A Phase 3, Multicenter, Open-label, Randomized Study Comparing the Efficacy and Safety of AG-221 (CC-90007) Versus Conventional Care Regimens in Older Subjects With Late Stage Acute Myeloid Leukemia Harboring an Isocitrate Dehydrogenase 2 Mutation
Acute myeloid leukaemia (AML) is a form of cancer that is common in older patients. Mutations
in the isocitrate dehydrogenase enzyme 2 (IDH2) have been found in approximately 15% of
patients with AML.
The outcome of first line chemotherapy treatment is poor and many patients fail to attain
complete remission (CR, ie refractory) or will eventually relapse. There is no single
standard of care for relapsed or refractory AML. Since the prognosis is very poor there is a
great need for new therapies.
Inhibition of the mutant IDH2 enzyme may represent a promising targeted therapy for AML.
AG-221 is a small molecule inhibitor of the IDH2 enzyme, designed to preferentially target
the mutant IDH2 variants. Data from the ongoing first-in-human study has shown AG-221 to be
generally well tolerated and demonstrated CR in patients with IDH2 mutation positive relapsed
or refractory AML.
The study purpose is to test the safety and efficacy of AG-221 compared with conventional
care regimens (CCR), which include best supportive care (BSC) only, azacitidine plus BSC,
low-dose cytarabine plus BSC or intermediate-dose cytarabine plus BSC, in patients with late
stage AML refractory to or relapsed after second or third line therapy and positive for the
IDH2 mutation. Patients will be randomly assigned to receive open-label tablets of AG-221 or
one of the CCR on continuous 28-day treatment cycles. The trial duration is expected to be 78
months which includes 42 months enrollment, approximately 7 months treatment and a follow-up
Study procedures include: vital signs, physical exams, ECGs, ECHO, urine/blood samples, bone
marrow aspirates and/or biopsies and peripheral blood to test for IDH2 and assess treatment
response. Bone marrow, blood, cheek swab samples will be used for genetic tests.
This study is being sponsored by Celgene Corporation. Approximately 316 participants will
take part in the study.
Phase II Study of Combined Tretinoin and Arsenic Trioxide for Patients With Newly Diagnosed Acute Promyelocytic Leukemia Followed by Risk-Adapted Postremission Therapy
Induction will consist of tretinoin 45 mg/m2 po daily (rounded up to the nearest 10mg) in two
divided doses (25 mg/m2 in patients <20 years of age) for 35 days and ATO 0.15 mg/kg IV daily
for 35 doses given 5-7 days per week. The drugs will then be discontinued, and the patient
will be followed until a clinical complete remission is achieved. Idarubicin 12 mg/m2 IV for
4 doses will be added during induction on day 2 if the presenting WBC is >10,000/μl, or if
the WBC increases to 5,000/μl on day 5, 10,000/μl on day 10, or 15,000/μl on day 15, because
of the increased risk of the APL differentiation syndrome and relapse in these patients.
Dexamethasone 10 mg twice daily with be given on days 1-14 of induction as prophylaxis for
the APL differentiation syndrome. All patients will then receive four courses of
consolidation with tretinoin 45 mg/m2 po daily (rounded up to the nearest 10mg) (25 mg/m2 in
patients <20 years of age) for 15 days and ATO 0.15 mg/kg IV for 25 doses.
Patients with high-risk disease or who received Idarubicin during Induction may receive
intrathecal cytarabine as CNS prophylaxis given by the treating physician during
consolidation, at the discretion of the site PI. High-risk patients will also receive
maintenance therapy with additional courses of tretinoin and ATO every 3 months for 2 years.
Each maintenance course will consist of tretinoin 45 mg/m2 po daily (25 mg/m2 in patients <20
years of age) for 15 days and ATO 0.15 mg/kg IV for 10 doses. Disease status will be
monitored with serial analyses of peripheral blood samples using RT-PCR for PML-RARα mRNA.
Patients will be followed until relapse, death, loss to follow-up, or removal from study.
Induction therapy can be given as an inpatient or outpatient. Consolidation and maintenance
treatments will be given as an outpatient. Consolidation may also be given at the patient's
local institution. Intrathecal cytarabine treatments will be administered as an outpatient.
HLA-mismatched Allogeneic Cellular Therapy (HMMACT) After Chemotherapy in High Risk Acute Myeloid Leukemia
I. To assess the feasibility of cytarabine based chemotherapy and human leukocyte antigen
(HLA)-mismatched allogeneic cellular therapy (HMMACT) in patients with high risk acute
myeloid leukemia (AML), with feasibility measured by induction mortality (IM) and complete
I. To obtain preliminary estimates of clinical outcome following cytarabine based
chemotherapy and HMMACT in patients with high risk AML, as measured by event free survival
(EFS) and overall survival (OS).
