Clinical trial NCT01241500: Randomized Study of ON 01910.Na in Refractory Myelodysplastic Syndrome Patients With Excess Blasts
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Myelodysplastic Syndromes
MDS
RAEB
Chronic Myelomonocytic Leukemia
Keywords: Myelodysplastic syndromes
MDS
Lead sponsor: Traws Pharma, Inc.
Sponsor class: INDUSTRY
Collaborators: name: The Leukemia and Lymphoma Society
First posted: 2010-11-16
Enrollment: 299
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Overall survival
timeFrame: Up to 18 months
Secondary outcomes:
measure: Overall response (complete and partial remission) according to 2006 IWG criteria
timeFrame: Changes measured at Week 4 from Baseline and every 8 Weeks thereafter
measure: Complete bone marrow response according to 2006 IWG criteria
timeFrame: Changes measured at Week 4 from Baseline and every 8 Weeks thereafter
measure: Hematological improvements according to 2006 IWG criteria
timeFrame: Weekly
measure: Scores of Quality of Life Questionnaire
timeFrame: Measured at Baseline and every 4 Weeks
measure: Adverse events
timeFrame: Weekly
measure: Change in Aneuploidy
timeFrame: Baseline and, only if abnormal at Baseline, Week 4 and every 8 Weeks thereafter
measure: Transition time to AML
timeFrame: Measured at Week 4 from date of randomization and every 8 Weeks thereafter
measure: Incidence of infections and bleeding episodes.
timeFrame: Every 4 Weeks
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Virginia G. Piper Cancer Center
state: Arizona
city: La Jolla
country: United States
facility: University of California San Diego Moores Cancer Center
state: California
city: Stanford
country: United States
facility: Stanford Cancer Center
state: California
city: New Haven
country: United States
facility: Yale Cancer Center
state: Connecticut
city: Washington
country: United States
facility: Georgetown University Hospital
state: District of Columbia
city: Jacksonville
country: United States
facility: Integrated Community Oncology Network
state: Florida
city: Miami Beach
country: United States
facility: Mount Sinai Comprehensive Cancer Centers
state: Florida
city: Miami
country: United States
facility: Innovative Medical Research of South Florida, Inc.
state: Florida
city: Pensacola
country: United States
facility: Woodlands Medical Specialists
state: Florida
city: Stuart
country: United States
facility: Martin Memorial Cancer Center
state: Florida
city: Weston
country: United States
facility: Cleveland Clinic Florida
state: Florida
city: Atlanta
country: United States
facility: Emory University Winship Cancer Institute
state: Georgia
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Chicago
country: United States
facility: University of Chicago Medical Center
state: Illinois
city: Evanston
country: United States
facility: North Shore Medical Center
state: Illinois
city: Maywood
country: United States
facility: Cardinal Bernardin Cancer Center
state: Illinois
city: Skokie
country: United States
facility: Edward H. Kaplan MD & Associates
state: Illinois
city: Westwood
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Baton Rouge
country: United States
facility: Mary Bird Perkins Cancer Center
state: Louisiana
city: Baltimore
country: United States
facility: University of Maryland Greenebaum Cancer Center
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins Hospital
state: Maryland
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: Southfield
country: United States
facility: Providence Cancer Center
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Summit
country: United States
facility: Overlook Hospital
state: New Jersey
city: Bronx
country: United States
facility: Albert Einstein College of Medicine
state: New York
city: Lake Success
country: United States
facility: North Shore - LIJ Health System
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: New York
country: United States
facility: Mount Sinai Medical Center
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Science Center
state: Oklahoma
city: Philadelphia
country: United States
facility: University of Pennsylvania Health System
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Greenville
country: United States
facility: Bon Secours St. Francois Health System
state: South Carolina
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center at Dallas
state: Texas
