Clinical trial NCT01928537: Efficacy and Safety of IV Rigosertib in MDS Patients With Excess Blasts Progressing After Azacitidine or Decitabine
Official title: Phase IIIB, Open-label, Multi-Center Study of the Efficacy and Safety of Rigosertib Administered as 72-hour Continuous Intravenous Infusions in Patients With Myelodysplastic Syndrome With Excess Blasts Progressing On or After Azacitidine or Decitabine
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Myelodysplastic Syndromes
Refractory Anemia With Excess Blasts
Chronic Myelomonocytic Leukemia
Cytopenia
Keywords: International Working Group
azacitidine
decitabine
Lead sponsor: Traws Pharma, Inc.
Sponsor class: INDUSTRY
First posted: 2013-08-26
Enrollment: 67
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

* 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.
* No medical need for induction chemotherapy.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
* Willing to adhere to the prohibitions and restrictions specified in this protocol.
* Patient must signed an informed consent form.

Exclusion Criteria:

* 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.
* Any other concurrent investigational agent or chemotherapy, radiotherapy, or immunotherapy.
* Prior treatment with low-dose cytarabine during the past 2 years.
* Investigational therapy within 4 weeks of Baseline/Day 1 visit.
* Psychiatric illness or social situation that would limit the patient's ability to tolerate and/or comply with study requirements.

Primary outcomes:
measure: Relationship of bone marrow blast response and overall survival.
timeFrame: Up to 2 years.
Secondary outcomes:
measure: Number of patients with overall hematologic response.
timeFrame: Up to 2 years after study enrollment.
measure: Number of patients with hematological improvement.
timeFrame: Up to 2 years after study enrollment.
measure: Number of patients with cytogenetic response.
timeFrame: Up to 2 years after study enrollment.
measure: Progression-free survival.
timeFrame: Up to 2 years after study enrollment.
measure: Number of patients who transition to Acute Myeloid Leukemia (AML)
timeFrame: Up to 2 years after study enrollment.
measure: Quality of Life Questionnaire
timeFrame: Up to 2 years after study enrollment.
measure: Infections.
timeFrame: Up to 2 years after study enrollment.
measure: Concentration of rigosertib in plasma.
timeFrame: Week 1 and week 3.
measure: Safety.
timeFrame: Study enrollment until 30 days after patient's last dose of rigosertib up to 2 years.
Other outcomes:
Locations:
city: Stanford
country: United States
facility: Stanford University Cancer Center
state: California
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Chicago
country: United States
facility: University of Chicago Medicine
state: Illinois
city: Westwood
country: United States
facility: University of Kansas Cancer Center and Medical Pavilion
state: Kansas
city: Baltimore
country: United States
facility: Greenbaum Cancer Center University of Maryland
state: Maryland
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: New York
country: United States
facility: Mount Sinai Medical Center
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: New York
country: United States
facility: New York Presbyterian Hospital-Weill Cornell Medical College
state: New York
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center-Parkland Hospital
state: Texas
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Clayton
country: Australia
facility: Monash Health, Monash Medical Centre
state: Victoria
city: East Melbourne
country: Australia
facility: Peter MacCallum Cancer Center
state: Victoria
city: Parkville
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Copenhagen
country: Denmark
facility: Rigshospitalet, Department of Hematology
state: Hovedstaden
city: Aarhus
country: Denmark
facility: Aarhus University Hospital
state: Jylland
city: Paris
country: France
facility: Hôpital Saint-Louis, Service d'Hématologie
state: IDF
city: Marseille
country: France
facility: Institute Paoli Calmettes
city: Frankfurt
country: Germany
facility: Universitätsklinikum Frankfurt, Goethe Universität
state: Hessen
city: Dresden
country: Germany
facility: University Hospital Carl Guslav Carus
city: Düsseldorf
country: Germany
facility: Marien Hospital, Onkologie
city: Göttingen
country: Germany
facility: Universitätsmedizin Göttingen
city: Köln
country: Germany
facility: Universitätsklinikum Köln Klinik I für Innere Medizin
city: München
country: Germany
facility: Technische Universität München, III. Medizinische Klinik
city: Firenze
country: Italy
facility: Azienda Ospedaliero-Universitaria Careggi
city: Novara
country: Italy
facility: AOU Maggiore della Carità, SCUD Ematologia
city: Rome
country: Italy
facility: Policlinico Umberto 1, Universita "Sapienza"
city: Salamanca
country: Spain
facility: Hospital Universitário de Salamanca
city: Lund
country: Sweden
facility: Skåne University Hospital,
state: Skåne
city: Gothenberg
country: Sweden
facility: Sahlgrenska University Hospital
state: Västra Götalandsregionen
city: Stockholm
country: Sweden
facility: Karolinska University Hospital, Huddinge
Study officials:
affiliation: Traws Pharma, Inc.
name: Steven M. Fruchtman, MD
role: STUDY_CHAIR
References:
citation: 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.
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: 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.
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.