II. To further evaluate the safety outcomes of induction and consolidation of cytarabine and
HMMACT in terms of serious infections (grade 4), time to recovery of absolute neutrophil
counts and platelets and incidence of graft versus host disease (GvHD).
III. To further evaluate the feasibility of this approach in terms of identifying a suitable
donor in this elderly population.
IV. To compare in preliminary manner the clinical outcomes of cytarabine and HMMACT in
patients with high risk AML as measured by complete response rate (CRR), event free survival
(EFS) and overall survival (OS) by donor/recipient HLA-C1 vs C2 pairs.
V. To characterize in a preliminary manner, the numbers of suppressor regulatory T cells
(Tregs), T helper 17 cells (Th17), and cytotoxic T cells during pre and post HMMACT
treatment, and with clinical outcomes in leukemia.
INDUCTION CHEMOTHERAPY: Patients receive mitoxantrone hydrochloride intravenously (IV) on
days 1-3 and cytarabine IV on days 1-7.
HMMACT: Patients receive filgrastim (G-CSF) mobilized peripheral blood stem cells (G-PBSC) on
day 9. After completion of study treatment, patients are followed up monthly for 3 years.
A Phase 3, Multicenter, Randomized, Open-Label Study of Guadecitabine (SGI-110) Versus Treatment Choice in Adults With Previously Treated Acute Myeloid Leukemia
This Phase 3, randomized, open-label, parallel-group multicenter study of the efficacy and
safety of guadecitabine in adults with previously treated AML will be conducted in
approximately 20 countries. There will be a 14-day screening period, a treatment period, a
safety follow-up visit, and a long-term follow-up period. The study is expected to last
approximately 2 years. Duration of individual subject participation will vary, and subjects
may continue to receive treatment for as long as they continue to benefit.
Approximately 404 subjects from approximately 100 study centers will be randomly assigned to
either guadecitabine or treatment choice (TC) in a 1:1 ratio (approximately 202 subjects per
group). TC is as follows:
- High intensity: intermediate or high dose cytarabine (HiDAC); mitoxantrone, etoposide,
and cytarabine (MEC); or fludarabine, cytarabine, G-CSF, +/- idarubicin (FLAG/FLAG-Ida).
- Low intensity: low dose cytarabine (LDAC), decitabine, or azacitidine.
- Best Supportive Care (BSC).
Guadecitabine will be given SC at a dose of 60 mg/m2 in 28-day cycles. In Cycle 1,
guadecitabine will be given for 10 days on Days 1-5 and Days 8-12. Cycle 2 will be either the
5-day regimen (Days 1-5) or 10-day regimen (Days 1-5 and 8-12) based on assessment of disease
response and hematologic recovery at the end of Cycle 1. In subsequent cycles, guadecitabine
treatment will be for 5 days only (Days 1-5).
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
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.
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.
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
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
Phase I Study of the Aurora Kinase a Inhibitor MLN8237 in Combination With the Histone Deacetylase Inhibitor Vorinostat in Lymphoid Malignancies
I. To determine the maximum-tolerated dose (MTD) of MLN8237 (alisertib) when given in
combination with vorinostat and to select a dose and schedule for further testing
(recommended Phase 2 dose: RP2D) in patients with lymphoid malignancies.
II. To describe the toxicities of MLN8237 when given in combination with vorinostat on a
III. To determine any clinical responses with MLN8237 in combination with vorinostat.
IV. To compare the plasma pharmacokinetics of MLN8237 when given alone and in combination
V. To perform immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH)
analysis to determine aurora kinase A (AURKA) expression in archival formalin-fixed
paraffin-embedded sections from the most recent available tumor specimens of patients.
VI. To perform correlative studies for apoptosis and proliferation on bone marrow and lymph
node specimens, where available, obtained from patients in the expanded cohort at RP2D.
OUTLINE: This is a dose-escalation study of alisertib.
Patients receive alisertib orally (PO) twice daily (BID) on days 1-7 or days 1-3 and 8-10,
and vorinostat PO BID on days 1-14 or days 1-5 and 8-12. Courses repeat every 21 days in the
absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for at least 30 days.
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
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.
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
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.
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.
