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Investigator-initiated clinical trial of DS-3032b in patients with MDM2 amplified intimal sarcoma (MADAME PRINCESA)

A Phase II study of DS-3032b in patients with MDM2 amplified intimal sarcoma

11

The median age was 33.0 years (range,20-72 years), and five patients had prior systemic therapies, including doxorubicin. All patients(n=11) underwent primary resection. One patient underwent postoperative radiotherapy. Seven patients had local recurrence at enrollment, and eight had distant metastases. Targeted DNA sequencing was performed using archived tumor tissue samples prior to enrollment in six patients, and amplified MDM2 was detected in all patients. The median follow-up was10.4 months (interquartile range, 4.4-22.6 months).

Eleven patients were enrolled in the safety lead-in (n=3) and expansion cohorts (n=8) from December 28, 2018, to July 17, 2020.One patient was excluded from the response assessment because of the detection of a TP53 mutation revealed after enrollment.

Eleven patients received one or more cycles of milademetan and were included in the safety analysis. The most common all-grade treatment-emergent adverse events (TEAE) were bone marrow suppression, including decreased platelet count[100% (grades 3-4, 90.9%)], decreased neutrophil count [90.9% (grades 3-4, 72.8%)], and anemia [72.7% (grades 3-4, 36.4%)],and gastrointestinal toxicity, including anorexia [90.9% (grades 3-4, 9.1%)] and nausea [72.7% (grades 3-4, 27.3%)].One patient withdrew from the study before the initiation of the fourth cycle owing to a prolonged platelet count decrease (grade 4). All patients (n=11) experienced treatment interruption due to grades 4 (n=4), 3 (n=6), and 2(n=1) decreased platelet count. Ten of the 11 patients needed a dose reduction: six for decreased platelet count, three for nausea, and one for fatigue. Of the four patients treated with milademetan for more than 6 months, three experienced two levels of dose reduction (120mg) and one experienced one level of dose reduction (200 mg). No treatment-related mortalities and cardiotoxicities were observed.

Of the 10 patients treated with milademetan, two achieved partial responses (PR) for an overall response rate (ORR) of 20.0% [95% confidence interval (CI), 2.5-55.6].One patient remained on study treatment for >22 months. The time to response (TTR) in the two patients was 2.1 and 6.2 months. One patient had 32.7% tumor shrinkage at the first imaging assessment (unconfirmed PR); however, she did not initiate the fourth cycloune owing to a prolonged platelet count decrease (grade 4) and withdrew from the study. After discontinuation of the study, imaging evaluation confirmed disease progression. The overall disease control rate (DCR) was 60.0% (95%CI,26.2-87.6). Six of the 10 patients showed the best response as stable disease (SD)>=3 months. The median progression-free survival (PFS) was 4.7 months (95% CI, 1.3-8.3; Supplementary). The proportions of patients without disease progression at 6 and 12 months were 40.0% (95% CI,12.3-67.0) and 20.0% (95% CI, 3.1-47.5), respectively. The PFS ratio was evaluable in only five of the 10 patients. In two of these five patients, the PFS ratio exceeded 1.3. Median OS was 12.2 months (95% CI,1.9-not reached; Supplementary). The proportions of patients surviving at 6 and 12 months were 70.0% (95% CI,32.9-89.2) and 58.3% (95% CI, 23.0-82.1), respectively. Very promising antitumor activity was observed in the two patients for >15 months. However, one of these patients had a history of anthracycline exposure. Genomic alterations were analyzed for all 10 patients, and gene expression was analyzed for 9 patients, using their archived tumor tissue samples in Supplementary. From these data, we could not find any molecular pathways clearly associated with the anti-tumor activity of milademetan. Focusing on 8 genes (CDK4, CDKN2A, CDKN2B, EGFR, ERBB3, MDM2, PDGFRA, TP53) that were known to be frequently affected in intimal sarcoma and 10 genes (AKT1, ATM, BBC3, CDKN1A, CDKN1C, CHEK2, MDM4, PMAIP1, PPM1D, TWIST1) that were reportedly associated with MDM2 inhibitor responses, we found that patients with good response were associated with TWIST1 copy number amplification (P=0.028) and tended to be negatively associated with CDKN2A copy number loss (P=0.071). Eight of the 10 patients had their cfDNA collected sequentially at baseline and during disease progression; however, one did not consent to the exploratory analysis study using cfDNA, and one had cfDNA collected at baseline but not during disease progression due to ongoing treatment. Of the eight patients, TP53 mutations in cfDNA were detected in one and five patients at baseline and disease progression, respectively.

