Efficacy and Safety of IV Rigosertib in MDS Patients With Excess Blasts Progressing After Azacitidine or Decitabine

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by Onconova Therapeutics, Inc.
Sponsor:
Information provided by (Responsible Party):
Onconova Therapeutics, Inc.
ClinicalTrials.gov Identifier:
NCT01928537
First received: August 21, 2013
Last updated: August 8, 2014
Last verified: August 2014
  Purpose

This study will examine the effect intravenously administered rigosertib has on the relationship between bone marrow blasts response and overall survival in myelodysplastic syndromes (MDS) patients who have 5-30% bone marrow blasts and who progressed on or after treatment with azacitidine or decitabine.


Condition Intervention Phase
Myelodysplastic Syndromes
Refractory Anemia With Excess Blasts
Chronic Myelomonocytic Leukemia
Cytopenia
Drug: rigosertib sodium
Phase 3

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase IIIB, Open-label, Multi-Center Study of the Efficacy and Safety of Rigosertib Administered as 72-hour Continuous Intravenous Infusions in Patients With Myelodysplastic Syndrome With Excess Blasts Progressing On or After Azacitidine or Decitabine

Resource links provided by NLM:


Further study details as provided by Onconova Therapeutics, Inc.:

Primary Outcome Measures:
  • Relationship of bone marrow blast response and overall survival. [ Time Frame: Up to 2 years. ] [ Designated as safety issue: No ]
    Bone marrow blast response is defined as bone marrow (BM) complete response, ≥ 50% BM blast decrease from pretreatment value, or stable BM response (no progression) according to the International Working Group (IWG) 2006 criteria. Overall survival is defined as the time from first study treatment to death from any cause. All patients will be followed until death and/or progression, even if they have discontinued treatment for whatever cause. Survival time of patients lost to follow-up will be censored at the time they were last known to be alive.


Secondary Outcome Measures:
  • Number of patients with overall hematologic response. [ Time Frame: Up to 2 years after study enrollment. ] [ Designated as safety issue: No ]
    Overall hematologic response (complete remission [CR], partial remission [PR], bone marrow complete response [BMCR], and stable disease [SD]) is defined according to 2006 International Working Group (IWG) response criteria.

  • Number of patients with hematological improvement. [ Time Frame: Up to 2 years after study enrollment. ] [ Designated as safety issue: No ]
    Hematological improvement (erythroid response, platelet response and neutrophil response) is defined according to 2006 International Working Group (IWG) response criteria.

  • Number of patients with cytogenetic response. [ Time Frame: Up to 2 years after study enrollment. ] [ Designated as safety issue: No ]
    Cytogenetic response is defined according to 2006 International Working Group (IWG) response criteria.

  • Progression-free survival. [ Time Frame: Up to 2 years after study enrollment. ] [ Designated as safety issue: No ]
    Progression-free survival is defined as time from date of first dose until date when progression is documented. Progression is defined according to 2006 International Working Group (IWG) response criteria.

  • Number of patients who transition to Acute Myeloid Leukemia (AML) [ Time Frame: Up to 2 years after study enrollment. ] [ Designated as safety issue: No ]
    Participants who progress to Acute Myeloid Leukemia (AML) during the study. AML is defined as an increase of at least 50% bone marrow blasts, and more than 20% bone marrow blasts for Refractory Anemia with Excess Blasts types 1 and 2 (RAEB-1 and RAEB-2) and Chronic Myelomonocytic Leukemia (CMML) patients and as an increase of at least 50% bone marrow blasts for Refractory Anemia with Excess Blasts in Transformation (RAEB-t) patients.

  • Quality of Life Questionnaire [ Time Frame: Up to 2 years after study enrollment. ] [ Designated as safety issue: No ]
    Change from baseline in responses in the European Organization for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire [QLQ]-C30 version 3. Questionnaire will be administered at baseline and at 4 week intervals.

  • Infections. [ Time Frame: Up to 2 years after study enrollment. ] [ Designated as safety issue: No ]
    Incidence of infections requiring treatment with intravenous antimicrobials and of bleeding episodes.

  • Concentration of rigosertib in plasma. [ Time Frame: Week 1 and week 3. ] [ Designated as safety issue: No ]
    Concentration of rigosertib in plasma will be measured by a validated High Performance Liquid Chromatography (HPLC) method.

  • Safety. [ Time Frame: Study enrollment until 30 days after patient's last dose of rigosertib up to 2 years. ] [ Designated as safety issue: Yes ]
    Counts of patients who have adverse events (AEs). Adverse events will be grouped by system organ class (SOC) and preferred term (PT) using the most recent version of the Medical Dictionary for Regulatory Activities (MedDRA), and will be summarized by worst grade according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0.


