A Phase I Study Investigating the Safety & Efficacy of Danvatirsen as Monotherapy Followed by Combination With Venetoclax in Patients With Relapsed/Refractory MDS & AML
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 38
- 试验地点
- 2
- 主要终点
- Response to Therapy as determined by Overall Response Rate
研究概览
简要总结
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).
Funding Source: FDA OOPD
详细描述
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. Venetoclax is a commercially available, potent, selective small molecule inhibitor of B-cell Lymphoma-2 (BCL-2), an anti-apoptotic protein found on some types of cancer cells. Prior studies have demonstrated a strong correlation between STAT3 & Myeloid cell leukemia-1 (MCL-1) overexpression. MCL-1 is a multi-domain anti-apoptotic protein belonging to the BCL-2 family, which regulates the intrinsic apoptosis pathways and plays a central role in mediating therapeutic resistance to novel therapies such as Venetoclax in MDS and AML.
While FDA approved therapies have moved the field forward in newly diagnosed AML, relapsed/refractory (R/R) MDS and R/R AML continue to have a dismal prognosis, with a median overall survival of 4-10 months.
The study team has designed an innovative clinical trial to study Danvatirsen as monotherapy followed by combination with venetoclax for the treatment of relapsed/refractory high-risk MDS/AML. The study team plans to incorporate several important pharmacodynamic endpoints that will provide a real-time assessment of the effect of STAT3 inhibition in MDS/AML stem & progenitor cells and the impact on target gene expression. These correlative studies will help identify subsets of patients that are most likely to respond to STAT3 inhibition. Although direct targeting and monitoring of aberrant stem cells has recently gained some traction in AML, it is a novel approach for the treatment of MDS.
This study has been designed as a Phase 1 dose-escalation protocol of 2 different sub-studies to evaluate the safety profile, determine the Maximum Tolerated Dose (MTD) of Danvatirsen monotherapy followed by combination with Venetoclax once safety of Danvatirsen monotherapy is established. Patients with intermediate/high/very high IPSS-R MDS or AML who have relapsed/or are refractory to all available frontline therapy with no FDA approved treatment options will be enrolled in both the sub-studies. The objective of determining the MTD is to be able to find the minimum safe and biologically effective dose to be the recommended Phase 2 dose. For both the sub-studies safety, efficacy and assessment of PK/PD will be used to inform the recommended phase 2 dose.
Arms/Groups are detailed in the 'Arms/Groups' module of this record. Dose-escalation for each substudy is as follows:
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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 2 cycles of hypomethylating agent based therapy (azacitidine / decitabine based) OR patients with rapid progression of disease regardless of number of cycles of therapy
- •At least 3 months from Allogenic stem cell transplantation and no clinical sign of active graft vs host disease (GVHD)
- •WBC must be <25,000 cells/uL and may be reduced with hydroxyurea to reach this goal prior to study start. Hydroxyurea can be administered on trial with an increase in WBC counts at the discretion of the PI
- •A bone marrow biopsy must be performed within the screening window (day-28-day-1) and tissue collected for correlative analysis for entrance to this trial. Correlative sample collection is essential 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 known Gilberts syndrome or if considered to be leukemia related)
- •Serum creatinine clearance ≥ 45 mL/min/1.73 m2 either measured or calculated using standard Cockroft-Gault formula
- •Subjects enrolled within childbearing ages of 18-50 years should use 2 forms of contraception while on study
排除标准
- •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)
研究组 & 干预措施
Danvatirsen Monotherapy
Patients will be enrolled in cohorts of 3 for the Danvatirsen dose escalation substudy. Based on the DLT of the first cohort of participants, subsequent cohorts will either be administered doses at the next higher dose level, de-escalated to the next lower dose level, or remain the same. Dose escalation discontinuations and MTD will be determined as described in the 'Detailed Study Description.' The total duration of 1 cycle is approximately 4 weeks (28 days). Proposed dose levels and treatment schedule are as follows:
Dose Level 1 (DL1): Danvatirsen Day 1 - Day 28 (1mg/kg loading dose on Cycle 1/Day 1 (C1D1), Cycle 1/Day 3 (C1D3); and Cycle 1/Day 5 (C1D5) followed by weekly 1mg/kg infusion for 3 weeks) Dose Level 2 (DL2): Danvatirsen Day 1 - Day 28 (2mg/kg loading dose on C1D1, C1D3, and C1D5 followed by weekly 2mg/kg infusion for 3 weeks) Dose Level 3 (DL3): Danvatirsen Day 1 - Day 28 (3mg/kg loading dose on C1D1, C1D3, and C1D5 followed by weekly 3mg/kg infusion for 3 weeks)
干预措施: Danvatirsen (Drug)
Danvatirsen + Venetoclax Combination Therapy
Patients will be enrolled in cohorts of 3 for the Danvatirsen + Venetoclax dose escalation substudy. Dose escalation administration will be as described in the Danvatirsen monotherapy substudy arm and dose escalation discontinuations and MTD will be determined as described in the 'Detailed Study Description.'
Up to 2 dose levels of Danvatirsen will be evaluated based on data from the Danvatirsen monotherapy arm. Dose 1 will be one level lower than the dose with expected target activity.
Venetoclax: 400 mg (or equivalent) administered as fixed dose daily (except for specific dose modifications described in the protocol) orally for 28 days per cycle. To mitigate risk of tumor lysis syndrome, during Cycle 1 Venetoclax will be dose escalated daily to the goal dose of 400mg daily (100mg on Day 1, 200mg on Day 2 and 400mg on Day 3, and onwards, or adjusted dose ramp-up per Venetoclax label if on concomitant azoles).
The three cycles are approximately 28 days each in duration.
干预措施: Danvatirsen + Venetoclax (Combination Product)
结局指标
主要结局
Response to Therapy as determined by Overall Response Rate
时间窗: From 21 days after initiation of study treatment to within 14 days following treatment discontinuation; up to 14 weeks total
Overall Response Rate (ORR) will be used to assess clinical activity in AML and MDS participants. ORR will be measured as the percentage of participants demonstrating an objective overall response based upon a composite of remission related measures for AML and MDS participants as defined below. For AML participants, ORR will be defined as any confirmed Complete Remission (CR) + Complete Remission with Incomplete hematologic recovery (CRi) + Partial Remission (PR). or, AML = CR + CRi + PR For MDS participants, ORR will be defined as any confirmed Complete Remission (CR) + Complete Remission with Partial Hematologic Recovery (CRh) + Hematologic Response (HR). or, MDS = CR + CRh + HR Higher percentage is indicative of increased clinical activity of the danvatirsen monotherapy and danvatirsen + venetoclax combination therapies.
次要结局
- Overall Survival(Up to 3 years after discontinuation of study treatment; up to 3.5 years total)
- 30 Day All-cause mortality(30 days after initiation of study treatment)
- 60 Day All-cause Mortality(60 days after initiation of study treatment)
- Duration of Response(Up to 3 years after discontinuation of study treatment; up to 3.5 years total)
- Event-free survival(Up to 3 years after discontinuation of study treatment; up to 3.5 years total)