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

Sponsor
Onconova Therapeutics, Inc. (Industry)
Overall Status
Completed
CT.gov ID
NCT01928537
Collaborator
(none)
67
35
1
46.9
1.9
0

Study Details

Study Description

Brief Summary

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 or Disease Intervention/Treatment Phase
  • Drug: rigosertib sodium
Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
67 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (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
Study Start Date :
Aug 1, 2013
Actual Primary Completion Date :
Jun 29, 2017
Actual Study Completion Date :
Jun 29, 2017

Arms and Interventions

Arm Intervention/Treatment
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
  • Outcome Measures

    Primary Outcome Measures

    1. Relationship of bone marrow blast response and overall survival. [Up to 2 years.]

      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 and overall survival. 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

    1. Number of patients with overall hematologic response. [Up to 2 years after study enrollment.]

      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.

    2. Number of patients with hematological improvement. [Up to 2 years after study enrollment.]

      Hematological improvement (erythroid response, platelet response and neutrophil response) is defined according to 2006 International Working Group (IWG) response criteria.

    3. Number of patients with cytogenetic response. [Up to 2 years after study enrollment.]

      Cytogenetic response is defined according to 2006 International Working Group (IWG) response criteria.

    4. Progression-free survival. [Up to 2 years after study enrollment.]

      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.

    5. Number of patients who transition to Acute Myeloid Leukemia (AML) [Up to 2 years after study enrollment.]

      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.

    6. Quality of Life Questionnaire [Up to 2 years after study enrollment.]

      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.

    7. Infections. [Up to 2 years after study enrollment.]

      Incidence of infections requiring treatment with intravenous antimicrobials and of bleeding episodes.

    8. Concentration of rigosertib in plasma. [Week 1 and week 3.]

      Concentration of rigosertib in plasma will be measured by a validated High Performance Liquid Chromatography (HPLC) method.

    9. Safety. [Study enrollment until 30 days after patient's last dose of rigosertib up to 2 years.]

      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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Locations

    Site City State Country Postal Code
    1 Stanford University Cancer Center Stanford California United States 94305
    2 Rush University Medical Center Chicago Illinois United States 60612
    3 University of Chicago Medicine Chicago Illinois United States 60637
    4 University of Kansas Cancer Center and Medical Pavilion Westwood Kansas United States 66205
    5 Greenbaum Cancer Center University of Maryland Baltimore Maryland United States 21201
    6 Dana Farber Cancer Institute Boston Massachusetts United States 02215
    7 Mayo Clinic Rochester Minnesota United States 55905
    8 Montefiore Medical Center Bronx New York United States 10461
    9 Mount Sinai Medical Center New York New York United States 10029
    10 Columbia University Medical Center New York New York United States 10032
    11 New York Presbyterian Hospital-Weill Cornell Medical College New York New York United States 10065
    12 University of Texas Southwestern Medical Center-Parkland Hospital Dallas Texas United States 75235
    13 University of Texas Southwestern Medical Center Dallas Texas United States 75390
    14 MD Anderson Cancer Center Houston Texas United States 77030
    15 Royal Adelaide Hospital Adelaide South Australia Australia 5000
    16 Monash Health, Monash Medical Centre Clayton Victoria Australia 3168
    17 Peter MacCallum Cancer Center East Melbourne Victoria Australia 3002
    18 Royal Melbourne Hospital Parkville Victoria Australia 3050
    19 Rigshospitalet, Department of Hematology Copenhagen Hovedstaden Denmark DK-2100
    20 Aarhus University Hospital Aarhus Jylland Denmark DK-8000
    21 Hôpital Saint-Louis, Service d'Hématologie Paris IDF France 75475
    22 Institute Paoli Calmettes Marseille France 13009
    23 Universitätsklinikum Frankfurt, Goethe Universität Frankfurt Hessen Germany 60590
    24 University Hospital Carl Guslav Carus Dresden Germany 01062
    25 Marien Hospital, Onkologie Düsseldorf Germany 40479
    26 Universitätsmedizin Göttingen Göttingen Germany 37075
    27 Universitätsklinikum Köln Klinik I für Innere Medizin Köln Germany 50973
    28 Technische Universität München, III. Medizinische Klinik München Germany 81675
    29 Azienda Ospedaliero-Universitaria Careggi Firenze Italy 50134
    30 AOU Maggiore della Carità, SCUD Ematologia Novara Italy 28100
    31 Policlinico Umberto 1, Universita "Sapienza" Rome Italy 00161
    32 Hospital Universitário de Salamanca Salamanca Spain 37007
    33 Skåne University Hospital, Lund Skåne Sweden SE-221 85
    34 Sahlgrenska University Hospital Gothenberg Västra Götalandsregionen Sweden 41345
    35 Karolinska University Hospital, Huddinge Stockholm Sweden SE-141 86

    Sponsors and Collaborators

    • Onconova Therapeutics, Inc.

    Investigators

    • Study Chair: Steven M. Fruchtman, MD, Onconova Therapeutics, Inc.

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    Onconova Therapeutics, Inc.
    ClinicalTrials.gov Identifier:
    NCT01928537
    Other Study ID Numbers:
    • Onconova 04-24
    • 2013-001124-19
    First Posted:
    Aug 26, 2013
    Last Update Posted:
    Jun 30, 2020
    Last Verified:
    Jul 1, 2018

    Study Results

    No Results Posted as of Jun 30, 2020