A Phase 1b/2 Study of Alvocidib Plus Decitabine in Patients With MDS
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|ClinicalTrials.gov Identifier: NCT03593915|
Recruitment Status : Recruiting
First Posted : July 20, 2018
Last Update Posted : November 12, 2018
Alvocidib, a cyclin-dependent kinase 9 (CDK 9) inhibitor, in time-sequential therapy demonstrated significant clinical activity in secondary AML patients with prior MDS. Patients with IPSS-R intermediate and above MDS have an increased risk of developing AML and may be treated with the same chemotherapy regimens used in patients with AML. Eight Phase I or II clinical trials have been completed in patients with AML, totaling more than 400 patients with both relapsed/refractory or newly diagnosed AML.
Preclinical studies have demonstrated that decitabine exposure increased the expression of NOXA, which is a specific antagonist of the survival factor MCL 1. Pharmacologic downregulation of MCL-1 via CDK 9 inhibition, as well as upregulation of the MCL-1 antagonist, NOXA, following decitabine exposure may result in enhanced antileukemic activity in MCL-1-dependent malignancies.
|Condition or disease||Intervention/treatment||Phase|
|Myelodysplastic Syndromes (MDS)||Combination Product: Alvocidib Plus Decitabine||Phase 1 Phase 2|
Patients will be enrolled in cohorts of 3-6 patients. Escalation of the alvocidib dose will follow a standard 3+3 design with sequential cohorts of 3 patients treated with incrementally higher doses of alvocidib until a dose-limiting toxicity (DLT) is observed and the MTD is established.
Once the MTD or preliminary RP2D is identified, the study will progress to Phase 2.
Phase 2 design is based on the Simon 2-stage minimax design (Simon 1989).
- Stage 1: Up to 15 evaluable patients will be enrolled and treated at the RP2D identified in the Phase 1b study.
- Stage 2: Ten patients will be enrolled to bring the total enrollment in Phase 2 (including Stage-1 patients) to 25 evaluable patients. Stage-2 patients will also receive the RP2D dose identified in the Phase 1b study. If 6 or more responses are observed in 25 patients, the conclusion will be that the combination regimen is worthy of further investigation.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||49 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase 1b/2, Open-label Clinical Study to Determine Preliminary Safety and Efficacy of Alvocidib When Administered in Sequence After Decitabine in Patients With MDS|
|Actual Study Start Date :||August 29, 2018|
|Estimated Primary Completion Date :||February 2022|
|Estimated Study Completion Date :||May 2022|
Experimental: Ph 1b and 2: Pts w/ previously untreated MDS
Combination Product: Alvocidib Plus Decitabine
Decitabine administered as a 1-hour intravenous (IV) infusion daily for 5 days at a dose of 20 mg/m2 followed on Day 8 by alvocidib as a loading dose over 30 minutes followed by a 4-hour IV infusion
The Phase 2 study will use the RP2D from the Phase 1b study and follow a Simon 2-stage minimax design
- PHASE 1b: Incidence of dose-limiting toxicities (DLTs) and treatment emergent adverse events. [ Time Frame: 28 days ]
DLTs as observed in Cy 1. Must be at least possibly related to alvocidib. Any Gr 4 nonhematologic toxicity. Gr 3 nonhematologic toxicity that does not resolve to ≤Gr 2 in 48 hours. Gr 3 diarrhea, mucositis, nausea, or vomiting will be considered dose limiting only if resolution to ≤Gr 2 requires >7 days. ≥Grade 3 neurotoxicity of any duration
≥Grade 3 creatinine elevation of any duration Anorexia, fever, neutropenic fever, and infections of any grade Myelosuppression will not be considered in evaluating DLTs in patients except where bone marrow hypoplasia occurs for >50 days with bone marrow (BM) cellularity ≤5% and no evidence of MDS/leukemia.
- PHASE 2: Objective response rate using revised International Working Group (IWG) criteria (2006) [ Time Frame: 3 months ]Baseline disease assessment performed at screening and subsequent response assessments
- PHASE 1b: Complete Response Rate (CRR: CRR: complete response [CR] / complete response with incomplete blood count recovery [CRi] / CRmarrow / partial response [PR] / hematologic improvement [HI]) [ Time Frame: 3 months ]Baseline disease assessment performed at screening and subsequent response assessments
- PHASE 1b and 2: Decitabine treatment effect on BH3 profiling results in peripheral blood to find the correlation between the rate of CR/CRi/CRmarrow/PR/HI and BH3 profiling by flow cytometry with an emphasis on MCL-1 dependence. [ Time Frame: 3 months ]Assessment of BH3 profiling in peripheral blood
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03593915
|Contact: Nissa Ashenbramer, BBAemail@example.com|
|Contact: Susan Smith, MSNfirstname.lastname@example.org|
|United States, Maryland|
|Johns Hopkins||Not yet recruiting|
|Baltimore, Maryland, United States, 21218|
|Contact: Amy DeZern, MD|
|Principal Investigator: Amy DeZern, MD|
|United States, Texas|
|US Oncology - Texas Oncology - Austin Midtown||Recruiting|
|Austin, Texas, United States, 78705|
|Contact: Jason Melear, MD 512-421-4163|
|Principal Investigator: Jason Melear, MD|
|US Oncology - Texas Oncology - San Antonio Medical Center||Recruiting|
|San Antonio, Texas, United States, 78240|
|Contact: Roger Lyons, MD|
|Principal Investigator: Roger Lyons, MD|
|US Oncology - Texas Oncology - Tyler||Recruiting|
|Tyler, Texas, United States, 75702|
|Contact: Habte Yimer, MD 903-579-9800|
|Principal Investigator: Habte Yimer, MD|
|United States, Washington|
|US Oncology - Northwest Cancer Specialists, P.C.||Recruiting|
|Vancouver, Washington, United States, 98684|
|Contact: David A Smith, MD|
|Principal Investigator: David A Smith, MD|
|Study Director:||Stephen Anthony, DO||Tolero Pharmaceuticals|