Oral Rigosertib in Low Risk MDS Patients Refractory to ESAs

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: Oral rigosertib


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oral rigosertib<br>Patients will take 560 mg oral rigosertib (two 280 mg capsules) in the morning and 280 mg (one 280 mg capsule) in the afternoon, in fasting conditions, for 21 consecutive days of 21-day cycle (continuous regimen). | Drug: Oral rigosertib<br>* Dose of 560 mg consists of two (2) 280 mg soft gel capsules of rigosertib.<br>* Other names: rigosertib sodium;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hematologic Improvement | The number of patients who achieve hematologic improvement will be documented. Hematologic improvement is defined by the 2006 International Working Group (IWG) response criteria for the erythroid, platelet and neutrophil lineages. | 24 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response | The number of patients with a complete remission or a partial remission will be documented. Complete remission and partial remission are defined according to 2006 IWG response criteria for MDS. Overall response = complete remission + partial remission. | Up to 2 years | 
| Duration of Response | The number of weeks a complete remission or a partial remission is observed in a patient will be documented. | Up to 2 years | 
| Number of Adverse Events | Specific safety parameters and procedures will include recording of medical history, medication history, physical examination, measurement of vital signs (blood pressure, temperature, respiration rate, and pulse), weight, laboratory evaluations, and toxicity and AE assessments. | Up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Erythrocyte transfusion, Erythropoiesis-stimulating agent, International Prognostic Scoring System