First-in-Human Phase I administration of YS110, a humanized

First‐in‐Human Phase I administration of YS110, a humanized monoclonal antibody directed against the CD26 molecule in cancer patients
Eric Angevin1, Véronique Trillet‐Lenoir2, Jérôme Alexandre3, Nicolas Isambert4, Fanny Valleix5, Thomas Podoll6, Itaru Miyashita7, Taketo Yamada8, Yutaro Kaneko9, Chikao Morimoto10
1Institut de Cancérologie Gustave Roussy (IGR), Villejuif, France, 2Centre Hospitalier
Lyon Sud, Lyon, France 3Hôpital Cochin, Paris, France 4Centre Georges‐François Leclerc, Dijon, France, 5FV‐Clinical, subcontractor for Harrison Clinical Research France SAS, Levallois‐Perret, France
6Y’s Therapeautics Inc., USA, San Francisco, USA 7Kissei Pharmaceutical Co., Ltd., Tokyo, Japan 8Keio University, School of Medicine Tokyo, Japan 9Y’s AC Co., Ltd., Tokyo, Japan 10Institute of Medical Science, The University of Tokyo, Tokyo, Japan
INTRODUCTION PHASE I TRIAL PRELIMINARY RESULTS
CD26
Primary objectives
Study population • CD26, a widely distributed 110‐kDa transmembrane glycoprotein with
intrinsic DPPIV activity and its truncated soluble form (sCD26/DPPIV)
also present influids, is known to play an important role in tumor
biology.
• To determine the maximum tolerated dose (MTD) and the
recommended dose (RD) of YS110 as mono‐therapy administered by
intravenous infusion at a schedule of once every two week for 3 doses to
patients with CD26‐positive advanced refractory mesothelioma or CD26‐
positive solid tumors.
• The safety population (n=25) included all patients who received at least one infusion
• The efficacy population (n=24) included all patients enrolled until 31 July 2012 to allow 6 weeks of follow up
• Data cutoff for both the safety and efficacy population was 31 August 2012
• PK and PD analysis were performed for 24 patients
• CD26 is frequently highly expressed on multiple cell types,
predominantly on epithelial and selected endothelial cells but also on
lymphocytes, hepatocytes and fibroblasts. In addition to its role in
proteolysis via the DPPIV activity, CD26 also acts as a receptor involved
in T‐cell co‐stimulation and immune regulation.
Primary objectives has been amended to intravenous infusion at a
schedule of once every week for 5 doses. New design has been
implemented on May 2012 and at data cut off 3 patients have been
treated.
Secondary objectives
Figure 1. The structure of CD26 showing the 3 major extracellular domains.
YS110
YS110 is a recombinant DNA‐derived humanized monoclonal antibody
that selectively binds with high affinity to the extracellular domain of the
CD26 antigen.
In vivo experiments with YS110 have demonstrated efficacy in clinically
relevant animal models of human CD26+ lymphomas and carcinomas.
The greatest effect was seen in human T‐cell lymphoma (Karpas 299)
xenograft models, with YS110 showing a complete response in a
majority of Nude mice and a dose‐dependent inhibition of tumor growth
in SCID mice.
• To determine the safety, tolerability, and pharmacokinetics of escalating
doses of YS110
• To evaluate the antitumor activity of YS110 according to the RECIST
criteria (or modified RECIST criteria for pleural mesothelioma)
• To perform immuno‐monitoring (immunophenotyping for T, B, NK cell
populations, and serum cytokines analysis using Elisa kits)
• To collect the survival data (progression‐free survival)
Dosing and administration
YS110 was administered once every two weeks at a dose from 0.1 mg/kg
to 2 mg/kg for 21 patients and schedule has been modified to a weekly
administration at a dose of 2 mg/kg for 4 patients.
High steroids prophylaxis have been implemented from 2 mg/kg dose
Patients
Patients with the following locally advanced inoperable and/ or
metastatic histologically/cytologically confirmed, and progressive CD26‐
positive solid tumors that are refractory to prior standard therapies
whatever the number of line of prior chemotherapy with confirmed
CD26‐positive expression in ≥ 20% of the tumor cells.
Archived paraffin embedded tumor biopsies will be used for CD26
screening by immunohistochemistry.
Figure 2. Dose response of YS110 in xenograft model of Karpas 299 cells in
Nude mice. YS110 showed potency at all doses tested when compared with
isotype control, with no major differences seen between doses
Preliminary efficacy
Screening rate: 112 patients screened Males: 64%
ECOG PS 0/1/2: 33%/59%/8%
Median age: 63 years (41‐74 years)
Median previous therapy regimens: 3 (2‐9) 88% ≥ 3 prior therapy regimens
CD26+ (%)
Pathology
All
Mesothelioma
60
56
Renal cell carcinoma
75
4*
showing no evidence of immune activation or cytokine release and no
effect on DPPIV activity.
The safety of YS110 has been assessed in cynomolgus monkeys. The
toxicity studies showed that cynomolgus monkeys treated with a single
dose of YS110 up to 100 mg/kg or 5 weekly doses up to 30 mg/kg
experienced no test article‐related changes except for transient and
reversible NK cell depletion, which was likely not due to the interaction
of YS110 with CD26. YS110 was well tolerated in these animals and
there was no cytokine release or tissue toxicity associated with YS110
dosing.
