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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT01241500
Other study ID # 04-21
Secondary ID
Status Completed
Phase Phase 3
First received
Last updated
Start date November 2010
Est. completion date October 3, 2018

Study information

Verified date July 2018
Source Onconova Therapeutics, Inc.
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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.


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.


Recruitment information / eligibility

Status Completed
Enrollment 299
Est. completion date October 3, 2018
Est. primary completion date October 3, 2018
Accepts healthy volunteers No
Gender All
Age group 18 Years and older
Eligibility Inclusion Criteria:

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

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

- RAEB-1 (5% - 9% BM blasts)

- RAEB-2 (10% - 19% BM blasts)

- CMML (10% - 20% BM blasts) and WBC < 13,000/µL

- RAEB-t (20% - 30% BM blasts), with following criteria:

- o WBC < 25 x 10E9/L at entry

- o Stable WBC at least 4 weeks prior to entry and not requiring intervention for WBC control with hydroxyurea, chemotherapy, or leukopheresis.

- At least one cytopenia (ANC < 1800/µL or platelet count < 100,000/µL or hemoglobin <10 g/dL)

- Progression according to 2006 International Working Group (IWG) criteria any time after start of azacitidine or decitabine during past 2 years; or failure to achieve complete or partial response or hematological improvement (according to 2006 IWG) after at least six 4-week cycles of azacitidine or four 6-week cycles of decitabine during past 2 years; or relapse after initial complete or partial response or hematological improvement (according to 2006 IWG criteria) observed after at least six 4-week cycles of azacitidine or four 6-week cycles of decitabine during past 2 years; or, intolerance to azacitidine or decitabine defined by drug-related =Grade 3 liver or renal toxicity leading to discontinuation during the past 2 years.

- Did not respond to, relapsed after, not eligible for, or opted not to do bone marrow transplantation

- Off other MDS treatments for at least 4 weeks; Filgrastim (G-CSF) and erythropoietin allowed before and during the study as clinically indicated.

- No need for induction chemotherapy

- ECOG status 0, 1 or 2

- Willing to adhere to protocol prohibitions and restrictions

- Patient (or a legally authorized representative) must sign informed consent form to indicate patient's understanding study's purpose and procedures and willingness to participate

Exclusion Criteria:

- Anemia due to factors other than MDS (including hemolysis or gastrointestinal bleeding) unless stabilized for 1 week after RBC transfusion.

- Any active malignancy within the past year, except basal cell or squamous cell skin cancer or carcinoma in situ of the cervix or breast

- Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia

- Active infection not adequately responding to appropriate therapy

- Total bilirubin =1.5 mg/dL not related to hemolysis or Gilbert's disease.

- Alanine transaminase (ALT)/aspartate transaminase (AST) =2.5 x upper limit of normal (ULN)

- Serum creatinine =2.0 mg/dL

- Ascites requiring active medical management including paracentesis, or hyponatremia (defined as serum sodium value of <130 mEq/L)

- Pregnant or lactating females

- Patients unwilling to follow strict contraception requirements (including condom use for males with sexual partners, and for females: prescription oral contraceptives [birth control pills], contraceptive injections, intrauterine device, double-barrier method [spermicidal jelly or foam with condoms or diaphragm], contraceptive patch, or surgical sterilization) before entry and throughout the study

- Females with reproductive potential who do not have a negative urine beta-human chorionic gonadotropin pregnancy test at screening

- Major surgery without full recovery or major surgery within 3 weeks of ON 01910.Na treatment start

- Uncontrolled hypertension (defined as systolic pressure =160 mmHg and/or diastolic pressure =110 mmHg)

- New onset seizures (within 3 months prior to first dose of ON 01910.Na) or poorly controlled seizures

- Any other concurrent investigational agent or chemotherapy, radiotherapy, or immunotherapy

- Prior treatment with low-dose cytarabine during past 2 years Investigational therapy within 4 weeks of starting ON 01910.Na

- Psychiatric illness or social situation that limits the patient's ability to tolerate and/or comply with study requirements

Study Design


Related Conditions & MeSH terms


Intervention

Drug:
ON 01910.Na
The dose of ON 01910.Na will be 1800 mg/24 hr as a continuous intravenous infusion for 72 hours every other week for the first 16 weeks then every 4 weeks afterwards. Infusion bags must be changed every 24 hours and a new infusion bag must be used for each of the subsequent 24 hours until completion of the total 72-hour infusion time.