S0910, A Phase II Study of Epratuzumab (NSC-716711) in Combination With Cytarabine and Clofarabine for Patients With Relapsed or Refractory Ph- Negative Precursor B-Cell Acute Lymphoblastic Leukemia
- To test whether the complete remission (CR) rate (CR and incomplete CR) in adult
patients with relapsed or refractory precursor B-cell acute lymphoblastic leukemia is
sufficiently high after treatment with cytarabine, clofarabine, and epratuzumab to
warrant further investigation.
- To estimate the frequency and severity of toxicities associated with the dosing schedule
of cytarabine, clofarabine, and epratuzumab used in this study.
- To investigate, preliminarily, the effect of laboratory correlates (minimal
post-treatment residual disease) and cytogenetic factors on prognosis in this patient
population. (Not reported here due to limited MRD data)
OUTLINE: This is a multicenter study.
Patients receive cytarabine IV over 2 hours on days 1-5, clofarabine IV over 1 hour on days
2-6, and epratuzumab IV over at least 1 hour on days 7, 14, 21, and 28 in the absence of
disease progression or unacceptable toxicity*.
NOTE: * Prophylactic intrathecal methotrexate is required for patients < 22 years of age, and
is recommended (but not required) for patients ≥ 22 years of age.
Blood samples, bone marrow samples, and/or tumor tissue samples may be collected for further
Patients are followed up every 3 months for 2 years, then annually for 3 years (until 5 years
A Pivotal Multicenter Trial of Moxetumomab Pasudotox in Relapsed/ Refractory Hairy Cell Leukemia
- Hairy cell leukemia (HCL) is an indolent B-cell leukemia comprising 2% of all leukemias,
or approximately 900 of the 44,000 new cases of leukemia/year in the US
- Over the last two decades, immunotoxin research has accumulated to support a role for
CD22-targeted therapy in the treatment of HCL.
- Moxetumomab pasudotox is a recombinant immunotoxin containing an Fv fragment of an
anti-CD22 monoclonal antibody and truncated Pseudomonas exotoxin.
- Moxetumomab pasudotox has demonstrated a high complete response (CR) rate in patients
with chemoresistant HCL and has shown activity in pediatric acute lymphoblastic leukemia
- Modification of the structure of moxetumomab pasudotox has greatly improved binding and
cytotoxicity toward CD22 expressing malignant cells compared to the precursor molecule.
Preclinical and clinical studies have demonstrated that this increase in binding
affinity results in improved antitumor activity and tolerability
- Currently there are no approved agents with significant efficacy for HCL patients after
failure of standard therapy
- This is a multicenter, single-arm study of moxetumomab pasudotox in patients with
relapsed/refractory hairy cell leukemia.
- 77 patients will be enrolled to receive moxetumomab pasudotox IV on days 1, 3 and 5 of
each 28 day cycle for a maximum of 6 cycles or until disease progression, unacceptable
toxicity occurs, the subject begins alternate therapy, or documented CR (for subjects
who have no assessable minimal residual disease and not to exceed 6 cycles). If less
than or equal to 2 of the first 25 patients do not achieve durable CR, no additional
patients will be accrued.
- The overall IRB accrual ceiling is currently set at 80 to allow for a small number of
patients that cannot be assessed for response.
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)
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
Randomized Phase II Study to Assess the Role of Nivolumab as Single Agent to Eliminate Minimal Residual Disease and Maintain Remission in Acute Myelogenous Leukemia (AML) Patients After Chemotherapy (REMAIN TRIAL)
I. To evaluate and compare the progression free survival rate after randomization in the two
treatment arms (nivolumab versus [vs.] observation).
I. To determine and compare the overall survival rates in the two arms. II. To determine and
compare the incidence of non-relapse mortality in the two arms.
III. To evaluate the toxicities of nivolumab as maintenance.
I. To analyze programmed cell death (PD)-ligand (L)1 expression on acute myeloid leukemia
(AML) cells from peripheral blood and/or bone marrow samples at diagnosis if available and at
the time of study enrollment.
II. To monitor AML minimal residual disease (MRD) by Wilms tumor 1 (WT1) polymerase chain
reaction (PCR) at enrollment and at subsequent defined time points in the nivolumab-treated
and control groups.
III. To perform an exploratory analysis on the frequencies, absolute numbers and subsets of T
cells (including regulatory T cells) in the nivolumab-treated and control groups with an
emphasis on activation markers.
IV. To perform deep sequencing of T cell receptor (TCR)-alpha and TCR-beta chains on
polyclonal T cells at baseline and at subsequent time points in the nivolumab and control
OUTLINE: Patients are randomized to 1 of 2 treatment arms.
