Randomized Study of ON 01910.Na in Refractory Myelodysplastic Syndrome Patients With Excess Blasts (ONTIME)

Phase III MultiCenter Randomized Controlled Study to Assess Efficacy and Safety of ON 01910.Na 72-Hr Continuous IV Infusion in MDS Patients With Excess Blasts Relapsing After or Refractory to or Intolerant to Azacitidine or Decitabine

The primary objective of this study is to compare overall survival (OS) in patients receiving ON 01910.Na + best supportive care (BSC) to OS of patients receiving BSC in a population of patients with myelodysplastic syndrome (MDS) with excess blasts (5% to 30% bone marrow blasts) who have failed azacitidine or decitabine treatment. This patient population has no available therapy and a short life expectancy (approximately 4 months). The high level of bone marrow activity of ON 01910.Na documented in Phase 1 and 2 studies has the potential to delay substantially the transition of MDS to Acute Myeloid Leukemia(AML), a very significant and severe complication, which shortens survival of these MDS patients.

Study Overview

• Status: Completed
• Conditions: Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia; MDS; RAEB
• Intervention / Treatment: Drug: ON 01910.Na

Detailed Description

This is a Phase III open-label, randomized, controlled, multicenter study (up to 50 centers). Approximately 270 patients with MDS classified as RAEB-1 and RAEB-2 using the WHO classification and as RAEB-t and chronic myelomonocytic leukemia (CMML) using the FAB classification who failed, became intolerant to, or progressed after treatment with 5-azacitidine or decitabine administered during the past 2 years, will be randomized in a 2:1 ratio into the following 2 treatment regimens:

• Best Supportive Care (BSC) + ON 01910.Na 1800 mg/24 hr administered as a 72-hr continuous intravenous (CIV) infusion on Days 1, 2, and 3 of a 2-week cycle (N = approximately 180 patients)
• BSC (N = approximately 90 patients).

Patients will be stratified at entry by bone marrow (BM) blasts (5% to 19% vs. 20% to 30%). After completing the first eight 2-week cycles (i.e., after 16 weeks of treatment), the frequency of further 72-hr CIV infusions will be decreased to an administration on Days 1, 2, and 3 of a 4-week cycle.

Patients will remain treated on study until 2006 International Working Group (IWG) progression criteria are met (i.e., 50% increase of BM blasts or worsening of cytopenias) or until death from any cause, whichever comes first.

Patients who progress to Acute Myeloid Leukemia (AML) while on study should be offered either standard treatment for AML or enrollment in an appropriate investigational study if they are eligible. These treatments with their start and end dates should be documented and patient survival time will be documented for all randomized patients.

Cross-over of BSC patients to ON 01910.Na after progression will not be allowed. However, patients in the BSC-only group will be allowed, as medically justified, access to low-dose cytarabine 20 mg/m2 subcutaneously (SC) once daily for the first consecutive 14 days of each 28-day cycle, up to 4 cycles, until progression or unacceptable toxicity develops. Low-dose cytarabine will be delayed as needed until recovery of blood counts. All study participants will be allowed, as medically justified, access to RBC and platelet transfusions and to growth factors (erythropoietin, Filgrastim [G-CSF]). Hydroxyurea will be allowed to manage blastic crisis with hyperleukocytosis when patients transition to leukemia.

