A Safety and Efficacy Study of Pracinostat and Azacitidine in Patients With High Risk Myelodysplastic Syndromes
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT03151304|
Recruitment Status : Terminated (Sponsor's decision as at the completion of the primary analysis, the data were considered mature)
First Posted : May 12, 2017
Results First Posted : March 2, 2022
Last Update Posted : March 2, 2022
This is a Phase 2, two-stage study of the safety and efficacy of pracinostat in combination with azacitidine in patients with IPSS-R high and very high risk myelodysplastic syndrome (MDS) who are previously untreated with hypomethylating agents (HMAs). Enrollment in this study will be limited to high/very high risk MDS because this group represents the highest unmet need, with median survival of less than 18 months.
Stage 1a will be conducted as an open-label single arm in up to 40 subjects to assess if this regimen with a lower pracinostat dose results in a discontinuation rate that meets a predefined threshold and in efficacy that justifies expansion of enrollment into Stage 1b.
A discontinuation rate of approximately ≤10% in Stage 1a, a rate comparable to that observed with azacitidine alone in study MEI-003 (NCT01873703), supports expansion into Stage 1b.
Stage 1b will be conducted as expansion of stage 1a. Approximately 20 additional subjects will be enrolled. Study drugs should be continued until disease progression or intolerable toxicity. It is important to note that the median time to achieving a response with azacitidine alone is 4 to 5 months. Furthermore, the median time to achieving a Complete Response (CR) in study MEI-003 (NCT01873703) was 4 cycles. Therefore, early (<6 months) discontinuation of trial therapy for 'no response' should be avoided. The Medical Monitor should be contacted prior to discontinuing a subject from the study to discuss the rationale for discontinuation.
|Condition or disease||Intervention/treatment||Phase|
|Myelodysplastic Syndromes||Drug: Pracinostat Drug: Azacitidine||Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||64 participants|
|Intervention Model:||Single Group Assignment|
|Intervention Model Description:||Two-Stage, Open-Label|
|Masking:||None (Open Label)|
|Official Title:||A Two-Stage, Open-Label Phase 2 Study of Pracinostat and Azacitidine in Patients With IPSS-R High and Very High Risk Myelodysplastic Syndromes Previously Untreated With Hypomethylating Agents|
|Actual Study Start Date :||June 1, 2017|
|Actual Primary Completion Date :||December 1, 2020|
|Actual Study Completion Date :||December 1, 2020|
Experimental: Stage 1a and 1b open-label pracinostat plus azacitidine
open-label single arm pracinostat plus azacitidine. Pracinostat: 45 mg administered orally 3 days each week for 3 consecutive weeks, followed by 1 week of rest, in 28-day cycles.
In later cycles (i.e., after Cycle 4), pracinostat dose reduction to 45 mg orally 3 days each week × 2 weeks (instead of 3 weeks) or dose interruption is allowed to manage toxicity such as fatigue, gastrointestinal toxicity, or myelosuppression.
Azacitidine: 75 mg/m2 for 7 days of each 28-day cycle. Administration will occur by subcutaneous (SC) injection, or IV infusion if SC injections are not tolerated, on one of two schedules:
45 mg capsule
Other Name: SB939
SC or IV injection
- Overall Response Rate (ORR) [ Time Frame: 36 months ]
Percentage of subjects with confirmed complete remission (CR), partial remission (PR) and marrow CR, as per modified International Working Group (IWG) criteria:
CR: Bone marrow: ≤5% myeloblasts with normal maturation of all cell lines; Peripheral blood Hemoglobin (Hb) ≥11 g/dL; Platelets ≥100 × 10^9/L; Neutrophils ≥1.0 × 10^9/L; Blasts 0%.
PR: All CR criteria if abnormal before treatment except: Bone marrow blasts decreased by ≥ 50% over pre-treatment but still >5%; Cellularity and morphology not relevant Marrow CR: Bone marrow: ≤5% myeloblasts and decrease by ≥50% over pre-treatment
- Complete Response (CR) Rate [ Time Frame: 36 months ]
Percentage of subjects with confirmed CR (i.e., 2 CRs at least 28 days apart) as per modified IWG criteria:
CR: Bone marrow: ≤5% myeloblasts with normal maturation of all cell lines; Peripheral blood Hb ≥11 g/dL; Platelets ≥100 × 109/L; Neutrophils ≥1.0 × 109/L; Blasts 0%.
