A Phase 3, Randomized, Open-Label, Crossover Study of ASTX727 (Cedazuridine and Decitabine Fixed-Dose Combination) Versus IV Decitabine in Subjects With Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML) [ASTX727-02]
This Phase 3 study will establish PK equivalence of ASTX727 to IV decitabine in approximately
118 evaluable subjects. Eligible subjects will receive both study treatments: oral
investigational drug ASTX727, and IV decitabine, as follows: subjects will be randomly
assigned 1:1 to receive ASTX727 or IV decitabine in Cycle 1 and then cross over to the other
therapy in Cycle 2.
In the ASTX727 cycle, subjects will receive the ASTX727 tablet Daily×5. Serial PK
measurements (blood draws) will be done on Days 1, 2, and 5, along with pre-dose PK
assessments on Days 1-5 and an assessment at 3 hours post dose on Day 3. Subjects will be
required to fast from food for 4 hours on days when receiving ASTX727: at least 2 hours
before and 2 hours after dosing.
In the IV decitabine cycle, subjects will receive a 1-hour infusion of IV decitabine 20
mg/m^2 Daily×5. Serial PK measurements will be done on Days 1 and 5, along with pre-dose and
1-hour post-infusion assessments on Day 3.
In Cycles ≥3, subjects will receive the ASTX727 tablet Daily×5 in 28-day cycles. (No PK
assessments will be done from Cycle 3 onward.)
A Phase II Randomized Study of Topotecan/Carboplatin With or Without Veliparib or Placebo in Advanced Myeloproliferative Disorders and CMML
PRIMARY OBJECTIVES:
I. To estimate the compare the complete response/complete response with incomplete recovery
(CR/CRi) rate of induction therapy with topotecan hydrochloride (topotecan)/carboplatin (T/C)
with or without veliparib (V) or placebo (P) in myeloproliferative disorder associated
leukemias and chronic myelomonocytic leukemia (CMML).
SECONDARY OBJECTIVES:
I. To evaluate and compare the toxicities of T/C/V versus (vs.) T/C/placebo. II. To compare
the 2-year disease-free survival (DFS) and overall survival (OS) in response to T/C/V vs.
T/C/placebo.
III. To detect and compare the presence of minimal residual disease (MRD) remaining after
T/C/V vs. T/C/placebo.
IV. Evaluate predictive biomarkers of response via assessment of pretreatment impaired
homologous recombination via assessment of: next generation sequencing (NGS) panel for genes
mutated in myeloid malignancies done as standard of care per institution; functional
impairment of deoxyribonucleic acid (DNA) damage response via assessment of pretreatment
samples radiation-induced RAD51 foci; topotecan-induced stabilization of topoisomerase I-DNA
covalent complexes, which has recently been observed to be a critical predictor of response
to combination of a topoisomerase I poison and PARP inhibitor in xenografts.
V. To evaluate veliparib exposure and contribution to response (efficacy and toxicity).
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM A: Patients receive veliparib orally (PO) twice daily (BID) on days 1-21 and topotecan
hydrochloride intravenously (IV) continuously over 24 hours and carboplatin IV continuously
over 24 hours on days 3-7. Treatment repeats every 28-63 days for up to 3 courses in the
absence of disease progression or unacceptable toxicity.
ARM B: Patients receive topotecan hydrochloride and carboplatin as in Arm A. Patients also
receive placebo PO BID on days 1-21. Treatment repeats every 28-63 days for up to 3 courses
in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 30 days.
A Phase I Dose Escalation Study With Expansion to Evaluate the Safety of SEPHB4-HSA in Combination With Cytarabine or Liposomal Vincristine in Patients With Relapsed or Refractory Acute Leukemia
PRIMARY OBJECTIVES:
I. Characterize the DLTs (dose limiting toxicities) and overall toxicity profile of
recombinant EphB4-HSA fusion protein (sEPHB4-HSA) as a single agent and in combination with
cytarabine or liposomal vincristine in patients with acute leukemia.
SECONDARY OBJECTIVES:
I. Estimate the clinical response (including minimal residual disease [MRD]) in blood and
bone marrow of sEPHB4-HSA in combination with cytarabine in patients with relapsed/refractory
acute myeloid leukemia.
II. Estimate the clinical response (including MRD) in blood and bone marrow of sEPHB4-HSA in
combination with liposomal vincristine in patients with relapsed/refractory acute lymphoid
leukemia.
III. Estimate the single agent clinical response of sEPHB4-HSA in blood and bone marrow of
patients with relapsed/refractory acute myeloid leukemia (AML) or acute lymphoid leukemia
(ALL).
IV. Assess pharmacokinetics of sEPHB4-HSA as a single agent and in combination with
cytarabine or liposomal vincristine in patients with leukemia.
EXPLORATORY OBJECTIVES:
I. Estimate progression-free survival and overall survival in patients treated with
sEPHB4-HSA in combination with cytarabine or liposomal vincristine.
II. Estimate percentage of patients proceeding to allogeneic stem cell transplantation.
III. Correlate expression of EPHB4 leukemic blasts and ephrinB2 in bone marrow
microenvironment with response to sEPHB4-HSA.
IV. Evaluate the effect of sEPHB4-HSA on downstream protein mediators of the EPHB4 pathway
(phosphorylated [p]AKT, pS6) on leukemic blasts and determine if these can be used as
biomarkers of response to treatment.
V. Profile the immuno-modulatory effects of sEPHB4-HSA on peripheral blood leukocytes and in
the tumor microenvironment.
