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

Sponsor

Onconova Therapeutics, Inc. (Industry)

Overall Status

Completed

CT.gov ID

NCT01241500

Collaborator

The Leukemia and Lymphoma Society (Other)

299

Enrollment

Locations

Arms

Actual Duration (Months)

3.4

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Myelodysplastic Syndromes MDS RAEB Chronic Myelomonocytic Leukemia	Drug: ON 01910.Na	Phase 3

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

299 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Nov 1, 2010

Actual Primary Completion Date :

Oct 3, 2018

Actual Study Completion Date :

Oct 3, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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).	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. Other Names: rigosertib
No Intervention: Best supportive care (BSC) Patients will receive best supportive care (BSC).

Arm

Intervention/Treatment

Experimental: 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).

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.

Other Names:

rigosertib

No Intervention: Best supportive care (BSC)

Patients will receive best supportive care (BSC).

Outcome Measures

Primary Outcome Measures

Overall survival [Up to 18 months]
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.

Secondary Outcome Measures

Overall response (complete and partial remission) according to 2006 IWG criteria [Changes measured at Week 4 from Baseline and every 8 Weeks thereafter]
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.
Complete bone marrow response according to 2006 IWG criteria [Changes measured at Week 4 from Baseline and every 8 Weeks thereafter]
Compare the BSC + ON 01910.Na group to the BSC group with respect to changes in bone marrow myeloblasts.
Hematological improvements according to 2006 IWG criteria [Weekly]
Compare the BSC + ON 01910.Na group to the BSC group with respect to in absolute neutrophil count (ANC), platelet count, and erythroid responses.
Scores of Quality of Life Questionnaire [Measured at Baseline and every 4 Weeks]
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.
Adverse events [Weekly]
Record adverse events according to CTCAE v4.
Change in Aneuploidy [Baseline and, only if abnormal at Baseline, Week 4 and every 8 Weeks thereafter]
Improvements of cytogenetics as evaluated by the change in aneuploidy in bone marrow according to 2006 IWG criteria.
Transition time to AML [Measured at Week 4 from date of randomization and every 8 Weeks thereafter]
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.
Incidence of infections and bleeding episodes. [Every 4 Weeks]
Incidence of infections (treated with intravenous antimicrobials) and bleeding episodes.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Virginia G. Piper Cancer Center	Scottsdale	Arizona	United States	85258
2	University of California San Diego Moores Cancer Center	La Jolla	California	United States	92093
3	Stanford Cancer Center	Stanford	California	United States	94305
4	Yale Cancer Center	New Haven	Connecticut	United States	06520
5	Georgetown University Hospital	Washington	District of Columbia	United States	20007
6	Integrated Community Oncology Network	Jacksonville	Florida	United States	32256
7	Mount Sinai Comprehensive Cancer Centers	Miami Beach	Florida	United States	33140
8	Innovative Medical Research of South Florida, Inc.	Miami	Florida	United States	33169
9	Woodlands Medical Specialists	Pensacola	Florida	United States	32503
10	Martin Memorial Cancer Center	Stuart	Florida	United States	34994
11	Cleveland Clinic Florida	Weston	Florida	United States	33331
12	Emory University Winship Cancer Institute	Atlanta	Georgia	United States	30322
13	Rush University Medical Center	Chicago	Illinois	United States	60612
14	University of Chicago Medical Center	Chicago	Illinois	United States	60637
15	North Shore Medical Center	Evanston	Illinois	United States	60201
16	Cardinal Bernardin Cancer Center	Maywood	Illinois	United States	60153
17	Edward H. Kaplan MD & Associates	Skokie	Illinois	United States	60076
18	University of Kansas Medical Center	Westwood	Kansas	United States	66205
19	Mary Bird Perkins Cancer Center	Baton Rouge	Louisiana	United States	70809
20	University of Maryland Greenebaum Cancer Center	Baltimore	Maryland	United States	21201
21	Johns Hopkins Hospital	Baltimore	Maryland	United States	21231
22	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115
