levels ranged from
28 to 109 g/mL. Of the 3 pts at 1 mg/kg, one showed stable disease (SD) for > 52 weeks and two had
progressive disease (PD) by week 5. Of the 6 pts at 3 mg/kg, one had partial response (PR) at week 9
and was confirmed at week 15, one had SD for > 5 weeks, and 4 had PD at week 5. One pt with PD
terminated the study before final safety evaluation, and must be replaced before assessment of the
3mg/kg dose level is complete. Thus, in preliminary studies, HCD122 appears to be safe and well
tolerated to date at doses of 1 mg/kg and 3 mg/kg weekly for 4 doses and shows promising anti-myeloma
activity. Enrollment is continuing to determine MTD.
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PANEL 1 INTRODUCTION
Multiple Myeloma
· Estimated 16,570 new cases and 11,310 deaths from multiple myeloma in the United
States in 20061
· Chemotherapy and stem cell transplantation have improved response and survival,
however, nearly all patients with MM will relapse or become refractory
· There is a need for additional therapeutic options to treat this cancer
HCD122 (formerly CHIR-12.12)
· HCD122 is a fully human, recombinant monoclonal antibody of the IgG1 isotype targeting
the human CD40 molecule
· Preclinical studies with HCD122 have demonstrated
Inhibition of CD40L-induced viability and growth in patient myeloma cells via direct
binding2
Inhibition of CD40L-induced phosphorylation of AKT, IB, and ERK2
Blocking of CD40L-mediated IL-6 and VEGF secretion2
Induction of potent ADCC activity against CD40-positive cell lines, not CD40-negative
cell line2
In vivo anti-tumor activity in multiple models and prolonged animal survival3
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PANEL 2 METHODS
Study Objectives
· Primary objective To determine the safety, pharmacokinetics, and pharmacodynamics of
HCD122 administered intravenously (IV) at escalating multiple doses to subjects with
multiple myeloma (MM) that is relapsed or refractory after prior treatment.
· Secondary objective To report the clinical response after various doses of IV HCD122 in
subjects with MM that is refractory or relapsed after prior treatment.
· Exploratory objective To assay potential biomarkers of HCD122 activity and correlate
them with pharmacokinetic and pharmacodynamic parameters following HCD122 infusion.
Study design
· A phase I, multi-center, open-label, dose escalation study
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PANEL 2 METHODS
Patients
· Eligible patients previously diagnosed with MM that is refractory or relapsed after prior
treatment. Other eligibility criteria included
Age 18 years
Adequate performance status
Adequate hematologic and organ function
Life expectancy > 3 months
· Exclusion criteria included
Prior allogenic bone marrow transplant
Known intracranial disease or epidural disease
Prior anaphylactic reaction to human immunoglobulin administration
Symptomatic hyperviscosity syndrome
Treatment with systemic corticosteroids
Active autoimmune disease requiring immunosuppressive therapy
Severe or uncontrolled medical disease (e.g., cardiac disease, active infection,
cirrhosis and chronic obstructive or chronic restrictive pulmonary disease)
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PANEL 2 METHODS
Treatment
· Treatment comprised a 4-week once-weekly intravenous infusions of HCD122 (1, 3, and
10 mg/kg)
· Retreatment option in patients with SD, MR, PR, or CR to the HCD122 treatment
Efficacy Assessment
· Response assessment will be based on the response criteria of the
European/International Bone Marrow Transplantation Registry (EBMT/IBMTR)
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PANEL 2 METHODS
Safety Assessment
· Adverse events were graded using National Cancer Institute Common Toxicity Criteria,
version 3.0
· DLT was defined as treatment related toxicity that occurs during the time period of study
drug administration and a 4-week observation time following final drug administration
Hematologic toxicity of grade 4, and at least one of the following:
Platelets < 25,000 cells/mm3 confirmed by repeat blood testing that requires a
platelet transfusion, results in a bleeding complication, or persists for more than
5 days;
Neutropenia < 500 cells/mm3 that persists for more than 5 days and/or requires
administration of neutrophil growth factor and/or results in neutropenic fever
with elevated temperature ( 101°F) confirmed on two occasions
Nonhematologic toxicity of CTC grade 3 or greater severity, excluding infusional
toxicities and excluding asymptomatic amylase and/or lipase elevations that are
reversible to grade 2 or less within 7 days , or
Infusional toxicity that is grade 4, or is grade 3 and occurs despite optimal
premedication
· MTD was defined as the dose level at which 1 of 6 patients experienced DLT with 2
patients experiencing DLT at the next-higher dose level
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PANEL 3 RESULTS
Patient Demographics
· Patient demographic characteristics are summarized in Table 1
Safety and Tolerability
· All 9 patients were evaluable for safety
· Commonly reported adverse events (occurring in 2 patients) are summarized by severity
in Table 2. Majority of these AEs were infusion associated reactions
Grade 1 or 2 chills (5 pts), nausea (3 pts), pyrexia (2 pts), and arthralgia (2 pts)
Almost all reported during the 1st infusion
Symptoms resolved within a short period of time once the infusion was interrupted
Patients were able to re-start the infusion at a decreased rate of one-half the previous
rate
For the 3 mg/kg dose cohort, the longest infusion time for 1st and subsequent
infusions were 6 hrs and 2.5 hrs, respectively.
