Efficacy and Safety of IV Rigosertib in MDS Patients With Excess Blasts Progressing After Azacitidine or Decitabine

NCT01928537 | Completed Phase 3 DMC

• 2 other identifiers: Onconova 04-242013-001124-19
• Study Type: interventional
• Target: 67
• Locations: 8 countries
• Sites: 35

Brief Summary

This study will examine the effect intravenously administered rigosertib has on the relationship between bone marrow blasts response and overall survival in myelodysplastic syndromes (MDS) patients who have 5-30% bone marrow blasts and who progressed on or after treatment with azacitidine or decitabine.

Conditions

Myelodysplastic Syndromes; Refractory Anemia With Excess Blasts; Chronic Myelomonocytic Leukemia; Cytopenia

Keywords

International Working Group; azacitidine; decitabine

Outcome Measures

Primary Outcomes (1)

• Relationship of bone marrow blast response and overall survival.

  Bone marrow blast response is defined as bone marrow (BM) complete response, ≥ 50% BM blast decrease from pretreatment value, or stable BM response (no progression) according to the International Working Group (IWG) 2006 criteria and overall survival. Overall survival is defined as the time from first study treatment to death from any cause. All patients will be followed until death and/or progression, even if they have discontinued treatment for whatever cause. Survival time of patients lost to follow-up will be censored at the time they were last known to be alive.

  Up to 2 years.

Secondary Outcomes (9)

• Number of patients with overall hematologic response.

  Up to 2 years after study enrollment.

• Number of patients with hematological improvement.

  Up to 2 years after study enrollment.

• Number of patients with cytogenetic response.

  Up to 2 years after study enrollment.

• Progression-free survival.

  Up to 2 years after study enrollment.

• Number of patients who transition to Acute Myeloid Leukemia (AML)

  Up to 2 years after study enrollment.

Study Arms (1)

rigosertib sodium

EXPERIMENTAL

Rigosertib sodium will be administered as a 72-hr continuous intravenous infusion consisting of 3 consecutive doses of 1800 mg over 24 hours on Days 1, 2, and 3 of a 14-day cycle for the first 8 cycles and then on Days 1, 2, and 3 of a 28-day cycle for the following cycles.

Drug: rigosertib sodium

Interventions

rigosertib sodium DRUG

Also known as: ON 01910.Na, SyB L-1101

rigosertib sodium

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosis of MDS confirmed within 6 weeks prior to Screening according to WHO criteria or French-American-British (FAB) classification.
• MDS classified as follows, according to WHO criteria and FAB classification:
• RAEB-1 (5% to 9% BM blasts)
• RAEB-2 (10% to 19% BM blasts)
• CMML (10% to 20% BM blasts) and white blood cells (WBC) \< 13,000/μL
• RAEB-t (20% to 30% BM blasts), meeting the following criteria: WBC \< 25,000/μL at study entry; or, Stable White Blood Cell (WBC) at least 4 weeks prior to Screening and not requiring intervention for WBC control with hydroxyurea, chemotherapy, or leukopheresis.
• At least one cytopenia (Absolute Neutrophil Count (ANC) \< 1800/μL or Platelet (PLT) count \< 100,000/μL or hemoglobin (Hgb) \< 10 g/dL).
• Progression (according to 2006 IWG criteria) at any time after initiation of subcutaneous or intravenous azacitidine or decitabine treatment per labeling during the past 2 years, defined as follows:
• For patients with ˂ 5% BMBL, ≥ 50% increase in BMBL to ˃ 5% BMBL
• For patients with 5-10% BMBL, ≥ 50% increase in BMBL to ˃ 10% BMBL
• For patients with 10-20% BMBL, ≥ 50% increase in BMBL to ˃ 20% BMBL
• For patients with 20-30% BMBL, ≥ 50% increase in BMBL to ˃ 30% BMBL
• Any of the following: ≥ 50% decrease from maximum remission/response levels in granulocytes or PLT; Decrease in Hgb concentration by ≥ 2 g/dL; or, Transfusion dependence, defined as administration of at least 4 RBC units in the past 8 weeks before Screening (patients must have Hgb values ˂ 9 g/dL prior to transfusion to be considered), in the absence of another explanation.
• Has failed to respond to, relapsed following, not eligible, or opted not to participate in bone marrow transplantation.
• Off all other treatments for MDS for at least 4 weeks, except for azacitidine or decitabine. Filgrastim (G-CSF) and erythropoietin are allowed before and during the study as clinically indicated.

You may not qualify if:

• Previous participation in a clinical study of IV or oral rigosertib.
• Anemia due to factors other than MDS (including hemolysis or gastrointestinal \[GI\] 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.
• Active infection not adequately responding to appropriate therapy.
• Total bilirubin ≥ 1.5 mg/dL not related to hemolysis or Gilbert's disease.
• ALT/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).
• Female patients who are pregnant or lactating.
• Patients who are unwilling to follow strict contraception requirements.
• Female patients with reproductive potential who do not have a negative urine beta-human chorionic gonadotropin (βHCG) pregnancy test at Screening.
• Major surgery without full recovery or major surgery within 3 weeks of Baseline/Cycle 1 Day 1 visit.
• Uncontrolled hypertension (defined as a systolic pressure ≥160 mmHg and/or a diastolic pressure ≥ 110 mmHg).
• New onset seizures (within 3 months prior to Baseline) or poorly controlled seizures.

