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
Trial status: Open for Enrollment
Why is this study being done?
This will be a Phase II, single-arm, multicenter study (approximately 15 centers). Up to 40 transfusion-dependent patients with Low- or Int-1 risk MDS by IPSS will be enrolled and treated with 560 mg oral rigosertib BID taken intermittently (2 weeks on/1 week off regimen). Cycles will be 3 weeks in length.
Enrollment will proceed as follows:
In the first cohort, 6 patients will be enrolled initially. If no more than 1 drug-related Grade 3 toxicity (based on NCI CTCAE) is observed during the first 21-day cycle in the first 6 enrolled patients, 4 additional patients will be enrolled to complete the first cohort. Up to 3 more successive cohorts of 10 patients each will be enrolled, provided there are at least 1 response in the first cohort (10 patients), 4 responses total in the first and second cohorts (20 patients), and 6 responses total in the first, second and third cohorts (30 patients).
The study will be stopped if any one of these responses is not met.
Who is eligible to participate?
- 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, ESA, 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.
- 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 who are unwilling to follow strict contraception requirements.
- Female patients with reproductive potential who do not have a negative 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.
- Psychiatric illness or social situation that would limit the patient's ability to tolerate and/or comply with study requirements.