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

NCT03459859 | Completed Phase 1 DMC FDA Drug

• 2 other identifiers: 20180054NCI-2019-06910
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief Summary

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).

Conditions

Acute Myelogenous Leukemia; AML; Advanced Myelodysplastic Syndromes; MDS

Outcome Measures

Primary Outcomes (2)

• Safety Profile of Combination Pevonedistat/LDAC Therapy: Rate of Toxicity in Study Participants

  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.

  From Cycle 1 Day 1 to End of Study, up to 18 months

• Maximum Tolerated Dose (MTD) and Recommended Phase 2 (RP2D) Dose of Pevonedistat in Combination with Low Dose Cytarabine (LDAC)

  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).

  From Cycle 1 Day 1 to End of Study, up to 18 months

Secondary Outcomes (7)

• Rate of Efficacy in Study Participants

  Up to 17 months

• Pharmacokinetics (PK): Maximum Plasma Concentration (Cmax) of Pevonedistat

  Cycle 1 Days 1, 2 3, and 5

• Pharmacokinetics (PK): Time to Cmax (Tmax) of Pevonedistat

  Cycle 1 Days 1, 2, 3, and 5

• Pharmacokinetics (PK): Area Under the Plasma Concentration-Time curve from time 0 to 24 hours post-dose of Pevonedistat (AUC24hr).

  Cycle 1 Days 1, 2, 3, and 5

• Pharmacokinetics (PK): Terminal disposition phase half-life (t1/2) of Plasma Concentration of Pevonedistat

  Cycle 1 Days 1, 2, 3, and 5

Study Arms (4)

Pevonedistat 10 LDAC 20

EXPERIMENTAL

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

Drug: Pevonedistat; Drug: Cytarabine

Pevonedistat 15 LDAC 20

EXPERIMENTAL

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

Drug: Pevonedistat; Drug: Cytarabine

Pevonedistat 20 LDAC 20

EXPERIMENTAL

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

Drug: Pevonedistat; Drug: Cytarabine

Pevonedistat 25 LDAC 20

EXPERIMENTAL

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

Drug: Pevonedistat; Drug: Cytarabine

Interventions

Pevonedistat DRUG

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

Also known as: MLN4924

Pevonedistat 10 LDAC 20; Pevonedistat 15 LDAC 20; Pevonedistat 20 LDAC 20; Pevonedistat 25 LDAC 20

Cytarabine DRUG

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

Also known as: ara-C

Pevonedistat 10 LDAC 20; Pevonedistat 15 LDAC 20; Pevonedistat 20 LDAC 20; Pevonedistat 25 LDAC 20

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• A. Confirmed diagnosis of one of the following:
• Relapsed/refractory Acute Myelogenous Leukemia (AML) where no alternative life prolonging therapy exists. Treatment naïve patients may also be considered eligible if in the opinion of the investigator, these patients are unlikely to benefit from alternative therapy (eg conventional chemotherapy, hypomethylating agents).
• Relapsed/refractory Myelodysplasic Syndrome (MDS) following at least two courses of a hypomethylating agent (eg azacitidine or decitabine). Patients intolerant of hypomethylating agents (irrespective of the number of cycles administered) will also be considered eligible. MDS eligibility limited to patients with intermediate, high or very high risk based on IPSS-R.
• B. Adult male or female patients 18 years of age or older.
• C. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2
• D. Patients must satisfy the following laboratory criteria:
• Albumin \> 2.7 g/dL
• Total bilirubin ≤ upper limit of normal (ULN) except in patients with Gilbert's syndrome. Patients with Gilbert's syndrome may enroll if direct bilirubin ≤1.5 x ULN of the direct bilirubin
• Alanine transaminase (ALT) and Aspartate transaminase (AST) must be ≤ 2.5 × ULN
• Creatinine 1.5 x ULN or calculated creatinine clearance \> 50ml/min
• Hemoglobin \> 8 g/dL (prior red blood cell (RBC) transfusion allowed). Patients may be transfused to achieve this value. Elevated indirect bilirubin due to post-transfusion hemolysis is allowed.
• White blood cell (WBC) count \< 50,000/µL before administration of PEVONEDISTAT on Cycle 1 Day 1. Note: Hydroxyurea may be used to control the level of circulating leukemic blast cell counts to not lower than 10,000/µL during the study.
• E. Suitable venous access to allow for all study related blood sampling (safety and research).
• F. Estimated life expectancy, in the judgment of the Investigator, which will permit receipt of at least 6 weeks of treatment.
• G. Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.

