Phase I trial of afatinib plus vinorelbine in Japanese patients with advanced solid tumors, including
breast cancer
Hirofumi Mukai, Norikazu Masuda, Hiroshi Ishiguro, Ayako Mitsuma, Takashi Shibata, Jun
Yamamura, Masakazu Toi, Aiko Watabe, Akiko Sarashina, Martina Uttenreuther-Fischer, Yuichi Ando
Journal: Cancer Chemotherapy and Pharmacology
Corresponding author:
Hirofumi Mukai
Division of Oncology/Hematology, National Cancer Center Hospital East, Kashiwa, Japan
Telephone: +81-4-7133-1111
Fax: +81-4-7134-6922
e-mail: hrmukai@east.ncc.go.jp
Supplementary Table 1 Summary of AEs over the first treatment cycles and all treatment cycles
Dose level 1
Dose level 2
Dose level 2a
Dose level 3
Afatinib (20 mg QD) + vinorelbine
Afatinib (40 mg QD) + vinorelbine
Afatinib (40 mg QD) + vinorelbine
Afatinib (40 mg QD) + vinorelbine (25
(25
mg/m2/week)
(25
n= 3
mg/m2/week)
(20
n=5
mg/m2/week)
mg/m2/week)
n=3
n=6
Cycle 1
All Cycles
Cycle 1
All Cycles
Cycle 1
All Cycles
Cycle 1
All Cycles
3 (100.0)
3 (100.0)
5 (100.0)
5 (100.0)
3 (100.0)
3 (100.0)
6 (100.0)
6 (100.0)
AEs leading to
discontinuation of study
druga
0
0
2 (40.0)
4 (80.0)
0
1 (33.3)
0
1 (16.7)
Serious AEsb
1 (33.3)
2 (66.7)
2 (40.0)
4 (80.0)
0
0
0
2 (33.3)
Grade 1
0
0
0
0
0
0
0
0
Grade 2
0
0
0
0
2 (66.7)
2 (66.7)
2 (33.3)
1 (16.7)
Grade 3
2 (66.7)
1 (33.3)
0
0
1 (33.3)
1 (33.3)
4 (66.7)
2 (33.3)
Grade 4
1 (33.3)
2 (66.7)
5 (100.0)
5 (100.0)
0
0
0
2 (33.3)
Grade 5
0
0
0
0
0
0
0
1 (16.7)c
Treatment-related AEs,
n (%)
Highest CTCAE grade for
AEs
AE adverse event, CTCAE Common Terminology Criteria for Adverse Events, QD once-daily
a
All events were considered to be treatment-related; AEs leading to discontinuation comprised: grade 3 febrile neutropenia (n = 1), biliary tract and hepatic
infection (both grade 3, n = 1), grade 4 hyperamylasemia (n = 1) and increased lipase and amylase (both grade 4, n = 1) at dose level 2; grade 2 interstitial
pneumonia occurring post-treatment (n = 1) at dose level 2a and grade 1 interstitial pneumonia (n = 1) at dose level 3.
b
Eight patients had serious AEs (any causality), events comprised: cardiac tamponade (not related, n = 1) and biliary tract infection plus abdominal hepatic
function (both unrelated, n = 1) at dose level 1; febrile neutropenia, n = 2; bacteraemia, biliary tract infection, and hepatic infection (n = 1); pharyngitis,
increased amylase and increased lipase (n = 1) at dose level 2; pulmonary embolism (not related) plus ILD (n = 1) and febrile neutropenia plus malignant
pleural effusion (n = 1) at dose level 3.
c
General physical health deterioration.
Supplementary Fig. 1 Study design protocol, showing the original and amended protocols
a
In Level 2a and 3, vinorelbine dose omission allowed for absolute neutrophil count <1500/mm3. Compared
with dose level 2, dose level 3 allowed dose modifications as used in a phase III clinical trial of this combination
[19] (dose omission for vinorelbine and dose reduction for afatinib).
DLT dose-limiting toxicity, QD once-daily
Supplementary Fig. 2 Confirmed partial response in the target lesion (liver) in a patient with breast
cancer after two months of afatinib 40 mg QD and vinorelbine 20 mg/m2/week. (A) Baseline scan on
January 17 2012; (B) Scan at week 8 on March 8 2012
A
B