A Phase III, International, Randomized, Controlled Study of Rigosertib Versus Physician's Choice of Treatment in Patients With Myelodysplastic Syndrome After Failure of a Hypomethylating Agent
This is a Phase III, open-label, randomized, controlled, international study (approximately
100 sites). Approximately 225 patients < 80 years of age with MDS classified as RAEB-1,
RAEB-2, or RAEB-t who received AZA or DEC for ≤ 9 months and had their last dose of AZA or
DEC within 6 months prior to screening will be stratified by:
- Very high risk (VHR) vs non-VHR per IPSS-R, and
- Geographic region (North America vs Europe vs Asia; because approved products and
standard of care may vary by region), and randomly assigned in a 2:1 ratio to one of
the following 2 treatment groups:
- Rigosertib 1800 mg/24 hr administered as a 72 hr CIV infusion on Days 1, 2, and 3 of a
2 week cycle for the first 8 cycles, and on Days 1, 2, and 3 of a 4-week cycle
thereafter (N = approximately 150 patients);
- Physician's Choice of alternative treatment, which may include any approved or
standard-of-care therapy, based on frequently used treatment for MDS after receipt of
HMAs (N = approximately 75 patients). Experimental therapies are not allowed on the PC
Patients will be treated until 2006 IWG progression criteria are met (ie, 50% increase of BM
blasts or worsening of cytopenias) or until an unacceptable toxicity or intolerance.
For all randomized patients who discontinue study treatment, subsequent therapies with their
start and end dates, as well as survival time after treatment discontinuation, will be
documented at least monthly until death.
Patients in the PC group who progress will not be allowed to cross over to rigosertib.
All patients in both treatment groups will be allowed, as medically justified, access to RBC
and platelet transfusions and to growth factors (granulocyte colony-stimulating factor
(G-CSF), erythropoietin, and thrombopoietin).
SWOG-S1117: A Randomized Phase II Study of Azacitidine in Combination with Lenalidomide (NSC-703813) vs. Azacitidine Alone vs. Azacitidine in Combination with Vorinostat (NSC-701852) for Higher-Risk Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML)
I. To select based on response rate (complete remission, partial remission, or hematologic
improvement) either the combination of lenalidomide and azacitidine or the combination of
vorinostat and azacitidine for further testing against single-agent azacitidine among
patients with higher-risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia
(CMML). (Phase II) II. To compare overall survival between the combination arm selected in
the Phase II portion of the trial to single-agent azacitidine among patients with higher-risk
myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML). (Phase III)
I. To estimate relapse-free survival, overall survival and cytogenetic response rate of
patients treated on each regimen.
II. To estimate the frequency and severity of toxicities of the three regimens in this
III. To investigate in a preliminary manner the frequency of subgroups from prestudy
cytogenetic studies and correlate these subgroups with clinical outcomes in this patient
IV. To collect specimens for banking for use in future research studies.
I. To evaluate the prevalence of a pre-specified list of molecular lesions (48 total
II. To assess associations of these lesions with outcomes (response, event-free survival,
relapse-free survival, and overall survival).
III. To develop a deoxyribonucleic acid (DNA) methylation biomarker predictive of response to
DMTi treatment in MDS.
IV. To harness gene expression profiles as clinical biomarkers of primary resistance to DMTi
OUTLINE: Patients are randomized to 1 of 3 treatment arms. In Phase III, patients are
randomized to 1 of 2 treatment arms (the combination arm selected in Phase II or the
single-agent azacitidine arm).
ARM I: Patients receive azacitidine subcutaneously (SC) or intravenously (IV) on days 1-7 or
days 1-5 and 8-9, and lenalidomide orally (PO) once daily (QD) on days 1-21.
ARM II: Patients receive azacitidine as in Arm I.
ARM III: Patients receive azacitidine as in Arm I and vorinostat PO twice daily (BID) on days
In all arms, treatment repeats every 28 days for up to 5 years in the absence of disease
progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for up to 5