PMID- 36258088
OWN - NLM
STAT- MEDLINE
DCOM- 20230119
LR  - 20230125
IS  - 1865-3774 (Electronic)
IS  - 0925-5710 (Print)
IS  - 0925-5710 (Linking)
VI  - 117
IP  - 1
DP  - 2023 Jan
TI  - Phase I dose-escalation study of milademetan in patients with relapsed or 
      refractory acute myeloid leukemia.
PG  - 68-77
LID - 10.1007/s12185-022-03464-z [doi]
AB  - Long-term survival in patients with acute myeloid leukemia (AML) remains low, and 
      current treatment modalities are inadequate. Milademetan (DS-3032, RAIN-32), a 
      small-molecule specific murine double minute 2 inhibitor, has shown a p53 
      status-dependent antitumor effect in vitro studies. This is the first phase I 
      study report of milademetan monotherapy in relapsed/refractory (R/R) AML patients 
      evaluating the safety, tolerability, pharmacokinetics, and preliminary tumor 
      response for further clinical development. Fourteen patients received 90 
      (starting dose, n = 4), 120 (n = 6), or 160 mg (n = 4) of oral milademetan once 
      daily in a 14/28 treatment cycle. The median total treatment duration was 1.5 
      cycles. Dose-limiting toxicity did not occur, and the maximum tolerated dose was 
      not reached. Thus, the recommended dose was defined as 160 mg. The most common 
      adverse events (AEs) were decreased appetite (64.3%), febrile neutropenia (50%), 
      nausea (42.9%), and anemia (35.7%). No deaths or AEs leading to treatment 
      discontinuation occurred. Five serious treatment-emergent AEs occurred in 4 
      patients. Plasma concentration increased linearly with milademetan dose. However, 
      trends in the safety and efficacy of oral milademetan in patients with R/R AML 
      warrant further clinical investigation. This study can inform future milademetan 
      studies in hematologic malignancies.
CI  - (c) 2022. The Author(s).
FAU - Sekiguchi, Naohiro
AU  - Sekiguchi N
AD  - National Hospital Organization Disaster Medical Center, Tokyo, Japan.
FAU - Kasahara, Senji
AU  - Kasahara S
AD  - Gifu Municipal Hospital, Gifu, Japan.
FAU - Miyamoto, Toshihiro
AU  - Miyamoto T
AD  - Kyushu University Hospital, Fukuoka, Japan.
FAU - Kiguchi, Toru
AU  - Kiguchi T
AD  - Dokkyo Medical University Saitama Medical Center, Saitama, Japan.
AD  - Chugoku Central Hospital, Hiroshima, Japan.
FAU - Ohno, Hitoshi
AU  - Ohno H
AD  - Tenri Hospital, Nara, Japan.
FAU - Takagi, Taiga
AU  - Takagi T
AD  - Daiichi Sankyo Co., Ltd, Tokyo, Japan.
FAU - Tachibana, Masaya
AU  - Tachibana M
AD  - Daiichi Sankyo Co., Ltd, Tokyo, Japan.
FAU - Sumi, Hiroyuki
AU  - Sumi H
AD  - Daiichi Sankyo Co., Ltd, Tokyo, Japan.
FAU - Kakurai, Yasuyuki
AU  - Kakurai Y
AD  - Daiichi Sankyo Co., Ltd, Tokyo, Japan.
FAU - Yamashita, Tomonari
AU  - Yamashita T
AD  - Daiichi Sankyo Co., Ltd, Tokyo, Japan.
FAU - Usuki, Kensuke
AU  - Usuki K
AUID- ORCID: 0000-0002-1216-4470
AD  - Department of Hematology, NTT Medical Center Tokyo, 5‑9‑22 Higashi‑Gotanda, 
      Shinagawa‑ku, Tokyo, 141‑8625, Japan. kensuke.usuki@gmail.com.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
DEP - 20221019
PL  - Japan
TA  - Int J Hematol
JT  - International journal of hematology
JID - 9111627
RN  - R3I80TLN7S (milademetan)
SB  - IM
MH  - Animals
MH  - Humans
MH  - *Leukemia, Myeloid, Acute/drug therapy
PMC - PMC9813109
OTO - NOTNLM
OT  - Acute myeloid leukemia
OT  - MDM2 protein
OT  - Milademetan
OT  - Phase-1 clinical trial
OT  - Tumor suppressor protein p53
COIS- Naohiro Sekiguchi received research funds from Ono, A2 Healthcare, Astellas, 
      Janssen, MSD, Otsuka, Pfizer, PPD-SNBL, Sumimoto Dainippon, Daiichi Sankyo, and 
      Bristol Myers Squibb. Senji Kasahara received research funds from Daiichi Sankyo. 
      Toshihiro Miyamoto received research funds from Daiichi Sankyo and speaker fees 
      from Bristol Myers Squibb, Otsuka, MSD, Astellas, Astellas Amgen, Celgene, 
      AbbVie, and Takeda. Toru Kiguchi received speaker fees from Bristol Myers Squibb 
      and Novartis, as well as research funds from Bristol Myers Squibb, Daiichi 
      Sankyo, Otsuka, MSD, Takeda, Astella, Nippon Shinyaku, Novartis, Sumimoto 
      Dainippon, Janssen, SymBio, Celgene, and Sanofi. Hitoshi Ohno received research 
      funds from Daiichi Sankyo. Taiga Takagi, Masaya Tachibana, Hiroyuki Sumi, 
      Yasuyuki Kakurai, and Tomonari Yamashita are employees of Daiichi Sankyo. Kensuke 
      Usuki received speaker fees from Novartis as well as research funds from 
      Astellas, Alexion, AbbVie, Gilead, SymBio, Daiichi Sankyo, Sumimoto Dainippon, 
      Chugai, Otsuka, Novartis, Bristol Myers Squibb, Takeda, Astellas Amgen, Apellis, 
      and Nippon Shinyaku.
EDAT- 2022/10/19 06:00
MHDA- 2023/01/07 06:00
PMCR- 2022/10/19
CRDT- 2022/10/18 23:30
PHST- 2022/05/27 00:00 [received]
PHST- 2022/09/30 00:00 [accepted]
PHST- 2022/09/30 00:00 [revised]
PHST- 2022/10/19 06:00 [pubmed]
PHST- 2023/01/07 06:00 [medline]
PHST- 2022/10/18 23:30 [entrez]
PHST- 2022/10/19 00:00 [pmc-release]
AID - 10.1007/s12185-022-03464-z [pii]
AID - 3464 [pii]
AID - 10.1007/s12185-022-03464-z [doi]
PST - ppublish
SO  - Int J Hematol. 2023 Jan;117(1):68-77. doi: 10.1007/s12185-022-03464-z. Epub 2022 
      Oct 19.