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

NCT ID: NCT01241500

Last Updated: 2020-06-30

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 299 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-11-30
• Study Completion Date: 2018-10-03

Brief Summary

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.

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.

Conditions

Myelodysplastic Syndromes; MDS; RAEB; Chronic Myelomonocytic Leukemia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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).

Group Type: EXPERIMENTAL

ON 01910.Na

Intervention Type: DRUG

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.

Best supportive care (BSC)

Patients will receive best supportive care (BSC).

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

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.

Intervention Type: DRUG

Other Intervention Names

rigosertib

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

The Leukemia and Lymphoma Society

OTHER

Sponsor Role: collaborator

Traws Pharma, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Steven M. Fruchtman, MD

Role: STUDY_CHAIR

Traws Pharma, Inc.

Locations

Virginia G. Piper Cancer Center

Scottsdale, Arizona, United States

University of California San Diego Moores Cancer Center

La Jolla, California, United States

Stanford Cancer Center

Stanford, California, United States

Yale Cancer Center

New Haven, Connecticut, United States

Georgetown University Hospital

Washington D.C., District of Columbia, United States

Integrated Community Oncology Network

Jacksonville, Florida, United States

Innovative Medical Research of South Florida, Inc.

Miami, Florida, United States

Mount Sinai Comprehensive Cancer Centers

Miami Beach, Florida, United States

Woodlands Medical Specialists

Pensacola, Florida, United States

Martin Memorial Cancer Center

Stuart, Florida, United States

Cleveland Clinic Florida

Weston, Florida, United States

Emory University Winship Cancer Institute

Atlanta, Georgia, United States

Rush University Medical Center

Chicago, Illinois, United States

University of Chicago Medical Center

Chicago, Illinois, United States

North Shore Medical Center

Evanston, Illinois, United States

Cardinal Bernardin Cancer Center

Maywood, Illinois, United States

Edward H. Kaplan MD & Associates

Skokie, Illinois, United States

University of Kansas Medical Center

Westwood, Kansas, United States

Mary Bird Perkins Cancer Center

Baton Rouge, Louisiana, United States

University of Maryland Greenebaum Cancer Center

Baltimore, Maryland, United States

Johns Hopkins Hospital

Baltimore, Maryland, United States

Dana-Farber Cancer Institute

Boston, Massachusetts, United States

University of Michigan Comprehensive Cancer Center

Ann Arbor, Michigan, United States

Providence Cancer Center

Southfield, Michigan, United States

Mayo Clinic

Rochester, Minnesota, United States

Hackensack University Medical Center

Hackensack, New Jersey, United States

Overlook Hospital

Summit, New Jersey, United States

North Shore - LIJ Health System

Lake Success, New York, United States

Weill Cornell Medical College

New York, New York, United States

Mount Sinai Medical Center

New York, New York, United States

Albert Einstein College of Medicine

The Bronx, New York, United States

Cleveland Clinic

Cleveland, Ohio, United States

University of Oklahoma Health Science Center

Oklahoma City, Oklahoma, United States

University of Pennsylvania Health System

Philadelphia, Pennsylvania, United States

Medical University of South Carolina

Charleston, South Carolina, United States

Bon Secours St. Francois Health System

Greenville, South Carolina, United States

University of Texas Southwestern Medical Center at Dallas

Dallas, Texas, United States

University of Texas M. D. Anderson Cancer Center

