Phase I study of nimotuzumab, a humanized anti-epidermal

1
Phase I study of nimotuzumab, a humanized
anti-epidermal growth factor receptor (EGFR) IgG1
monoclonal antibody in Japanese patients with
solid tumors
155
Narikazu Boku1, Kentaro Yamazaki1, Toshiaki
Takahashi1, Akira Fukutomi1, Masaki Miyazaki2,
Taroh Satoh2, Isamu Okamoto2, Nobuyuki
Yamamoto1, Kazuhiko Nakagawa2, Masahiro Fukuoka3
1Shizuoka Cancer Center, Shizuoka, Japan, 2Kinki
University School of Medicine, Osaka, Japan,
3Kinki University Sakai Hospital, Osaka, Japan
Abstract
Results (Cont.)
Treatment and Assessment Plan
Background Nimotuzumab is a humanized IgG1
monoclonal antibody to epidermal growth factor
receptor (EGFR). The antibody has demonstrated
absence of severe skin toxicity commonly caused
by other EGFR-targeting antibodies. The primary
objective of this phase I open-label dose
escalation study was to evaluate safety and
pharmacokinetics (PK) of Nimotuzumab in Japanese
patients with solid tumors. Secondary endpoints
included tumor response and human antibody
against nimotuzumab (HAHA), pharmacodynamics (PD)
and biomarker. Methods Thirteen patients with
advanced solid tumors who had failed in prior
standard therapies were enrolled in two centers.
Nimotuzumab was given intravenously weekly at the
dose levels of 100, 200 and 400 mg/body. Skin
biopsies and serum samples were collected for PD
analysis before treatment and after fourth
infusion. For biomarker analysis, blood and
formalin fixed and paraffin embedded tumor
samples before treatment were collected.
Results Twelve patients were treated except 1
patient who received other therapy prior to
receiving the first administration. Mean
treatment cycle (4 weeks per cycle) was 4 (range
1-10) in these 12 patients. Neither dose limiting
toxicity nor grade 3 drug-related adverse events
including infusion reaction were observed, and
maximum tolerated dose was not reached. Common
drug-related adverse events were grade 1 or 2
skin rash (58), which were localized and did not
show relation to the dose levels. No HAHA
appeared during the whole treatment course.
AUC0-inf, Cmax and t1/2 increased and the
clearance decreased in a dose dependent manner.
While neither complete nor partial response was
obtained, 8 patients (73) showed stable disease
(gt 4 weeks). Median and mean time to progression
(TTP) was 14 and 19 weeks, respectively. Among 8
patients whose pre-treatment tumor samples were
obtained, 5 patients with amplified gene copy
number of EGFR showed longer TTP than the other 3
patients. Conclusions Nimotuzumab was well
tolerated up to 400 mg/body weekly in Japanese
patients with advanced solid tumors. Further
biomarker analysis is currently ongoing.

• Nimotuzumab was administrated over 30 minutes,
  every week without premedication

Figure 3 Time to onset/recovery of skin rash
(N12)
Time to onset of skin rash (Day)

• In this study, the most common drug-related AE
  was skin rash/acne (58, 7/12). Occurrence of
  rash were localized partially of arm or abdomen.
• There was no relation between incidence of rash
  and the dose levels.
• There might be a difference in time to onset of
  rash between the lowest dose and other doses.
• There was no difference in time to recovery of
  rash, and the recovery was seen without stopping
  dose in all patients.

Figure 2 Summary of treatment and assessment plan
Day 1
Day 29
Day 22
Day 8
Day 15
30 min. iv
1 course
Next course

• Safety Assessments

• Laboratory tests Weekly (1st course), every 2
  weeks (2nd course-)
• Vital signs (BT, BP, pulse) Pre-dosing, during,
  end and after 1hr at infusion (1st course)
  , Pre-dosing and end at infusion (2nd course-)
• Chest CT or X-ray (with KL-6) Every course
• ECG End of 1st course and then at least every 2
  courses
• Other adverse events Weekly
• All AEs were evaluated according to NCI-CTC
  version 3.0

Time to recovery of skin rash (Day)

• Tumor Measurements

• Pharmacokinetics

• CT/MRI End of 1st course and then at least every
  2 courses
• Response was evaluated according to RECIST
  criteria (ver. 1.0)

• The serum nimotuzumab at the end of each
  administration gradually increased in the second
  and in the third administration, and thereafter
  remained almost constant.

• Pharmacokinetics and HAHA

Figure 4 Pharmacokinetic of Nimotuzumab (N11)

• Pharmamokinetics
• Day 1 pre-dose, 5min, 1hr, 3hr, 8hr,
  24hr, 48hr, 72hr
• Day 8, 15, 22, 29, 36, 50 pre-dose, 5min
• ELISA assay
• HAHA
• Day0, 29 and then every 2 courses
• ELISA assay

400 mg
Introduction
200 mg
Serum concentration (µg/mL)

• Biomarkers

• Nimotuzumab is an IgG1 humanized monoclonal
  antibody that recognized an epitope located on
  the extracellular domain of the human EGFR.
• Clinical efficacy has been shown in
  adult/pediatric glioma and on head and neck
  cancer, and it drug has been approved more than
  20 countries outside Japan.
• Clinical trials with this antibody on several
  cancer indications have shown that the common
  side effects observed for antibodies and drugs
  inhibiting the EGFR signal pathway are negligible
  in case of Nimotuzumab.
• This unique safety profile may contribute to a
  long term treatment and a better quality of life
  to patients.