• Study Type: Interventional
• Enrollment (Actual): 299
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Antwerp, Belgium, 2060
    • Ziekenhuis Netwerk Antwerpen
  • Gent, Belgium, 9000
    • Universitair Ziekenhuis Gent
  • Yvoir, Belgium, 5530
    • CHU de Mont-Godinne
  • West-vlaanderen
    • Roeselare, West-vlaanderen, Belgium, 8800
      • H. Hartziekenhuis Roeselare-Menen vzw
• France
  • Angers, France, 49033
    • CHU Angers Service de Medecine D - Maladies du Sang
  • Avignon, France, 84000
    • CHU Avignon Centre Hospitalier Henri Dufaut
  • Bobigny, France, 93009
    • Hôpital Avicenne Hématologie Clinique
  • Caen, France, 14000
    • CHU Caen Hématologie Clinique
  • Clermont-Ferrand, France, 63000
    • CHU Estaing Service d'hématologie
  • Lille, France, 59037
    • CHU Lille Hôpital Claude Huriez
  • Limoges, France, 87042
    • CHU Limoges Hopital Dupuytren
  • Marseille, France, 13009
    • Institute Paoli Calmettes
  • Nice, France, 6202
    • Hôpital de L'Archet I
  • Paris, France, 75571
    • Hopital Saint-Antoine
  • Paris, France, 75004
    • Hôtel Dieu Sce Hématologie Clinique
  • Perpignan, France, 66046
    • CHU Perpignan Centre Hospitalier Hôpital Saint-Jean
  • Rouen, France, 76038
    • Crlcc Henri Becquerel
  • Strasbourg, France, 67091
    • Chu-Strasbourg-Hopital Civil
  • Toulouse, France, 31059
    • Hôpital Purpan
• Germany
  • Dresden, Germany, 01307
    • Universitätsklinikum Dresden
  • Düsseldorf, Germany, 40225
    • Heinrich-Heine-Universität Düsseldorf
  • Frankfurt am Main, Germany, 60590
    • Klinikum der Johann Wolfgang-Goethe-Universität
  • Hamburg, Germany, 20246
    • Universitätsklinikum Hamburg-Eppendorf
  • Köln, Germany, 50924
    • Universitätsklinikum zu Köln
  • Mannheim, Germany, 68167
    • Universitätsmedizin Mannheim
  • Minden, Germany, 32429
    • Johannes-Wesling-Klinikum Minden
  • München, Germany, 81675
    • Klinikum rechts der Isar der Technischen Universitat Munchen
  • Ulm, Germany, 89081
    • Universitatsklinikum Ulm
  • Nordrhein-westfalen
    • Bonn, Nordrhein-westfalen, Germany, 53127
      • Universitatsklinikum Bonn
• Italy
  • Alessandria, Italy, 15100
    • Azienda ospedaliera Santi Antonio e Biagio e Cesare Arrigo
  • Bologna, Italy, 40138
    • Azienda Ospedaliero-Universitaria di Bologa Policlinico S. Orsola-Malpighi
  • Catania, Italy, 95124
    • Azienda Ospedaliera-Universitairia Vittorio Emanuele-Ferrarotto-Santo Bambino
  • Firenze, Italy, 50134
    • Azienda Ospedaliera Universitaria Careggi di Firenze
  • Genova, Italy, 16132
    • Azienda Ospedaliera Universitaria San Martino
  • Novara, Italy, 28100
    • Azienda Osperdaliera Universitaria Maggiore della Carità
  • Roma, Italy, 00161
    • Università degli Studi La Sapienza
  • Torino, Italy, 10126
    • Azienda Ospedaliero Universitaria San Giovanni Battista Di Torino
  • SI
    • Siena, SI, Italy, 53100
      • Azienda Ospedaliera Universitaria Senese Policlinico Santa Maria alle Scotte
• Spain
  • Madrid, Spain, 28006
    • Hospital Universitario La Princesa
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
  • Málaga, Spain, 29010
    • Hospital Clinico Universitario Virgen de la Victoria
  • Palma de Mallorca, Spain, 07012
    • Hospital Universitario Son Espases
  • Salamanca, Spain, 37007
    • Hospital Clínico Universitario de Salamanca
  • Valencia, Spain, 46010
    • Hospital Clínico Universitario de Valencia
  • Valencia, Spain, 46009
    • Hospital Universitari I Politecnic La Fe
  • Asturias
    • Oviedo, Asturias, Spain, 33006
      • Hospital Universitario Central de Asturias
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85258
      • Virginia G. Piper Cancer Center
  • California
    • La Jolla, California, United States, 92093
      • University of California San Diego Moores Cancer Center
    • Stanford, California, United States, 94305
      • Stanford Cancer Center
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale Cancer Center
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Georgetown University Hospital
  • Florida
    • Jacksonville, Florida, United States, 32256
      • Integrated Community Oncology Network
    • Miami, Florida, United States, 33169
      • Innovative Medical Research of South Florida, Inc.
    • Miami Beach, Florida, United States, 33140
      • Mount Sinai Comprehensive Cancer Centers
    • Pensacola, Florida, United States, 32503
      • Woodlands Medical Specialists
    • Stuart, Florida, United States, 34994
      • Martin Memorial Cancer Center
    • Weston, Florida, United States, 33331
      • Cleveland Clinic Florida
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University Winship Cancer Institute
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
    • Chicago, Illinois, United States, 60637
      • University of Chicago Medical Center
    • Evanston, Illinois, United States, 60201
      • North Shore Medical Center
    • Maywood, Illinois, United States, 60153
      • Cardinal Bernardin Cancer Center
    • Skokie, Illinois, United States, 60076
      • Edward H. Kaplan MD & Associates
  • Kansas
    • Westwood, Kansas, United States, 66205
      • University of Kansas Medical Center
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70809
      • Mary Bird Perkins Cancer Center
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Greenebaum Cancer Center
    • Baltimore, Maryland, United States, 21231
      • Johns Hopkins Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber Cancer Institute
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Comprehensive Cancer Center
    • Southfield, Michigan, United States, 48075
      • Providence Cancer Center
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
    • Summit, New Jersey, United States, 07901
      • Overlook Hospital
  • New York
    • Bronx, New York, United States, 10461
      • Albert Einstein College Of Medicine
    • Lake Success, New York, United States, 11042
      • North Shore - LIJ Health System
    • New York, New York, United States, 10021
      • Weill Cornell Medical College
    • New York, New York, United States, 10029
      • Mount Sinai Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Science Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania Health System
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
    • Greenville, South Carolina, United States, 29601
      • Bon Secours St. Francois Health System
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center at Dallas
    • Houston, Texas, United States, 77030
      • University of Texas M. D. Anderson Cancer Center
    • San Antonio, Texas, United States, 78229
      • Cancer Care Centers of South Texas
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Research Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• MDS diagnosis confirmed within 6 weeks prior to entry according to WHO or FAB classification

