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Interim analysis of an ongoing phase II trial assessing safety and efficacy of R-IDEA
as salvage therapy in patients with relapsed/refractory DLBCL：
An intergroup study of the society of lymphoma treatment in Japan (SoLT-J) and the west japan hematology/oncology group (WestJHOG)
Eisei Kondo1, Kazuhiko Yamamoto2, Taro Masunari3, Katsuhiro Miura4, Jun Takizawa5, Yasufumi Masaki6, Tadashi Matsumura7, Yasushi Hiramatsu8, Jun Murakami9, Hideki Tsujimura10,
Naoto Tomita11, Yoshinobu Maeda1, Masatoshi Kanno12
university hospital, Okayama, 2Okayama Citizens' Hospital, Okayama, 3Chugoku central hospital, Fukuyama, 4Nihon University School of Medicine, Tokyo, 5Niigata University Faculty of Medicine, Niigata, 6Kanazawa Medical University, Ishikawa, 7Himeji
St.Mary's Hospital, Himeji, 8Himeji Red-corss Hospital, Himeji, 9Toyama university hospital, Toyama, 10Chiba Cancer Center, 11Chiba, Yokohama City University Graduate School of Medicine, Yokohama, 12Nara Medical University School of Medicine, Kashihara, Japan
Deparment of General medicine, Okayama University Graduate
School of Medicine, Dentistry and Pharmaceutical Sciences
R-IDEA
↓↓ ↓↓
11
9
Firstline
chemotherapy
R-CHOP
R-CHOP like
18
2
ECOG PS
0
1
2
3
4
10
5
3
0
1
> ULN
I-II
III-IV
13
8
12
secondary ageadjusted IPI
0
1
2
5
6
9
Disease status
Primary
refractory
Relapse
3
5 (< 1y from Dx)
12(> 1y from Dx)
serum LDH
Stage
HDT/ASCT
(n=9)
Poor mobilization
(n=3)
0
Mobilization adjusted response rate (MARR)
9/20 (45%)
Figure 2. Adverse events during R-IDEA
60
1
50
2
3
40
Days of apheresis
Total CD34+ cells
(x106/kg)
No. <2.0x106 /kg
2
2.64
3
(1-6)
(0.17-43.7)
(15%)
2
Years after relapse
Sensitive relapse
(CR/PR after R-IDEA: n=12)
Non-sensitive relapse (n=8)
P=0.0003
0
1
4
30
20
Table 3. Results of CD34+ cell harvests
1
3
4
1.00
Sex
Male
Female
Relapsed from > 1 year
after initial diagnosis
0.75
59.5
(42-65)
SD/PD
(n=3)
Refractory or
Relapsed from < 1 year
after initial diagnosis
0
1
2
P=0.085
3
4
saaIPI = 0
saaIPI = 1
2
3
Years after relapse
saaIPI = 2
P=0.044
0
1
2
3
4
1.00
Age
Median
(range)
CR/PR
(n=12)
0.00
Table 2. Patient characteristics
Progression free survival
0.25
Evaluation (PET-CT)
0.50
div
0.25
750mg/m2 x2
0.00
Ara-C
PBSC harvest
PD n=2
1.00
↓
0.75
↓
0.50
↓
0.25
div
0.00
150mg/m2
10
0
WBC Nt
Hb
Plt AST ALT ALP T-Bil Cr
FN
0.75
Etoposide
R-IDEA
PD n=2
Sensitive relapse
(CR/PR after R-IDEA: n=12)
Non-sensitive relapse (n=8)
P=0.002
0
1
2
Years after relapse
3
Relapsed from > 1 year
after initial diagnosis
0.50
↓ ↓
Refractory or
Relapsed from < 1 year
after initial diagnosis
0.25
↓
P=0.023
0.00
↓
0
1
2
4
3
4
1.00
div
Overall survival
saaIPI = 0
0.75
40 mg/body
R-IDEA
PD n=1
0.50
↓
saaIPI = 1
0.25
↓
Overall survival
↓
P=0.13
saaIPI = 2
0.00
Eisei Kondo : [email protected]
div ↓
div
Conclusions
R-IDEA is feasible and well tolerated in pts
with rel/ref DLBCL. Primary refractory and
early relapsed DLBCL pts had a poorer
prognosis. New treatment strategy seems to
be warranted for the high risk pts.
relapsed/refractory DLBCL (n=20)
Progression free survival
Dexamethazone
5
Probability
0.50
0.75
Ifosfamide
1300 mg/m2
4
1.00
375 mg/m2
3
0.00
This study includes pts aged 18-65 years
with primary refractory or first relapse
CD20 ＋
DLBCL after anthracyclinecontaining CTx.
The R-IDEA regimen
consisits of R 375mg/m2 on day 1, IFO
1.3g/m2, ETP 150mg/m2 on days 2-4, Dex
33mg IV on days 2-5 and Ara-C 750mg/m2
twice daily on days 3-4. R-IDEA was
administered every 21 days for a total of 3
cycles. PBSCs were harvested after cycle 3.
