Controlled Study of Rigosertib Versus Physician's Choice of Treatment in MDS Patients After Failure of an HMA (INSPIRE)

A Phase III, International, Randomized, Controlled Study of Rigosertib Versus Physician's Choice of Treatment in Patients With Myelodysplastic Syndrome After Failure of a Hypomethylating Agent

The study's primary objective [in a population of patients with MDS after failure of treatment with azacitidine (AZA) or decitabine (DAC)], is to compare the overall survival (OS) of patients in the rigosertib group vs the Physician's Choice group, in all patients and in a subgroup of patients with IPSS-R very high risk.

Study Overview

• Status: Terminated
• Conditions: Myelodysplastic Syndrome; MDS; Refractory Anemia With Excess Blasts; RAEB
• Intervention / Treatment: Drug: rigosertib; Drug: best supportive care (BSC); Drug: best supportive care (BSC); Drug: Any approved or standard-of-care therapy

Detailed Description

This is a Phase III, open-label, randomized, controlled, international study. Approximately 360 patients < 82 years of age with MDS classified as RAEB-1, RAEB-2, or RAEB-t who received AZA or DAC for ≤ 9 months and/or ≤ 9 cycles over 12 months and had their last dose of AZA or DAC within 6 months prior to screening will be stratified by:

• Very high risk (VHR) vs non-VHR per IPSS-R, and
• Geographic region (North America vs Europe vs Asia; because approved products and standard of care may vary by region), and randomly assigned in a 2:1 ratio to one of the following 2 treatment groups:
• Rigosertib 1800 mg/24 hr administered as a 72 hr CIV infusion on Days 1, 2, and 3 of a 2 week cycle for the first 8 cycles, and on Days 1, 2, and 3 of a 4-week cycle thereafter (N = approximately 240 patients);
• Physician's Choice of alternative treatment, which may include any approved or standard-of-care therapy that the patient has not shown to be hypersensitive to, based on frequently used treatment for MDS, as per institutional guidelines, after receipt of HMAs (N = approximately 120 patients). The drugs used in the Physician's Choice arm should be used according to the recommendations, if clinically appropriate, provided in the corresponding Summary of Product Characteristics (SmPC) and Prescribing Information of these drugs. Experimental therapies are not allowed on the PC arm.

Patients will be treated until 2006 IWG progression criteria are met (ie, 50% increase of BM blasts or worsening of cytopenias) or until an unacceptable toxicity or intolerance.

For all randomized patients who discontinue study treatment, subsequent therapies with their start and end dates, as well as survival time after treatment discontinuation, will be documented at least monthly until death.

Patients in the PC group who progress will not be allowed to cross over to rigosertib.

All patients in both treatment groups will be allowed, as medically justified, access to RBC and platelet transfusions and to growth factors (granulocyte colony-stimulating factor (G-CSF), erythropoietin, and thrombopoietin).

