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

Myelodysplastic Syndromes Clinical Trial

— ONTIME  

Official title:

Phase III MultiCenter Randomized Controlled Study to Assess Efficacy and Safety of ON 01910.Na 72-Hr Continuous IV Infusion in MDS Patients With Excess Blasts Relapsing After or Refractory to or Intolerant to Azacitidine or Decitabine

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01241500
• Other study ID #: 04-21
• Status: Completed
• Phase: Phase 3
• 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
• 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

Related Conditions & MeSH terms

• Chronic Myelomonocytic Leukemia
• Leukemia, Myelomonocytic, Chronic
• Leukemia, Myelomonocytic, Juvenile
• MDS
• Myelodysplastic Syndromes
• Preleukemia
• RAEB
• Syndrome

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

External Links

•   Leukemia and Lymphoma Society
•   The Myelodysplastic Syndromes Foundation