Abstract 1048
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.
Resources from the same session
3409 - Effect and safety of immune checkpoint inhibitors for brain metastases from non-small cell lung cancer
Presenter: Toshihiko Iuchi
Session: Poster Display session 1
Resources:
Abstract
3683 - Impact of Radiotherapy on efficacy of anti-programmed death 1 (PD-1) antibodies in metastatic NSCLC
Presenter: Evangeline Samuel
Session: Poster Display session 1
Resources:
Abstract
3924 - Pembrolizumab frontline monotherapy in patients with NSCLC and high PD-L1 expression: Real World Data from a European Cohort with focus on subgroups of interest
Presenter: Giannis Mountzios
Session: Poster Display session 1
Resources:
Abstract
3970 - Patients with metastatic non-small cell lung cancer and PD-L1 expression in Germany. Treatment and first outcome from the prospective German Registry Platform CRISP (AIO-TRK-0315)
Presenter: Martin Sebastian
Session: Poster Display session 1
Resources:
Abstract
5350 - The efficacy and safety of pembrolizumab as a first-line therapy in PD-L1 50% positive advanced NSCLC (HOPE-001)
Presenter: Motohiro Tamiya
Session: Poster Display session 1
Resources:
Abstract
3832 - Osimertinib in epidermal growth factor receptor (EGFR) T790M advanced non-small cell lung cancer (NSCLC): analysis of patients with central nervous system (CNS) metastases in a real-world study (ASTRIS)
Presenter: Giulio Metro
Session: Poster Display session 1
Resources:
Abstract
4082 - Real-world (RW) treatment patterns and outcomes for second-line (2L) therapy and beyond in patients (pts) with epidermal growth factor receptor-mutated (EGFRm) advanced NSCLC receiving a first-line (1L) first- or second-generation (1G/2G) EGFR tyrosine kinase inhibitor (TKI)
Presenter: Riyaz Shah
Session: Poster Display session 1
Resources:
Abstract
2855 - Impact of ramucirumab (RAM) + erlotinib (ERL) on EGFR mutations in circulating tumor DNA – The 1st report of a biomarker study in Japanese patients from RELAY: Global Ph3 study of ERL + RAM or placebo (PL) in 1L metastatic NSCLC with EGFR activating mutations
Presenter: Kazuto Nishio
Session: Poster Display session 1
Resources:
Abstract
2911 - Apatinib combined with EGFR - TKI in treating advanced non-small cell lung cancer with EGFR - TKI resistance
Presenter: Ruifen Tian
Session: Poster Display session 1
Resources:
Abstract
2100 - Updated analysis of a phase I trial of afatinib (Afa) and bevacizumab (Bev) in chemo-naïve patients (pts) with advanced non-small-cell lung cancer (NSCLC) harboring EGFR-mutations: OLCSG1404
Presenter: Takashi Ninomiya
Session: Poster Display session 1
Resources:
Abstract