The Efficacy and Safety of Selinisole Combined With Azacitidine and Venetoclax in the Treatment of Newly Diagnosed High-risk Myeloid Tumors With TP53 Mutations

Official title

The Efficacy and Safety of Selinisole Combined With Azacitidine and Venetoclax in the Treatment of Newly Diagnosed High-risk Myeloid Tumors With TP53 Mutations: A Multicenter, Single-arm, Prospective Study

Overview

Patients with high-risk myeloid tumors accompanied by TP53 mutations have a poor survival prognosis, and there are still many unmet treatment needs. The current treatment regimens have many limitations. Selinisol, as a novel export protein inhibitor, has good anti-tumor activity. The current preclinical and preliminary clinical research results abroad suggest its effectiveness and safety. This study aims to evaluate the efficacy and safety of AZA combined with selinisole (with or without venetoclax) in the treatment of patients with high-risk myeloid tumors with TP53 mutations through a multicenter, prospective clinical study.

Detailed description

At present, AZA combined with venetocla (" AV regimen ") has become the standard first-line regimen for elderly patients with AML who are intolerant to intensive chemotherapy, but its efficacy in TP53-mutated patients still needs to be improved (ORR approximately 30%-40%). In recent years, several early clinical studies have preliminarily verified the safety and efficacy of AZA combined with selinisole and AZA combined with selinisole + venetoclax regimens. A Phase Ib study presented at the 2023 ASH conference demonstrated that the ORR of patients with relapsed/refractory MDS/AML treated with AZA combined with selinisole reached 42%, among which the ORR of TP53-mutated patients was 38%, and the median OS was 8.5 months, significantly better than historical data. Another study explored the efficacy of the combination of AZA, selinisol and venetoclax in the treatment of R/R AML, involving 12 patients. The preliminary results showed that the ORR of this regimen could reach 91.7%, and the CRR was 42.7%, with good tolerance. The main adverse reactions were controllable gastrointestinal reactions and cytopenia. These clinical data further confirm the application potential of the AZA combined with selinisole (with or without venetoclax) regimen in high-risk myeloid tumors with TP53 mutations, laying a solid foundation for conducting large-scale clinical research.

Interventions

• Drug Selinexor
  Azacitidine +Selinexor ± venetoclax were administered (Selinexor: 60mg/ week, qw\*4 weeks; azacitidine: 100mg/m2\*d1-d7; venetoclax, 100mg d1-14). The specific medication duration can be adjusted by the researcher based on the patient's specific condition. A time window of 14 to 28 days is allowed. Each treatment cycle lasts for 30 days until disease progression or the occurrence of intolerable toxicity, whichever comes first.

Primary outcome measures

• 3 and 6 months overall response rate (ORR) [Time frame: 3 and 6 months]
• 3 and 6 months complete response rate (CRR) [Time frame: 3 and 6 months]

Secondary outcome measures (4)

• Progression-free survival (PFS); [Time frame: 6 months]
• Overall survival (OS); [Time frame: 6 months]
• The incidence of cumulative infection and significant bleeding; [Time frame: 6 months]
• Incidence of adverse reaction events. [Time frame: 6 months]

Eligibility criteria

Inclusion criteria

• Age ≥18 years old; Gender is not limited.
• The presence of TP53 mutations (According to the 5th Edition of the WHO Classification of hematopoietic and lymphoid tumors and the International Consensus Classification (ICC 2022), the definition of myeloid tumors with TP53 mutations is: pathogenic/potentially pathogenic variations of the TP53 gene are detected through molecular technologies such as next-generation sequencing (NGS), and any of the following conditions are met: The frequency of variant alleles (VAF) is ≥10%, or there are multiple TP53 mutations (≥2 mutations), or both TP53 mutations and 17p deletion (del(17p)) are present.
• For the initial treatment of myeloid tumors, the diagnosis was made through peripheral blood and bone marrow examinations and exclusion tests (according to the fifth edition of the WHO and ICC consensus） :

3.1 MDS (IPSS-R/IPSS-M at high risk or above; or complex karyotype/alone -5/-5q, -7/-7q, i (17q), inv (3)/t(3;3); Or bone marrow blasts ≥10%; 3.2 AML (bone marrow/peripheral blood blasts ≥20%; and high-risk cytogenetic or molecular abnormalities exist); 3.3 MPN (High risk score above threat; or presence of any one of ASXL1, SRSF2, EZH2, IDH1/2, or U2AF1 gene mutations; or bone marrow blasts ≥10%); 3.4 MDS/MPN (IPSS-R high-risk or above; or bone marrow blast granulocytes ≥10%).

• Voluntarily join this study, sign the informed consent form with good compliance, and be willing to cooperate with regular follow-ups for efficacy evaluation and side effect monitoring.
• Before treatment, the patient's total bilirubin (TBIL) was less than 1.5 times the upper limit of the normal value (ULN), and the alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were less than 3 times the ULN.
• ECOG score ≤2 points.

Exclusion criteria

• Patients who have transplant plans within three months;
• All laboratory or clinical records of HIV infection, previous clinical history of hepatitis C, previous hepatitis B infection, or evidence of active hepatitis during screening. Laboratory tests during the screening period suggest hepatitis C infection or hepatitis B infection. (Defined as a positive HBsAg test. Additionally, if the HBsAg test is negative but HBcAb is positive, regardless of the HBsAb status, HBV DNA testing is required. If it is positive, the subject should be excluded.)
• Suffering from mental disorders or other conditions and unable to cooperate with the requirements of research, treatment and monitoring;
• Pregnant patients or those who cannot take appropriate contraceptive measures during the treatment period;
• Those suspected of being allergic to the experimental drug or any of its excipients;
• Active heart disease is defined as one or more of the following:

① A history of uncontrolled or symptomatic angina pectoris;

② Myocardial infarction less than 6 months from the time of enrollment in the study;

③ There is a history of arrhythmia that requires drug treatment or has severe clinical symptoms;

④ Uncontrolled or symptomatic congestive heart failure (NYHA grade 2)

⑤ The ejection fraction is lower than the lower limit of the normal range.

• Patients who the researchers consider unsuitable to participate in this trial, such as those whose safety or compliance with the study procedures may be affected by any other medical, social or psychological factors.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Peking union medical college hospital — Beijing

Identifiers

NCT: NCT07632170 · Selinexor+AZA+/-VEN

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