Houston, Texas, United States

Cancer Care Centers of South Texas

San Antonio, Texas, United States

Fred Hutchinson Cancer Research Center

Seattle, Washington, United States

Medical College of Wisconsin

Milwaukee, Wisconsin, United States

H. Hartziekenhuis Roeselare-Menen vzw

Roeselare, West-vlaanderen, Belgium

Ziekenhuis Netwerk Antwerpen

Antwerp, , Belgium

Universitair Ziekenhuis Gent

Ghent, , Belgium

CHU de Mont-Godinne

Yvoir, , Belgium

CHU Angers Service de Medecine D - Maladies du Sang

Angers, , France

CHU Avignon Centre Hospitalier Henri Dufaut

Avignon, , France

Hôpital Avicenne Hématologie Clinique

Bobigny, , France

CHU Caen Hématologie Clinique

Caen, , France

CHU Estaing Service d'hématologie

Clermont-Ferrand, , France

CHU Lille Hôpital Claude Huriez

Lille, , France

CHU Limoges Hopital Dupuytren

Limoges, , France

Institute Paoli Calmettes

Marseille, , France

Hôpital de L'archet I

Nice, , France

Hôtel Dieu Sce Hématologie Clinique

Paris, , France

Hôpital Saint-Antoine

Paris, , France

CHU Perpignan Centre Hospitalier Hôpital Saint-Jean

Perpignan, , France

CRLCC Henri Becquerel

Rouen, , France

Chu-Strasbourg-Hopital Civil

Strasbourg, , France

Hôpital Purpan

Toulouse, , France

Universitätsklinikum Bonn

Bonn, North Rhine-Westphalia, Germany

Universitätsklinikum zu Köln

Cologne, , Germany

Universitätsklinikum Dresden

Dresden, , Germany

Heinrich-Heine-Universität Düsseldorf

Düsseldorf, , Germany

Klinikum der Johann Wolfgang-Goethe-Universität

Frankfurt am Main, , Germany

Universitätsklinikum Hamburg-Eppendorf

Hamburg, , Germany

Universitätsmedizin Mannheim

Mannheim, , Germany

Johannes-Wesling-Klinikum Minden

Minden, , Germany

Klinikum Rechts der Isar der Technischen Universität München

München, , Germany

Universitätsklinikum Ulm

Ulm, , Germany

Azienda Ospedaliera Universitaria Senese Policlinico Santa Maria alle Scotte

Siena, SI, Italy

Azienda Ospedaliera Santi Antonio e Biagio e Cesare Arrigo

Alessandria, , Italy

Azienda Ospedaliero-Universitaria di Bologa Policlinico S. Orsola-Malpighi

Bologna, , Italy

Azienda Ospedaliera-Universitairia Vittorio Emanuele-Ferrarotto-Santo Bambino

Catania, , Italy

Azienda Ospedaliera Universitaria Careggi di Firenze

Florence, , Italy

Azienda Ospedaliera Universitaria San Martino

Genova, , Italy

Azienda Osperdaliera Universitaria Maggiore della Carità

Novara, , Italy

Università degli Studi La Sapienza

Roma, , Italy

Azienda Ospedaliero Universitaria San Giovanni Battista di Torino

Torino, , Italy

Hospital Universitario Central de Asturias

Oviedo, Principality of Asturias, Spain

Hospital Universitario La Princesa

Madrid, , Spain

Hospital Universitario La Paz

Madrid, , Spain

Hospital Clínico Universitario Virgen de la Victoria

Málaga, , Spain

Hospital Universitario Son Espases

Palma de Mallorca, , Spain

Hospital Clínico Universitario de Salamanca

Salamanca, , Spain

Hospital Universitari i Politècnic La Fe

Valencia, , Spain

Hospital Clínico Universitario de Valencia

Valencia, , Spain

Countries

United States; Belgium; France; Germany; Italy; Spain

References

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.

Reference Type: BACKGROUND

PMID: 21924492 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 27104980 (View on PubMed)

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.

Reference Type: RESULT

PMID: 26968357 (View on PubMed)

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.

Reference Type: RESULT

PMID: 27400247 (View on PubMed)

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

Reference Type: RESULT

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.

Reference Type: RESULT

Related Links

http://www.lls.org/

Leukemia and Lymphoma Society

http://mds-foundation.org/

The Myelodysplastic Syndromes Foundation

Other Identifiers

04-21

Identifier Type: -

Identifier Source: org_study_id