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
arm.
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).
A Randomized Phase II/III 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)
PRIMARY OBJECTIVES:
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)
SECONDARY OBJECTIVES:
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
patient population.
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
population.
IV. To collect specimens for banking for use in future research studies.
TERTIARY OBJECTIVES:
I. To evaluate the prevalence of a pre-specified list of molecular lesions (48 total
lesions).
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
in MDS.
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
3-9.
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
years.
A Phase I/II Multicenter Study Combining Guadecitabine, a DNA Methyltransferase Inhibitor, With Atezolizumab, an Immune Checkpoint Inhibitor, in Patients With Intermediate or High-Risk Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia
PRIMARY OBJECTIVES:
I. To identify a safe dose of guadecitabine in combination with atezolizumab and to assess
the safety and tolerability of the combination in patients with myelodysplastic syndrome
(MDS) who are refractory to or have lost their confirmed response to one or more
hypomethylating agents (HMAs) and in patients with newly diagnosed MDS.
II. To evaluate the efficacy of guadecitabine in combination with atezolizumab for the
treatment of patients with MDS who are refractory to or have lost their confirmed response to
one or more HMAs.
III. To evaluate the efficacy of guadecitabine in combination with atezolizumab for the
treatment of patients with newly diagnosis MDS.
SECONDARY OBJECTIVES:
I. To measure the impact of the combination of guadecitabine and atezolizumab on overall
survival among patients with relapsed/refractory MDS.
II. To measure the impact of the combination of guadecitabine and atezolizumab on overall
survival among patients with treatment-naive MDS.
III. To evaluate the impact of the combination of guadecitabine and atezolizumab on the
duration of response in patients with relapsed/refractory MDS and treatment-naive MDS.
IV. To evaluate the impact of the combination of guadecitabine and atezolizumab on
transfusion-dependence among patients with relapsed/refractory and treatment-naive MDS.
TERTIARY OBJECTIVES:
I. To determine the baseline expression/methylation of programmed cell death protein 1 (PD-1)
in T cells among patients with relapsed, refractory and treatment-naive MDS.
II. To quantify the impact of combination therapy with guadecitabine and atezolizumab on PD-1
expression/methylation in T cells.
III. To correlate response with expression/methylation of PD-1 by T cells and with expression
of programmed cell death-ligand 1 (PD-L1) in the bone marrow of patients with MDS treated
with guadecitabine and atezolizumab.
IV. To investigate the expression of tumor antigens on MDS blasts during combination therapy
with guadecitabine and atezolizumab V. To investigate the specific T-cell subsets in MDS
blood and bone marrow during combination therapy with guadecitabine and atezolizumab.
VI. To investigate the specific antigens (epitopes) which are recognized by T-cells in MDS
blood and bone marrow during combination therapy with guadecitabine and atezolizumab.
OUTLINE: This is a phase I, dose-escalation study of guadecitabine followed by a phase II
study.
Patients receive guadecitabine subcutaneously (SC) on days 1-5 and atezolizumab intravenously
(IV) over 30-60 minutes on days 8 and 22. Courses repeat every 28 days for up to 24 months in
the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 30 or 90 days and every 6
months thereafter.
A Pilot/Safety Study of sEphB4-HSA in Combination With a Hypomethylating Agent (HMA) for Patients With Relapsed or Refractory Myelodysplastic Syndrome (MDS) and AML Previously Treated With a Hypomethylating Agent
PRIMARY OBJECTIVES:
I. To describe the toxicities and assess the tolerability of recombinant EphB4-HSA fusion
protein (sEphB4-HSA) in combination with an approved hypomethylating agent (HMA) among
patients with myelodysplastic syndrome (MDS) who are refractory to or have lost their
response to one or more HMAs and among patients with relapsed/refractory acute myeloid
leukemia (AML) previously treated with a HMA.
SECONDARY OBJECTIVES:
I. To measure the expression of EphB4 among marrow and peripheral blood blasts in patients
with MDS & AML at baseline and over the course of treatment.
II. To measure the expression of immune check-point activating ligands (such as PD-L1, PD-L2)
on marrow and peripheral blood blasts in patients treated with HMA and sEphB4-HSA in
combination.
III. To profile immune subsets (activated and exhausted T cells, natural killer [NK] cells, T
regulatory cells, and myeloid derived suppressor cells) in the peripheral blood and marrow in
patients treated with HMA and sEphB4-HSA in combination.
IV. To assess efficacy of sEphB4-HSA in combination with an HMA as manifest by International
Working Group (IWG) response criteria, as well as time to development of acute myeloid
leukemia (AML) in patients with MDS and time to progression.
OUTLINE:
Patients receive recombinant EphB4-HSA fusion protein intravenously (IV) over 60 minutes on
days 1 and 15. Patients also receive azacitidine IV or subcutaneously (SC) on days 1-7 or
days 1-5 and 8-9, or decitabine IV on days 1-5. Administration of recombinant EphB4-HSA
fusion protein occurs before or after the HMA (not concurrently). Treatment repeats every 28
days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 6 months.
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