• MDS classified as follows, according to WHO and FAB classification:

  • RAEB-1 (5% - 9% BM blasts)
  • RAEB-2 (10% - 19% BM blasts)
  • CMML (10% - 20% BM blasts) and WBC < 13,000/μL
  • RAEB-t (20% - 30% BM blasts), with following criteria:
  • o WBC < 25 x 10E9/L at entry
  • o Stable WBC at least 4 weeks prior to entry and not requiring intervention for WBC control with hydroxyurea, chemotherapy, or leukopheresis.
• At least one cytopenia (ANC < 1800/µL or platelet count < 100,000/µL or hemoglobin <10 g/dL)
• Progression according to 2006 International Working Group (IWG) criteria any time after start of azacitidine or decitabine during past 2 years; or failure to achieve complete or partial response or hematological improvement (according to 2006 IWG) after at least six 4-week cycles of azacitidine or four 6-week cycles of decitabine during past 2 years; or relapse after initial complete or partial response or hematological improvement (according to 2006 IWG criteria) observed after at least six 4-week cycles of azacitidine or four 6-week cycles of decitabine during past 2 years; or, intolerance to azacitidine or decitabine defined by drug-related ≥Grade 3 liver or renal toxicity leading to discontinuation during the past 2 years.
• Did not respond to, relapsed after, not eligible for, or opted not to do bone marrow transplantation
• Off other MDS treatments for at least 4 weeks; Filgrastim (G-CSF) and erythropoietin allowed before and during the study as clinically indicated.
• No need for induction chemotherapy
• ECOG status 0, 1 or 2
• Willing to adhere to protocol prohibitions and restrictions
• Patient (or a legally authorized representative) must sign informed consent form to indicate patient's understanding study's purpose and procedures and willingness to participate