Estimated Enrollment: 90
Study Start Date: August 2013
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: September 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: rigosertib sodium
Rigosertib sodium will be administered as a 72-hr continuous intravenous infusion consisting of 3 consecutive doses of 1800 mg over 24 hours on Days 1, 2, and 3 of a 14-day cycle for the first 8 cycles and then on Days 1, 2, and 3 of a 28-day cycle for the following cycles.
Drug: rigosertib sodium
Other Names:
  • ON 01910.Na
  • SyB L-1101

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of MDS confirmed within 6 weeks prior to Screening according to WHO criteria or French-American-British (FAB) classification.
  • MDS classified as follows, according to WHO criteria and FAB classification:

    • RAEB-1 (5% to 9% BM blasts)
    • RAEB-2 (10% to 19% BM blasts)
    • CMML (10% to 20% BM blasts) and white blood cells (WBC) < 13,000/μL
    • RAEB-t (20% to 30% BM blasts), meeting the following criteria: WBC < 25,000/μL at study entry; or, Stable White Blood Cell (WBC) at least 4 weeks prior to Screening and not requiring intervention for WBC control with hydroxyurea, chemotherapy, or leukopheresis.
  • At least one cytopenia (Absolute Neutrophil Count (ANC) < 1800/μL or Platelet (PLT) count < 100,000/μL or hemoglobin (Hgb) < 10 g/dL).
  • Progression (according to 2006 IWG criteria) at any time after initiation of subcutaneous or intravenous azacitidine or decitabine treatment per labeling during the past 2 years, defined as follows:

    • For patients with ˂ 5% BMBL, ≥ 50% increase in BMBL to ˃ 5% BMBL
    • For patients with 5-10% BMBL, ≥ 50% increase in BMBL to ˃ 10% BMBL
    • For patients with 10-20% BMBL, ≥ 50% increase in BMBL to ˃ 20% BMBL
    • For patients with 20-30% BMBL, ≥ 50% increase in BMBL to ˃ 30% BMBL
    • Any of the following: ≥ 50% decrease from maximum remission/response levels in granulocytes or PLT; Decrease in Hgb concentration by ≥ 2 g/dL; or, Transfusion dependence, defined as administration of at least 4 RBC units in the past 8 weeks before Screening (patients must have Hgb values ˂ 9 g/dL prior to transfusion to be considered), in the absence of another explanation.
  • Has failed to respond to, relapsed following, not eligible, or opted not to participate in bone marrow transplantation.
  • Off all other treatments for MDS for at least 4 weeks, except for azacitidine or decitabine. Filgrastim (G-CSF) and erythropoietin are allowed before and during the study as clinically indicated.
  • No medical need for induction chemotherapy.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
  • Willing to adhere to the prohibitions and restrictions specified in this protocol.
  • Patient must signed an informed consent form.

Exclusion Criteria:

  • Previous participation in a clinical study of IV or oral rigosertib.
  • Anemia due to factors other than MDS (including hemolysis or gastrointestinal [GI] bleeding) unless stabilized for 1 week after RBC transfusion.
  • Any active malignancy within the past year, except basal cell or squamous cell skin cancer or carcinoma in situ of the cervix or breast.
  • Uncontrolled intercurrent illness including.
  • Active infection not adequately responding to appropriate therapy.
  • Total bilirubin ≥ 1.5 mg/dL not related to hemolysis or Gilbert's disease.
  • ALT/AST ≥ 2.5 x upper limit of normal (ULN).
  • Serum creatinine ≥ 2.0 mg/dL.
  • Ascites requiring active medical management including paracentesis, or hyponatremia (defined as serum sodium value of <130 mEq/L).
  • Female patients who are pregnant or lactating.
  • Patients who are unwilling to follow strict contraception requirements.
  • Female patients with reproductive potential who do not have a negative urine beta-human chorionic gonadotropin (βHCG) pregnancy test at Screening.
  • Major surgery without full recovery or major surgery within 3 weeks of Baseline/Cycle 1 Day 1 visit.
  • Uncontrolled hypertension (defined as a systolic pressure ≥160 mmHg and/or a diastolic pressure ≥ 110 mmHg).
  • New onset seizures (within 3 months prior to Baseline) or poorly controlled seizures.
  • Any other concurrent investigational agent or chemotherapy, radiotherapy, or immunotherapy.
  • Prior treatment with low-dose cytarabine during the past 2 years.
  • Investigational therapy within 4 weeks of Baseline/Day 1 visit.
  • Psychiatric illness or social situation that would limit the patient's ability to tolerate and/or comply with study requirements.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01928537

Contacts
Contact: Michael Kurman, MD 609 281-7086 mkurman@onconova.us

  Show 29 Study Locations
Sponsors and Collaborators
Onconova Therapeutics, Inc.
Investigators
Study Director: Michael Kurman, MD Onconova Therapeutics, Inc.
  More Information

Publications:
Responsible Party: Onconova Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT01928537     History of Changes
Other Study ID Numbers: Onconova 04-24, 2013-001124-19
Study First Received: August 21, 2013
Last Updated: August 8, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Onconova Therapeutics, Inc.:
International Working Group
azacitidine
decitabine

Additional relevant MeSH terms:
Myelodysplastic Syndromes
Preleukemia
Anemia
Anemia, Refractory
Anemia, Refractory, with Excess of Blasts
Leukemia
Leukemia, Myelomonocytic, Chronic
Leukemia, Myelomonocytic, Acute
Hematologic Diseases
Bone Marrow Diseases
Neoplasms by Histologic Type
Neoplasms
Leukemia, Myeloid
Myelodysplastic-Myeloproliferative Diseases
Precancerous Conditions
Azacitidine
Decitabine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Enzyme Inhibitors

ClinicalTrials.gov processed this record on August 21, 2014