Clinical trial NCT02562443: Controlled Study of Rigosertib Versus Physician's Choice of Treatment in MDS Patients After Failure of an HMA
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Myelodysplastic Syndrome
MDS
Refractory Anemia With Excess Blasts
RAEB
Keywords: Myelodysplastic Syndrome
MDS
Lead sponsor: Traws Pharma, Inc.
Sponsor class: INDUSTRY
First posted: 2015-09-29
Enrollment: 372
Sex: ALL
Minimum age (years): 18
Maximum age (years): 81
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

Eligibility criteria: 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%).

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