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Azacitidine

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Enzyme Inhibitors

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:

* Schedule 1 - daily therapy on Days 1 through 7
* Schedule 2 - 5-2-2 schedule in which subjects receive azacitidine for 5 consecutive days (Days 1 through 5) with rest on Days 6 and 7, and resume azacitidine dosing the first two days of the next week (Days 8 and 9) of each 28-day cycle

Pracinostat

Richard Ghalie, MD

Ehab Atallah, MD

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.

A Safety and Efficacy Study of Pracinostat and Azacitidine in Patients With High Risk Myelodysplastic Syndromes

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

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

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%.

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

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

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

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.

Percentage of subjects with leukemic transformation at landmark time point of 6 months

time from the first day of study drug administration (Day 1) to failure or death from any cause

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

time from the first day of study drug administration (Day 1) to death on study

Percentage of subjects with leukemic transformation at landmark time point of 12 months

Percentage of subjects with leukemic transformation at landmark time point of 18 months

Percentage of subjects with leukemic transformation at landmark time point of 24 months

Helsinn Healthcare SA

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:

* Schedule 1 - daily therapy on Days 1 through 7
* Schedule 2 - 5-2-2 schedule in which subjects receive azacitidine for 5 consecutive days (Days 1 through 5) with rest on Days 6 and 7, and resume azacitidine dosing the first two days of the next week (Days 8 and 9) of each 28-day cycle

Pracinostat: 45 mg capsule

Azacitidine: SC or IV injection

Stage 1a and 1b Open-label Pracinostat Plus Azacitidine

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Body Mass Index (BMI)

Francesco Scarci, Clinical Operations Manager

Overall Response Rate (ORR)

Complete Response (CR) Rate

Overall Hematologic Improvement (HI) Response Rate

Clinical Benefit Rate

Rate of Cytogenetic CR

Duration of Response (DoR)

Rate of Leukemic Transformation

Event-free Survival (EFS)

Progression-free Survival (PFS)

Overall Survival (OS)

Overall Study

Histone Deacetylase Inhibitors

60 mg of pracinostat by mouth 3 times a week for 3 weeks followed by 1 week of rest repeated every 28 days.

75 mg/m2 Azacitidine for 7 days of each 28 day cycle, via subcutaneous (SC) injection or intravenous infusion if SC injections are intolerable

Placebo by mouth 3 times a week for 3 weeks followed by 1 week of rest repeated every 28 days.

75 mg/m2 Azacitidine for 7 days of each 28 day cycle, via subcutaneous (SC) injection or intravenous infusion if SC injections are intolerable

pracinostat

Placebo

Active comparator 75 mg/m2 Azacitidine for 7 days of each 28 day cycle, via subcutaneous (SC) injection or intravenous infusion if SC injections are intolerable

Guillermo Garcia-Manero, MD

The purpose of this randomized, double-blind, placebo-controlled study is to determine the safety and efficacy of pracinostat compared to placebo when combined with azacitidine, and FDA approved treatment for Myelodysplastic Syndrome (MDS).

Phase 2 Study of Pracinostat With Azacitidine in Patients With Previously Untreated Myelodysplastic Syndrome

A Phase 2 Randomized Double-Blind Placebo-Controlled Study of Pracinostat in Combination With Azacitidine in Patients With Previously Untreated International Prognostic Scoring System (IPSS) Intermediate Risk-2 or High-Risk Myelodysplastic Syndrome (MDS)

Estimate the relative efficacy, measured by complete remission rate of treatment wiht pracinostat plus azacitidine versus placebo plus azacitidine

Estimate the overall response rate \[ORR = CR + complete remission + partial response (PR)\]

Estimate the overall hematologic improvement (HI) response rate by review of hematologic lab values each cycle including bone marrow blast counts, platelets and erythrocytes.

Estimate the progression-free survival (PFS) duration of pracinostat plus azacitidine and the relative benefit of that combination versus placebo plus azacitidine as assessed by the PFS hazard ratio

Estimate the rate of leukemic transformation at landmark time points (6 months, 12 months, 18 months, and 24 months) using clinical review of hematologic lab counts each cycle

Estimate the overall survival (OS) duration of pracinostat plus azacitidine and the relative benefit of that combination versus placebo plus azacitidine as assessed by the OS hazard ratio

Assess the adverse event (AE) profile of pracinostat and placebo when combined with azacitidine by clinical review of safety events by grade, relationship and event outcomes.

Central Nervous System Depressants

Other Dietary Supplements

Decitabine

Benzocaine

Tannic Acid

Pracinostat in combination with HMA treatment (either azacitidine or decitabine) used in initial single agent treatment for that patient

Histone deacetylase inhibitor (HDACi) Pracinostat is to be taken before HMA administration 3 times/week (e.g., Monday, Wednesday, and Friday) for 3 weeks, followed by 1 week of rest as a 28-day cycle. Pracinostat administration will be at the clinic on Day 1 of Cycles 1 and 2 and subject will self-administer at home on all other days

All patients will receive the dose and schedule of azacitadine to which they previously failed to respond. (e.g. 75 mg/m2 via subcutaneous (SC) injection or intravenous infusion if SC injections are intolerable; 7 days of each 28 day cycle, either Days 1-7, or Days 1-5, rest on Days 6-7, and azacitadine dosing on Days 8-9)

All patients will receive the dose and schedule of decitabine to which they previously failed to respond. Common 28 day treatment regimens include: 20 mg/m2 IV for either 5 or 10 days of each 28-day cycle, 10 mg/m2 given intravenously daily for first 10 days of each 28 day cycle, or 20 mg/m2 given subcutaneously daily for the first 5 days of each 28 day cycle.

