Clinical trial NCT01904682: Oral Rigosertib in Low Risk MDS Patients Refractory to ESAs
Official title: A Single-arm Study to Assess the Efficacy and Safety of Oral Rigosertib in Transfusion-dependent, Low or Intermediate-1, Myelodysplastic Syndrome Patients Based on the International Prognostic Scoring System
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Myelodysplastic Syndromes
Keywords: Erythrocyte transfusion
Erythropoiesis-stimulating agent
International Prognostic Scoring System
Lead sponsor: Traws Pharma, Inc.
Sponsor class: INDUSTRY
First posted: 2013-07-22
Enrollment: 45
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: The study will enroll low risk MDS patients who need red blood cell transfusions and who are refractory to or are not using erythropoiesis-stimulating agents. The purpose of the study is to determine whether oral rigosertib treatment results in hematological improvements according to the 2006 International Working Group criteria in these patients. The study will also record any side effects that may occur during the study.

Detailed description: This will be a Phase II, single-arm, multicenter study (approximately 15 centers). Approximately 40 transfusion-dependent patients with Low- or Int-1 risk Myelodysplastic Syndrome (MDS) by International Prognostic Scoring System (IPSS) will be enrolled and treated with oral rigosertib administered twice daily for 21 consecutive days of a 21-day cycle (continuous regimen) in order to obtain at least 35 evaluable patients treated for at least 8 weeks. Patients will take 560 mg rigosertib (two 280 mg capsules) in the morning and 280 mg (one 280 mg capsule) in the afternoon, in fasting conditions. All patients on intermittent regimen at the time of Amendment 2 of the Protocol will be switched to the continuous regimen, including patients on reduced doses.

Eligibility criteria: Inclusion Criteria:

* Diagnosis of MDS according to World Health Organization (WHO) criteria (Appendix 2) or French-American-British (FAB) classification that must be confirmed by bone marrow (BM) aspirate and/or biopsy within 6 weeks prior to Screening.
* Myelodysplastic syndrome (MDS) classified as Low risk or Int-1 risk, according to International Prognostic Scoring System (IPSS) classification; in addition, patients should never have been classified as Int-2 or High-risk since their MDS was diagnosed;
* Transfusion dependency defined by transfusion of at least 4 units of Red blood cells (RBC) within 56 days before Screening (pre-transfusion Hgb values values must be ≤ 9 g/dL to be taken into account).
* Refractory to 8- to 12-week course of Erythropoiesis-stimulating agent (ESA) administered within the past 2 years before enrollment, or erythropoietin (EPO) level ˃ 500 mU/mL and off ESA for at least 8 weeks before Screening.
* Off all other treatments for MDS (azacitidine, decitabine, lenalidomide, chemotherapy, immunotherapy) for at least 2 weeks prior to Screening.
* Eastern Cooperative Oncology Group(ECOG) performance status of 0, 1 or 2.
* Willing to adhere to the prohibitions and restrictions specified in this protocol.
* The patient must signed an informed consent form (ICF) indicating that s/he understands the purpose of, and procedures required for, the study and is willing to participate.

Exclusion Criteria:

* Ongoing clinically significant anemia due to factors such as iron, vitamin B12, or folate deficiencies, auto-immune or hereditary hemolysis, or gastrointestinal (GI) bleeding.
* Serum ferritin \< 50 ng/mL.
* Hypoplastic MDS (cellularity \<10%)
* 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 ≥ 2.0 mg/dL not related to hemolysis or Gilbert's disease.
* Alanine transaminase (ALT) or aspartate transaminase (AST) ≥ 2.5 x the upper limit of normal (ULN).
* Serum creatinine ≥ 2.0 mg/dL.
* Ascites requiring active medical management including paracentesis.
* Hyponatremia (defined as serum sodium value of \< 130 mEq/L).
* Female patients who are pregnant or lactating.
* Patients of childbearing potential who are unwilling to follow strict contraception requirements.
* Female patients with reproductive potential who do not have a negative blood or urine pregnancy test at Screening.
* Major surgery without full recovery or major surgery within 3 weeks of Screening.
* Uncontrolled hypertension (defined as a systolic pressure ≥ 160 mmHg and/or a diastolic pressure ≥ 110 mmHg).
* New onset seizures (within 3 months prior to the first dose of rigosertib) or poorly controlled seizures.
* Any other concurrent investigational agent or chemotherapy, radiotherapy, or immunotherapy.
* Chronic use (˃ 2 weeks) of corticosteroids (˃ 10 mg/24 hr equivalent prednisone) within 4 weeks of Screening.
* Investigational therapy within 4 weeks of Screening.
* Allergy to a local anaesthetic.
* Psychiatric illness or social situation that would limit the patient's ability to tolerate and/or comply with study requirements.

Primary outcomes:
measure: Hematologic Improvement
timeFrame: 24 Weeks
Secondary outcomes:
measure: Overall Response
timeFrame: Up to 2 years
measure: Duration of Response
timeFrame: Up to 2 years
measure: Number of Adverse Events
timeFrame: Up to 2 years
Other outcomes:
Locations:
city: Stanford
country: United States
facility: Stanford University School of Medicine
state: California
city: Aurora
country: United States
facility: Anschutz Cancer Pavilion University of Colorado
state: Colorado
city: Washington
country: United States
facility: Washington Cancer Institute at Medstar Washington Hospital Center
state: District of Columbia
city: Chicago
country: United States
facility: The University of Chicago
state: Illinois
city: Baltimore
country: United States
facility: Greenbaum Cancer Center University of Maryland
state: Maryland
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: New Brunswick
country: United States
facility: Rutgers Cancer Institute of New Jersey
state: New Jersey
city: New York
country: United States
facility: Mount Sinai Medical Center
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Paris
country: France
facility: Hôpital Saint-Louis, Service d'Hématologie
state: IDF
city: Düsseldorf
country: Germany
facility: Heinrich Heine Universität
state: NRW
city: Köln
country: Germany
facility: Universitätsklinikum Köln
state: NRW
city: Dresden
country: Germany
facility: Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden
state: Saxony
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: 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: 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.