Controlled Study of Rigosertib Versus Physician's Choice of Treatment in MDS Patients After Failure of an HMA
- Conditions
- Myelodysplastic SyndromeRAEBRefractory Anemia With Excess BlastsMDS
- Interventions
- Registration Number
- NCT02562443
- Lead Sponsor
- Traws Pharma, Inc.
- Brief Summary
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.
- 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).
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 372
-
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
-
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
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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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description rigosertib + best supportive care (BSC) best supportive care (BSC) - Physician's Choice (PC) + best supportive care (BSC) Any approved or standard-of-care therapy - Physician's Choice (PC) + best supportive care (BSC) best supportive care (BSC) - rigosertib + best supportive care (BSC) rigosertib -
- Primary Outcome Measures
Name Time Method Overall survival of all randomized patients and overall survival of patients scored as IPSS-R very high risk. Up to 30 Months The overall survival (OS) of all randomized patients (ITT population), and the overall survival of patients scored as IPSS-R very high risk.
- Secondary Outcome Measures
Name Time Method Overall survival of patients with monosomy 7 chromosomal aberrations. Up to 30 Months 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.
Percent of patients with bone marrow blast response rate according to 2006 IWG criteria. Up to 30 Months 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.
Percent of patients with hematologic improvement (HI) (erythroid, platelet and neutrophil responses) according to 2006 IWG criteria. Up to 30 Months Compare rigosertib vs PC in regard to the number and percent of patients who meet the 2006 IWG criteria.
Overall survival of patients with trisomy 8 chromosomal aberrations. Up to 30 Months 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.
Percent of patients with response according to 2006 IWG criteria. Up to 30 Months 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.
Scores of Quality of Life Questionnaire. At Baseline, at Week 4, Every 4 Weeks thereafter, and at the End-of-treatment. 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.
Trial Locations
- Locations (158)
New York Medical College
🇺🇸Valhalla, New York, United States
USC Norris Comprehensive Cancer Center
🇺🇸Los Angeles, California, United States
University of Maryland Greenebaum Cancer Center
🇺🇸Baltimore, Maryland, United States
Icon Cancer Care Icon South Brisbane
🇦🇺South Brisbane, Queensland, Australia
Hanusch Hospital
🇦🇹Vienna, Austria
Tartu University Hospital
🇪🇪Tartu, Estonia
Princess Margaret Cancer Centre
🇨🇦Toronto, Ontario, Canada
UCLA Medical Center
🇺🇸Los Angeles, California, United States
Hôpital Claude Huriez, CHRU Lille
🇫🇷Lille Cedex, France
Hôpital l'Archet 1
🇫🇷Nice Cedex 3, France
Mid Florida Hematology and Oncology Centers
🇺🇸Orange City, Florida, United States
Universitätsklinikum Carl Gustav Carus
🇩🇪Dresden, Germany
UF Health Shands Cancer Hospital
🇺🇸Gainesville, Florida, United States
Rush University Medical Center
🇺🇸Chicago, Illinois, United States
University of Wisconsin Clinical Science Center
🇺🇸Madison, Wisconsin, United States
University Hospital Hradec Kralove
🇨🇿Hradec Kralove, Czechia
University Hospital Ostrava, Department of Hematooncology
🇨🇿Ostrava Poruba, Czechia
Klinički bolnicki centar Sestre milosrdnice
🇭🇷Zagreb, Croatia
Hospital of the University of Pennsylvania
🇺🇸Philadelphia, Pennsylvania, United States
Sunnybrook Research Institute
🇨🇦Toronto, Ontario, Canada
Institut Paoli-Calmettes
🇫🇷Marseille, France
Hôpital Saint Louis
🇫🇷Paris Cedex 10, France
Universitätsklinikum Frankfurt am Main
🇩🇪Frankfurt, Germany
Mount Sinai School of Medicine
🇺🇸New York, New York, United States
Advanced Research Institute, Inc
🇺🇸Saint Petersburg, Florida, United States
University Hospital Brno
🇨🇿Brno, Czechia
UT Southwestern Medical Center
🇺🇸Dallas, Texas, United States
Royal Hobart Hospital
🇦🇺Hobart, Tasmania, Australia
CHRU Tours Hôspital Bretonneau
🇫🇷Tours, France
Marshfield Clinic - Marshfield Center
🇺🇸Marshfield, Wisconsin, United States
Policlinico Universitario Tor Vergata
🇮🇹Roma, Italy
Loyola University Chicago at Loyola University Medical Center
🇺🇸Maywood, Illinois, United States
Salzburg University Hospital
🇦🇹Salzburg, Austria
Institut de Cancérologie du Gard
🇫🇷Nimes Cedex 9, France
Rutgers Cancer Institute of New Jersey
🇺🇸New Brunswick, New Jersey, United States
General University Hospital
🇨🇿Prague 2, Czechia
Marien Hospital Düsseldorf
🇩🇪Düsseldorf, Germany
Institute of Hematology and Blood Transfusion
🇨🇿Prague 2, Czechia
Azienda Ospedaliero-Universitaria Maggiore della Carità
🇮🇹Novara, Italy
A.O.U. Pisana, Divisione di Ematologia - University Hospital of Pisa
🇮🇹Pisa, Italy
Hôpital civil, Strasbourg
🇫🇷Strasbourg Cedex, France
Ospedale S. Eugenio - S. Eugenio Hospital
🇮🇹Roma, Italy
The Chaim Sheba Medical Center
🇮🇱Tel Hashomer, Israel
Hospital Universitario Vall d'Hebron
🇪🇸Barcelona, Spain
Azienda Ospedaliera Santa Maria di Terni
🇮🇹Terni, Italy
Linköping University Hospital
🇸🇪Linköping, Östergötland, Sweden
Hospital Son Llàtzer
🇪🇸Palma de Mallorca, Balearic Islands, Spain
Cittá della Salute e della Scienza di Torino
🇮🇹Torino, Italy
Azienda Ospedaliera Spedali Civili
🇮🇹Brescia, Italy
Uppsala University Hospital
🇸🇪Uppsala, Sweden
The Royal Liverpool University Hospital
🇬🇧Liverpool, United Kingdom
Fundación Jiménez Díaz
🇪🇸Madrid, Spain
Hospital Universitario Virgen de la Victoria
🇪🇸Málaga, Spain
St Bartholomew's Hospital, Barts Health NHS Trust
🇬🇧London, United Kingdom
Karolinska University Hospital
🇸🇪Stockholm, Huddinge, Sweden
Skåne University Hospital, Department of Hematology
🇸🇪Lund, Sweden
Hospital Universitario Gregorio Marañón
🇪🇸Madrid, Spain
King's College Hospital NHS Foundation Trust
🇬🇧London, United Kingdom
Hospital Duran i Reynals - Instituto Catalán de Oncología
🇪🇸Hospitalet de Llobregat, Barcelona, Spain
Hospital Universitari Germans Trias i Pujol
🇪🇸Barcelona, Spain
Hospital Universitari i Politècnic La Fe
🇪🇸Valencia, Spain
University of Illinois Cancer Center
🇺🇸Chicago, Illinois, United States
Tufts Medical Center
🇺🇸Boston, Massachusetts, United States
Seattle Cancer Care Alliance (SCCA)
🇺🇸Seattle, Washington, United States
Indiana University Health Hospital
🇺🇸Indianapolis, Indiana, United States
UC San Diego Moores Cancer Center
🇺🇸La Jolla, California, United States
Cancer Specialists of North Florida
🇺🇸Fleming Island, Florida, United States
Columbia University Medical Center
🇺🇸New York, New York, United States
The Valley Hospital
🇺🇸Ridgewood, New Jersey, United States
Albert Einstein Medical Center, Cancer Center
🇺🇸Philadelphia, Pennsylvania, United States
Emily Couric Clinical Cancer Center
🇺🇸Charlottesville, Virginia, United States
CHD Vendée
🇫🇷La Roche Sur Yon Cedex 9, France
Centre Hospitalier Lyon-Sud
🇫🇷Pierre-Bénite, France
Polyclinic S. Orsola-Malpighi
🇮🇹Bologna, Italy
Azienda Ospedaliero Universitaria Careggi
🇮🇹Firenze, Italy
Kokura Memorial Hospital
🇯🇵Kitakyushu, Fukuoka, Japan
State Budgetary Healthcare Institution of Moscow City
🇷🇺Moscow, Russian Federation
Hospital Universitario Salamanca
🇪🇸Salamanca, Spain
University Hospital and University of Bern; Inselspital Bern
🇨🇭Bern, Switzerland
Aberdeen Royal Infirmary
🇬🇧Aberdeen, Scotland, United Kingdom
The University of Kansas Cancer Center
🇺🇸Westwood, Kansas, United States
Christian Medical College
🇮🇳Vellore, Tamil Nadu, India
CancerCare Manitoba
🇨🇦Winnipeg, Manitoba, Canada
Oita Prefectural Hospital
🇯🇵Oita, Japan
National Hospital Organization Kyushu Cancer Center
🇯🇵Fukuoka-shi, Japan
Kagoshima University Hospital
🇯🇵Kagoshima, Japan
Japanese Red Cross Kyoto Daini Hospital
🇯🇵Kyoto, Japan
Nagasaki University Hospital
🇯🇵Nagasaki, Japan
Japanese Red Cross Nagoya Daini Hospital
🇯🇵Nagoya-shi, Japan
Niigata University Medical and Dental Hospital
🇯🇵Niigata, Japan
National Hospital Organization Okayama Medical Center
🇯🇵Okayama, Japan
Kindai University Hospital
🇯🇵Osakasayama-shi, Japan
Hokkaido University Hospital
🇯🇵Sapporo-shi, Japan
Tohoku University Hospital
🇯🇵Sendai-shi, Japan
Semmelweis University Medical School
🇭🇺Budapest, Hungary
Somogy County Kaposi Mór Teaching Hospital
🇭🇺Kaposvár, Hungary
University of Pécs 1st Department of Internal Medicine
🇭🇺Pécs, Hungary
Hemato Oncology Clinic Pvt. Ltd
🇮🇳Ahmedabad, Gujarat, India
Tata Memorial Hospital
🇮🇳Mumbai, Maharashtra, India
Jaslok Hospital and Research Center
🇮🇳Mumbai, Maharashtra, India
Sahyadri Clinical Research and Development Center
🇮🇳Pune, Maharashtra, India
Institute Of Hematology And Transfusion Medicine
🇮🇳Kolkata, West Bengal, India
Cork University Hospital
🇮🇪Cork, Ireland
Adelaide and Meath Hospital, Incorporating the National Children's Hospital
🇮🇪Dublin, Ireland
State Autonomous Healthcare Institution of Kemerovo region "Kemerovo Regional Clinical Hospital n.a. S.V. Belyaev",
🇷🇺Kemerovo, Russian Federation
University Hospital Waterford
🇮🇪Waterford, Ireland
Ha'Emek Medical Center
🇮🇱'Afula, Israel
Soroka University Medical Center
🇮🇱Beer Sheva, Israel
Rambam Medical Center
🇮🇱Haifa, Israel
Hadassah Medical Center
🇮🇱Jerusalem, Israel
Kaplan Medical Center
🇮🇱Rehovot, Israel
NTT Medical Center Tokyo
