Working...
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03459859
Recruitment Status : Recruiting
First Posted : March 9, 2018
Last Update Posted : July 11, 2019
Sponsor:
Collaborator:
Takeda
Information provided by (Responsible Party):
Justin Watts, University of Miami

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).

Condition or disease Intervention/treatment Phase
Acute Myelogenous Leukemia AML Advanced Myelodysplastic Syndromes MDS Drug: Pevonedistat Drug: Cytarabine Phase 1

Detailed Description:

This is a phase 1, dose escalation study of PEVONEDISTAT (formerly MLN4924) in combination with fixed doses of low dose Cytarabine (LDAC) utilizing a traditional 3+3 design. Eligible patients will be enrolled in cohorts of three starting at Dose Level 1. Dose escalation will proceed provided that:

  1. All patients enrolled on the previous cohort have completed the first cycle of treatment (28 days)
  2. The number of patients who experience dose limiting toxicity (DLT) is within the appropriate guidelines (i.e., 0 out of 3; 1 out of 6).
  3. Dose levels for escalation/de-escalation:

    • Dose Level -1: Pevonedistat 10 mg/m2, LDAC 20 mg/m2
    • Dose Level 1 (starting dose): Pevonedistat 15mg/m2, LDAC 20 mg/m2
    • Dose Level 2: Pevonedistat 20 mg/m2, LDAC 20 mg/m2
    • Dose Level 3: Pevonedistat 25 mg/m2, LDAC 20 mg/m2

A more conservative dose-escalation, with evaluation of intermediate doses and/or expansion of an existing dose level, is permissible if such measures are needed for patient safety or for a better understanding of Pevonedistat dose-related toxicity, exposure, or pharmacodynamics. Such changes will be discussed among the protocol investigators and will be approved by the appropriate regulatory agencies.

Up to 16 cycles of 28 days are planned. If patients are receiving clinical benefit, treatment can continue beyond 16 cycles.

Patients will be followed for a minimum of 30 days after the last dose of Pevonedistat/LDAC combination therapy. After this 30 day period, patients will be followed only for the resolution of any ongoing adverse events. Resolution is defined as a return to baseline status or the stabilization of an event with the expectation that it will remain chronic. Any follow-up visit scheduled after this 30 day period will be done at the discretion of the Principal Investigator (PI) or treating physician.


Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Dose escalation, traditional 3:3 design
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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)
Actual Study Start Date : May 21, 2018
Estimated Primary Completion Date : March 2022
Estimated Study Completion Date : March 2023


Arm Intervention/treatment
Experimental: Pevonedistat 10 LDAC 20
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
Administered intravenous (IV) infusion over one hour on Days 1, 3 and 5 of each cycle, after administration of LDAC per protocol.
Other Name: MLN4924

Drug: Cytarabine
Low dose Cytarabine (LDAC) administered subcutaneously (SC) daily for 10 days of every 28-day cycle.
Other Name: ara-C

Experimental: Pevonedistat 15 LDAC 20
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
Administered intravenous (IV) infusion over one hour on Days 1, 3 and 5 of each cycle, after administration of LDAC per protocol.
Other Name: MLN4924

Drug: Cytarabine
Low dose Cytarabine (LDAC) administered subcutaneously (SC) daily for 10 days of every 28-day cycle.
Other Name: ara-C

Experimental: Pevonedistat 20 LDAC 20
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
Administered intravenous (IV) infusion over one hour on Days 1, 3 and 5 of each cycle, after administration of LDAC per protocol.
Other Name: MLN4924

Drug: Cytarabine
Low dose Cytarabine (LDAC) administered subcutaneously (SC) daily for 10 days of every 28-day cycle.
Other Name: ara-C

Experimental: Pevonedistat 25 LDAC 20
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
Administered intravenous (IV) infusion over one hour on Days 1, 3 and 5 of each cycle, after administration of LDAC per protocol.
Other Name: MLN4924

Drug: Cytarabine
Low dose Cytarabine (LDAC) administered subcutaneously (SC) daily for 10 days of every 28-day cycle.
Other Name: ara-C




Primary Outcome Measures :
  1. Safety Profile of Combination Pevonedistat/LDAC Therapy: Rate of Toxicity in Study Participants [ Time Frame: From Cycle 1 Day 1 to End of Study, up to 18 months ]
    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.

  2. Maximum Tolerated Dose (MTD) and Recommended Phase 2 (RP2D) Dose of Pevonedistat in Combination with Low Dose Cytarabine (LDAC) [ Time Frame: From Cycle 1 Day 1 to End of Study, up to 18 months ]
    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).


Secondary Outcome Measures :
  1. Rate of Efficacy in Study Participants [ Time Frame: Up to 17 months ]

    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.


  2. Pharmacokinetics (PK): Maximum Plasma Concentration (Cmax) of Pevonedistat [ Time Frame: Cycle 1 Days 1, 2 3, and 5 ]
    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.

  3. Pharmacokinetics (PK): Time to Cmax (Tmax) of Pevonedistat [ Time Frame: Cycle 1 Days 1, 2, 3, and 5 ]
    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.