OUTLINE: This is a dose-escalation study of recombinant EphB4-HSA fusion protein.
Participants are randomized to 1 of 2 arms.
ARM A: Participants receive recombinant EphB4-HSA fusion protein intravenously (IV) over 60
minutes on days 1, 8, 15, and 22 and cytarabine IV over 4 hours on days 1-5. Treatment
repeats every 28 days for up to 2 courses in the absence of disease progression or
unacceptable toxicity.
ARM B: Participants receive recombinant EphB4-HSA fusion protein IV over 60 minutes on days
1, 8, 15, and 22 and vincristine liposomal IV over 60 minutes on days 1, 8, 15, and 22.
Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or
unacceptable toxicity.
After completion of study treatment, participants are followed up at 3 months.
Phase 1B/II Study of Escalating Doses of Pevonedistat (TAK-924, Formerly MLN4924) Administered in Combination With Standard Induction Chemotherapy (Cytarabine and Idarubicin) in Newly Diagnosed High Risk Acute Myelogenous Leukemia (AML)
PRIMARY OBJECTIVES:
I. To determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of
pevonedistat in combination with cytarabine and idarubicin in newly diagnosed high-risk acute
myeloid leukemia. (Phase Ib) II. To determine the composite complete response rate (complete
remission [CR] or complete remission with incomplete blood count recovery [CRi]) of
pevonedistat in combination with cytarabine and idarubicin in newly diagnosed high-risk acute
myeloid leukemia. (Phase II)
SECONDARY OBJECTIVES:
I. To evaluate plasma pharmacokinetic (PK) profiles of pevonedistat when used in combination
with cytarabine and idarubicin in the phase Ib part of the study.
II. To evaluate the relapse free (RFS), overall survival (OS), safety and tolerability of
pevonedistat in combination with cytarabine and idarubicin in the phase II part of the study.
TERTIARY OBJECTIVES:
I. To evaluate the pharmacodynamics (PD) effects of pevonedistat in combination with
cytarabine and idarubicin in acute myelogenous leukemia (AML) blasts.
II. To evaluate potential predictive biomarkers of response to pevonedistat in combination
with cytarabine and idarubicin in AML.
III. To determine the CR without minimal residual disease rate (CR MRD-) of pevonedistat in
combination with cytarabine and idarubicin in newly diagnosed acute myeloid leukemia.
OUTLINE: This is a phase Ib, dose escalation study of pevonedistat followed by a phase II
study.
INDUCTION: Patients receive idarubicin intravenously (IV) over 10-15 minutes on days 1-3,
cytarabine IV over 1-3 hours on days 1-7, and pevonedistat IV over 60 minutes on days 1, 3,
and 5. Patients with gross residual disease on day 14 bone marrow may receive a second course
of induction chemotherapy.
CONSOLIDATION: Patients who achieve CR and will not undergo bone marrow transplant receive
cytarabine IV over 3 hours every 12 hours on days 1, 3, and 5. Treatment repeats every 28-35
days for 4 courses in the absence of disease progression or unaccepted toxicity.
After completion of study treatment, patients are followed up for at least 30 days, and then
every 3 months for 2 years.
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
360 patients < 82 years of age with MDS classified as RAEB-1, RAEB-2, or RAEB-t who received
AZA or DAC for ≤ 9 months and/or ≤ 9 cycles over 12 months and had their last dose of AZA or
DAC 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 240 patients);
- Physician's Choice of alternative treatment, which may include any approved or
standard-of-care therapy that the patient has not shown to be hypersensitive to, based
on frequently used treatment for MDS, as per institutional guidelines, after receipt of
HMAs (N = approximately 120 patients). The drugs used in the Physician's Choice arm
should be used according to the recommendations, if clinically appropriate, provided in
the corresponding Summary of Product Characteristics (SmPC) and Prescribing Information
of these drugs. 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).
Open | Myelodysplastic Syndromes (MDS) | Multisite
A Multi-center, Randomized, Double-blind, Placebo-controlled Clinical Trial of Deferasirox in Patients With Myelodysplastic Syndromes (Low/Int-1 Risk) and Transfusional Iron Overload
A screening period lasting up to 35 days with two screening visits (Visit 1 and Visit 2 - at
least 14 days apart) was used to assess patient eligibility. Eligible patients were
randomized in a 2:1 ratio in deferasirox and placebo arms respectively. All patients who were
randomized in this study started study treatment at 10 mg/kg/day and could be titrated up to
40 mg/kg/day based on dose modification guidelines.
Patients who met a non-fatal event, as specified in the protocol, discontinued from the study
treatment and were followed for safety (28 days) and then evaluated with visits every three
months if they agreed to move into the post treatment evaluation phase. Subsequent to the
evaluation period, or at the end of treatment if a patient and treating physician decided
that a patient would not participate in the evaluation period, patients were followed by
phone monitoring every six months for their need for iron chelation therapy (ICT) and
survival follow-up (OS) until study end.
Patients who did not meet a non-fatal event continued study treatment as long as the patient
and the treating physician felt it was in the best interest for the patient or until the
study terminated. After termination of study treatment, all patients continued to be followed
for safety and endpoints during the evaluation period at visits occurring every three months.
Subsequent to the evaluation period, or at the end of treatment if a patient and treating
physician decided that a patient would not participate in the evaluation period, patients
were followed every 6 months for ICTs and OS.
Not recruiting | Myelodysplastic Syndromes (MDS) | Multisite
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 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.
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.
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