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Study Title Principal Investigator
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.
Recruiting | | Not Multisite
Kevin Kelly
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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.
Recruiting | | Not Multisite
Akil Merchant
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AN OPEN-LABEL PHASE 1B STUDY OF PF-04449913 (GLASDEGIB) IN COMBINATION WITH AZACITIDINE IN PATIENTS WITH PREVIOUSLY UNTREATED HIGHER-RISK MYELODYSPLASTIC SYNDROME, ACUTE MYELOID LEUKEMIA, OR CHRONIC MYELOMONOCYTIC LEUKEMIA
Recruiting | | Multisite
Pfizer Center
A Phase 1B Study of AMG-232 in Combination With Decitabine in Acute Myeloid Leukemia
PRIMARY OBJECTIVES: I. To evaluate the toxicities of MDM2 inhibitor AMG-232 (AMG-232) in combination with decitabine (20 mg/m^2 for 10 days), and to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of AMG-232 in combination with a standard dose of decitabine. SECONDARY OBJECTIVES: I. To evaluate the pharmacokinetic (PK) profiles of AMG-232 and decitabine when used in combination. II. To evaluate tumor suppressor protein 53 (p53) signaling induced by AMG-232 and decitabine as measured by macrophage inhibitory cytokine-1 (MIC-1) induction. III. To correlate AMG-232 and decitabine exposure with pharmacodynamics endpoints (efficacy, toxicity, changes in p53 signaling). EXPLORATORY OBJECTIVES: I. To evaluate the response rate (RR) and progression free survival (PFS) of AMG-232 and decitabine in acute myeloid leukemia (AML). II. To evaluate potential predictive biomarkers of response to AMG-232 and decitabine in AML. III. To evaluate the pharmacodynamic (PD) effects of AMG-232 and decitabine in AML blasts. IV. To determine the variability of decitabine incorporation into genomic deoxyribonucleic acid (DNA) and correlate with systemic pharmacokinetics and exposure-response relationships. OUTLINE: This is a dose-escalation study of MDM2 inhibitor AMG-232. Patients receive decitabine intravenously (IV) over 1 hour on days 1-10 and MDM2 inhibitor AMG-232 orally (PO) once daily (QD) on days 4-10 and 18-24. Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 30 days.
Recruiting | | Multisite
Kevin Kelly
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A Phase IB/II Multi-Arm Study With Venetoclax in Combination With Cobimetinib and Venetoclax in Combination With Idasanutlin in Patients Aged >/= 60 Years With Relapsed or Refractory Acute Myeloid Leukemia Who Are Not Eligible for Cytotoxic Therapy
Recruiting | | Multisite
Clinical Trials
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.)
Recruiting | | Multisite
James Lowder
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.
Recruiting | | Multisite
Casey O'Connell
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 period. 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.
Recruiting | | Multisite
Kazunobu Kato
A Phase 2/3 Multicenter, Open-label, 3-arm, 2-Stage Randomized Study of ASP2215 (Gilteritinib), Combination of ASP2215 Plus Azacitidine and Azacitidine Alone in the Treatment of Newly Diagnosed Acute Myeloid Leukemia With FLT3 Mutation in Patients Not Eligible for Intensive Induction Chemotherapy
Patients considered an adult according to local regulation at the time of obtaining informed consent may participate in the study. Safety Cohort Prior to initiation of the randomized trial, 8 to 12 patients will be enrolled to evaluate the safety and tolerability of ASP2215 given with azacitidine therapy in the study population. Randomized Trial Approximately 323 patients will be randomized in a 2:1 ratio to receive ASP2215 plus azacitidine (Arm AC) or azacitidine only (Arm C). Earlier protocol versions included a 1:1:1 randomization ratio to receive Arm A: ASP2215, Arm AC: ASP2215 + azacitidine or Arm C: azacitidine. Randomization to Arm A was removed in the current protocol version. Patients previously randomized to Arm A should continue following treatment and assessments as outlined in the protocol. Patients will enter the screening period up to 14 days prior to the start of treatment. Patients will be administered treatment over 28-day cycles.
Recruiting | | Multisite
Medical Director
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