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Proffered Paper session - Sarcoma

1521O - A phase II biomarker-driven study evaluating the clinical efficacy of an MDM2 inhibitor, milademetan, in patients with intimal sarcoma, an ultra-rare cancer with highly life-threatening unmet medical needs (NCCH1806/MK004)

Date

21 Sep 2021

Session

Proffered Paper session - Sarcoma

Presenters

Yuki Kojima

Citation

Annals of Oncology (2021) 32 (suppl_5): S1111-S1128. 10.1016/annonc/annonc712

Authors

Y. Kojima1, T. Shimizu2, K. Yonemori1, T. Koyama2, N. Matsui3, M. Kamikura3, S. Tomatsuri3, H.S. Okuma1, T. Shimoi1, E. Noguchi1, K. Sudo1, A. Hirakawa4, R. Sadachi3, N.T. Okita3, K. Nakamura5, N. Yamamoto6, Y. Fujiwara7

Author affiliations

  • 1 Department Of Medical Oncology, National Cancer Center Hospital, 1040045 - 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 Clinical Biostatistics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 113-8510 - Tokyo/JP
  • 5 Clinical Trial Support Office, National Cancer Center Research Institiute - Tsukiji Campus, 1040045 - Tokyo/JP
  • 6 Department Of Experimental Therapeutics, National Cancer Center Hospital, 1040045 - Chuo-ku, Tokyo/JP
  • 7 Head, Pharmaceutical and Medical Devices Agency, 100-0013 - Tokyo/JP
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Resources

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Abstract 1521O

Background

Intimal sarcoma is an ultra-rare, high-grade malignant neoplasm arising in the intima of large blood vessels, most frequently the pulmonary arteries and aorta. As murine double minute 2 (MDM2) amplification is found in over 70% of intimal sarcomas, inhibition of MDM2 could provide clinical benefit in this patient population. This study was conducted to evaluate the activity of milademetan, a novel specific small-molecule inhibitor of MDM2 in intimal sarcoma patients as a sub-study under the nationwide large registry for rare cancers in Japan (MASTERKEY Project).

Methods

Between December 2018, and January 2021, we conducted an open-label phase 2 trial in patients with MDM2 amplified, TP53 wild type, intimal sarcoma. Patients were eligible if they had an ECOG PS of 0-2, measurable disease, and adequate organ function. Patients received 260 mg of milademetan orally qdx3 every 14 days twice in a 28 days cycle, until disease progression or unacceptable toxicity. Primary endpoint was objective response rate, assessed by central review. Secondary endpoints included safety, PK profile, disease control rate, progression-free survival, and overall survival.

Results

A total of 11 patients, age: 20-72 (median:33.0), were enrolled and treated. One patient was excluded from response assessment due to detection of TP53 mutation, revealed after enrollment. Median follow-up was 8.2 months (IQR 4.4-18.6). Of the ten evaluable patients, two had partial responses. Response rate and disease control rate were 20% (95% CI 2.5-55.6) and 50% (95% CI 18.7-81.3), respectively. The most common grade 3 and 4 treatment-related adverse events were cytopenic in nature, including: thrombocytopenia (10/11 [90.9%]), neutropenia (8/11 [72.7%]) and luekocytopenia (6/11 [54.5%]). No treatment-related mortality was observed.

Conclusions

Milademetan showed acceptable safety profile with some clinical activity in patients with intimal sarcoma with MDM2 amplification. These results suggest that MDM2 inhibitor may be a potential promising therapeutic option for this life-threatening unmet medical needs.

Clinical trial identification

JMA-IIA00402.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Daiichi Sankyo.