🇯🇵Shinagawa-ku, Japan
Tulane Medical Center
🇺🇸New Orleans, Louisiana, United States
John Theurer Cancer Center at Hackensack University Medical Center
🇺🇸Hackensack, New Jersey, United States
Greenville Health System (GHS) Cancer Institute
🇺🇸Greenville, South Carolina, United States
Monash Health, Monash Medical Centre
🇦🇺Melbourne, Victoria, Australia
Hospital of the Elisabethinen Linz GmbH
🇦🇹Linz, Austria
Antwerp Hospital Network Stuivenberg
🇧🇪Antwerp, Belgium
University Hospital Ghent
🇧🇪Ghent, Belgium
University Hospital Leuven, Campus Gasthuisberg
🇧🇪Leuven, Belgium
CHU UCL Namur - Site Godinne
🇧🇪Yvoir, Belgium
Jewish General Hospital
🇨🇦Montreal, Quebec, Canada
Klinički bolnički centar Osijek
🇭🇷Osijek, Croatia
Clinical Hospital Merkur
🇭🇷Zagreb, Croatia
Klinički bolnički centar Zagreb
🇭🇷Zagreb, Croatia
Tokyo Medical University Hospital
🇯🇵Shinjuku-ku, Japan
Dokkyo Medical University Hospital
🇯🇵Tochigi, Japan
Sapporo Medical University Hospital
🇯🇵Sapporo, Hokkaido, Japan
Tokushima University Hospital
🇯🇵Tokushima, Japan
Yamagata University Hospital
🇯🇵Yamagata, Japan
Saiseikai Yokohamashi Nanbu Hospital
🇯🇵Yokohama-shi, Japan
University of Fukui Hospital
🇯🇵Yoshida, Japan
Independent Public Healthcare Facility University Hospital in Cracow, Clinical Department of Hematology
🇵🇱Kraków, Poland
Kanazawa University Hospital
🇯🇵Kanazawa, Ishikawa, Japan
University Hospital Zurich
🇨🇭Zurich, Switzerland
Yokohama City University Hospital
🇯🇵Yokohama-shi, Kanagawa, Japan
Shimane University Hospital
🇯🇵Izumo, Shimane, Japan
Japanese Red Cross Medical Center
🇯🇵Shibuya, Tokyo, Japan
Akita University Hospital
🇯🇵Akita, Japan
North Estonia Medical Centre
🇪🇪Tallinn, Estonia
Independent Public Health Care Facility of the Ministry of Internal Affairs with Warmia and Mazury Oncology Centre in Olsztyn
🇵🇱Olsztyn, Poland
MTZ Clinical Research Sp. z o.o.
🇵🇱Warsaw, Poland
Jósa András Teaching Hospital
🇭🇺Nyíregyháza, Hungary
St. John's Medical College Hospital
🇮🇳Bangalore, Karnataka, India
Sourasky Medical Center
🇮🇱Tel Aviv, Israel
Chugoku Central Hospital of the Mutual Aid Association of Public School Teachers
🇯🇵Fukuyama, Hiroshima, Japan
Kobe City Hospital Organization Kobe City Medical Center General Hospital
🇯🇵Kobe, Japan
MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital
🇯🇵Bunkyo-ku, Japan
Tokai Central Hospital of the Mutual Aid Association of Public School Teachers
🇯🇵Kakamigahara, Japan
Saitama Medical Center
🇯🇵Kawagoe, Japan
National Hospital Organization Kumamoto Medical Center
🇯🇵Kumamoto, Japan
Ludwik Rydygier Provinicial Hospital in Suwalki, Department of Clinical Oncology and Hematology
🇵🇱Suwalki, Poland
Independent Public University Hospital No. 1 in Wroclaw, Department of Hematology, Blood Cancers and Bone Marrow
🇵🇱Wroclaw, Poland
FSBI "Russian Scientific Research Hematology and Tranfusiology Institute of the Federal Biomedical Agency"
🇷🇺Saint Petersburg, Russian Federation
Royal Bournemouth Hospital
🇬🇧Bournemouth, Dorset, United Kingdom
University of Minnesota Physicians Bone Marrow Transplant Clinic
🇺🇸Minneapolis, Minnesota, United States
Mayo Clinic
🇺🇸Rochester, Minnesota, United States