· Grade 3 or 4 lab abnormalities are summarized by severity in Table 3
Decreases in total lymphocytes are a desired pharmacodynamic effect of HCD122
and are not listed in Table 3
· Dose-limiting toxicities (DLT) and maximum tolerated dose (MTD)
DLT (Grade 4 thrombocytopenia) in 1 patient at 3.0 mg/kg
MTD has not been reached yet
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PANEL 3 RESULTS
Table 1. Patient Demographics (N = 9)
Age, years
Median (range)
65 (46 81)
Sex, n (%)
Male
4 (44)
Female
5 (56)
ECOG Performance status, n (%)
0 or 1
9 (100)
2
0 (0)
Time from initial diagnosis, years
Median (range)
2.2 (0.7 9.3)
Number of prior therapies
Median (range)
3 (2 10)
M-Spike
Heavy Chain
IgG
6
IgA
1
Light Chain
Lambda
1
Kappa
1
microglobulin, mg/dL
2
Median (range)
2.7 (1.8 6.8)
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PANEL 3 RESULTS
Table 2. Adverse Events Occurring in 2 Patients by severity (n = 9)
Patients, n (%)
Preferred Term
Grade 1 or 2
Grade 3 or 4
Chillsa
6 (67)
0
Nauseaa
5 (56)
0
Headache
3 (33)
0
Arthralgiaa
2 (22)
0
Bone pain
2 (22)
0
Dizziness
2 (22)
0
Dyspnosea
2 (22)
0
Fatigue
2 (22)
0
Haemorrhoids
2 (22)
0
Pharyngolaryngeal pain
2 (22)
0
Pyrexiaa
2 (22)
0
a 50% of the reported events were infusion associated
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PANEL 3 RESULTS
Table 3. Grade 3 or 4 Laboratory Abnormalities (n = 9)
Patients, n (%)
Laboratory Test
Grade 3
Grade 4
Plateleta
0
2 (22)
Lipase, serumb
2 (22)
0
WBC
2 (22)
0
Amylase, serumc
1 (11)
0
Hemoglobin
1 (11)
0
Neutrophils, absolute value
1 (11)
0
aPlatelet count decreased to grade 4 in 1 patient (3 mg/kg cohort) during the first infusion and was
considered as a DLT. Another grade 4 platelet decrease occurred in 1 patient (3 mg/kg cohort) on Day
156, and the patient completed HCD122 treatment on Day 22.
bAsymptomatic grade 3 lipase elevation occurred on Day 8 pre-infusion in 1 patient (1 mg/kg cohort)
whose baseline enzyme level was normal. Lipase value decreased to grade 1 on Day 14 and returned to
normal on Day 43. The second patient (3 mg/kg cohort) had asymptomatic lipase elevation on Day 78.
Patient's lipase was grade 1 at the baseline and remained grade 1 during HCD122 therapy. The
treatment was completed on Day 22.
cAsymptomatic grade 3 amylase elevation occurred on Day 99 in 1 patient (3 mg/kg cohort). Patient's
amylase level was grade 2 at the baseline, and remained grade 1 or 2 during HCD122 treatment. The
treatment was completed on Day 22.
