Pevonedistat and Azacitidine in MDS or MDS/MPN Patients Who Fail Primary Therapy With DNA Methyl Transferase Inhibitors
Condition: Myelodysplastic Syndromes; Myeloproliferative Neoplasm
MeSH terms: Myelodysplastic Syndromes; Myeloproliferative Disorders
Intervention: Azacitidine Subcutaneous Injection or Intravenous Infusion; Pevonedistat Infusion; Bone Marrow Biopsy & Aspirate
Intervention description: 75 mg/m2; 20 mg/m2; Removal of a small piece of bone and bone marrow by inserting a needle into hip bone.
Intervention MeSH terms: Azacitidine; Pevonedistat
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 71.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This study will evaluate the treatment combination of pevonedistat and azacitidine in the
      setting of DNA methyltransferase inhibitor(s) failure in patients with relapsed/refractory
      myelodysplastic syndrome or myelodysplastic syndrome/myeloproliferative neoplasm.
    

Eligibility criteria:

        Inclusion:

          -  Signed and dated voluntary written informed consent 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             consent may be withdrawn by the patient at any time without prejudice to future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.

          -  Male or female ≥ 18 years of age.

          -  Morphologically confirmed diagnosis of MDS or MDS/MPN in accordance with WHO
             diagnostic criteria.

          -  ECOG performance status of 0, 1 or 2.

          -  Expected survival ≥ 3 months after consenting.

          -  Refractory/relapsed disease following DNMTi failure. Refractory disease defined as
             either:

               -  failure to achieve an objective response after at least 4 cycles of DNMTi
                  therapy, or

               -  failure to achieve an objective response with clear progressive disease on bone
                  marrow biopsy after at least 2 cycles of DNMTi therapy. Relapsed disease is
                  defined as having progressive disease after achieving an objective response after
                  at least 2 cycles of DNMTi therapy.

        Previous DNMTi therapy may include 5'azacitidine, decitabine, or DNMTi therapy currently in
        clinical trials (e.g. SGI-110 (guadecitabine), ASTX727 or CC-486).To be considered DNMTi
        treatment failure, during each prior treatment cycle, patients must have received
        equivalent to minimum dosing of:

        decitabine 15mg/m2 daily x 5 days, or

        5'azacitidine 50mg/m2 IV/SC daily x 5 days,

        SGI-110 (guadecitabine) 60mg/m2 SC daily x 5 days, or

        oral DNMTi therapy with ASTX727 20/100mg daily x 5 days, or

        oral DNMTi therapy with CC-486 200mg daily x 14 days

          -  Recovery to ≤ Grade 1 or baseline of any toxicity due to prior systemic treatments,
             excluding alopecia.

          -  Patient consent to collection of fresh bone marrow biopsy and aspirate for exploratory
             research obtained from a procedure performed no more than 28 days prior to initiating
             treatment on Cycle 1, Day 1. Requirement for bone marrow biopsy may be waived with
             approval of the study chair in the event that a bone marrow biopsy cannot be obtained.

          -  Clinical laboratory values as specified below:

               -  Serum albumin > 2.7 g/dL

               -  Total bilirubin ≤ 1.5 x ULN

               -  ALT and AST ≤ 2 x ULN

               -  Calculated creatinine clearance ≥ 50 mL/min (per the Cockcroft-Gault formula)

               -  WBC ≤ 50,000/µL (use of hyroxyurea is permitted)

          -  Hgb <8g/dL should be transfused to provide adequate tissue perfusion as per the
             discretion of the investigators and local practice. Rechecking Hgb level prior to
             start on Cycle 1 Day 1 is not necessary as long as patients do not have inadequate
             oxygenation, underlying cardiopulmonary compromise, and/or any other reason deemed
             clinically significant to delay therapy per the investigator.

          -  Women of childbearing potential must have a negative serum pregnancy test; and
             additionally agree to simultaneously use at least 2 methods of effective contraception
             or abstain from heterosexual intercourse from the time of signing consent, and until 4
             months after patient's last dose of protocol-indicated treatment. Periodic abstinence
             (e.g. calendar,ovulation, symptothermal, postovulation methods for the female partner)
             and withdrawal are not acceptable methods of contraception.