Pts in a CR/PR after R-IDEA and who got
successful mobilization (>2 million of CD34+
cells/kg) received HDT/ASCT. Primary
endpoint was mobilization adjusted response
rate (MARR; [CR] + [PR] - mobilization
failure).
Rituximab
2
Overall survival
0.25 0.50 0.75
Methods
1
Dose
Progression free survival
0.00 0.25 0.50 0.75 1.00
High dose chemotherapy (HDT) with
autologous stem cell support (ASCT) has
been
proven
effective
in
relapsed(rel)/refractory(ref) Diffuse large
B cell lymphoma (DLBCL), but the benefit is
limited to the patients (pts) who are
sensitive to salvage chemotherapy (CTx) and
are able to mobilize sufficient peripheral
blood stem cells (PBSCs). The salvage CTx
regimen IDEA was previously reported as
effective (ORR; 67.6%) and feasible to
mobilize PBSCs (77.8%). (Nishimori et al.
Antican Res 2009) Accordingly, we designed
a multicenter phase II trial addressing
safety and efficacy of IDEA plus
Rituximab(R)
in
rel/ref
DLBCL
pts
(UMIN000004892). Herein, we report the
interim analysis on the first 20 enrolled pts.
Figure 1. Consort flow diagram
Table 1. R-IDEA regimen
Cycles
Aim
1.00
1Okayama
0
1
2
3
4
適格規準
・組織学的に確認されたCD20陽性びまん性大細胞型B細胞リンパ腫の初回再発ま
たは初回難治性例
・測定可能な病変を有すること。
・年齢18歳以上65歳以下
・Performance Status（ECOG）：0～2の症例
・重篤な臓器障害のない症例
・初回治療にてアントラサイクリン系薬剤を含む化学療法を受けている症例
・自己末梢血幹細胞移植併用大量化学療法の適格症例である症例
・本研究への参加について患者本人の同意が得られている。ただし、未成年の場
合は代諾者及び本人から文書による同意が得られていること。
主要評価項目（Primary Endpoint）
末梢血幹細胞採取成功率を補正した
R-IDEA第3コース終了時の全奏効率(Mobilization-adjusted overall response
MARR)
副次的評価項目（Secondary Endpoints）
２年無増悪生存割合 progression-free survival (PFS)
2年全生存割合overall survival (OS)、治療全体の奏効率（CR,PR）、導入化学療
IDEA）の奏効率（CR,PR）
移植適格割合、移植施行割合、末梢血幹細胞採取効率
有害事象発生頻度、二次がん発生割合
登録患者数の設定根拠・登録期間・観察期間
dose
2
mg/m
1
3
4
Rituximab
375
Ifosfamide (I)
1300 mg/m2
div
↓
↓
↓
Dexamethazone (D) 40 mg/body
Etoposide (E)
150mg/m2
div
div
↓
↓
↓
↓
↓
↓
Ara-C (A)
div
750mg/m2 x2
div
2
5
・・・・ 21
↓
↓
↓↓ ↓↓
予定登録患者数：40人
患者数設定根拠： 本試験のprimary endpointはMARRであり、R-IDEA療法に
MARRが他の救援化学療法のそれを上回ると仮説した。CORAL study において、
ICE群のMARR 52.3%(奏効率63%、採取不良10％)、R-DHAP群MARR 54.5%
64%、採取不良8％)であることから、 R-IDEA療法の閾値MARRを50%、期待
70%とし、α=0.05（片側）、β=0.2のもとで必要症例数を算出すると37例となり、
脱落例を10％と仮定して40 症例を最終必要症例数とした。中間解析として20例
おいて安全性とMARRを検討し、R-IDEA療法の安全性と効果を確認する。MARR
45%（20例中9例）に達しない場合にはプロトコールは中止される。なお、安全
が確認され、かつ第一段階の20例の評価をおこなった時点で9例以上のMARRが
認されれば最終段階まで症例を集積する。
Eisei Kondo1, Kazuhiko Yamamoto2, Taro Masunari3, Katsuhiro Miura4, Jun Takizawa5, Yasufumi Masaki6, Tadashi Matsumura7, Yasushi Hiramatsu8, Jun Murakami9, Hideki Tsujimura10,
11
1
12
Naoto Tomita , Yoshinobu Maeda , Masatoshi Kanno
1Okayama
university hospital, Okayama, 2Okayama Citizens' Hospital, Okayama, 3Chugoku central hospital, Fukuyama, 4Nihon University School of Medicine, Tokyo, 5Niigata University Faculty of Medicine, Niigata, 6Kanazawa Medical University, Ishikawa, 7Himeji
St.Mary's Hospital, Himeji, 8Himeji Red-corss Hospital, Himeji, 9Toyama university hospital, Toyama, 10Chiba Cancer Center, 11Chiba, Yokohama City University Graduate School of Medicine, Yokohama, 12Nara Medical University School of Medicine, Kashihara, Japan