Exclusion Criteria:

• Anemia due to factors other than MDS (including hemolysis or gastrointestinal 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, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia
• Active infection not adequately responding to appropriate therapy
• Total bilirubin ≥1.5 mg/dL not related to hemolysis or Gilbert's disease.
• Alanine transaminase (ALT)/aspartate transaminase (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)
• Pregnant or lactating females
• Patients unwilling to follow strict contraception requirements (including condom use for males with sexual partners, and for females: prescription oral contraceptives [birth control pills], contraceptive injections, intrauterine device, double-barrier method [spermicidal jelly or foam with condoms or diaphragm], contraceptive patch, or surgical sterilization) before entry and throughout the study
• Females with reproductive potential who do not have a negative urine beta-human chorionic gonadotropin pregnancy test at screening
• Major surgery without full recovery or major surgery within 3 weeks of ON 01910.Na treatment start
• Uncontrolled hypertension (defined as systolic pressure ≥160 mmHg and/or diastolic pressure ≥110 mmHg)
• New onset seizures (within 3 months prior to first dose of ON 01910.Na) or poorly controlled seizures
• Any other concurrent investigational agent or chemotherapy, radiotherapy, or immunotherapy
• Prior treatment with low-dose cytarabine during past 2 years Investigational therapy within 4 weeks of starting ON 01910.Na
• Psychiatric illness or social situation that limits the patient's ability to tolerate and/or comply with study requirements

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: ON 01910.Na + best supportive care (BSC); Patients will receive ON 01910.Na 1800 mg/24 hr as a continuous intravenous infusion for 72 hours every other week for the first 16 weeks then every 4 weeks afterwards and best supportive care (BSC).	Drug: ON 01910.Na; The dose of ON 01910.Na will be 1800 mg/24 hr as a continuous intravenous infusion for 72 hours every other week for the first 16 weeks then every 4 weeks afterwards. Infusion bags must be changed every 24 hours and a new infusion bag must be used for each of the subsequent 24 hours until completion of the total 72-hour infusion time.; Other Names: rigosertib
NO_INTERVENTION: Best supportive care (BSC); Patients will receive best supportive care (BSC).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	Overall survival (OS) is defined as the time from randomization to death from any cause. All patients will be followed until death or progression, even if they have discontinued treatment for whatever cause. Patients lost to follow-up will be censored at the time last known alive. The OS primary analysis will compare the active ON 01910.Na regimen to BSC once a total number of 223 deaths has been reached.	Up to 18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response (complete and partial remission) according to 2006 IWG criteria	Compare the BSC + ON 01910.Na group to the BSC group with respect to changes in bone marrow myeloblasts, hemoglobin, peripheral neutrophils, platelets and blasts.	Changes measured at Week 4 from Baseline and every 8 Weeks thereafter
Complete bone marrow response according to 2006 IWG criteria	Compare the BSC + ON 01910.Na group to the BSC group with respect to changes in bone marrow myeloblasts.	Changes measured at Week 4 from Baseline and every 8 Weeks thereafter
Hematological improvements according to 2006 IWG criteria	Compare the BSC + ON 01910.Na group to the BSC group with respect to in absolute neutrophil count (ANC), platelet count, and erythroid responses.	Weekly
Scores of Quality of Life Questionnaire	Compare the BSC + ON 01910.Na group to the BSC group with respect to scores of Quality-of-life (QOL)(using the European Organization for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire [QLQ]-C30 version 3.	Measured at Baseline and every 4 Weeks
Adverse events	Record adverse events according to CTCAE v4.	Weekly
Change in Aneuploidy	Improvements of cytogenetics as evaluated by the change in aneuploidy in bone marrow according to 2006 IWG criteria.	Baseline and, only if abnormal at Baseline, Week 4 and every 8 Weeks thereafter
Transition time to AML	Transition time to AML: Defined for RAEB-1 and RAEB-2 MDS and chronic myelomonocytic leukemia (CMML) patients (with BM blasts from 10% to 20% for CMML) by an increase of at least 50% BM blasts and more than 20% BM blasts; Defined for RAEB-t by an increase of at least 50% BM blasts.	Measured at Week 4 from date of randomization and every 8 Weeks thereafter
Incidence of infections and bleeding episodes.	Incidence of infections (treated with intravenous antimicrobials) and bleeding episodes.	Every 4 Weeks

