A Phase I Study Investigating the Safety & Efficacy of Danvatirsen as Monotherapy Followed by Combination With Venetoclax in Patients With Relapsed/Refractory MDS & AML

Description

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). \[(FDA OOPD)\]This is a Phase 1 study investigating the safety and efficacy of Danvatirsen as a monotherapy followed by combination with Venetoclax in patients with intermediate/high/very high myelodysplastic syndromes (MDS) as determined by revised International Prognostic Scoring System (IPSS-R) or acute myeloid leukemia (AML) who have relapsed or are refractory to frontline therapy. Danvatirsen is a next generation, high affinity, antisense oligonucleotide inhibitor of signal transducer and activator of transcription 3 (or STAT3) that has shown preclinical activity in vitro and good intracellular uptake in vivo in primary patient MDS and AML stem cells. STAT3 is a transcription factor that is overexpressed and dysregulated in several malignancies. Ven

Trial Eligibility

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 4 cycles of hypomethylating agent based therapy (azacitidine / decitabine based) OR patients with rapid progression of disease regardless of number of cycles of therapy * WBC must be \<25,000 and may be reduced with hydroxyurea to reach this goal prior to study start * At least 3 months from Allogenic stem cell transportation and no clinical sign of active graft vs host disease (GVHD) * 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

Study Info

Interventions

Locations Recruiting

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