An official website of the United States government
Government Funding Lapse Because of a lapse in government funding, the information on this website may not be up to date, transactions submitted via the website may not be processed, and the agency may not be able to respond to inquiries until appropriations are enacted.
The NIH Clinical Center (the research hospital of NIH) is open. For more details about its operating status, please visit cc.nih.gov.
Updates regarding government operating status and resumption of normal operations can be found at opm.gov.
Danvatirsen With or Without Venetoclax for the Treatment of Patients with Relapsed or Refractory Myelodysplastic Syndrome and Acute Myeloid Leukemia
Trial Status: active
This phase I trial tests the safety, side effects, and best dose of danvatirsen alone or in combination with venetoclax for treating patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). Chemotherapy drugs, such as danvatirsen, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy with danvatirsen may kill more cancer cells. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Giving danvatirsen with or without venetoclax may be safe and tolerable in treating patients with relapsed or refractory MDS or AML.
Inclusion Criteria
Subjects must be at least 18 years of age at the time of signing the informed consent form (ICF); must voluntarily sign an ICF; and be able to meet all study requirements
Morphologically confirmed diagnosis of AML or MDS in accordance with World Health Organization (WHO) diagnostic criteria
Subjects with relapsed/refractory AML who are refractory or relapsed to all conventional therapy and do not have any Food and Drug Administration (FDA) approved or standard therapeutic options & subjects with intermediated/high/very high IPSS-R MDS who are refractory or relapsed to at least 6 cycles of hypomethylating agent based therapy (azacitidine / decitabine based)
White blood cell (WBC) must be < 25,000 and may be reduced with hydroxyurea to reach this goal prior to study start
A post-consent bone marrow biopsy must be performed and tissue collected for correlative analysis for entrance to this trial. Correlative sample collection will not be optional on this study
Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
Recovery to ≤ grade 1 or baseline for any toxicities considered to be due to prior systemic treatments, excluding alopecia
Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/ Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 3x upper limit of normal (ULN) or ≤ 5x ULN if considered to be leukemia related
Direct bilirubin ≤ 1.5 x ULN or ≤ 3x ULN (in patients with know Gilberts syndrome or if considered to be leukemia related)
Serum creatinine clearance ≥ 60 mL/min/1.73 m^2 either measured or calculated using standard Cockcroft-Gault formula
Exclusion Criteria
Acute promyelocytic leukemia
Low or very low risk MDS by IPSS-R after failure/progression of first line therapy with hypomethylating agents
Active, uncontrolled infection. Patients with infection under active treatment and controlled with antibiotics are eligible. Use of prophylactic anti-microbials per institutional standards is allowed
Active documented central nervous system (CNS) leukemia. Patients with a known history of CNS leukemia will be eligible if they have at least two most recent consecutive lumbar punctures (LPs) showing clearance of CNS disease and no active/progressive symptoms thought to be related to the CNS disease
Concurrent treatment with a non-permitted concomitant medication
Concurrent anticancer treatment, major surgery, or the use of any investigational drug within 14 days before the start of trial treatment
Other malignancy currently being treated or likely to need treatment in next 6 months with the exception of basal or squamous cell carcinoma of the skin or cervical carcinoma in situ, surgically removed malignancies or malignancies definitively treated with chemotherapy, radiation (XRT) and/or surgery with no evidence of active malignancy or not anticipated to need treatment in next 6 months or malignancies on maintenance therapy (e.g. tamoxifen for breast cancer) will be allowed after discussion and approval by both multiple principal investigators (MPIs)
Pregnant or breastfeeding females
Known current alcohol or drug abuse
Clinically significant cardiovascular disease within the past 6 months (e.g. percutaneous intervention, coronary artery bypass graft, documented New York Heart Association (NYHA) class III/IV cardiac heart failure, unstable angina or myocardial infarction (MI), poorly controlled atrial or ventricular arrhythmia) as determined by the investigator
Any psychiatric condition that would prohibit the understanding or rendering of informed consent
Legal incapacity or limited legal capacity to sign consent and/or participate in the trial
Any condition deemed by the investigator to make the patient a poor candidate for clinical trial and/or treatment with investigational agents
Previous exposure to the investigational agent (danvatirsen) or to other STAT3 inhibitors
Additional locations may be listed on ClinicalTrials.gov for NCT05986240.
I. Establish the safety (maximum tolerated dose [MTD]), recommended phase 2 dose (RP2D) of danvatirsen monotherapy followed by combination with venetoclax for the treatment of relapsed/refractory (R/R) int/high/very-high-risk International Prognostic Scoring System-Revised (IPSS-R) myelodysplastic syndrome (MDS) or R/R acute myeloid leukemia (AML).
SECONDARY OBJECTIVES:
I. To determine the on-target activity of danvatirsen (STAT3 inhibition) in hematopoietic stem and progenitor cells.
II. To correlate the responses observed from danvatirsen monotherapy and combination with venetoclax with a STAT3 gene expression signature.
III. To determine the duration of response (DOR), event-free survival (EFS), overall survival (OS), 30- and 60-day all cause mortality, minimal residual disease clearance in responders (based on multiparametric flow-cytometry, number bridged to stem cell transplant [SCT]).
IV. Establish the efficacy (complete response [CR]+marrow CR for MDS, CR+complete response with incomplete bone marrow recovery [CRi] for AML) of danvatirsen monotherapy followed by combination with venetoclax for the treatment of R/R int/high/very-high-risk IPSS-R MDS or R/R AML.
EXPLORATORY OBJECTIVE:
I. Analyze the ribonucleic acid (RNA) sequencing profile of responders versus (vs.) non-responders pretreatment as well as on-treatment.
OUTLINE: This is a dose-escalation study of danvatirsen alone and in combination with venetoclax. Patients are assigned to 1 of 2 arms.
ARM I: Patients receive danvatirsen intravenously (IV) on day 1, 3 and 5 and then weekly for 3 weeks. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients should be removed from the study after 6 cycles in the absence of clinical benefit. Patients undergo bone marrow biopsy and aspiration and blood sample collection throughout the study.
ARM II: Patients receive dancatirsen IV on day 1, 3 and 5 and then weekly for 3 weeks and venetoclax orally (PO) daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients should be removed from the study after 6 cycles in the absence of clinical benefit. Patients undergo bone marrow biopsy and aspiration and blood sample collection throughout the study.
After completion of study treatment, patients are followed up at 28 days and every 3 months for up to 3 years.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationMontefiore Medical Center-Weiler Hospital
