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

Background

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

JMA-IIA00402.

Editorial acknowledgement

Legal entity responsible for the study

National Cancer Center.

Funding

Japan Agency for Medical Research and Development.

Disclosure

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.