The 6-week regimen utilizes a dose of 15 mg/m2 by continuous intravenous infusion over 3 hours repeated every 8 hours for 3 days repeated every 6 weeks.

The purpose of this open label study is to determine whether combining pracinostat (study drug) with Vidaza (azacitidine) or Dacogen (decitabine) will improve clinical responses in Myelodysplastic Syndrome (MDS) patients who have failed an initial single agent hypomethylating agent (HMA), and to provide additional safety and efficacy data.

Phase 2 Study Adding Pracinostat to a Hypomethylating Agent (HMA) in Patients With MDS Who Failed to Respond to Single Agent HMA

A Phase II Simon Two-Stage Study of the Addition of Pracinostat to a Hypomethylating Agent (HMA) in Patients With Myelodysplastic Syndrome (MDS) Who Have Failed to Respond or Maintain a Response to the HMA Alone

Clinical Improvement Rate defined as the proportion of patients with CR, Marrow CR, PR, and HI.

Overall Response Rate (ORR), defined as the proportion of patients with CR, PR, Marrow CR, HI, SD, transfusion independence, and cytogenetic responses according to the IWG criteria

Complete response (CR) rate, defined as the proportion of patients with a confirmed CR (i.e., confirmed by a CBC at least 4 weeks after CR) according to the IWG criteria

Hematologic improvement (HI) rate, defined as the proportion of patients who demonstrate major hematologic improvement as defined by the IWG criteria. Only patients with pre-treatment abnormal values will be considered for this endpoint at 8 weeks.

Duration of Response (for patients who have achieved CR, PR, or HI), defined as the time from the initial determination of response to the time of disease progression or death on study, whichever occurs first. For patients who are alive and have not experienced disease progression on study (prior to receiving subsequent/new treatment or stem cell transplant), duration of response will be censored at the day of the last adequate disease assessment.

Progression-Free survival (PFS), defined as the time from first day of study drug administration (Day 1) to either disease progression or death. Patients who have not progressed or are alive will be censored at the date of last adequate disease assessment

Event Free Survival (EFS) defined as the time from first day of study drug administration (Day 1) to failure or death from any cause according to the IWG response criteria. Patients who have not progressed, are alive or died without progression will be censored at the date of last adequate disease assessment

Overall Survival (OS), defined as the time from the first day of study drug administration (Day 1) to death on study. Patients who are alive will be censored at the date last known alive.

Assess the adverse event (AE) profile of pracinostat combined with either azacitidine or decitabine by clinical review of safety events by grade, relationship and event outcomes.

Marrow CR rate, defined as bone marrow \<5% myeloblasts and decrease by \> 50% over pretreatment according to IWG criteria.

Transfusion independence, defined as during the treatment period the patient had no RBC transfusions during any 56 consecutive days or more.

Stable disease rate defined as failure to achieve at least a PR, but no evidence of progression for \> 8 weeks according to IWG criteria.

Cytogenetic response rate, defined as complete disappearance of the chromosomal abnormality without appearance of new abnormalities, or partial response of at least 50% reduction of the chromosomal abnormality according to IWG criteria.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Safety and Efficacy Study of Pracinostat and Azacitidine in Patients With High Risk Myelodysplastic Syndromes	NCT03151304	Myelodysplastic...	Pracinostat Azacitidine	18 Years -	Helsinn Healthcare SA
A Safety and Efficacy Study of Pracinostat and Azacitidine in Patients With High Risk Myelodysplastic Syndromes	NCT03151304	Myelodysplastic...	Pracinostat Azacitidine	18 Years -	Helsinn Healthcare SA
Phase 2 Study of Pracinostat With Azacitidine in Patients With Previously Untreated Myelodysplastic Syndrome	NCT01873703	Myelodysplastic...	pracinostat Placebo Azacitidine	18 Years -	Helsinn Healthcare SA
Phase 2 Study of Pracinostat With Azacitidine in Patients With Previously Untreated Myelodysplastic Syndrome	NCT01873703	Myelodysplastic...	pracinostat Placebo Azacitidine	18 Years -	Helsinn Healthcare SA
Phase 2 Study Adding Pracinostat to a Hypomethylating Agent (HMA) in Patients With MDS Who Failed to Respond to Single Agent HMA	NCT01993641	Myelodysplastic... MDS	pracinostat Azacitidine Decitabine	18 Years -	Helsinn Healthcare SA

Spots Global Cancer Trial Database for pracinostat

Every month we try and update this database with for pracinostat cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for pracinostat

Every month we try and update this database with for pracinostat cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for pracinostat cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.