Danvatirsen Monotherapy Followed by Combination With Venetoclax in Relapsed/Refractory MDS & AML

• Status: Recruiting
• Trial end date: 2028-07-01
• Target enrollment: 0
• Participant gender: All

Summary

This is a Phase 1 study investigating the safety and efficacy of Danvatirsen as a monotherapy followed by combination with Venetoclax in patients with relapsed/refractory myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML). [(FDA OOPD)]

• Phase: Phase 1
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: Montefiore Medical Center
• Collaborators: Flamingo Therapeutics NV; M.D. Anderson Cancer Center
• Treatments: Venetoclax

Criteria

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 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)

• 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

• Must have adequate hepatic and renal function as follows:

ALT (SGPT) and/or AST (SGOT) ≤ 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 m2 either measured or calculated using standard Cockroft-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 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 (as noted in protocol appendix)

• 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, 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 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 NYHA class III/IV cardiac heart failure, unstable angina or 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