  4. Pharmacokinetics (PK): Area Under the Plasma Concentration-Time curve from time 0 to 24 hours post-dose of Pevonedistat (AUC24hr). [ Time Frame: Cycle 1 Days 1, 2, 3, and 5 ]
    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.

  5. Pharmacokinetics (PK): Terminal disposition phase half-life (t1/2) of Plasma Concentration of Pevonedistat [ Time Frame: Cycle 1 Days 1, 2, 3, and 5 ]
    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.

  6. Pharmacodynamics (PD): Induction Levels of CRL substrates [ Time Frame: Baseline, Cycle 1 Days 1, 2, and 5; and End of Study, up to 18 months (+/- 10 days) ]
    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).

  7. Pharmacodynamics (PD): Induction Levels of Pathway Markers [ Time Frame: Baseline, Cycle 1 Days 1, 2, and 5; and End of Study, up to 18 months (+/- 10 days) ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

A. Confirmed diagnosis of one of the following:

  1. 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).
  2. 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:

  1. Albumin > 2.7 g/dL
  2. 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
  3. Alanine transaminase (ALT) and Aspartate transaminase (AST) must be ≤ 2.5 × ULN
  4. Creatinine 1.5 x ULN or calculated creatinine clearance > 50ml/min
  5. 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.
  6. 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.

H. Female patients who:

  1. Are postmenopausal (see Appendix for definition) for at least 1 year before the screening visit, OR
  2. Are surgically sterile, OR
  3. If they are of childbearing potential:

    • Agree to practice 1 highly effective method and 1 additional effective (barrier) method of contraception, at the same time, from the time of signing the informed consent through 4 months after the last dose of study drug (female and male condoms should not be used together), OR
    • Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception).

I. Male patients, even if surgically sterilized (ie, status postvasectomy), who:

  1. Agree to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug (female and male condoms should not be used together), OR
  2. Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods for the female partner] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception).

J. Able to undergo bone marrow aspiration at screening.

Exclusion Criteria:

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:

  1. Uncontrolled high blood pressure (ie, systolic blood pressure > 180 mm Hg, diastolic blood pressure > 95 mm Hg).
  2. 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;
  3. 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.
  4. Implantable cardioverter defibrillator;
  5. 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.
  6. Moderate to severe aortic and/or mitral stenosis or other valvulopathy (ongoing);
  7. Pulmonary hypertension.
  8. Patients with Grade 2 or higher prolonged rate corrected QT (QTc) interval (≥ 481msec), calculated according to institutional guidelines.
  9. 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..
  10. Known moderate to severe chronic obstructive pulmonary disease (COPD), interstitial lung disease, and pulmonary fibrosis.

G. Active uncontrolled infection or severe infectious disease, such as severe pneumonia, meningitis, or septicemia.

H. Known human immunodeficiency virus (HIV) seropositive.

I. Known hepatitis B surface antigen seropositive (Note: Patients who have isolated positive hepatitis B core antibody (ie, in the setting of negative hepatitis B surface antigen and negative hepatitis B surface antibody) must have an undetectable hepatitis B viral load. Patients who have positive hepatitis C antibody may be included if they have an undetectable hepatitis C viral load.)

J. Known or suspected active hepatitis C infections (Patients who are hepatitis C surface antigen-positive are eligible).

K. Females of child bearing potential who refuse to either practice 2 effective methods of contraception at the same time or abstain from heterosexual intercourse from the time of signing the informed consent through 30 days after the last dose of study drug.

L. Males of child bearing potential who refuse to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug. (Includes males surgically sterilized - i.e. status post vasectomy).

M. Female patients who are both lactating and breastfeeding or have a positive serum pregnancy test during the screening period or a positive urine pregnancy test on Day 1 before first dose of study drug.

N. Female patients who intend to donate eggs (ova) during the course of this study or 4 months after receiving their last dose of study drug(s).

O. Male patients who intend to donate sperm during the course of this study or 4 months after receiving their last dose of study drug(s).

P. Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of study procedures.

Q. Symptomatic central nervous system (CNS) involvement.

R. Diagnosed or treated for another malignancy within 2 years before randomization or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone resection.

S. Known hepatic cirrhosis or severe pre-existing hepatic impairment.

T. Systemic anti-neoplastic therapy or radiotherapy within 14 days before the first dose of any study drug, except for hydroxyurea.

U. Patients with uncontrolled coagulopathy or bleeding disorder.

V. Life-threatening illness unrelated to cancer.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03459859


Locations
Layout table for location information
United States, Florida
University of Miami Recruiting
Miami, Florida, United States, 33136
Contact: Justin Watts, MD    305-243-3084    jwatts@med.miami.edu   
Sponsors and Collaborators
Justin Watts
Takeda
Investigators
Layout table for investigator information
Principal Investigator: Justin Watts, MD University of Miami

Layout table for additonal information
Responsible Party: Justin Watts, Assistant Professor of Medicine, University of Miami
ClinicalTrials.gov Identifier: NCT03459859     History of Changes
Other Study ID Numbers: 20180054
First Posted: March 9, 2018    Key Record Dates
Last Update Posted: July 11, 2019
Last Verified: July 2019

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Layout table for MeSH terms
Leukemia
Preleukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Syndrome
Disease
Pathologic Processes
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Cytarabine
Pevonedistat
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Enzyme Inhibitors