• Study Type: Interventional
• Enrollment (Actual): 372
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Queensland
    • South Brisbane, Queensland, Australia, 4101
      • Icon Cancer Care Icon South Brisbane
  • Tasmania
    • Hobart, Tasmania, Australia, 7000
      • Royal Hobart Hospital
  • Victoria
    • Melbourne, Victoria, Australia, 3168
      • Monash Health, Monash Medical Centre
• Austria
  • Linz, Austria, 4020
    • Hospital of the Elisabethinen Linz GmbH
  • Salzburg, Austria, 5020
    • Salzburg University Hospital
  • Vienna, Austria, 1140
    • Hanusch Hospital
• Belgium
  • Antwerp, Belgium, 2060
    • Antwerp Hospital Network Stuivenberg
  • Ghent, Belgium, 9000
    • University Hospital Ghent
  • Leuven, Belgium, 3000
    • University Hospital Leuven, Campus Gasthuisberg
  • Yvoir, Belgium, B-5530
    • CHU UCL Namur - site Godinne
• Canada
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 0V9
      • CancerCare Manitoba
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Cancer Centre
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Research Institute
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
      • Jewish General Hospital
• Croatia
  • Osijek, Croatia, 31000
    • Klinicki bolnicki centar Osijek
  • Zagreb, Croatia, 10000
    • Klinički bolnički centar Sestre Milosrdnice
  • Zagreb, Croatia, 10000
    • Clinical Hospital Merkur
  • Zagreb, Croatia, 10000
    • Klinički bolnički centar Zagreb
• Czechia
  • Brno, Czechia, 625 00
    • University Hospital Brno
  • Hradec Kralove, Czechia, 500 05
    • University Hospital Hradec Kralove
  • Ostrava Poruba, Czechia, 708 52
    • University Hospital Ostrava, Department of Hematooncology
  • Prague 2, Czechia, 128 00
    • General University Hospital
  • Prague 2, Czechia, 128 20
    • Institute of Hematology and Blood Transfusion
• Estonia
  • Tallinn, Estonia, 13419
    • North Estonia Medical Centre
  • Tartu, Estonia, 51014
    • Tartu University Hospital
• France
  • La Roche Sur Yon Cedex 9, France, 85925
    • CHD Vendée
  • Lille Cedex, France, 59037
    • Hôpital Claude Huriez, CHRU Lille
  • Marseille, France, 13009
    • Institut Paoli-Calmettes
  • Nice Cedex 3, France, 06202
    • Hôpital l'Archet 1
  • Nimes Cedex 9, France, 30029
    • Institut de cancerologie du Gard
  • Paris Cedex 10, France, 75475
    • Hôpital Saint Louis
  • Pierre-Bénite, France, 69495
    • Centre Hospitalier Lyon-Sud
  • Strasbourg Cedex, France, 67091
    • Hôpital civil, Strasbourg
  • Tours, France, 37044
    • CHRU Tours Hôspital Bretonneau
• Germany
  • Dresden, Germany, 01307
    • Universitätsklinikum Carl Gustav Carus
  • Düsseldorf, Germany, 40479
    • Marien Hospital Dusseldorf
  • Frankfurt, Germany, 60590
    • Universitätsklinikum Frankfurt am Main
• Hungary
  • Budapest, Hungary, 1083
    • Semmelweis University Medical School
  • Kaposvár, Hungary, 7400
    • Somogy County Kaposi Mór Teaching Hospital
  • Nyíregyháza, Hungary, 4400
    • Josa Andras Teaching Hospital
  • Pécs, Hungary, 7624
    • University of Pécs 1st Department of Internal Medicine
• India
  • Gujarat
    • Ahmedabad, Gujarat, India, 380009
      • Hemato Oncology Clinic Pvt. Ltd
  • Karnataka
    • Bangalore, Karnataka, India, 560034
      • St. John's Medical College Hospital
  • Maharashtra
    • Mumbai, Maharashtra, India, 400012
      • Tata Memorial Hospital
    • Mumbai, Maharashtra, India, 400026
      • Jaslok Hospital and Research Center
    • Pune, Maharashtra, India, 411004
      • Sahyadri Clinical Research and Development Center
  • Tamil Nadu
    • Vellore, Tamil Nadu, India, 632004
      • Christian medical college
  • West Bengal
    • Kolkata, West Bengal, India, 700073
      • Institute of Hematology and Transfusion Medicine
• Ireland
  • Cork, Ireland
    • Cork University Hospital
  • Dublin, Ireland, Dublin 24
    • Adelaide and Meath Hospital, Incorporating the National Children's Hospital
  • Waterford, Ireland
    • University Hospital Waterford
• Israel
  • 'Afula, Israel, 1834111
    • Ha'Emek Medical Center
  • Beer Sheva, Israel, 84101
    • Soroka University Medical Center
  • Haifa, Israel, 31096
    • Rambam Medical Center
  • Jerusalem, Israel, 91120
    • Hadassah Medical Center
  • Rehovot, Israel, 76100
    • Kaplan Medical Center
  • Tel Aviv, Israel, 64239
    • Sourasky Medical Center
  • Tel Hashomer, Israel, 52621
    • The Chaim Sheba Medical Center