ARM I: Patients receive nivolumab intravenously (IV) over 60 minutes once every 2 weeks.
Treatment repeats every 2 weeks for 46 courses in the absence of disease progression or
ARM II: Patients undergo standard of care clinical observation for up to 2 years. Upon
disease relapse, patients may cross-over to Arm I.
After completion of study treatment, patients are followed up periodically for 2 years, every
6 months for 1 year, and then yearly thereafter.
A Phase II Study of Blinatumomab and POMP (Prednisone, Vincristine, Methotrexate, 6-Mercaptopurine) for Patients ≥ 65 Years of Age With Newly Diagnosed Philadelphia-Chromosome Negative (Ph-) Acute Lymphoblastic Leukemia (ALL) and of Dasatinib, Prednisone and Blinatumomab for Patients ≥ 65 Years of Age With Newly Diagnosed Philadelphia-Chromosome Positive (Ph+) ALL, Relapsed/Refractory Philadelphia-Chromosome Positive (Ph+) ALL, and Philadelphia-Chromosome-Like Signature (Ph-Like) ALL With Known or Presumed Activating Dasatinib-Sensitive Mutations or Kinase Fusions (DSMKF)
I. To evaluate the 3-year survival rate in elderly patients with newly diagnosed Philadelphia
(Ph)-negative acute lymphoblastic leukemia (ALL) treated with blinatumomab followed by POMP
(prednisone, vincristine sulfate, methotrexate, and mercaptopurine) maintenance.
II. To evaluate in a preliminary manner (feasibility study) the safety of dasatinib-steroid
based induction followed by blinatumomab treatment in combination with dasatinib followed by
dasatinib-based maintenance in patients with newly diagnosed Ph-positive ALL,
relapsed/refractory Ph-positive ALL, and Ph-like dasatinib-sensitive mutations or kinase
fusions (DSMKF) ALL (newly-diagnosed relapsed or refractory).
I. To evaluate toxicities in these patient populations treated with these regimens.
II. To estimate the rates of complete response (CR), complete remission with incomplete count
recovery (CRi) and disease-free survival in Ph-negative patients.
III. To estimate disease-free and overall survival in Ph-positive ALL and Ph-like DSMKF ALL.
IV. To estimate in each cohort the rate of minimal residual disease (MRD) negativity, and the
time to achieve MRD negativity (exploratory analysis).
V. To determine whether anti-idiotype antibodies directed against blinatumomab develop with
blinatumomab treatment in this study.
OUTLINE: Patients are assigned to 1 of 2 treatment cohorts according to Philadelphia
COHORT I (PHILADELPHIA CHROMOSOME NEGATIVE PATIENTS):
INDUCTION: Patients receive blinatumomab intravenously (IV) continuously over 24 hours on
days 1-28. Treatment repeats every 42 days for 2 courses in the absence of disease
progression or unacceptable toxicity.
RE-INDUCTION: Patients not achieving CR or CRi after Induction, receive blinatumomab IV
continuously over 24 hours on days 1-28 in the absence of disease progression or unacceptable
POST-REMISSION: Patients receive blinatumomab IV continuously over 24 hours on days 1-28.
Treatment repeats every 42 days for 3 courses in the absence of disease progression or
MAINTENANCE: Patients receive prednisone orally (PO) on days 1-5, vincristine sulfate IV on
day 1, mercaptopurine PO on days 1-28, and methotrexate PO on days 1, 8, 15, and 22.
Treatment repeats every 28 days for 18 courses in the absence of disease progression or
COHORT II (PHILADELPHIA CHROMOSOME POSITIVE PATIENTS):
INDUCTION: Patients receive dasatinib PO twice daily (BID) on days 1-84 and prednisone PO on
days 1-24 with tapering on days 25-32 in the absence of disease progression or unacceptable
RE-INDUCTION: Patients receive blinatumomab IV continuously over 24 hours on days 1-28.
Treatment repeats every 42 days for 2 courses in the absence of disease progression or
POST-REMISSION: Patients receive blinatumomab IV continuously over 24 hours on days 1-28 and
dasatinib PO once daily (QD) on days 1-42. Treatment repeats every 42 days for 3 courses in
the absence of disease progression or unacceptable toxicity.
MAINTENANCE: Patients receive dasatinib PO BID on days 1-28 and prednisone PO on days 1-5.
Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for 2 years,
every 6 months for 2 years, and then annually until 10 years from initial registration.