- Overall Hematologic Improvement (HI) Response Rate [ Time Frame: 36 months ]
Percentage of subjects demonstrating major hematologic improvement according to modified IWG:
Erythroid response (pre-treatment, <11 g/dL): Hb increase by ≥1.5 g/dL; Relevant reduction of units of RBC transfusions by an absolute number of at least 4 RBC transfusions/8 weeks compared with the pre-treatment transfusion number in the previous 8 weeks. Only RBC transfusions given for a Hb of ≤9.0 g/dL pre-treatment will count in the RBC transfusion response evaluation.
Platelet response (pre-treatment, <100 × 10^9/L): Absolute increase of ≥30 × 10^9/L for patients starting with >20 × 10^9/L platelets; Increase from <20 × 10^9/L to >20 × 10^9/L and by at least 100%.
Neutrophil response (pre-treatment, <1.0 × 10^9/L): At least 100% increase and an absolute increase >0.5 × 10^9/L.
Progression or relapse after HI: at least 1 of the following:
- At least 50% decrement from maximum response levels in granulocytes or platelets
- Reduction in Hb by≥1.5 g/dL
- Transfusion dependence
- Clinical Benefit Rate [ Time Frame: 36 months ]Percentage of subjects with confirmed CR, PR, Marrow CR, and HI with clinical benefit rate, defines as rate of CR + PR + HI + Marrow CR. All subjects who achieve hematologic CR, PR, marrow CR, or hematologic improvement on the erythrocytic lineage per modified IWG response criteria will be considered responders
- Rate of Cytogenetic CR [ Time Frame: 36 months ]
Percentage of subjects with confirmed CR by cytogenetic assessment. Complete cytogenetic response is defined per modified IWG response criteria:
Complete: Disappearance of the chromosomal abnormality without appearance of new ones Partial: At least 50% reduction of the chromosomal abnormality
- Duration of Response (DoR) [ Time Frame: 36 months ]For subjects who have achieved CR, PR, Marrow CR, or HI, DoR is defined as the time from the initial determination of response to the time of disease progression or death on study, whichever occurs first.
- Rate of Leukemic Transformation [ Time Frame: 6 months ]Percentage of subjects with leukemic transformation at landmark time point of 6 months
- Event-free Survival (EFS) [ Time Frame: 36 months ]time from the first day of study drug administration (Day 1) to failure or death from any cause
- Progression-free Survival (PFS) [ Time Frame: 36 months ]
time from the first day of study drug administration (Day 1) to disease recurrence or progression as defined by the IWG criteria, or death on study:
Disease progression for subjects with:
Less than 5% blasts: ≥50% increase in blasts to >5% blasts 5%-10% blasts: ≥50% increase to >10% blasts 10%-20% blasts: ≥50% increase to >20% blasts 20%-30% blasts: ≥50% increase to >30% blasts
Any of the following:
At least 50% decrement from maximum remission/response in granulocytes or platelets Reduction in Hb by ≥2 g/dL Transfusion dependence
- Overall Survival (OS) [ Time Frame: form day 1 to death on study, assessed up to 36 months ]time from the first day of study drug administration (Day 1) to death on study
- Rate of Leukemic Transformation [ Time Frame: 12 months ]Percentage of subjects with leukemic transformation at landmark time point of 12 months
- Rate of Leukemic Transformation [ Time Frame: 18 months ]Percentage of subjects with leukemic transformation at landmark time point of 18 months
- Rate of Leukemic Transformation [ Time Frame: 24 months ]Percentage of subjects with leukemic transformation at landmark time point of 24 months
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): NCT03151304
|Study Director:||Richard Ghalie, MD||MEI Pharma|
|Study Chair:||Ehab Atallah, MD||Medical College of Wisconsin adn Froedtert Hospital|