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Pevonedistat

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Dose Level -1: Pevonedistat 10 mg/m2, low dose Cytarabine (LDAC) 20 mg/m2 for up to 16 cycles of 28 days each, per protocol

Dose Level 1 (Starting Dose): Pevonedistat 15 mg/m2, low dose Cytarabine (LDAC) 20 mg/m2 for up to 16 cycles of 28 days each, per protocol

Dose Level 2: Pevonedistat 20 mg/m2, low dose Cytarabine 20 mg/m2 for up to 16 cycles of 28 days each, per protocol

Dose Level 3: Pevonedistat 25 mg/m2, low dose Cytarabine (LDAC) 20 mg/m2 for up to 16 cycles of 28 days each, per protocol

Administered intravenous (IV) infusion over one hour on Days 1, 3 and 5 of each cycle, after administration of LDAC per protocol.

Low dose Cytarabine (LDAC) administered subcutaneously (SC) daily for 10 days of every 28-day cycle.

Justin Watts, MD

The investigators hypothesize that the combination of Pevonedistat/Low-Dose Cytarabine (LDAC) therapy will be tolerable, that a recommended phase 2 dose of Pevonedistat in combination with LDAC will be identified, and that the combination therapy will show evidence of clinical activity in adult patients with Relapsed/Refractory Acute Myelogenous Leukemia (AML) and Advanced Myelodysplastic Syndromes (MDS).

Pevonedistat and Low Dose Cytarabine in Adult Patients With AML and MDS

An Open-Label, Dose Escalation, Phase 1 Study of PEVONEDISTAT, a Novel Inhibitor of the NEDD8-Activating Enzyme (NAE), in Combination With Low Dose Cytarabine (LDAC) in Adult Patients With Acute Myelogenous Leukemia (AML) and Advanced Myelodysplastic Syndromes (MDS)

Rate of toxicity in study participants receiving at least one dose of combination Pevonedistat/LDAC protocol therapy, including determination of dose limiting toxicities (DLTs), serious adverse events (SAEs), and AEs. Toxicity will be assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.03.

Determination of the MTD and RP2D of PEVONEDISTAT administered intravenously in patients with AML and advanced MDS when given in combination with low dose cytarabine (LDAC).

Rate of complete response (CR) and partial response (PR) in study participants to Pevonedistat/LDAC combination therapy. Response will be determined using serial blood and bone marrow sampling throughout the course of treatment, and assessed according to revised/modified International Working Group (IWG) Response Criteria - Cheson et al. 2003 for AML and Cheson et al. 2006 for MDS.

Morphologic complete remission (CR), cytogenetic CR, and molecular CR will be assessed based on blood counts, marrow blast percentage, cytogenetic studies and mutational analysis on every occasion the bone marrow is examined to assess for response.

Pharmacokinetic effects of IV-administered PEVONEDISTAT in plasma will be measured when combined with LDAC. Cmax is the maximum (or peak) plasma concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administrated and before the administration of a second dose. Pharmacokinetics (PK) parameters will be determined using serial blood sampling at specified time points to determine PK effects of PEVONEDISTAT in plasma when combined with LDAC. Non-compartmental methods of analysis will be used to determine PEVONEDISTAT PK parameters following IV dosing of patients in Cycle 1.

Pharmacokinetic effects of IV-administered PEVONEDISTAT in plasma will be measured when combined with LDAC. Tmax is the time it takes a drug or other substance to reach the maximum concentration (Cmax). Pharmacokinetics (PK) parameters will be determined using serial blood sampling at specified time points to determine PK effects of PEVONEDISTAT in plasma when combined with LDAC. Non-compartmental methods of analysis will be used to determine PEVONEDISTAT PK parameters following IV dosing of patients in Cycle 1.

Pharmacokinetic effects of IV-administered PEVONEDISTAT in plasma will be measured when combined with LDAC. The area under the plasma concentration-time curve from time 0 to 24 hours post-dose (AUC24hr) will be assessed. Pharmacokinetics (PK) parameters will be determined using serial blood sampling at specified time points to determine PK effects of PEVONEDISTAT in plasma when combined with LDAC. Non-compartmental methods of analysis will be used to determine PEVONEDISTAT PK parameters following IV dosing of patients in Cycle 1.

Pharmacokinetic effects of IV-administered PEVONEDISTAT in plasma will be measured when combined with LDAC. Terminal phase half-life (t1/2) will be assessed. Half-life (t1/2) is the amount of time it takes for the drug concentration in the plasma to decline by half. Pharmacokinetics (PK) parameters will be determined using serial blood sampling at specified time points to determine PK effects of PEVONEDISTAT in plasma when combined with LDAC. Non-compartmental methods of analysis will be used to determine PEVONEDISTAT PK parameters following IV dosing of patients in Cycle 1.

Pharmacodynamics (PD) measurements will be obtained from serial blood and bone marrow sampling at specified time points to describe the PD effects of PEVONEDISTAT when combined with LDAC. The following endpoints will be analyzed: Induction of Cullin Ring Ligase (CRL) substrates by immunoblotting (e.g. nuclear factor (erythroid-derived 2)-like 2 (NRF2), chromatin licensing and DNA replication factor 1 (CDT1), pIKB and others).

Pharmacodynamics (PD) measurements will be obtained from serial blood and bone marrow sampling at specified time points to describe the PD effects of PEVONEDISTAT when combined with LDAC. The following endpoints will be analyzed: Induction of pathway markers (eg SQ01 by polymerase chain reaction (PCR) in peripheral blood mononuclear cells) as well as other known indicators of pathway inhibition.

Spots Global Cancer Trial Database for Pevonedistat and Low Dose Cytarabine in Adult Patients With AML and MDS

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