IRB Study Number 25-720
Status Recruiting
Phase Phase 3
Location Cleveland Clinic Main Campus
Institute Taussig Cancer Institute
Description
5.1. Primary objectives
To evaluate the efficacy of Lisaftoclax in combination with azacitidine (AZA) vs. placebo plus AZA in newly diagnosed adult subjects with higher risk myelodysplastic syndrome (HR-MDS). Complete remission (CR) rate and overall survival (OS) are the dual primary endpoints.
5.2. Secondary objectives
To compare the effect of lisaftoclax and AZA in subjects with newly diagnosed HR-MDS on the composite complete remission rate [CRc=CR+ CRL+CRh+ CRequ], overall response rate [ORR = CR(or CRequ)+ PR + CRL + CRh + HI], the proportion of subjects with transfusion independence (TI) for at least 8 weeks (56 days) during the trial, time to transformation to acute myeloid leukemia (AML), time to response (TTR), duration of response (DOR), 30-day mortality rate, hematopoietic stem cell transplantation (HSCT).
To evaluate the safety of lisaftoclax plus AZA vs. the control group in subjects with newly diagnosed HR-MDS.
To evaluate the population pharmacokinetics (Pop PK) following treatment with lisaftoclax plus AZA.
To evaluate Patient-Reported Outcome (PRO) measures of lisaftoclax plus AZA vs. placebo plus AZA based on EORTC QLQ C30 (V3).
To evaluate Health Economics Outcomes Research (HEOR) measures of lisaftoclax plus AZA vs. placebo plus AZA based on EuroQol 5 Dimension (EQ-5D).
To compare the CR + PR rate of lisaftoclax and AZA with the control arm per IWG 2006 criteria.
5.3. Exploratory objectives
To evaluate the potential correlation between biomarkers in bone marrow or peripheral blood samples and the efficacy of lisaftoclax plus AZA in the treatment of HR-MDS.
To investigate potential resistance mechanisms by analyzing bone marrow or blood samples during disease progression.
Depending on the subject’s disease status, the investigator may conduct bone marrow minimal residual disease (MRD) testing under certain circumstances to evaluate the depth of disease remission (upon request and approval from the Sponsor in advance).
Inclusion Criteria
Aged ≥ 18 years old.
Newly Diagnosed MDS is defined according to 2022 World Health Organization classification (5th Edition), with presence of < 20% bone marrow blasts per bone marrow biopsy/aspirate at screening, as well as with Revised International Prognostic Scoring System (IPSS-R) score >3 (intermediate, high, or very high).
Subjects eligible for hematopoietic stem cell transplantation (HSCT) who are not scheduled for HSCT prior to the start of study Day 1 (C1D1); or subjects who are not eligible for HSCT.
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
Able to receive oral medication.
Life expectancy ≥ 3 months.
Adequate organ functions as defined below:
Creatinine clearance ≥ 30 ml/min (calculated with Cockcroft formula, as shown in Annex 3)
Total bilirubin < 1.5 × ULN (except Gilbert's syndrome, hyperbilirubinemia due to regular blood transfusions as assessed by the investigator)
Aspartate aminotransferase (ALT) and alanine aminotransferase (AST) ≤ 2.5 × ULN
Negative urine or serum pregnancy test prior to dosing in women of childbearing potential. Women of childbearing potential (postmenopausal women must have been postmenopausal for at least 12 months to be considered of non-childbearing potential) and their partners are willing to use contraception as deemed effective by the investigator during treatment and for at least 6 months after the last dose of study drug.
Subjects must have the ability to understand and show the willingness of voluntarily to give a written informed consent form that must be signed prior to performing any trial-specific study procedures.
Subjects should be able to complete study procedures and follow-up examinations.
Exclusion Criteria
1) Previous diagnosis of:
Therapy-related MDS (t-MDS) (per WHO definition)
MDS evolving from a pre-existing myeloproliferative neoplasms (MPNs)
MDS/MPN: including chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), juvenile myelomonocytic leukemia (JMML), and unclassifiable MDS/MPN
MDS with advanced myelofibrosis (MF ≥ grade 3), or MDS with severe autoimmune hemolysis
2) Have received any previous anti-tumor therapy for MDS.
3) Any of the following cardiac abnormalities (as determined by the study physician based on clinical examination assessments):
Any history of myocardial infarction within 6 months
Congestive heart failure (CHF) (New York Heart Association [NYHA] Class III or IV) or left ventricular ejection fraction (LVEF) < 40%
Symptomatic ventricular arrhythmia uncontrolled by medication
Any history of familial long QT syndrome
The average QT interval calculated from 3 electrocardiogram (ECG) readings (1 to 3 minutes apart) is > 470 (Using Fridercia's correction: QTcF = QT/RR0.33)
4) Second malignancies or previous malignancies with a disease-free interval of less than 1 year at the time of signing the informed consent (except for subjects with adequately resected cutaneous basal cell or squamous cell carcinoma or resected carcinoma in situ).
5) Have history of HSCT.
6) Other clinically significant uncontrolled symptoms, including but not limited to: uncontrolled active systemic infection (virus, bacteria or fungi), known clinically active hepatitis B or C, or HIV infection. (as determined by the study physician based on clinical examination assessments).
7) Use of moderate or strong CYP3A4 inhibitors or inducers within 14 days prior to the first dose of study drugs.
8) Have malabsorption syndrome or other conditions and are not suitable for enteral drug administration.
9) Have any other conditions or illnesses which, in the investigator's judgment, makes them unsuitable for participation in this study.
7.3. Criteria for subjects’ discontinuation from study treatment
Each subject has the right to withdraw from study treatment at any time. Subject may also be discontinued from the study at any time if deemed necessary by the investigator for any of the following reasons:
The investigator determines that discontinuation from the treatment is in the subject's best interests;
Disease progression during the study;
The subject requires radiotherapy, cancer-related surgery or other anti-tumor drugs due to tumor progression during the study;
Unsatisfactory treatment effect; subjects cannot tolerate treatment even after dose modifications as recommended in the protocol due to toxicity;
Non-compliance with the study protocol；
The investigator will inform the Sponsor in advance before terminating the subject's treatment and document it. All subjects will be included in the safety data analysis set.
Any subject who withdraws from study treatment should return to the site for the end-of-treatment (EOT) visit, and the primary reason for the withdrawal should be clearly documented in the medical records and the case report form (CRF).
If subjects discontinue treatment due to an AE or SAE, the subject should complete all relevant procedures for withdrawal as well as follow-up. If the subject or investigator cannot comply with this procedure, reasons shall be clearly documented.
After discontinuation of treatment due to unacceptable adverse event(s), the subject will be followed until resolution or stabilization of the adverse event.
Study drug must be discontinued immediately in the event of a positive pregnancy test or if the subject reports pregnancy during the study. The investigator must report the pregnancy to the Sponsor within 24 hours after awareness.
All subjects have the right to voluntarily withdraw from the study at any time for any reason. Consent will be withdrawn if the subject refuses to continue participating in the study, refuses all tests and assessments, or refuses to perform any study-related activities.
The Sponsor has the right to save and use all collected data to conduct the study assessment. All collected biological samples will be saved and used for future analysis and research.
If a subject withdraws consent, the investigator should make every effort (e.g., telephone calls, emails, letters, etc.) to identify the reason (s) and document it clearly.
After withdrawal of consent, study treatment must be stopped immediately and no further study assessments will be performed. Unless follow-up is required for safety concerns, contact with the subject is not permitted.