Collaborators and Investigators

• Sponsor: Onconova Therapeutics, Inc.
• Collaborators: The Leukemia and Lymphoma Society

Publications and helpful links

General Publications

• Garcia-Manero G, Fenaux P. Comprehensive Analysis of Safety: Rigosertib in 557 Patients with Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML). Blood Dec 2016, 128 (22) 2011; ASH 2016.
• Seetharam M, Fan AC, Tran M, Xu L, Renschler JP, Felsher DW, Sridhar K, Wilhelm F, Greenberg PL. Treatment of higher risk myelodysplastic syndrome patients unresponsive to hypomethylating agents with ON 01910.Na. Leuk Res. 2012 Jan;36(1):98-103. doi: 10.1016/j.leukres.2011.08.022. Epub 2011 Sep 14.
• Athuluri-Divakar SK, Vasquez-Del Carpio R, Dutta K, Baker SJ, Cosenza SC, Basu I, Gupta YK, Reddy MV, Ueno L, Hart JR, Vogt PK, Mulholland D, Guha C, Aggarwal AK, Reddy EP. A Small Molecule RAS-Mimetic Disrupts RAS Association with Effector Proteins to Block Signaling. Cell. 2016 Apr 21;165(3):643-55. doi: 10.1016/j.cell.2016.03.045.
• Garcia-Manero G, Fenaux P, Al-Kali A, Baer MR, Sekeres MA, Roboz GJ, Gaidano G, Scott BL, Greenberg P, Platzbecker U, Steensma DP, Kambhampati S, Kreuzer KA, Godley LA, Atallah E, Collins R Jr, Kantarjian H, Jabbour E, Wilhelm FE, Azarnia N, Silverman LR; ONTIME study investigators. Rigosertib versus best supportive care for patients with high-risk myelodysplastic syndromes after failure of hypomethylating drugs (ONTIME): a randomised, controlled, phase 3 trial. Lancet Oncol. 2016 Apr;17(4):496-508. doi: 10.1016/S1470-2045(16)00009-7. Epub 2016 Mar 9.
• Navada SC, Silverman LR. The safety and efficacy of rigosertib in the treatment of myelodysplastic syndromes. Expert Rev Anticancer Ther. 2016 Aug;16(8):805-10. doi: 10.1080/14737140.2016.1209413. Epub 2016 Jul 15.
• Al-Kali A. Relationship of bone marrow blast (BMBL) response to overall survival (OS) in a multicenter study of rigosertib (Rigo) in patients (pts) with myelodysplastic syndrome (MDS) with excess blasts progressing on or after treatment with a hypomethylating agent (HMA). Journal of Clinical Oncology 2017 35:15_suppl, 7056-7056 ASCO 2017

Helpful Links

• Leukemia and Lymphoma Society
• The Myelodysplastic Syndromes Foundation

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 1, 2010
• Primary Completion (ACTUAL): October 3, 2018
• Study Completion (ACTUAL): October 3, 2018

Study Registration Dates

• First Submitted: November 1, 2010
• First Submitted That Met QC Criteria: November 15, 2010
• First Posted (ESTIMATE): November 16, 2010

Study Record Updates

• Last Update Posted (ACTUAL): June 30, 2020
• Last Update Submitted That Met QC Criteria: June 29, 2020
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Keywords: MDS; Myelodysplastic syndromes
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Myelodysplastic-Myeloproliferative Diseases; Leukemia; Leukemia, Myeloid; Syndrome; Myelodysplastic Syndromes; Preleukemia; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; ON 01910
• Other Study ID Numbers: 04-21