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Phase 1 dose escalation study of the MDM2 inhibitor milademetan as monotherapy and in combination with azacitidine in patients with myeloid malignancies.
DiNardo, Courtney D; Olin, Rebecca; Wang, Eunice S; Skikne, Barry; Rosenthal, Joseph; Kumar, Prasanna; Sumi, Hiroyuki; Hizukuri, Yoshiyuki; Hong, Ying; Patel, Parul; Seki, Takahiko; Duan, Tao; Lesegretain, Arnaud; Andreeff, Michael.
Afiliación
  • DiNardo CD; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
  • Olin R; University of California, San Francisco, California, USA.
  • Wang ES; Roswell Park Comprehensive Care Center, Buffalo, New York, USA.
  • Skikne B; University of Kansas Medical Center, Kansas City, Kansas, USA.
  • Rosenthal J; Department of Pediatrics, City of Hope, Duarte, California, USA.
  • Kumar P; Daiichi Sankyo Inc., Basking Ridge, New Jersey, USA.
  • Sumi H; Daiichi Sankyo Co., Tokyo, Japan.
  • Hizukuri Y; Daiichi Sankyo Co., Tokyo, Japan.
  • Hong Y; Daiichi Sankyo Inc., Basking Ridge, New Jersey, USA.
  • Patel P; Daiichi Sankyo Inc., Basking Ridge, New Jersey, USA.
  • Seki T; Daiichi Sankyo Inc., Basking Ridge, New Jersey, USA.
  • Duan T; Daiichi Sankyo Inc., Basking Ridge, New Jersey, USA.
  • Lesegretain A; Daiichi Sankyo Inc., Basking Ridge, New Jersey, USA.
  • Andreeff M; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Cancer Med ; 13(14): e70028, 2024 Jul.
Article en En | MEDLINE | ID: mdl-39030997
ABSTRACT

BACKGROUND:

Mouse double minute-2 homolog (MDM2) plays a key role in downregulating p53 activity in hematologic malignancies, and its overexpression is associated with poor outcomes.

METHODS:

This phase 1 study assessed the safety and efficacy of different dosing regimens of the MDM2 inhibitor milademetan as monotherapy and in combination with azacitidine (AZA) in patients with relapsed or refractory acute myeloid leukemia or high-risk myelodysplastic syndromes.

RESULTS:

Seventy-four patients (monotherapy, n = 57; milademetan-AZA combination, n = 17) were treated. The maximum tolerated dose of milademetan was 160 mg once daily given for the first 14-21 days of 28-day cycles as monotherapy and on Days 5-14 in combination with AZA. Dose-limiting toxicities were gastrointestinal, fatigue, or renal/electrolyte abnormalities. Treatment-emergent adverse events related to milademetan occurred in 82.5% and 64.7% of participants in the monotherapy and AZA combination arms, respectively. Two participants (4.2%) in the monotherapy arm achieved complete remission (CR), and 1 (2.1%) achieved CR with incomplete blood count recovery (CRi). Two participants (13.3%) achieved CRi in the combination arm. New TP53 mutations, detected only during milademetan monotherapy, were found pre-existing below standard detection frequency by droplet digital polymerase chain reaction.

INTERPRETATION:

Milademetan was relatively well tolerated in this population; however, despite signals of activity, clinical efficacy was minimal.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Azacitidina / Síndromes Mielodisplásicos / Leucemia Mieloide Aguda / Protocolos de Quimioterapia Combinada Antineoplásica / Dosis Máxima Tolerada / Proteínas Proto-Oncogénicas c-mdm2 Límite: Adult / Aged / Aged80 / Female / Humans / Male / Middle aged Idioma: En Revista: Cancer Med Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Azacitidina / Síndromes Mielodisplásicos / Leucemia Mieloide Aguda / Protocolos de Quimioterapia Combinada Antineoplásica / Dosis Máxima Tolerada / Proteínas Proto-Oncogénicas c-mdm2 Límite: Adult / Aged / Aged80 / Female / Humans / Male / Middle aged Idioma: En Revista: Cancer Med Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos