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

• Sponsor: Helsinn Healthcare SA
• Information provided by (Responsible Party): Helsinn Healthcare SA

Study Description

Brief Summary:

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 MDS who are previously untreated with 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, 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 CR in study MEI-003 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 Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	60 participants
Intervention Model:	Single Group Assignment
Intervention Model Description:	Two-Stage, Open-Label
Masking:	None (Open Label)
Primary Purpose:	Treatment
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
Estimated Primary Completion Date :	March 2020
Estimated Study Completion Date :	June 2020

Arms and Interventions

Arm

Intervention/treatment

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. Azacitine: 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

Drug: Pracinostat; 45 mg capsule; Other Name: SB939; Drug: Azacitidine; SC or IV injection

Outcome Measures

Primary Outcome Measures :

1. overall response rate (ORR), [ Time Frame: 36 months ]
   Determine the rate of overall response rate (ORR), defined as complete remission (CR), partial remission (PR) and marrow CR, of pracinostat plus azacitidine in high/very high risk MDS

Secondary Outcome Measures :

1. Complete response (CR) rate [ Time Frame: 36 months ]
   the proportion of subjects with confirmed CR (i.e., 2 CRs at least 28 days apart) according to the IWG criteria
2. Overall hematologic improvement (HI) response rate [ Time Frame: 36 months ]
   proportion of subjects who demonstrate major hematologic improvement as defined by the IWG criteria
3. Clinical benefit rate [ Time Frame: 36 months ]
   defined as rate of CR + PR + HI + Marrow CR
4. Rate of cytogenetic CR [ Time Frame: 36 months ]
   proportion of subjects with confirmed CR by cytogenetic assessment
5. Duration of response (DoR) [ Time Frame: 36 months ]
   the time from the initial determination of response to the time of disease progression or death on study, whichever occurs first
6. Rate of leukemic transformation [ Time Frame: 6, 12, 18 and 24 months ]
   transformation at landmark time points of 6 months, 12 months, 18 months, and 24 months
7. 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
8. 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
9. 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

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

1. Female or male subjects ≥18 years-of-age.

2. Histologically or cytologically documented diagnosis of MDS according to the World Health Organization (WHO) classification (Vardiman 2009, Arber 2016) with >5% and <20% bone marrow blasts by morphology and a peripheral white blood cell (WBC) count of <20,000/μL

   • If WBC ≥20,000/μL, cytoreduction with hydroxyurea is permitted prior to enrollment.
   • CMML-1 and CMML-2 subtypes
3. Classified as high or very high risk according to the Revised International Prognostic Scoring System (IPSS-R) risk category. CMML-1 and CMML-2 subtypes will be considered high-risk MDS and will not require IPSS-r scoring
4. Bone marrow biopsy (BMBx) and/or aspirate within 28 days prior to first study treatment.
5. Clinical indication for treatment with azacitidine.

6. Previously untreated with HMAs (prior therapy with transfusions, hematopoietic growth factors, or immunosuppressive therapy is allowed).

   a. subjects who require the start of an HMA (e.g., azacitidine) due to progressing MDS may receive up to 1 cycle of azacitidine within 30 days prior to planned first dose (Cycle 1 Day 1)

7. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.

8. Adequate organ function as evidenced by:

   • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × the upper limit of normal (ULN).
   • Total bilirubin ≤1.5 × ULN or total bilirubin of ≤2 mg/dL, whichever is higher. Total bilirubin < 3 x ULN for patients with Gilbert-Meulengracht Syndrome
   • Serum creatinine <1.5 mg/dL, or creatinine clearance>40 mL/min.
   • QTcF interval ≤450 msec using the mean of triplicate electrocardiograms (ECGs).

9. Female subjects of childbearing potential and male subjects with female partners of childbearing potential are required to use two forms of acceptable contraception, including one barrier method, during their participation in the study and for 30 days following last dose. Female subjects of childbearing potential must not be breastfeeding, or planning to breastfeed, and must have a negative pregnancy test ≤7 days before first study drug administration.