• Italy
  • Bologna, Italy, 40138
    • Polyclinic S. Orsola-Malpighi
  • Brescia, Italy, 25123
    • Azienda Ospedaliera Spedali Civili
  • Firenze, Italy, 50134
    • Azienda Ospedaliero Universitaria Careggi
  • Novara, Italy, 28100
    • Azienda Ospedaliero-Universitaria Maggiore della Carità
  • Pisa, Italy, 56126
    • A.O.U. Pisana, Divisione di Ematologia - University Hospital of Pisa
  • Roma, Italy, 00133
    • Policlinico Universitario Tor Vergata
  • Roma, Italy, 00144
    • Ospedale S. Eugenio - S. Eugenio Hospital
  • Terni, Italy, 05100
    • Azienda Ospedaliera Santa Maria di Terni
  • Torino, Italy, 10126
    • Città della Salute e della Scienza di Torino
• Japan
  • Akita, Japan, 010-8543
    • Akita University Hospital
  • Bunkyo-ku, Japan, 113-8677
    • Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital
  • Fukuoka-shi, Japan, 811-1395
    • National Hospital Organization Kyushu Cancer Center
  • Kagoshima, Japan, 890-8544
    • Kagoshima University Hospital
  • Kakamigahara, Japan, 504-8601
    • Tokai Central Hospital of the Mutual Aid Association of Public School Teachers
  • Kawagoe, Japan, 350-8550
    • Saitama Medical Center
  • Kobe, Japan, 650-0047
    • Kobe City Hospital Organization Kobe City Medical Center General Hospital
  • Kumamoto, Japan, 860-008,
    • National Hospital Organization Kumamoto Medical Center
  • Kyoto, Japan, 602-8026
    • Japanese Red Cross Kyoto Daini Hospital
  • Nagasaki, Japan, 852-8102
    • Nagasaki University Hospital
  • Nagoya-shi, Japan, 466-8650
    • Japanese Red Cross Nagoya Daini Hospital
  • Niigata, Japan, 951-8510,
    • Niigata University Medical and Dental Hospital
  • Oita, Japan, 870-8511
    • Oita Prefectural Hospital
  • Okayama, Japan, 701-1192
    • National Hospital Organization Okayama Medical Center
  • Osakasayama-shi, Japan, 589-8511
    • Kindai University Hospital
  • Sapporo-shi, Japan, 060-8648
    • Hokkaido University Hospital
  • Sendai-shi, Japan, 980-8574
    • Tohoku University Hospital
  • Shinagawa-ku, Japan, 141-8625
    • NTT Medical Center Tokyo
  • Shinjuku-ku, Japan, 160-0023
    • Tokyo Medical University Hospital
  • Tochigi, Japan, 321-0293
    • Dokkyo Medical University Hospital
  • Tokushima, Japan, 770-8503
    • Tokushima University Hospital
  • Yamagata, Japan, 990-9585
    • Yamagata University Hospital
  • Yokohama-shi, Japan, 234-8503
    • Saiseikai Yokohamashi Nanbu Hospital
  • Yoshida, Japan, 910-1193
    • University of Fukui Hospital
  • Fukuoka
    • Kitakyushu, Fukuoka, Japan, 802-8555
      • Kokura Memorial Hospital
  • Hiroshima
    • Fukuyama, Hiroshima, Japan, 720-0001
      • Chugoku Central Hospital of the Mutual Aid Association of Public School Teachers
  • Hokkaido
    • Sapporo, Hokkaido, Japan, 060-8556
      • Sapporo Medical University Hospital
  • Ishikawa
    • Kanazawa, Ishikawa, Japan, 920-8641
      • Kanazawa University Hospital
  • Kanagawa
    • Yokohama-shi, Kanagawa, Japan, 236-0004
      • Yokohama City University Hospital
  • Shimane
    • Izumo, Shimane, Japan, 693-8501
      • Shimane University Hospital
  • Tokyo
    • Shibuya, Tokyo, Japan, 150-8935
      • Japanese Red Cross Medical Center
• Poland
  • Kraków, Poland, 31-501
    • Independent Public Healthcare Facility University Hospital in Cracow, Clinical Department of Hematology
  • Olsztyn, Poland, 10-228
    • Independent Public Health Care Facility of the Ministry of Internal Affairs with Warmia and Mazury Oncology Centre in Olsztyn
  • Suwalki, Poland, 16-400
    • Ludwik Rydygier Provinicial Hospital in Suwalki, Department of Clinical Oncology and Hematology
  • Warsaw, Poland, 02-106
    • MTZ Clinical Research Sp. z o.o.
  • Wroclaw, Poland, 50-367
    • Independent Public University Hospital No. 1 in Wroclaw, Department of Hematology, Blood Cancers and Bone Marrow
• Russian Federation
  • Kemerovo, Russian Federation, 650066
    • State Autonomous Healthcare Institution of Kemerovo region "Kemerovo Regional Clinical Hospital n.a. S.V. Belyaev",
  • Moscow, Russian Federation, 129301
    • State Budgetary Healthcare Institution of Moscow City
  • Saint Petersburg, Russian Federation, 191024
    • FSBI "Russian Scientific Research Hematology and Tranfusiology Institute of the Federal Biomedical Agency"
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitario Vall d'Hebron
  • Barcelona, Spain, 08916
    • Hospital Universitari Germans Trias I Pujol