• Serial blood samples were collected during the first cycle and then at D43 of additionnal cycle
• Measurements of peripheral blood lymphocytes (PBL) subpopulations
• Measurements of cytokines: IL‐2, IL‐6 and TNF‐α dosage in serum
• Dipeptidyl peptidase IV (DPPIV) activity and Soluble CD26 antigen levels
Mesothelioma (2)
0.4
Renal carcinoma (1)
Mesothelioma (2)
1
Renal carcinoma (4)
Mesothelioma (6)
2
2
9
1
-
41
1‐9.5
SD
15
0,2‐1
‐
77
0.2 ‐ 13
SD
6
0.2 ‐ 1
-
Mesothelioma (3)
Renal carcinoma (3)
Mesothelioma (2)
Urothelial carcinoma (1)
Table 5. YS110 exposure Patient disposition, 0.1 mg/kg 0.4 mg/kg
n (%)
n=3
n=3
1 mg/kg
n=6
2 mg/kg
n=13
No objective response has been observed but 7 patients have been assessed
SD and received additional cycles.
Median stability: 5.5 months (2‐13.5 months).
Ongoing at cutoff
Discontinued at any time
0
0
0
0
Serious Adverse event
0
0
1 (16.6)
2 (15.4)
Pharmacokinetics
3 (100)
3* (100)
4 (66.7)
10* (77)
DLT
0
0
1 (16.6)
1 (7.7)
Investigator withdrawal
0
0
0
1 (7.7)
Peak blood serum concentrations of YS110 at the end of infusion correlated
with dose level:
 0.1 mg/kg: peak concentrations below level of quantitation (BLQ of 0.4 μg/mL) due to binding to soluble CD26
 0.4 mg/kg: peak concentrations in range of ~5 to10 μg/mL  1 mg/kg: peak concentrations in range of ~16 to24 μg/mL  2 mg/kg: peak concentrations in range of ~40 to 60 μg/mL However, elimination half‐life of about 1 day is shorter than expected and led
to concentrations of BLQ at day 8 for the two week infusion schedule.
Disease progression
Table 2. Patient disposition
* Best response SD
The most common adverse drug reactions (AEs) are usually grade 1 or 2
and include hypersensitivity, asthenia, chills, pyrexia, nausea, diarrhea,
headache, flushing. Some adverse drug reactions grade 3 have been
reported and are mainly hypersensitivity. 4 of 25 patients (16%) in the
safety set experienced grade 3 hypersensitivity reactions.
All Grade 3 Grade 4
Grades 0
0
15 (15.3)
6 (6)
0
13 (13.3)
Table 3. Most frequent adverse event (>10%) regardless of study drug relationship (N=98)
Pharmacodynamics
YS110 was well tolerated in these studies, with additional studies
4
0.1
Treatment Best Infusions duration Response
(months)
* patients received weekly infusion during 5 weeks
Hypersensitivity
Figure 3. In vivo direct effect of humanized anti‐CD26 mAb: ADCC depletion model.
3
Cancer type (n)
Table 1. Screening rate
Patients disposition and safety
Asthenia
Figure 4. Anti‐CD26 Immunohistochemistry in Mesothelioma
1
2
Patients characteristics (N=25)
Adverse Drug Reactions n (%)
YS110 treatment leads to tumor regression and enhanced survival in
BALB/c mice implanted with human malignant mesothelioma.
Dose Cohort level
(mg/kg)
2 DLTS (1 grade 3 hypersensitivity reaction and 1 anaphylactic reaction )
have been reported since the beginning. Both have been reported as
SUSARs. High steroids prophylaxis has been implemented to reduce
hypersensitivity reactions such as chills, flushing, hypotension, respiratory
disorders.
Grade Anaphylactic reaction
1
3
Hypersensitivity
2
3
Table 4. DLTs/SUSARs reported CONCLUSIONS
• YS110 on a two weeks infusion dosing schedule was well tolerated
in heavy pretreated solid tumors patients
• Encouraging anti‐tumor efficacy was demonstrated as evidenced
by secondary objectives
• PK data demonstrated shorter half‐life than expected which led to
modifying the dosing schedule from two weeks to one week.
• Encouraging safety profile has been obtained
• Encouraging anti‐tumor efficacy remains to be confirmed at higher
dose levels and extension cohorts
• Dose escalation will be completed by June 2013.
REFERENCES
Dose level
(mg/kg)
DLTs / SUSARs
Weekly dosing has been implemented and initial data indicate that YS110
concentrations are maintained above quantitative levels between doses.
Morimoto C. and Schlossman S.F, Immunol Rev 1998, 161, 55‐70 ; Inamoto et al, Clin Cancer Res
2006, 12, 3470‐7; Dang N.H. and Morimoto C., Histol Histopathol 2002, 17(4), 1213‐26; Inamoto et
al, Clin Cancer Res 2007, 13, 4191‐200.
ACKNOWLEDGMENTS
The authors would like to thank the sites staff who participated in the study as well as the members of the YS110 project team. This study is supported by a JST funding.