A Study to Evaluate the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of Idasanutlin Monotherapy in Participants With Hydroxyurea-Resistant/Intolerant Polycythemia Vera
Condition: Polycythemia Vera
MeSH terms: Polycythemia Vera; Polycythemia
Intervention: Idasanutlin
Intervention description: All participants will receive 150 milligrams (mg) idasanutlin orally, once daily for 5 days, every 28 days, until treatment discontinuation or end of study (up to 2 years). Intra-participant dose-escalation to 200 mg daily for 5 days may be permitted after Cycle 3 for those who demonstrate no hematocrit (Hct) control and/or for those with inadequately controlled leukocytosis and/or thrombocytosis in which the investigator judges that better control is important.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 27.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: polycythemia vera; PV; P vera; myeloproliferative diseases; hematologic diseases; myeloproliferative neoplasm; MPN

Summary:

      This is an open-label, single-arm study of idasanutlin monotherapy in participants with
      hydroxyurea (HU)-resistant/intolerant Polycythemia vera (PV). The study will include two
      phases: initial phase and expansion phase. The initial phase will assess the safety and
      efficacy of idasanutlin monotherapy in ruxolitinib naïve and ruxolitinib-resistant or
      intolerant patients, respectively. If the initial phase shows promising results for
      ruxolitinib-resistant or intolerant patients, an expansion phase will be opened to further
      characterize the efficacy of idasanutlin.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Documentation that the participant has met the revised 2016 World Health Organization
             (WHO) criteria for the diagnosis of polycythemia vera (PV)

          -  Hematocrit at screening and at initiation of idasanutlin greater than (>)40%

          -  Phlebotomy-dependent participants with splenomegaly by magnetic resonance imaging
             (MRI) or computerized tomography (CT) imaging (greater than or equal to [≥]450 cubic
             centimeters [cm^3]) or without splenomegaly (less than [<]450 cm^3 or prior
             splenectomy)

          -  Resistance to/intolerance to hydroxyurea according to modified European Leukemia Net
             (ELN) criteria

          -  For participants in the ruxolitinib intolerant or resistant group, in addition to
             previous hydroxyurea intolerance/resistance: Therapy-resistant PV after at least 6
             months of treatment with ruxolitinib, as defined in the protocol; Ruxolitinib
             intolerance, as defined in the protocol; and Documentation of adverse events likely
             caused by ruxolitinib (assessment of attending physician) and that are of a severity
             that preclude further treatment with ruxolitinib (as per judgment of the attending
             physician and the patient)

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1

          -  Participants must be willing to submit the blood sampling and bone marrow sampling for
             the pharmacokinetic (PK) and pharmacodynamic analyses and exploratory biomarkers

          -  Adequate hepatic and renal function

          -  Ability and willingness to comply with the study protocol procedures, including
             clinical outcome assessment measures

          -  For women of childbearing potential: agreement to use contraceptive methods that
             result in a failure rate of less than (<)1% per year during the treatment period and
             for at least 6 weeks after the last dose of idasanutlin

          -  For men: Agreement to use contraceptive measures, and agreement to refrain from
             donating sperm during the treatment period and for at least 90 days after the last
             dose of idasanutlin

        Exclusion Criteria:

          -  Meets the criteria for post-PV myelofibrosis as defined by the International Working
             Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT)

          -  Blast phase disease (>20% blasts in the marrow or peripheral blood)

          -  Clinically-significant thrombosis within 3 months of screening

          -  Participants who must receive CYP2C8 inhibitors, substrates and inducers, strong
             CYP3A4 inducers, or OATP1B1/3 substrates while on study. These must be discontinued 7
             days (inhibitors and substrates) or 14 days (inducers) prior to start of study
             medication

          -  Previously treated with murine double minute 2 (MDM2) antagonist therapies or
             receiving interferon-alpha, anagrelide, or ruxolitinib within 28 days or 5 half-lives
             (whichever is shorter), or hydroxyurea within 1 day, or receiving any other
             cytoreductive or investigational agents within 28 days or 5 half-lives (whichever is
             shorter) of initial dose. Aspirin is permitted per treatment guidelines for PV unless
             medically contraindicated

          -  Patients with evidence of electrolyte imbalance such as hypokalemia, hyperkalemia,
             hypocalcemia, hypercalcemia, hypomagnesemia, and hypermagnesemia of Grade >1
             intensity, as per the National Cancer Institute Common Terminology Criteria for
             Adverse Events (NCI CTCAE), version 4.0, prior to dosing on Cycle 1 Day 1. Treatment
             for correction of electrolyte imbalances is permitted to meet eligibility

          -  Neutrophil count <1.5 × 10^9/Liter (L) prior to dosing on Cycle 1 Day 1

          -  Platelet count less than or equal to (≤)150 × 10^9/L prior to dosing on Cycle 1 Day 1

          -  Women who are pregnant or breastfeeding

          -  Ongoing serious non-healing wound, ulcer, or bone fracture

          -  History of major organ transplant

          -  Uncontrolled intercurrent illness including, but not limited to hepatitis, concurrent
             malignancy that could affect compliance with the protocol or interpretation of
             results, hepatitis A, B, and C, human immunodeficiency virus (HIV)-positive, ongoing
             or active infection, clinically significant cardiac disease (New York Heart
             Association Class III or IV), symptomatic congestive heart failure, unstable angina
             pectoris, ventricular arrhythmia, or psychiatric illness/social situations that would
             limit compliance with study requirements. Concurrent malignancy exceptions include:
             Curatively treated carcinoma in situ of the cervix, good-prognosis ductal carcinoma in
             situ of the breast, basal- or squamous-cell skin cancer, Stage I melanoma, or
             low-grade, early-stage localized prostate cancer. Any previously treated early-stage
             non-hematological malignancy that has been in remission for at least 2 years is also
             permitted.

          -  Patients with active gastrointestinal conditions (Crohn's disease, ulcerative colitis,
             diverticulosis associated colitis, and Behçet's disease)

          -  Clinically significant toxicity (other than alopecia) from prior therapy that has not
             resolved to Grade ≤1 (according to the NCI CTCAE, v4.0) prior to Cycle 1 Day 1

          -  Cardiovascular disease, such as: uncontrolled arterial hypertension; symptomatic
             congestive heart failure or ejection fraction below 55% at screening, or left
             ventricular hypertrophy; any significant structural abnormality of the heart at
             screening echocardiogram; unstable angina pectoris; presence or history of any type of
             supraventricular and ventricular arrhythmias, including lone atrial fibrillation or
             flutter