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PANEL 4 RESULTS
Pharmacokinetics and Immunogenicity
· Single- and multiple-dose pharmacokinetics are summarized in Table 4
Antibody levels increase with dose level
Antibody levels increase week-to-week
· Immunogenicity
Human Anti-Human Antibodies (HAHA) were analyzed by ELISA assay (limit of
detection is 13 ng/mL)
No immunogenic response in any patient who completed 4 once-weekly doses of
HCD122
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PANEL 4 RESULTS
Table 4. Single- and multiple-dose pharmacokinetics (mean ± SD, n = 9)
Dose
Infusion
Cmin
Cmax
AUC
Half-Life
0-168hr
(n)
(g/mL)
(g/mL)
(g*hr/mL)
(hr)
1st
0.10 ± 0.18
15.7 ± 2.3
699.3 ± 100.5
30.3 ± 3.1
1 mg/kg
(3)
4th
2.68 ± 4.12
22.1 ± 1.6
1826.7 ± 930.2
46.5 ± 36.1
1st
16.18 ± 12.07
56.6 ± 18.5
3627.2 ± 2049.6
87.6 ± 107.9
3 mg/kg
(6a)
280.5 ± 285.8b
13263.5 ± 8405.7b
126.1 ± 65.2b
62.68 ± 36.36b
4th
aThe 4th infusion only 5 profiles available
bIf excluding one outlier (Patient ID #07205), the Cmin, Cmax, AUC0-168 hr, and half-life would be
47.22 ± 23.46 g/mL, 108.7 ± 60.6 g/mL, 10184.5 ± 556.8 g*hr/mL, and 159.0 ± 556.82 hr,
respectively.
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PANEL 4 RESULTS
Clinical Efficacy
· All 9 patients were evaluable for efficacy
Partial response in 1 patient (Table 5)
Stable disease in 2 patients (Table 5)
Disease progression in 6 patients
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PANEL 4 RESULTS
Table 5. Summary of Patients with Partial Response and Stable Disease
Disease
Duration
Dose
Disease Stage at
Number of
Assessment
(weeks)
(mg/kg)
Initial Diagnosis
Prior
(as of
iv
(Year)
Treatments
15Nov06)
weekly x 4
Partial Response
33
3
III
10
(1996)
Stable Diseasea
52+
1
III
2
(2003)
Stable Disease
10
3
III
2
(2004)
aPatient received HCD122 re-treatment at 1 mg/kg for 4 doses in weeks 39 42.
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PANEL 5 CONCLUSIONS
· HCD122 was well tolerated in patients with relapsed and refractory MM
The majority of adverse events were mild to moderate in severity
MTD has not been reached with doses up to 3 mg/kg once-a-week for 4 weeks
· Preliminary pharmacokinetic profile of HCD122 demonstrated more than dose-
proportional increase in C
and AUC and a 4 10 day plasma half-life
max
· No immunogenicity has been observed in MM patients to date
· HCD122 monotherapy achieved a partial response in 1 out of the 6 patients treated
at the 3 mg/kg dose
· HCD122 represents a promising novel investigational agent for relapsed and
refractory MM
· Dose escalation continues. Two additional patients are completing 4 week infusions
at 3mg/kg
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PANEL 5 REFERENCES
1.
American Cancer Society: Cancer Facts and Figures 2006. Atlanta, Ga: American
Cancer Society, 2006
2.
Tai YT, Li X, Tong X, Santos D, Otsuki T, Catley L, Tournilhac O, Podar K,
Hideshima T, Schlossman R, Richardson P, Munshi NC, Luqman M, Anderson KC.
Human anti-CD40 antagonist antibody triggers significant antitumor activity against
human multiple myeloma. Cancer Res. 2005 Jul 1;65(13):5898-906
3.
Long L, Tong X, Patawaran M, Aukerman L, Jallal B, Luqman M. Antagonist anti-
CD40 antibody CHIR-12.12 causes tumor regression and prolongs survival in
multiple myeloma xenograft models. 2005 IMF Oral Presentation and Abstract No. 3
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PANEL 5 COMPANY LOGO
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