  • Madrid, Spain, 28040
    • Fundacion Jimenez Diaz
  • Madrid, Spain, 28007
    • Hospital Universitario Gregorio Marañon
  • Málaga, Spain, 29010
    • Hospital Universitario Virgen de la Victoria
  • Salamanca, Spain, 37007
    • Hospital Universitario Salamanca
  • Valencia, Spain, 46026
    • Hospital Universitari i Politècnic La Fe
  • Balearic Islands
    • Palma de Mallorca, Balearic Islands, Spain, 07198
      • Hospital Son Llatzer
  • Barcelona
    • Hospitalet de Llobregat, Barcelona, Spain, 08908
      • Hospital Duran I Reynals - Instituto Catalan de Oncologia
• Sweden
  • Lund, Sweden, 222 82
    • Skåne University Hospital, Department of Hematology
  • Uppsala, Sweden, 751 81
    • Uppsala University Hospital
  • Huddinge
    • Stockholm, Huddinge, Sweden, 141 57
      • Karolinska University Hospital
  • Östergötland
    • Linköping, Östergötland, Sweden, 581 85
      • Linkoping University Hospital
• Switzerland
  • Bern, Switzerland, 3010
    • University Hospital and University of Bern; Inselspital Bern
  • Zurich, Switzerland, 8091
    • University Hospital Zurich
• United Kingdom
  • Liverpool, United Kingdom, L7 8XP
    • The Royal Liverpool University Hospital
  • London, United Kingdom, SE5 9RS
    • King's College Hospital NHS Foundation Trust
  • London, United Kingdom, EC1A 7BE
    • St Bartholomew's Hospital, Barts Health NHS Trust
  • Dorset
    • Bournemouth, Dorset, United Kingdom, BH7 7DW
      • Royal Bournemouth Hospital
  • Scotland
    • Aberdeen, Scotland, United Kingdom, AB25 2ZN
      • Aberdeen Royal Infirmary
• United States
  • California
    • La Jolla, California, United States, 92093
      • UC San Diego Moores Cancer Center
    • Los Angeles, California, United States, 90033
      • USC Norris Comprehensive Cancer Center
    • Los Angeles, California, United States, 90095
      • UCLA Medical Center
  • Florida
    • Fleming Island, Florida, United States, 32003
      • Cancer Specialists of North Florida
    • Gainesville, Florida, United States, 32608
      • UF Health Shands Cancer Hospital
    • Orange City, Florida, United States, 32763
      • Mid Florida Hematology and Oncology Centers
    • Saint Petersburg, Florida, United States, 33710
      • Advanced Research Institute, Inc
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
    • Chicago, Illinois, United States, 60612
      • University of Illinois Cancer Center
    • Maywood, Illinois, United States, 60153
      • Loyola University Chicago at Loyola University Medical Center
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Health Hospital
  • Kansas
    • Westwood, Kansas, United States, 66205
      • The University of Kansas Cancer Center
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Tulane Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Greenebaum Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota Physicians Bone Marrow Transplant Clinic
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • John Theurer Cancer Center at Hackensack University Medical Center
    • New Brunswick, New Jersey, United States, 08903
      • Rutgers Cancer Institute of New Jersey
    • Ridgewood, New Jersey, United States, 07450
      • The Valley Hospital
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • New York, New York, United States, 10029
      • Mount Sinai School of Medicine
    • Valhalla, New York, United States, 10595
      • New York Medical College
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of the University of Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19141
      • Albert Einstein Medical Center, Cancer Center
  • South Carolina
    • Greenville, South Carolina, United States, 29605
      • Greenville Health System (GHS) Cancer Institute
  • Texas
    • Dallas, Texas, United States, 75390-9015
      • UT Southwestern Medical Center
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center
  • Virginia
    • Charlottesville, Virginia, United States, 22903
      • Emily Couric Clinical Cancer Center
  • Washington
    • Seattle, Washington, United States, 98109
      • Seattle Cancer Care Alliance (SCCA)
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Clinical Science Center
    • Marshfield, Wisconsin, United States, 54449
      • Marshfield Clinic - Marshfield Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 79 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• MDS classified as follows:

  • RAEB-1 per World Health Organization (WHO) MDS criteria (5% to <10% BM blasts)
  • RAEB-2 per WHO MDS criteria (10% to <20% BM blasts)
  • RAEB-t per French-American-British (FAB) classification (20% to 30% BM blasts)
• At least one cytopenia (ANC < 1800/µL or platelet count < 100,000/µL or hemoglobin [Hgb] < 10 g/dL)
• Progression (according to 2006 IWG criteria) at any time after initiation of AZA or DAC treatment or Failure to achieve complete or partial response or hematological improvement (HI) (according to 2006 IWG) after at least six 4-week cycles of AZA or either four 4-week or four 6-week cycles of DAC administered or Relapse after initial complete or partial response or HI (according to 2006 IWG criteria)
• Duration of prior HMA therapy ≤ 9 months and/or total ≤ 9 cycles of prior HMA therapy in ≤ 12 months
• Last dose of AZA or DAC within 6 months before the planned date of randomization; however, must be off these treatments for ≥ 4 weeks before randomization
• Has failed to respond to, relapsed following, not eligible for, or opted not to participate in allogeneic stem cell transplantation
• Off all treatments for MDS (including AZA and DAC) for ≥ 4 weeks before randomization; growth factors (G-CSF, erythropoietin and thrombopoietin) and transfusions are allowed before and during the study as clinically indicated
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
• Willing to adhere to protocol prohibitions and restrictions
• Patient must sign informed consent form to indicate patient's understanding study's purpose and procedures and willingness to participate. Should patient be incapable of giving consent, the patient's legally authorized representative (as defined by local regulation) must give consent. However, should patient, in any manner, choose not to participate this takes precedence and will be respected.
• Patients with 5q- syndrome should have failed to respond to or progressed on treatment with lenalidomide, where available and indicated

