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Poster Display session 1

1048 - A Phase 2 biomarker-driven study evaluating the clinical efficacy of an MDM2 inhibitor, milademetan, in patients with intimal sarcoma, a disease with a high unmet need


28 Sep 2019


Poster Display session 1


Tumour Site



Kan Yonemori


Annals of Oncology (2019) 30 (suppl_5): v683-v709. 10.1093/annonc/mdz283


K. Yonemori1, T. Shimizu2, T. Koyama2, N. Matsui3, H.S. Okuma1, E. Noguchi1, K. Sudo1, A. Hirakawa4, T. Sukigara3, S. Fujitani5, K. Nakamura3, K. Tamura1, N. Yamamoto6, Y. Fujiwara3

Author affiliations

  • 1 Department Of Breast And Medical Oncology, National Cancer Center Hospital, 104-0045 - Tokyo/JP
  • 2 Department Of Experimental Therapeutics, National Cancer Center Hospital, 104-0045 - Tokyo/JP
  • 3 Clinical Research Support Office, National Cancer Center Hospital, 104-0045 - Tokyo/JP
  • 4 Department Of Biostatistics And Bioinformatics, The University of Tokyo, 11130033 - Tokyo/JP
  • 5 Department Of Oncology Medical Science, Daiichi Sankyo Co.,Ltd, 140-8710 - Tokyo/JP
  • 6 Department Of Experimental Therapeutics, National Cancer Center Hospital, 104-0045 - Tokyo/JP


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Abstract 1048


Intimal sarcoma is an extremely rare, high-grade malignant neoplasm arising in the tunica intima of large blood vessels, most frequently the pulmonary arteries and aorta. In human tumors that retain wild-type p53 protein, p53 activity is often inhibited by interaction with murine double minute 2 (MDM2). As MDM2 amplification is found in over 70% of intimal sarcomas, inhibition of MDM2 could provide clinical benefit in this patient population. Milademetan is a novel specific small-molecule inhibitor of MDM2 that disrupts the MDM2-p53 interaction in tumor cells. A cell-free study using recombinant MDM2 and p53 proteins demonstrated inhibition of MDM2-p53 binding by milademetan (IC50: 5.57nM). Treatment with milademetan resulted in a concentration-dependent increase of p21 and PUMA mRNA levels in an osteosarcoma cell line harboring MDM2 gene-amplification. Milademetan also inhibited cell growth in different cell lines with wild-type p53 (GI50s: 0.043 - 0.276μM), but not p53 mutant or null cell lines (GI50s: >10μM). We focus on targeting MDM2-p53 axis with milademetan in patients with intimal sarcoma.

Trial design

This is a phase II, open-label, 2-part study at a single site. Eligible patients will be at least 18 years old with intimal sarcoma who also have MDM2 amplification (≧4-fold). Part 1 (safety lead-in cohort) will enroll 3 subjects to evaluate the safety, tolerability, and pharmacokinetics (PK) of milademetan (260 mg qdx3 every 14 days twice in a 28-days cycle). Part 2 of the study will enroll an open-ended number of subjects. Overall, enrollment of ≥ 5 subjects with advanced intimal sarcoma is planned in the next 3 years. The primary endpoint of the study is objective response rate which will be assessed in all subjects enrolled in Parts 1 and 2 who have received milademetan. Due to the absence of any effective treatment for intimal sarcoma, at least 1 patient with objective response will be regarded as clinically meaningful. Secondary endpoints include safety, pharmacokinetics, disease control rate, progression-free survival, and overall survival. Enrollment began in Dec 2018. As of 1 Apr 2019, 3 subjects have been enrolled into Part 1.

Clinical trial identification


Editorial acknowledgement

Legal entity responsible for the study

National Cancer Center.


Japan Agency for Medical Research and Development.


K. Yonemori: Honoraria (self): Taiho; Honoraria (self): Novartis; Honoraria (self): Eisai; Honoraria (self): Pfizer; Honoraria (self): ONO. T. Shimizu: Advisory / Consultancy: Takeda Oncology; Honoraria (self): Ono Pharmaceutical; Honoraria (institution): Ono Pharma Taiwan CO., LTD.; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Taiho Pharmaceutical ; Honoraria (self): Chugai Pharmaceutical; Research grant / Funding (self): Takeda Oncology; Research grant / Funding (self): PharmaMar; Research grant / Funding (self): Bristol-Myers Squibb Japan; Research grant / Funding (self): Daiichi Sankyo,; Shareholder / Stockholder / Stock options: SymBio Pharmaceuticals; Research grant / Funding (self): Five Prime Therapeutics; Research grant / Funding (self): 3D Medicine; Research grant / Funding (self): Chordia Therapeutics; Research grant / Funding (self): AbbVie; Research grant / Funding (self): AstraZeneca; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (self): Novartis. A. Hirakawa: Advisory / Consultancy: Ono Pharmaceuticals Co., Ltd.; Advisory / Consultancy: Kissei Co., Ltd.; Advisory / Consultancy: AbbVie GK; Advisory / Consultancy: Nippon Boehringer Ingelheim Co., Ltd.; Advisory / Consultancy: Astellas Pharm Inc.; Advisory / Consultancy: Nippon ShinyakuCo., Ltd.; Advisory / Consultancy: Sumitomo Dainippon Pharma Co., Ltd.; Advisory / Consultancy: Torii Pharmaceutical Co. Ltd. S. Fujitani: Full / Part-time employment: DaiichiSankyo. N. Yamamoto: Research grant / Funding (self): Astellas; Speaker Bureau / Expert testimony, Research grant / Funding (self): Chugai; Advisory / Consultancy, Research grant / Funding (self): Eisai; Research grant / Funding (self): Taiho; Speaker Bureau / Expert testimony, Research grant / Funding (institution): BMS; Speaker Bureau / Expert testimony, Research grant / Funding (self): Pfizer; Research grant / Funding (self): Novartis; Speaker Bureau / Expert testimony, Research grant / Funding (self): Eli Lilly; Research grant / Funding (self): AbbVie; Honoraria (self): Daiichi-Sankyo; Research grant / Funding (self): Bayer; Advisory / Consultancy, Research grant / Funding (self): Boehringer Ingelheim; Research grant / Funding (self): Kyowa-Hakko Kirin; Advisory / Consultancy, Research grant / Funding (self): Takeda; Speaker Bureau / Expert testimony, Research grant / Funding (self): ONO; Research grant / Funding (self): Janssen Pharma; Research grant / Funding (self): MSD; Research grant / Funding (self): Merck; Advisory / Consultancy: Otsuka; Advisory / Consultancy: Cimic. Y. Fujiwara: Honoraria (self): Astellas; Honoraria (self): Daiichi-Sankyo; Honoraria (self): BMS; Honoraria (self): SRL. All other authors have declared no conflicts of interest.

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