city: Houston
country: United States
facility: University of Texas M. D. Anderson Cancer Center
state: Texas
city: San Antonio
country: United States
facility: Cancer Care Centers of South Texas
state: Texas
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Roeselare
country: Belgium
facility: H. Hartziekenhuis Roeselare-Menen vzw
state: West-vlaanderen
city: Antwerp
country: Belgium
facility: Ziekenhuis Netwerk Antwerpen
city: Gent
country: Belgium
facility: Universitair Ziekenhuis Gent
city: Yvoir
country: Belgium
facility: CHU de Mont-Godinne
city: Angers
country: France
facility: CHU Angers Service de Medecine D - Maladies du Sang
city: Avignon
country: France
facility: CHU Avignon Centre Hospitalier Henri Dufaut
city: Bobigny
country: France
facility: Hôpital Avicenne Hématologie Clinique
city: Caen
country: France
facility: CHU Caen Hématologie Clinique
city: Clermont-Ferrand
country: France
facility: CHU Estaing Service d'hématologie
city: Lille
country: France
facility: CHU Lille Hôpital Claude Huriez
city: Limoges
country: France
facility: CHU Limoges Hopital Dupuytren
city: Marseille
country: France
facility: Institute Paoli Calmettes
city: Nice
country: France
facility: Hôpital de L'archet I
city: Paris
country: France
facility: Hôtel Dieu Sce Hématologie Clinique
city: Paris
country: France
facility: Hôpital Saint-Antoine
city: Perpignan
country: France
facility: CHU Perpignan Centre Hospitalier Hôpital Saint-Jean
city: Rouen
country: France
facility: CRLCC Henri Becquerel
city: Strasbourg
country: France
facility: Chu-Strasbourg-Hopital Civil
city: Toulouse
country: France
facility: Hôpital Purpan
city: Bonn
country: Germany
facility: Universitätsklinikum Bonn
state: Nordrhein-westfalen
city: Dresden
country: Germany
facility: Universitätsklinikum Dresden
city: Düsseldorf
country: Germany
facility: Heinrich-Heine-Universität Düsseldorf
city: Frankfurt am Main
country: Germany
facility: Klinikum der Johann Wolfgang-Goethe-Universität
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf
city: Köln
country: Germany
facility: Universitätsklinikum zu Köln
city: Mannheim
country: Germany
facility: Universitätsmedizin Mannheim
city: Minden
country: Germany
facility: Johannes-Wesling-Klinikum Minden
city: München
country: Germany
facility: Klinikum Rechts der Isar der Technischen Universität München
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
city: Siena
country: Italy
facility: Azienda Ospedaliera Universitaria Senese Policlinico Santa Maria alle Scotte
state: SI
city: Alessandria
country: Italy
facility: Azienda Ospedaliera Santi Antonio e Biagio e Cesare Arrigo
city: Bologna
country: Italy
facility: Azienda Ospedaliero-Universitaria di Bologa Policlinico S. Orsola-Malpighi
city: Catania
country: Italy
facility: Azienda Ospedaliera-Universitairia Vittorio Emanuele-Ferrarotto-Santo Bambino
city: Firenze
country: Italy
facility: Azienda Ospedaliera Universitaria Careggi di Firenze
city: Genova
country: Italy
facility: Azienda Ospedaliera Universitaria San Martino
city: Novara
country: Italy
facility: Azienda Osperdaliera Universitaria Maggiore della Carità
city: Roma
country: Italy
facility: Università degli Studi La Sapienza
city: Torino
country: Italy
facility: Azienda Ospedaliero Universitaria San Giovanni Battista di Torino
city: Oviedo
country: Spain
facility: Hospital Universitario Central de Asturias
state: Asturias
city: Madrid
country: Spain
facility: Hospital Universitario La Princesa
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Málaga
country: Spain
facility: Hospital Clínico Universitario Virgen de la Victoria
city: Palma de Mallorca
country: Spain
facility: Hospital Universitario Son Espases
city: Salamanca
country: Spain
facility: Hospital Clínico Universitario de Salamanca
city: Valencia
country: Spain
facility: Hospital Universitari i Politècnic La Fe
city: Valencia
country: Spain
facility: Hospital Clínico Universitario de Valencia
Study officials:
affiliation: Traws Pharma, Inc.
name: Steven M. Fruchtman, MD
role: STUDY_CHAIR
References:
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.
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: 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: 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: 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
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.