        Women of child bearing potential are defined as those not surgically sterile or not
        post-menopausal. If a female patient has not had a bilateral tubal ligation, a bilateral
        oophorectomy, or a complete hysterectomy; or has not been amenorrheic for at least 1 year
        in the absence of an alternative medical cause, then patient will be considered a female of
        childbearing potential. Postmenopausal status in females under 55 years of age should be
        confirmed with a serum FSH level within laboratory reference range for postmenopausal
        women.

        - Men, even if surgically sterilized (i.e. status post-vasectomy), who are sexually active
        with women of childbearing potential must agree to follow instructions for effective
        barrier contraception from the time of signing consent and until 4 months after last dose
        of protocol-indicated treatment. Periodic abstinence (e.g. calendar, ovulation,
        symptothermal, postovulation methods for the female partner) and withdrawal are not
        acceptable methods of contraception.

        Exclusion:

          -  Diagnosis of acute myeloid leukemia (i.e. ≥ 20% peripheral or marrow blasts).

          -  Any HSCT within 6 months prior to signing informed consent.

          -  Any patient who is eligible for HSCT at the time of study screening.

          -  Clinically significant graft versus host disease (GVHD) or GVHD requiring initiation
             of treatment or treatment escalation within 21 days, and/or > Grade 1 persistent or
             clinically significant non-hematologic toxicity related to HSCT

          -  Any previous treatment with pevonedistat or other NEDD8 inhibitor.

          -  Treatment with any investigational products within 14 days before the first dose of
             protocol-indicated treatment.

          -  Systemic antineoplastic therapy or radiotherapy within 14 days before the first dose
             of any study drug.

          -  Major surgery requiring general anesthesia within 14 days before the first dose of any
             study drug or a scheduled surgery during study period. (Placement of a central line or
             port-a-catheter is acceptable within this time frame and does not exclude the
             patient.)

          -  Treatment with clinically significant metabolic CYP3A inducers within 14 days before
             the first dose of study drug. Clinically significant CYP3A inducers are not permitted
             during the study.

          -  Prolonged QTc interval > 500 msec, calculated according to Fredericia's formula

          -  Known cardiopulmonary disease defined as having one or more of the following:

               -  Uncontrolled high blood pressure (i.e. systolic > 180 mmHg or diastolic > 95
                  mmHg);

               -  Symptomatic cardiomyopathy;

               -  Ischemic heart disease; Patients with acute coronary syndrome, myocardial
                  infarction, and/or revascularization (e.g. coronary artery bypass graft, stent)
                  within 6 months of first dose of study drug are excluded; Patients with a history
                  of ischemic heart disease who have had revascularization greater than 6 months
                  before screening and who are without cardiac symptoms may enroll;

               -  Arrhythmia (e.g. history of polymorphic ventricular fibrillation or torsade de
                  pointes). Patients with symptomatic atrial fibrillation (Afib) incompletely
                  controlled medically, or controlled by device (e.g. pacemaker) or by ablation in
                  the past 6 months are excluded. However, patients with stable, AFib for a period
                  of at least 6 months, whose Afib is controlled with medication, or who have a
                  history of paroxysmal AFib are permitted to enroll;

               -  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),

               -  Moderate to severe aortic and/or mitral stenosis or other valvulopathy (ongoing).
                  Mild regurgitation is not excluded;

               -  Pulmonary hypertension.

          -  Female patients who are both lactating and breastfeeding, who have a positive serum
             pregnancy test during screening, or who plan to become pregnant while in the trial or
             within 90 days after receiving protocol-directed treatment.

          -  Active uncontrolled infection. Patients with infection under active treatment and
             controlled with antibiotics are not excluded.

          -  Known Childs class B or C hepatic cirrhosis or severe pre-existing hepatic impairment.

          -  Known hepatitis B surface antigen seropositivity or known or suspected active
             hepatitis C infection. Note: Patients who have isolated positive hepatitis B core
             antibody (i.e. in the setting of negative hepatitis B surface antigen and negative
             hepatitis B surface antibody) must have an undetectable hepatitis B viral load.

          -  Known human immunodeficiency virus (HIV) seropositivity.

          -  Any serious concurrent condition that could, in the investigator's opinion,
             significantly interfere with completion of study procedures or protocol compliance.

          -  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).

          -  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).