   Male subjects must also refrain from donating sperm during their participation in the study.

10. Voluntary written informed consent before performance of any study-related procedure not part of normal medical care.
11. Have the willingness and ability to understand the nature of this study and to comply with the study and follow-up procedures.

Exclusion Criteria:

1. Bone marrow blasts ≥20%, indicating a diagnosis of acute myeloid leukemia (AML).

2. Received any of the following within the specified time frame prior to administration of study medication:

   • Any investigational agent within 14 days or 5 half-lives prior to enrollment, whichever is longer.
   • Hydroxyurea within 48 hours prior to first day of study treatment.
   • Hematopoietic growth factors: erythropoietin, granulocyte colony stimulating factor (G-CSF), granulocyte macrophage colony stimulating factor (GM-CSF), or thrombopoietin receptor agonists at least 7 days (14 days for Aranesp), prior to study enrollment.
   • Major surgery within 28 days prior to first study treatment.
3. Subjects who have not recovered from side effects of previous therapy.

4. Cardiopulmonary function criteria:

   • Current unstable arrhythmia requiring treatment.
   • History of symptomatic congestive heart failure (New York Heart Association [NYHA] Class III or IV).
   • History of myocardial infarction, pulmonary embolism or cerebrovascular accident within 6 months of enrollment.
   • Current unstable angina.
5. Prior treatment for MDS with HDAC inhibitors Zolinza (vorinostat), Belenodaq (belinostat), Farydak (panobinostat), Istodax (romidepsin/depsipetide), or investigational agent with significant action as an HDAC inhibitor.
6. Clinical evidence of central nervous system involvement.
7. Subjects with gastrointestinal (GI) tract disease causing the inability to take oral medication, malabsorption syndrome, a requirement for intravenous (IV) alimentation, prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn's disease, ulcerative colitis).
8. Uncontrolled infection with human immunodeficiency virus (HIV) or chronic hepatitis B or C.
9. Life-threatening illness unrelated to cancer or any serious medical or psychiatric illness that could, in the Investigator's opinion, potentially interfere with participation in this study.
10. Presence of a malignant disease within the last 12 months, with the exception of adequately treated in-situ carcinomas, basal or squamous cell carcinoma, non-melanomatous skin cancer, or malignancies treated with curative intent and no evidence of active disease in prior 12 months and felt to be low risk for recurrence. Other malignancies may be considered after consultation withthe Medical Monitor
11. An unwillingness or inability (including breastfeeding women, prohibited concomitant medications, uncontrolled infections, psychological, familial, sociological, or geographical conditions) to comply with study and/or follow-up procedures as outlined in the protocol
12. Known hypersensitivity to any components of pracinostat, azacitidine or mannitol
13. Current smoking or vaporizing of tobacco or cannabis-related products (use of patches, chewing tobacco, or nicotine gum is permitted). Subjects who stopped smoking at least 8 days prior to first pracinostat dosing can be, provided they refrain from smoking during the whole study.

Contacts and Locations

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Sponsors and Collaborators

Helsinn Healthcare SA

Investigators

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Study Director:	Richard Ghalie, MD	MEI Pharma
Study Chair:	Ehab Atallah, MD	Medical College of Wisconsin adn Froedtert Hospital

More Information

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Responsible Party:	Helsinn Healthcare SA
ClinicalTrials.gov Identifier:	NCT03151304 History of Changes
Other Study ID Numbers:	MEI-011
First Posted:	May 12, 2017
Last Update Posted:	March 14, 2019
Last Verified:	August 2018

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Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by Helsinn Healthcare SA:

MDS

Additional relevant MeSH terms:

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Syndrome; Myelodysplastic Syndromes; Preleukemia; Disease; Pathologic Processes; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions	Neoplasms; Azacitidine; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Enzyme Inhibitors