Exclusion Criteria:

• Previous participation in a clinical study of IV or oral rigosertib; patients who failed screening for other rigosertib studies may be screened for participation
• Eligible to receive induction chemotherapy, such as 7-10 days of cytosine arabinoside plus 2-3 days of an anthracycline, or high-dose cytarabine
• Suitable candidate to receive allogeneic stem cell transplantation; patient is eligible for study if a suitable candidate refuses to undergo an allogeneic stem cell transplant or a suitable donor cannot be found
• Any active malignancy within the past year, except basal cell or squamous cell skin cancer or carcinoma in situ that is unlikely to progress in two years
• Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure or unstable angina pectoris
• 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 or eGFR (estimated Glomerular Filtration Rate) < 40 mL/min.

• Known active HIV, hepatitis B or hepatitis C, where active is defined as follows:

  • HIV or hepatitis C - presence of viral load
  • Hepatitis B - antigen positive
• Uncorrected hyponatremia (defined as serum sodium value of <130 mEq/L)

• Female patients of child-bearing potential and male patients with sexual partners of child-bearing potential who are unwilling to follow strict contraception requirements before entry and throughout the study, up to and including the 30-day non-treatment follow-up period. Examples of acceptable contraception methods include:

  • estrogen-gestagen based contraceptives associated with inhibition of ovulation (oral, intravaginal, transdermal),
  • gestagen-only based contraceptives associated with inhibition of ovulation (oral, injectable, implantable),
  • intra-uterine devices (IUDs),
  • intra-uterine hormone-releasing systems (IUSs),
  • bilateral tubal occlusion
  • vasectomized partner
  • sexual abstinence in accordance with an individual's lifestyle
• Female patients of child-bearing potential (pre-menopausal and not surgically sterilized) who are breast-feeding or have a positive blood beta-human chorionic gonadotropin pregnancy test at Screening
• Major surgery without full recovery or within 3 weeks before planned randomization;
• Uncontrolled hypertension
• New onset seizures (within 3 months before planned randomization) or poorly controlled seizures
• Any other concurrent investigational agent or chemotherapy, radiotherapy, immunotherapy, or corticosteroids (prednisone up to 20 mg/day or its equivalent is permitted for chronic conditions)
• Treatment with cytarabine at any dose, lenalidomide, or any other therapy targeted to the treatment of MDS (other than growth factors and other supportive care measures) within 4 weeks of planned randomization
• Investigational therapy within 4 weeks of planned randomization
• Psychiatric illness or social situation that would limit the patient's ability to tolerate and/or comply with study requirements.
• Patient previously diagnosed with AML (defined as a bone marrow or peripheral blood blast percentage of >30%).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: rigosertib + best supportive care (BSC)	Drug: rigosertib; Patients will receive intravenous rigosertib 1800 mg/24 hr for 3 days every 2 weeks for first 8 cycles, then every 4 weeks thereafter + best supportive care (BSC).; Other Names: ON 01910.Na; Drug: best supportive care (BSC); Patients will receive best supportive care (BSC): azacitidine (AZA) and/or decitabine (DAC) are permitted.; Drug: best supportive care (BSC); Patients will receive best supportive care (BSC).
Active Comparator: Physician's Choice (PC) + best supportive care (BSC)	Drug: best supportive care (BSC); Patients will receive best supportive care (BSC): azacitidine (AZA) and/or decitabine (DAC) are permitted.; Drug: best supportive care (BSC); Patients will receive best supportive care (BSC).; Drug: Any approved or standard-of-care therapy; Patients will receive Physician's Choice of Treatment or alternative treatment which may include any approved or standard-of-care therapy, based on frequently used treatment for MDS (no experimental therapy) + best supportive care.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival of all randomized patients and overall survival of patients scored as IPSS-R very high risk.	The overall survival (OS) of all randomized patients (ITT population), and the overall survival of patients scored as IPSS-R very high risk.	Up to 30 Months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival of patients with monosomy 7 chromosomal aberrations.	Evaluate OS of patients with monosomy 7 chromosomal aberrations in the rigosertib vs PC group. Overall survival is the time (months) from date of randomization to date of death or date last known to be alive at the time of date cut-off.	Up to 30 Months