23	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan	United States	48109
24	Providence Cancer Center	Southfield	Michigan	United States	48075
25	Mayo Clinic	Rochester	Minnesota	United States	55905
26	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
27	Overlook Hospital	Summit	New Jersey	United States	07901
28	Albert Einstein College of Medicine	Bronx	New York	United States	10461
29	North Shore - LIJ Health System	Lake Success	New York	United States	11042
30	Weill Cornell Medical College	New York	New York	United States	10021
31	Mount Sinai Medical Center	New York	New York	United States	10029
32	Cleveland Clinic	Cleveland	Ohio	United States	44195
33	University of Oklahoma Health Science Center	Oklahoma City	Oklahoma	United States	73104
34	University of Pennsylvania Health System	Philadelphia	Pennsylvania	United States	19104
35	Medical University of South Carolina	Charleston	South Carolina	United States	29425
36	Bon Secours St. Francois Health System	Greenville	South Carolina	United States	29601
37	University of Texas Southwestern Medical Center at Dallas	Dallas	Texas	United States	75390
38	University of Texas M. D. Anderson Cancer Center	Houston	Texas	United States	77030
39	Cancer Care Centers of South Texas	San Antonio	Texas	United States	78229
40	Fred Hutchinson Cancer Research Center	Seattle	Washington	United States	98109
41	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
42	H. Hartziekenhuis Roeselare-Menen vzw	Roeselare	West-vlaanderen	Belgium	8800
43	Ziekenhuis Netwerk Antwerpen	Antwerp		Belgium	2060
44	Universitair Ziekenhuis Gent	Gent		Belgium	9000
45	CHU de Mont-Godinne	Yvoir		Belgium	5530
46	CHU Angers Service de Medecine D - Maladies du Sang	Angers		France	49033
47	CHU Avignon Centre Hospitalier Henri Dufaut	Avignon		France	84000
48	Hôpital Avicenne Hématologie Clinique	Bobigny		France	93009
49	CHU Caen Hématologie Clinique	Caen		France	14000
50	CHU Estaing Service d'hématologie	Clermont-Ferrand		France	63000
51	CHU Lille Hôpital Claude Huriez	Lille		France	59037
52	CHU Limoges Hopital Dupuytren	Limoges		France	87042
53	Institute Paoli Calmettes	Marseille		France	13009
54	Hôpital de L'archet I	Nice		France	6202
55	Hôtel Dieu Sce Hématologie Clinique	Paris		France	75004
56	Hôpital Saint-Antoine	Paris		France	75571
57	CHU Perpignan Centre Hospitalier Hôpital Saint-Jean	Perpignan		France	66046
58	CRLCC Henri Becquerel	Rouen		France	76038
59	Chu-Strasbourg-Hopital Civil	Strasbourg		France	67091
60	Hôpital Purpan	Toulouse		France	31059
61	Universitätsklinikum Bonn	Bonn	Nordrhein-westfalen	Germany	53127
62	Universitätsklinikum Dresden	Dresden		Germany	01307
63	Heinrich-Heine-Universität Düsseldorf	Düsseldorf		Germany	40225
64	Klinikum der Johann Wolfgang-Goethe-Universität	Frankfurt am Main		Germany	60590
65	Universitätsklinikum Hamburg-Eppendorf	Hamburg		Germany	20246
66	Universitätsklinikum zu Köln	Köln		Germany	50924
67	Universitätsmedizin Mannheim	Mannheim		Germany	68167
68	Johannes-Wesling-Klinikum Minden	Minden		Germany	32429
69	Klinikum Rechts der Isar der Technischen Universität München	München		Germany	81675
70	Universitätsklinikum Ulm	Ulm		Germany	89081
71	Azienda Ospedaliera Universitaria Senese Policlinico Santa Maria alle Scotte	Siena	SI	Italy	53100
72	Azienda Ospedaliera Santi Antonio e Biagio e Cesare Arrigo	Alessandria		Italy	15100
73	Azienda Ospedaliero-Universitaria di Bologa Policlinico S. Orsola-Malpighi	Bologna		Italy	40138
74	Azienda Ospedaliera-Universitairia Vittorio Emanuele-Ferrarotto-Santo Bambino	Catania		Italy	95124
75	Azienda Ospedaliera Universitaria Careggi di Firenze	Firenze		Italy	50134
76	Azienda Ospedaliera Universitaria San Martino	Genova		Italy	16132
77	Azienda Osperdaliera Universitaria Maggiore della Carità	Novara		Italy	28100
78	Università degli Studi La Sapienza	Roma		Italy	00161
79	Azienda Ospedaliero Universitaria San Giovanni Battista di Torino	Torino		Italy	10126
80	Hospital Universitario Central de Asturias	Oviedo	Asturias	Spain	33006
81	Hospital Universitario La Princesa	Madrid		Spain	28006
82	Hospital Universitario La Paz	Madrid		Spain	28046
83	Hospital Clínico Universitario Virgen de la Victoria	Málaga		Spain	29010
84	Hospital Universitario Son Espases	Palma de Mallorca		Spain	07012
85	Hospital Clínico Universitario de Salamanca	Salamanca		Spain	37007
86	Hospital Universitari i Politècnic La Fe	Valencia		Spain	46009
87	Hospital Clínico Universitario de Valencia	Valencia		Spain	46010