• Tumor paraffin samples (Day 0)
• EGFR, Akt, MAPK, etc, EGFR gene amplification
  and mutations
• Serum samples (Day 0, 15, 29)
• MIP-1ß, IL-1, TNF, VEGF, etc
• Blood samples (Day 0)
• FcR and SNPs

100 mg
Time (hours)
Figure 5 Pharmacokinetics of Nimotuzumab
(N11) (1St infusion of course 1)

• Pharmacodynamics

• Skin biopsy samples (Day 0, post infusion of Day
  29)
• EGFR, Akt, MAPK, etc using IHC

Table 1 Safety profile of Nimotuzumab for common
side effects of EGFR antibody
Cmax
AUC0-inf
18,000
12,000
µgh/mL
µg/mL
6,000

• DLT Criteria and MTD Definition

0
100
200
400
100
200
400
Dose (mg)
Dose (mg)
CLt
120
mL/h
60
Information from four completed clinical trials
from home page of YM BioSciences inc. (Toronto,
Canada),.

• MTD is defined as the lowest dose at which more
  than 33 patients experience DLT during the
  first course.

• The reason for the low toxicity of Nimotuzumab,
  might be explained by
• 1. its intermediate affinity (KD 10-9 M) that
  requires a rather large number of EGFR receptors
  per cell for the antibody to show cytotoxicity
  and antitumor activity 1,2,
• 2. the difference of binding properties (bivalent
  binding vs monovalent), compared with other
  anti-EGFR antibodies, such as Cetuximab and
  Panitumumab 3,4.
• These results have been shown by several
  experimental and computational techniques.
• In the latest year, using computer model of
  Nimotuzumab-EGFR complex, Nimotuzumab binds to
  the EGFR domain III and blocks EGF, while
  permitting EGFR domain I to approach domain III
  and adopts its active conformation with basal
  level of EGF ligand independent dimerization 5.
  It is speculated by these models that Nimotuzumab
  is less toxic for normal epithelial cells because
  it does not disrupt the basal level of EGFR
  signaling.

0
100
200
400
Dose (mg)
Results
Table 7 Pharmacokinetic Parameters (N11) (1st
infusion of course 1)

• Patients Characteristics

• Thirteen patients were enrolled. One patient
  experienced disease progression prior to
  receiving the first administration, and was
  excluded from the following analysis.

Table 3 Patients demographics (N12)
Figure 1 Nimotuzumab inhibit EGFR-mediated
signaling by different mechanisms
Among treated 12 pts, one patient of 100 mg dose
level was judged to be ineligible and was
excluded from pharmacokinetics analysis

• HAHA response

• HAHA testing was negative for all patients (N12).

• Antitumor Activity

Table 8 Preliminary antitumor activity (N11)

• Treatment Courses and Dose modifications

Among treated 12 pts, one patient of 100 mg dose
level was judged to be ineligible and was
excluded from efficacy analysis
Table 4 Treatment course and dose modification
(N12)
Previous Studies

• Biomarkers (tumor)

Figure 6 A comparison of EGFR gene and
preliminary efficacy (N9)

• Phase?studies were performed in several countries.

Table 2 Phase I studies of Nimotuzumab
One patient was postponed for one week the
administration for the reason other than adverse
event.

• Safety

• Neither dose limiting toxicity nor grade 3
  drug-related AEs including infusion reaction were
  observed.

• In Cuba, a study with single administration
  enrolled 12 pts.
• No patient experienced severe adverse events
  and expressed human anti-human antibody (HAHA) to
  Nimotuzumab.
• The Canadian study, with the same schedule of
  this Japanese phase I study, enrolled 17 pts, and
  MTD was not reached.
• At 100 mg dose level, one patient experienced
  grade 3 fatigue and decreased hemoglobin
  corresponding to DLT.
• SD was observed in 8 pts of 12 colorectal
  cancer patients evaluable for efficacy, and there
  was one PR in a patient with mesothelioma at 200
  mg dose level.

• There was no cases showed abnormality to Mg2.

Table 5 Drug-related adverse events (All
courses) (N12)

• Pharmacodymanics

• Pharmacodynamics analysis is currently ongoing.

Objectives
Conclusion

• Safety
• Pharmacokinetics
• HAHA response
• Anti-tumor response
• Exploratory biomarker analysis
• Pharmacodynamics

Primary endpoint

• SAFETY
• No DLT was observed at any dose. Therefore the
  MTD could not be reached to 400 mg.
• Common drug-related adverse event was skin rash,
  but it was mild and limited partially surface of
  body.
• HAHA testing was negative for all patients.
• Consequently, Nimotuzumab was considered to be
  well tolerated.
• PHARMACOKINETICS
• Cmax and AUC0-inf increased dose-dependently.
• CLt decreased dose-dependently, and the extent of
  decrease in CLt at 200 to 400 mg was smaller than
  that at 100 to 200 mg.

Secondary endpoints
Study Design

• This is an open-label, 2 centers, phase?study.

• Eligibility Criteria

Table 6 Drug-related adverse events of
laboratory test (All courses) (N12)
Inclusion Criteria

• Solid tumors - failed in prior standard
  therapies
• Age 20 - 75 years
• ECOG PS 0 or 1
• PaO2 70 mmHg
• Adequate bone marrow, hepatic, and renal function
• Written informed consent

Acknowledgments

• We are thankful to Prof. Kazuto Nishio and Dr.
  Tadahiro Oonishi for support of biomarker
  analysis, Dr Yutaka Ariyoshi and Dr. Kiyohiko
  Hatake for medical advice.
• This study was supported by Daiichi-Sankyo Inc,
  Japan

Exclusion Criteria
References

• Previous EGFR-targeting therapy
• Brain metastasis requiring medication for symptom
  control
• Persistent diarrhea gt Grade 2
• Pleural effusion/ascites requiring drainage.
• Interstitial pneumonia or pulmonary fibrosis
  documented by CT scan

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