Overall survival of patients with trisomy 8 chromosomal aberrations.	Evaluate OS of patients with trisomy 8 chromosomal aberrations in the rigosertib vs PC group. Overall survival is the time (months) from date of randomization to date of death or date last known to be alive at the time of date cut-off.	Up to 30 Months
Percent of patients with response according to 2006 IWG criteria.	Responses of complete remission (CR), partial remission (PR), mCR, SD, failure, and PD will be determined by 2006 IWG criteria. The number and percent of patients with CR, PR, mCR, SD, Failure, or PD will be summarized by treatment group.	Up to 30 Months
Scores of Quality of Life Questionnaire.	Compare rigosertib vs PC in regard to the the scores of the EuroQol EQ-5D-5L Questionnaire. The EuroQol EQ-5D-5L Questionnaire includes five levels of severity in each of the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression and a visual analogue scale.	At Baseline, at Week 4, Every 4 Weeks thereafter, and at the End-of-treatment.
Percent of patients with bone marrow blast response rate according to 2006 IWG criteria.	Compare rigosertib vs PC in regard to the bone marrow blast responses of marrow complete response (mCR ≥ 50% decrease of BMBL vs pretreatment values to a value ≤ 5%), marrow partial response (mPR, ≥ 50% decrease of BMBL vs pretreatment values to a value > 5%), stable disease (SD, no mCR or mPR, but no progressive disease (PD), and PD (≥ 50% BMBL increase relative to baseline or nadir) will be assessed. The number and percent of patients with mCR, mPR, SD, or PD will be summarized by treatment group. Responses of complete remission (CR), partial remission (PR), mCR, SD, failure, and PD will be determined by 2006 International Working Group (IWG) criteria.	Up to 30 Months
Percent of patients with hematologic improvement (HI) (erythroid, platelet and neutrophil responses) according to 2006 IWG criteria.	Compare rigosertib vs PC in regard to the number and percent of patients who meet the 2006 IWG criteria.	Up to 30 Months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory Objective: Bone Marrow Genomic Mutational Status	Bone marrow genomic mutational status.	At screening, every 8 week during study treatment, and at the end of study treatment
Exploratory Objective: Transition to Acute Myelogenous Leukemia (AML)	Transformation time to AML (defined as a bone marrow or peripheral blood blast percentage >30%).	Through study completion, an average of 8 months
Safety Objective: Number of Patients with AEs.	Treatment-emergent adverse events (TEAEs) will be graded according to NCI CTCAE version 4, grouped by MedDRA preferred term, and summarized by worst grade of severity per patient by treatment group.	Monthly, through study completion
Safety Objective: Rigosertib population pharmacokinetics (PK).	Blood samples for population PK analysis will be taken in rigosertib patients	At Cycle 1 (Week 1) and Cycle 2 (Week 3), on Day 1 of the infusion, 1 hr after its start and on Day 2 of the infusion, 6 hr after its start

Collaborators and Investigators

• Sponsor: Onconova Therapeutics, Inc.

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.
• 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.
• 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.
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Study record dates

Study Major Dates

• Study Start (Actual): December 2, 2015
• Primary Completion (Actual): July 26, 2020
• Study Completion (Actual): July 26, 2021

Study Registration Dates

• First Submitted: September 25, 2015
• First Submitted That Met QC Criteria: September 25, 2015
• First Posted (Estimate): September 29, 2015

Study Record Updates

• Last Update Posted (Actual): September 26, 2022
• Last Update Submitted That Met QC Criteria: September 22, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: MDS; Myelodysplastic Syndrome
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Anemia; Precancerous Conditions; Syndrome; Myelodysplastic Syndromes; Preleukemia; Anemia, Refractory, with Excess of Blasts; Anemia, Refractory; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; ON 01910
• Other Study ID Numbers: Onconova 04-30; 2015-001476-22 (EudraCT Number)