Locations

Country Name City State
Belgium Ziekenhuis Netwerk Antwerpen Antwerp
Belgium Universitair Ziekenhuis Gent Gent
Belgium H. Hartziekenhuis Roeselare-Menen vzw Roeselare West-vlaanderen
Belgium CHU de Mont-Godinne Yvoir
France 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 Hôpital Saint-Antoine Paris
France Hôtel Dieu Sce Hématologie Clinique 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
Germany Universitätsklinikum Bonn Bonn Nordrhein-westfalen
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 Universitätsklinikum zu Köln Köln
Germany Universitätsmedizin Mannheim Mannheim
Germany Johannes-Wesling-Klinikum Minden Minden
Germany Klinikum Rechts der Isar der Technischen Universität München München
Germany Universitätsklinikum Ulm Ulm
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 Firenze
Italy Azienda Ospedaliera Universitaria San Martino Genova
Italy Azienda Osperdaliera Universitaria Maggiore della Carità Novara
Italy Università degli Studi La Sapienza Roma
Italy Azienda Ospedaliera Universitaria Senese Policlinico Santa Maria alle Scotte Siena SI
Italy Azienda Ospedaliero Universitaria San Giovanni Battista di Torino Torino
Spain Hospital Universitario La Paz Madrid
Spain Hospital Universitario La Princesa Madrid
Spain Hospital Clínico Universitario Virgen de la Victoria Málaga
Spain Hospital Universitario Central de Asturias Oviedo Asturias
Spain Hospital Universitario Son Espases Palma de Mallorca
Spain Hospital Clínico Universitario de Salamanca Salamanca
Spain Hospital Clínico Universitario de Valencia Valencia
Spain Hospital Universitari i Politècnic La Fe Valencia
United States University of Michigan Comprehensive Cancer Center Ann Arbor Michigan
United States Emory University Winship Cancer Institute Atlanta Georgia
United States Johns Hopkins Hospital Baltimore Maryland
United States University of Maryland Greenebaum Cancer Center Baltimore Maryland
United States Mary Bird Perkins Cancer Center Baton Rouge Louisiana
United States Dana-Farber Cancer Institute Boston Massachusetts
United States Albert Einstein College of Medicine Bronx New York
United States Medical University of South Carolina Charleston South Carolina
United States Rush University Medical Center Chicago Illinois
United States University of Chicago Medical Center Chicago Illinois
United States Cleveland Clinic Cleveland Ohio
United States University of Texas Southwestern Medical Center at Dallas Dallas Texas
United States North Shore Medical Center Evanston Illinois
United States Bon Secours St. Francois Health System Greenville South Carolina
United States Hackensack University Medical Center Hackensack New Jersey
United States University of Texas M. D. Anderson Cancer Center Houston Texas
United States Integrated Community Oncology Network Jacksonville Florida
United States University of California San Diego Moores Cancer Center La Jolla California
United States North Shore - LIJ Health System Lake Success New York
United States Cardinal Bernardin Cancer Center Maywood Illinois
United States Innovative Medical Research of South Florida, Inc. Miami Florida
United States Mount Sinai Comprehensive Cancer Centers Miami Beach Florida
United States Medical College of Wisconsin Milwaukee Wisconsin
United States Yale Cancer Center New Haven Connecticut
United States Mount Sinai Medical Center New York New York
United States Weill Cornell Medical College New York New York
United States University of Oklahoma Health Science Center Oklahoma City Oklahoma
United States Woodlands Medical Specialists Pensacola Florida
United States University of Pennsylvania Health System Philadelphia Pennsylvania
United States Mayo Clinic Rochester Minnesota
United States Cancer Care Centers of South Texas San Antonio Texas
United States Virginia G. Piper Cancer Center Scottsdale Arizona
United States Fred Hutchinson Cancer Research Center Seattle Washington
United States Edward H. Kaplan MD & Associates Skokie Illinois
United States Providence Cancer Center Southfield Michigan
United States Stanford Cancer Center Stanford California
United States Martin Memorial Cancer Center Stuart Florida
United States Overlook Hospital Summit New Jersey
United States Georgetown University Hospital Washington District of Columbia
United States Cleveland Clinic Florida Weston Florida
United States University of Kansas Medical Center Westwood Kansas

Sponsors (2)

Lead Sponsor Collaborator
Onconova Therapeutics, Inc. The Leukemia and Lymphoma Society

Countries where clinical trial is conducted

United States,  Belgium,  France,  Germany,  Italy,  Spain, 

References & Publications (6)

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 hypomethyla

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. — View 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; — View 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.

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. Review. — View Citation

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. — View Citation

Outcome

Type Measure Description Time frame Safety issue
Primary Overall survival Overall survival (OS) is defined as the time from randomization to death from any cause. All patients will be followed until death or progression, even if they have discontinued treatment for whatever cause. Patients lost to follow-up will be censored at the time last known alive. The OS primary analysis will compare the active ON 01910.Na regimen to BSC once a total number of 223 deaths has been reached. Up to 18 months
Secondary Overall response (complete and partial remission) according to 2006 IWG criteria Compare the BSC + ON 01910.Na group to the BSC group with respect to changes in bone marrow myeloblasts, hemoglobin, peripheral neutrophils, platelets and blasts. Changes measured at Week 4 from Baseline and every 8 Weeks thereafter
Secondary Complete bone marrow response according to 2006 IWG criteria Compare the BSC + ON 01910.Na group to the BSC group with respect to changes in bone marrow myeloblasts. Changes measured at Week 4 from Baseline and every 8 Weeks thereafter
Secondary Hematological improvements according to 2006 IWG criteria Compare the BSC + ON 01910.Na group to the BSC group with respect to in absolute neutrophil count (ANC), platelet count, and erythroid responses. Weekly
Secondary Scores of Quality of Life Questionnaire Compare the BSC + ON 01910.Na group to the BSC group with respect to scores of Quality-of-life (QOL)(using the European Organization for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire [QLQ]-C30 version 3. Measured at Baseline and every 4 Weeks
Secondary Adverse events Record adverse events according to CTCAE v4. Weekly
Secondary Change in Aneuploidy Improvements of cytogenetics as evaluated by the change in aneuploidy in bone marrow according to 2006 IWG criteria. Baseline and, only if abnormal at Baseline, Week 4 and every 8 Weeks thereafter
Secondary Transition time to AML Transition time to AML: Defined for RAEB-1 and RAEB-2 MDS and chronic myelomonocytic leukemia (CMML) patients (with BM blasts from 10% to 20% for CMML) by an increase of at least 50% BM blasts and more than 20% BM blasts; Defined for RAEB-t by an increase of at least 50% BM blasts. Measured at Week 4 from date of randomization and every 8 Weeks thereafter
Secondary Incidence of infections and bleeding episodes. Incidence of infections (treated with intravenous antimicrobials) and bleeding episodes. Every 4 Weeks
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