Disclosure

T. Shimizu: Financial Interests, Personal, Speaker’s Bureau: AbbVie; Financial Interests, Personal, Speaker’s Bureau: Daiichi-Sankyo; Financial Interests, Personal, Speaker’s Bureau: Eisai; Financial Interests, Personal, Speaker’s Bureau: Takeda Oncology; Financial Interests, Personal, Speaker’s Bureau: MSD; Financial Interests, Personal, Advisory Board: Daiichi-Sankyo; Financial Interests, Personal, Advisory Board: AbbVie; Financial Interests, Personal, Advisory Board: akeda Oncology; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: AbbVie; Financial Interests, Institutional, Research Grant: Daiichi-Sankyo; Financial Interests, Institutional, Research Grant: Takeda Oncology; Financial Interests, Institutional, Research Grant: Eli Lilly; Financial Interests, Institutional, Research Grant: LOXO Oncology; Financial Interests, Institutional, Research Grant: Bristol-Myers Squibb; Financial Interests, Institutional, Research Grant: Eisai; Financial Interests, Institutional, Research Grant: Incyte; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: Chordia Therapeutics; Financial Interests, Institutional, Research Grant: ymbio Pharmaceuticals; Financial Interests, Institutional, Research Grant: 3D-Medicine; Financial Interests, Institutional, Research Grant: Five Prime; Financial Interests, Institutional, Research Grant: Five Prime; Financial Interests, Institutional, Research Grant: Astellas; Financial Interests, Institutional, Principal Investigator: Novartis; Financial Interests, Institutional, Principal Investigator: AbbVie; Financial Interests, Institutional, Principal Investigator: Daiichi-Sankyo; Financial Interests, Institutional, Principal Investigator: Takeda Oncology; Financial Interests, Institutional, Principal Investigator: Eli Lilly; Financial Interests, Institutional, Principal Investigator: LOXO Oncology; Financial Interests, Institutional, Principal Investigator: Bristol-Myers Squibb; Financial Interests, Institutional, Principal Investigator: Eisai; Financial Interests, Institutional, Principal Investigator: Incyte; Financial Interests, Institutional, Principal Investigator: AstraZeneca; Financial Interests, Institutional, Principal Investigator: Pfizer; Financial Interests, Institutional, Principal Investigator: Chordia Therapeutics; Financial Interests, Institutional, Principal Investigator: Symbio Pharmaceuticals; Financial Interests, Institutional, Principal Investigator: 3D-Medicine; Financial Interests, Institutional, Principal Investigator: Five Prime; Financial Interests, Institutional, Principal Investigator: PharmaMar; Financial Interests, Institutional, Principal Investigator: Astellas. K. Yonemori: Financial Interests, Personal, Advisory Board: Astrazeneca; Financial Interests, Personal, Speaker’s Bureau: Chugai; Financial Interests, Personal, Speaker’s Bureau: Novartis; Financial Interests, Personal, Speaker’s Bureau: Eisai; Financial Interests, Personal, Speaker’s Bureau: Pfizer; Financial Interests, Personal, Speaker’s Bureau: Astrazeneca; Financial Interests, Personal, Speaker’s Bureau: Takeda Oncology; Financial Interests, Personal, Advisory Board: Takeda Oncology; Financial Interests, Personal, Advisory Board: Eisai. T. Koyama: Financial Interests, Personal, Speaker’s Bureau: Sysmex; Financial Interests, Personal, Speaker’s Bureau: Chugai; Financial Interests, Institutional, Principal Investigator: PACT. N. Yamamoto: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: Chugai; Financial Interests, Personal, Invited Speaker: Chugai; Financial Interests, Personal, Advisory Board: Cimic; Financial Interests, Personal, Invited Speaker: Daiichi-Sankyo; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Invited Speaker: Eli Lilly; Financial Interests, Personal, Invited Speaker: ONO; Financial Interests, Personal, Advisory Board: Otsuka; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: Sysmex; Financial Interests, Personal, Advisory Board: Takeda; Financial Interests, Institutional, Principal Investigator: AbbVie; Financial Interests, Institutional, Principal Investigator: Astellas; Financial Interests, Institutional, Principal Investigator: Bayer; Financial Interests, Institutional, Principal Investigator: BMS; Financial Interests, Institutional, Principal Investigator: Boehringer Ingelheim; Financial Interests, Institutional, Principal Investigator: Chiome Bioscience; Financial Interests, Institutional, Principal Investigator: Chugai; Financial Interests, Institutional, Principal Investigator: Daiichi-Sankyo; Financial Interests, Institutional, Principal Investigator: Eisai; Financial Interests, Institutional, Principal Investigator: Eli Lilly; Financial Interests, Institutional, Principal Investigator: GSK; Financial Interests, Institutional, Principal Investigator: Janssen Pharma; Financial Interests, Institutional, Principal Investigator: Kyowa-Hakko Kirin; Financial Interests, Institutional, Principal Investigator: MERCK; Financial Interests, Institutional, Principal Investigator: MSD; Financial Interests, Institutional, Principal Investigator: Novartis; Financial Interests, Institutional, Principal Investigator: ONO; Financial Interests, Institutional, Principal Investigator: Otsuka; Financial Interests, Institutional, Principal Investigator: Pfizer; Financial Interests, Institutional, Principal Investigator: Sumitomo Dainippon; Financial Interests, Institutional, Principal Investigator: Taiho; Financial Interests, Institutional, Principal Investigator: Takeda. Y. Fujiwara: Financial Interests, Personal, Speaker’s Bureau: AstraZeneca; Financial Interests, Personal, Speaker’s Bureau: Chugai; Financial Interests, Personal, Speaker’s Bureau: Daiichi-Sankyo; Financial Interests, Personal, Speaker’s Bureau: Bristol-Myers Squibb; Financial Interests, Personal, Speaker’s Bureau: SRL inc; Financial Interests, Personal, Speaker’s Bureau: Santen Pharmaceutical. All other authors have declared no conflicts of interest.

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