Sponsors & Collaborators

• Traws Pharma, Inc.: lead

Study Sites (35)

Stanford University Cancer Center

Stanford, California, 94305, United States

Location

Rush University Medical Center

Chicago, Illinois, 60612, United States

Location

University of Chicago Medicine

Chicago, Illinois, 60637, United States

Location

University of Kansas Cancer Center and Medical Pavilion

Westwood, Kansas, 66205, United States

Location

Greenbaum Cancer Center University of Maryland

Baltimore, Maryland, 21201, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Mount Sinai Medical Center

New York, New York, 10029, United States

Location

Columbia University Medical Center

New York, New York, 10032, United States

Location

New York Presbyterian Hospital-Weill Cornell Medical College

New York, New York, 10065, United States

Location

Montefiore Medical Center

The Bronx, New York, 10461, United States

Location

University of Texas Southwestern Medical Center-Parkland Hospital

Dallas, Texas, 75235, United States

Location

University of Texas Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Royal Adelaide Hospital

Adelaide, South Australia, 5000, Australia

Location

Monash Health, Monash Medical Centre

Clayton, Victoria, 3168, Australia

Location

Peter MacCallum Cancer Center

East Melbourne, Victoria, 3002, Australia

Location

Royal Melbourne Hospital

Parkville, Victoria, 3050, Australia

Location

Rigshospitalet, Department of Hematology

Copenhagen, Capital Region, DK-2100, Denmark

Location

Aarhus University Hospital

Aarhus, Jylland, DK-8000, Denmark

Location

Hôpital Saint-Louis, Service d'Hématologie

Paris, IDF, 75475, France

Location

Institute Paoli Calmettes

Marseille, 13009, France

Location

Universitätsklinikum Frankfurt, Goethe Universität

Frankfurt am Main, Hesse, 60590, Germany

Location

Universitätsklinikum Köln Klinik I für Innere Medizin

Cologne, 50973, Germany

Location

University Hospital Carl Guslav Carus

Dresden, 01062, Germany

Location

Marien Hospital, Onkologie

Düsseldorf, 40479, Germany

Location

Universitätsmedizin Göttingen

Göttingen, 37075, Germany

Location

Technische Universität München, III. Medizinische Klinik

München, 81675, Germany

Location

Azienda Ospedaliero-Universitaria Careggi

Florence, 50134, Italy

Location

AOU Maggiore della Carità, SCUD Ematologia

Novara, 28100, Italy

Location

Policlinico Umberto 1, Universita "Sapienza"

Rome, 00161, Italy

Location

Hospital Universitário de Salamanca

Salamanca, 37007, Spain

Location

Skåne University Hospital,

Lund, Skåne County, SE-221 85, Sweden

Location

Sahlgrenska University Hospital

Gothenberg, Västra Götalandsregionen, 41345, Sweden

Location

Karolinska University Hospital, Huddinge

Stockholm, SE-141 86, Sweden

Location

Related Publications (5)

• Olnes MJ, Shenoy A, Weinstein B, Pfannes L, Loeliger K, Tucker Z, Tian X, Kwak M, Wilhelm F, Yong AS, Maric I, Maniar M, Scheinberg P, Groopman J, Young NS, Sloand EM. Directed therapy for patients with myelodysplastic syndromes (MDS) by suppression of cyclin D1 with ON 01910.Na. Leuk Res. 2012 Aug;36(8):982-9. doi: 10.1016/j.leukres.2012.04.002. Epub 2012 Apr 21.

  PMID: 22524974 BACKGROUND

• 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.

  PMID: 21924492 BACKGROUND

• Silverman LR, Greenberg P, Raza A, Olnes MJ, Holland JF, Reddy P, Maniar M, Wilhelm F. Clinical activity and safety of the dual pathway inhibitor rigosertib for higher risk myelodysplastic syndromes following DNA methyltransferase inhibitor therapy. Hematol Oncol. 2015 Jun;33(2):57-66. doi: 10.1002/hon.2137. Epub 2014 Apr 29.

  PMID: 24777753 BACKGROUND

• 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

  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.

  RESULT

MeSH Terms

Conditions

Myelodysplastic Syndromes; Anemia, Refractory, with Excess of Blasts; Leukemia, Myelomonocytic, Chronic; Cytopenia

Interventions

ON 01910

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Anemia, Refractory; Anemia; Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Myelodysplastic-Myeloproliferative Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Steven M. Fruchtman, MD

  Traws Pharma, Inc.

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 21, 2013
• First Posted: August 26, 2013
• Study Start: August 1, 2013
• Primary Completion: June 29, 2017
• Study Completion: June 29, 2017
• Last Updated: June 30, 2020

Record last verified: 2018-07

Locations

ES (1); DK (2); AU (4); IT (3); DE (6); SE (3); US (14); FR (2)