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

NCT03151304 | Terminated Phase 2 Results FDA Drug

• 1 other identifier: MEI-011
• Study Type: interventional
• Target: 64
• Locations: 1 country
• Sites: 25

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 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.

Conditions

Myelodysplastic Syndromes

Keywords

MDS

Outcome Measures

Primary Outcomes (1)

• Overall Response Rate (ORR)

  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

  36 months

Secondary Outcomes (12)

• Complete Response (CR) Rate

  36 months

• Overall Hematologic Improvement (HI) Response Rate

  36 months

• Clinical Benefit Rate

  36 months

• Rate of Cytogenetic CR

  36 months

• Duration of Response (DoR)

  36 months

Study Arms (1)

Stage 1a and 1b open-label pracinostat plus azacitidine

EXPERIMENTAL

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

Drug: Pracinostat; Drug: Azacitidine

Interventions

Pracinostat DRUG

45 mg capsule

Also known as: SB939

Stage 1a and 1b open-label pracinostat plus azacitidine

Azacitidine DRUG

SC or IV injection

Stage 1a and 1b open-label pracinostat plus azacitidine

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Female or male subjects ≥18 years-of-age.
• 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.
• chronic myelomonocytic leukemia CMML-1 and CMML-2 subtypes
• 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
• Bone marrow biopsy (BMBx) and/or aspirate within 28 days prior to first study treatment.
• Clinical indication for treatment with azacitidine.
• 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)
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
• 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).

You may not qualify if:

• Bone marrow blasts ≥20%, indicating a diagnosis of acute myeloid leukemia (AML).
• 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.
• Subjects who have not recovered from side effects of previous therapy.
• 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.
• Prior treatment for MDS with histone deacetylase (HDAC) inhibitors Zolinza (vorinostat), Belenodaq (belinostat), Farydak (panobinostat), Istodax (romidepsin/depsipetide), or investigational agent with significant action as an HDAC inhibitor.
• Clinical evidence of central nervous system involvement.
• 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).

Sponsors & Collaborators

• Helsinn Healthcare SA: lead

Study Sites (25)

City of Hope

Duarte, California, 91010, United States

Location

Scripps Cancer Center-Mercy

San Diego, California, 92103, United States

Location

Georgia Cancer Center at Augusta University

Augusta, Georgia, 30912, United States

Location

georgia cancer Center

Augusta, Georgia, 30912, United States

Location

Pontchartrain cancer Center

Covington, Louisiana, 70433, United States

Location

RCCA MD LLC (The Center for Cancer and Blood Disorders)

Bethesda, Maryland, 20817, United States

Location

Michigan Center of Medical Research

Farmington Hills, Michigan, 48334, United States

Location

Michigan State University, Breslin Cancer Center

Lansing, Michigan, 48910, United States

Location

university of minnesota medical Center, Fairview

Minneapolis, Minnesota, 55455, United States

Location

Mercy Medical Research Institute

Springfield, Missouri, 65807, United States

Location

New Mexico Cancer care Alliance

Albuquerque, New Mexico, 87131, United States

Location

University of Rochester Medical Center

Rochester, New York, 14642, United States

Location

Stony Brook University

Stony Brook, New York, 11794, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

Southeastern Medical Oncology Center

Goldsboro, North Carolina, 27534, United States

Location

Oncology Hematology Care

Cincinnati, Ohio, 45242, United States

Location

University Hospitals Cleveland Medical Center

Cleveland, Ohio, 44106, United States

Location

Cancer Centers of Southwest Oklahoma

Lawton, Oklahoma, 73501, United States

Location

Oklahoma Cancer Specialists and Research Institute

Tulsa, Oklahoma, 74146, United States

Location

Providence Portland Medical center

Portland, Oregon, 97213, United States

Location

UT Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

UVA Health System Division of Hematology & Oncology

Charlottesville, Virginia, 22908, United States

Location

Swedish Cancer Institute

Seattle, Washington, 98104, United States

Location

Universityof Wisconsin Clinical Science Center

Madison, Wisconsin, 53792, United States

Location

Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

MeSH Terms

Conditions

Myelodysplastic Syndromes

Interventions

SB939 compound; Azacitidine

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Results Point of Contact

• Title: Francesco Scarci, Clinical Operations Manager
• Organization: Helsinn Healthcare

francesco.scarci@helsinn.com

+41 (0)91 985 2121

Study Officials

• Richard Ghalie, MD

  MEI Pharma

  STUDY DIRECTOR

• Ehab Atallah, MD

  Medical College of Wisconsin adn Froedtert Hospital

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Two-Stage, Open-Label

Study Record Dates

• First Submitted: May 5, 2017
• First Posted: May 12, 2017
• Study Start: June 1, 2017
• Primary Completion: December 1, 2020
• Study Completion: December 1, 2020
• Last Updated: March 2, 2022
• Results First Posted: March 2, 2022

Record last verified: 2022-02

Locations

US (25)