In patients with MDM2-amplified intimal sarcoma, milademetan was shown to be clinically effective with sustained response. The results suggest that TWIST1 amplification and CDKN2A loss are associated with the anti-tumor activity of MDM2 inhibitors, while acquired TP53 mutation is associated with resistance of MDM2 inhibitors.

June. 17, 2023

https://doi.org/10.1158/2159-8290.CD-23-0419

No

Kan Yonemori

National Cancer Center Hospital

5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan

NCCH1806_1809_office@ml.res.ncc.go.jp

Naoko Matsui

National Cancer Center Hospital

5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan

+81-3-3542-2511

NCCH1806_1809_office@ml.res.ncc.go.jp

COMPLETED

Dec. 17, 2018

Interventional

Single arm phase 2 trial

open(masking not used)

No

2

1.Has a histologically or cytologically documented intimal sarcoma
2.Has a tumor harboring an amplified MDM2 determined previously or at screening by IHC, FISH or NGS
3.Refractory to conventional chemotherapy or unresectable setting, or for which no standard treatment is available
4.Performance Status (ECOG) 0 - 2
5.Enrolled in MASTER KEY Registry study
6.Has measurable disease as per RECIST v1.1
7.Has adequate bone marrow function, renal function and hepatic function, defined as:
1)Absolute neutrophil count 1500 / mm3
2)Hemoglobin 8.0 g/dL
3)Platelet count 100000/ mm3
4)AST≦100 U/L(if liver metastases are present, 150U/L)
5)ALT 100 U/L(if liver metastases are present, 150U/L)
6)Bilirubin 2.0mg/dL
7)Creatinine clearance 45 mL/min or creatinine 1.5 mg/dL
8.Provides written informed consent
9.Had treatment free time, defined as
1)Systemic anticancer therapy, including antibody-based therapy, within 3 weeks before study drug treatment; or treatment with nitrosoureas or mitomycin C within 6 weeks before study drug treatment
2)Hormonal therapy within 3 weeks before study drug treatment
3)Radiation therapy or major surgery within 3 weeks before study drug treatment or palliative radiation therapy within 2 weeks before study drug treatment
4)Major surgery within 3 weeks before study drug treatment or minor surgery within 2 weeks before study drug

1.Has a concomitant medical condition , defined as below,
Acute myocardial infarction, unstable angina, arrhythmia requiring treatment, coronary artery or peripheral artery bypass, active or uncontrolled thromboembolism, autoimmune disease requiring systemic treatment, uncontrolled infection requiring systemic treatment (intravenous antibiotics, antivirals, or antifungals) or active gastrointestinal ulcer
2.Has medical history, complication or imaging sign of clinically significant lung disease such as intestinal lung disease, pneumonitis, lung fibrosis, severe radiation pneumonitis
3.Has clinically active brain metastases, defined as untreated and symptomatic, or requiring therapy with steroids or anticonvulsants to control associated symptoms.
4.Has known human immunodeficiency virus infection, active hepatitis B defined as HBs antigen or positive HBV-DNA , or C infection define as anti-HCV antibody
5.Though HBs antigen-negative, HBs antibody-positive and/or HBc antibody-positive, and HBV-DNA quantitative test positive
6.Women of child-bearing potential. Women lactating (nursing) or within 28 days after delivery
7.Given no consent to contraception while taking study drug and for 6 months after study drug discontinuation
8.Has concurrent malignancy

Both

Intimal sarcoma harboring MDM2 amplification

Intervention type:DRUG Name of intervention:DS-3032b Dose form / Japanese Medical Device Nomenclature:CAPSULE Route of administration / Site of application:ORAL Dose per administration:260 260 mg Dosing frequency / Frequency of use:OTHER, SPECIFY Once daily, 3 days on 11 days off Planned duration of intervention:Until patient meets protocol treatment discontinuation criteria Intended dose regimen:DS-3032b monotherapy detailes of teratment arms:Patients are administered DS-3032b monotherapy until they meet treatment discontinuation criteria Comparative intervention name: Dose form / Japanese Medical Device Nomenclature: Route of administration / Site of application: Dose per administration: Dosing frequency / Frequency of use: Planned duration of intervention: Intended dose regimen:

Number of patients with objective response (central review)

Objective response rate (central review, institutional review), disease control rate (CR+PR+SD) (central review), progression-free survival, overall survival and frequency of adverse events related to investigational drug

Nov. 28, 2018