Symptoms and General Pathology

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Myelodysplastic Syndromes

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Fludarabine

Fludarabine phosphate

Melphalan

Busulfan

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Antineoplastic Agents, Alkylating

Alkylating Agents

This is a single arm phase II trial to assess the efficacy (decrease the transplant related mortality) and safety of peri-transplant Palifermin in combination with a preparative regimen with busulfan, melphalan, fludarabine, and anti-thymocyte globulin (ATG), and a T cell depleted stem cell transplant from a histocompatible related or unrelated donor in patients with advanced MDS and AML evolved from MDS. The addition of Palifermin is to decrease the toxicity and the infection rate associated with this regimen and transplant type and to foster earlier immune reconstitution.

Patients will receive Palifermin 60 mcg/kg/day IV on three consecutive days with the last dose administered no less than 24 and no more than 48 hr prior to start of cytoreduction. The preparative regimen to be used for transplants will consist: of busulfan administered in 12 doses over three days of 0.8 mg/kg IV for patients \> or = to 4 years of age or 1.0 mg/kg IV for patients \< 4 years of age; melphalan 70 mg/m2 IV x 2 days; and, fludarabine 25 mg/m2 IV x 5 days

Busulfan, Melphalan, Fludarabine, Anti-Thymocyte Globulin, Palifermin, Stem cell transplant

Roni Tamari, MD

This study will see if the researchers can lower that risk by giving the patient Palifermin. This drug helps protect the lining of the mouth, throat, and stomach. These areas typically get sores or ulcers while the blood cell counts are very low. The patient can get infections in or from these sores. Palifermin might also help the immune system recover faster. It is currently approved for patients who receive their own stem cells. That is called an autologous transplant. This study will test the use of Palifermin for T-cell depleted allogeneic stem cell transplants.

Busulfan, Melphalan, and Fludarabine With Peri-transplant Palifermin, Followed by a T-Cell Depleted Hematopoietic Stem Cell Transplant From HLA Matched or Mismatched Related or Unrelated Donors in Patients With Advanced Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML)

A Phase II Trial of Busulfan, Melphalan, and Fludarabine With Peri-transplant Palifermin, Followed by a T-Cell Depleted Hematopoietic Stem Cell Transplant From HLA Matched or Mismatched Related or Unrelated Donors in Patients With Advanced Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML)

Memorial Sloan Kettering Cancer Center

This is a single arm phase II trial to assess the efficacy (decrease the transplant related mortality) and safety of peri-transplant Palifermin in combination with a preparative regimen with busulfan, melphalan, fludarabine, and anti-thymocyte globulin (ATG), and a T cell depleted stem cell transplant from a histocompatible related or unrelated donor in patients with advanced MDS and AML evolved from MDS. The addition of Palifermin is to decrease the toxicity and the infection rate associated with this regimen and transplant type and to foster earlier immune reconstitution.

Busulfan, Melphalan, Fludarabine, Anti-Thymocyte Globulin, Palifermin, Stem cell transplant: Patients will receive Palifermin 60 mcg/kg/day IV on three consecutive days with the last dose administered no less than 24 and no more than 48 hr prior to start of cytoreduction. The preparative regimen to be used for transplants will consist: of busulfan administered in 12 doses over three days of 0.8 mg/kg IV for patients \> or = to 4 years of age or 1.0 mg/kg IV for patients \< 4 years of age; melphalan 70 mg/m2 IV x 2 days; and, fludarabine 25 mg/m2 IV x 5 days

Palifermin

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Dr. Roni Tamari, MD

To Reduce the Early Transplant-related Mortality.

To Improve the Quality of Immune Reconstitution Following Transplantation.

To Reduce the Incidence Rate of Fatal Post Transplant Infectious Complications.

Overall Study

Anti-Infective Agents

Cytarabine

Pevonedistat

Antimetabolites

Antiviral Agents

Enzyme Inhibitors

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Busulfan, Melphalan, and Fludarabine With Peri-transplant Palifermin, Followed by a T-Cell Depleted Hematopoietic Stem Cell Transplant From HLA Matched or Mismatched Related or Unrelated Donors in Patients With Advanced Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML)	NCT00629798	Acute Myeloid L... Advanced Myelod...	Busulfan, Melph...	- 65 Years	Memorial Sloan Kettering Cancer Center
Pevonedistat and Low Dose Cytarabine in Adult Patients With AML and MDS	NCT03459859	Acute Myelogeno... AML Advanced Myelod... MDS	Pevonedistat Cytarabine	18 Years -	University of Miami

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