You may not qualify if:

• A. Treatment with clinically significant metabolic enzyme inducers within 14 days before the first dose of the study drug. Strong CYP3A inhibitors and CYP3A inducers are not permitted during the study.
• B. Therapy with any investigational products, anti-neoplastic therapy, or radiotherapy within 14 days prior to Cycle 1 Day 1. Patients actively receiving hydroxyurea are eligible and may continue to receive hydroxyurea during protocol treatment.
• C. Candidates for standard and/or potentially curative treatments (a candidate is defined as a patient that is both eligible and willing to have these treatments)
• D. Major surgery within 14 days before the first dose of any study drug or a scheduled surgery during study period.
• E. Grade 2 or higher diarrhea as defined by NCI CTCAE Version 4.03 despite optimal anti-diarrheal supportive care within 7 days prior to Cycle1 Day1.
• F. Known cardiopulmonary disease defined as one of the following:
• Uncontrolled high blood pressure (ie, systolic blood pressure \> 180 mm Hg, diastolic blood pressure \> 95 mm Hg).
• Cardiomyopathy or history of ischemic heart disease; patients with ischemic heart disease who have had acute coronary syndrome (ACS), MI, and/or revascularization greater than 6 months before screening and who are without cardiac symptoms may enroll;
• Clinically significant arrhythmia including:,history of polymorphic ventricular fibrillation or torsade de pointes); permanent atrial fibrillation \[a fib\], defined as a fib for ≥6 months; persistent a fib, defined as sustained afib \>7 days and/or requiring cardioversion in the 4 weeks before screening; Grade 3 a fib defined as symptomatic and incompletely controlled medically, or controlled with device (e.g., pacemaker), or ablation. Patients with paroxysmal a fib are permitted to enroll. However, patients with \< Grade 3 atrial fibrillation (a fib) for a period of at least 6 months may enroll provided that their rate is controlled on a stable regimen.
• Implantable cardioverter defibrillator;
• Congestive heart failure (New York Heart Association (NYHA) Class III or IV; or Class II with a recent decompensation requiring hospitalization or referral to a heart failure clinic within 4 weeks before screening), myocardial infarction and/or revascularization (eg, coronary artery bypass graft, stent) within 6 months of first dose of study drug.
• Moderate to severe aortic and/or mitral stenosis or other valvulopathy (ongoing);
• Pulmonary hypertension.
• Patients with Grade 2 or higher prolonged rate corrected QT (QTc) interval (≥ 481msec), calculated according to institutional guidelines.
• Left ventricular ejection fraction (LVEF) \< 50% as assessed by echocardiogram or radionuclide angiography - LVEF assessment is not required for screening, and will only be done at the investigators discretion if clinically indicated..

Sponsors & Collaborators

• Justin Watts, MD: lead
• Takeda: collaborator

Study Sites (1)

University of Miami

Miami, Florida, 33136, United States

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

pevonedistat; Cytarabine

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Study Officials

• Justin Watts, MD

  University of Miami

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor of Medicine

Model Details: Dose escalation, traditional 3:3 design

Study Record Dates

• First Submitted: March 3, 2018
• First Posted: March 9, 2018
• Study Start: May 21, 2018
• Primary Completion: June 25, 2021
• Study Completion: June 25, 2021
• Last Updated: December 28, 2021

Record last verified: 2021-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)