Inclusion Criteria: 

• Ability to understand and willingness to sign a written informed consent form and comply with the study protocol according to ICH and local regulations.
• Adults > 18 years of age.
• There must be documentation that the patient has met the revised 2016 WHO criteria for the diagnosis of polycythemia vera (Arber et al. 2016).  Diagnosis requires the presence of all three major criteria, or the first two major criteria and the minor criterion. To verify that the criteria have been met, appropriate laboratory or pathology reports must be submitted during screening demonstrating that the patient has documentation of these diagnostic criteria. These reports do not have to exactly coincide with the original date of diagnosis.
  • Hemoglobin > 16.5 g/dL in men, > 16.0 g/dL in women OR Hct > 49% in men, > 48% in women, OR other evidence of increased red cell mass.
  • Bone marrow biopsy showing hypercellularity for age with trilineage growth (panmyelosis) including prominent erythroid, granulocytic and megakaryocytic proliferation with pleomorphic, mature megakaryocytes (differences in size).
  • Presence of JAK2V617F or JAK2 exon 12 mutation.
  • Serum erythropoietin level below the reference range for normal.
    • NOTE: Major criterion number b) may not be required in cases with sustained absolute erythrocytosis: hemoglobin levels > 18.5 g/dL in men (Hct, 55.5%) or > 16.5 g/dL in women (Hct, 49.5%) if major criterion c) and the minor criterion are present.
• Hct at screening and initiation of idasanutlin > 40%.
• Phlebotomy-dependent patients with splenomegaly by magnetic resonance imaging (MRI) or computerized tomography (CT) imaging (≥ 450 cm^3) or without splenomegaly (< 450 cm^3 or prior splenectomy).
• Phlebotomy dependence is defined as at least one phlebotomy within 16 weeks before screening.
• Resistance to/intolerance to hydroxyurea according to modified ELN criteria (Barosi et al. 2010):
• Resistance to HU is defined at a dose ≥ 2 g/day or a maximum tolerated dose < 2 g/day resulting in at least one of the following:
  • Need for phlebotomy to maintain Hct < 45% after 3 months of HU;
  • Platelet (PLT) count > 400 x 10^9/L and white blood cell (WBC) count > 10 x 10^9/L after 3 months of HU;
  • Failure to reduce splenomegaly extending > 10 cm below the costal margin by > 50%, as measured by palpation after 3 months of HU.
• Intolerance to HU is defined as at least one of the following:
  • Absolute neutrophil count (ANC) < 1.0 x 10^9/L;
  • PLT count < 100 x 10^9/L or hemoglobin < 100 g/L (i.e., 10 g/dL) at the lowest dose of HU required to achieve a response;
  • Presence of leg ulcers or other unacceptable HU-related non-hematologic toxicities (such as mucocutaneous manifestations, GI symptoms, pneumonitis, or fever at any dose of HU).
• For patients previously exposed to ruxolitinib, inclusion requires the following in addition to previous treatment for myeloproliferative disorder with HU:
  • Therapy resistant PV after at least 6 months of treatment with ruxolitinib, defined by at least one of following:
    • Need for phlebotomy to achieve Hct < 45%, at least two over 6 months;
    • Uncontrolled leukocytosis (WBC count > 10 x 10^9/L);
    • Uncontrolled thrombocytosis (PLT count > 400 x 10^9/L);
    • Failure to achieve a > 50% reduction in palpable splenomegaly measuring > 5 cm from the left costal margin or failure to become non-palpable in palpable splenomegaly measuring 0-5 cm;
    • Inadequately controlled disease-related symptoms (e.g., pruritus, headache, night sweats, excluding fatigue) after excluding other causes.
• Ruxolitinib intolerance defined as at least one of following at lowest dose of ruxolitinib to achieve adequate response:
  • Cytopenia defined as one or more of the following:
    • Neutropenia, ANC < 1.0 x 10^9/L;
    • Thrombocytopenia, PLT count < 100 x 10^9/L;
    • Anemia, hemoglobin < 10 g/dL.
  • Life threatening infections deemed associated with ruxolitinib or other infections complications possibly associated with ruxolitinib (shingles, TB, hepatitis reactivation) at any time during study treatment.
  • Non-melanoma skin cancer (recurrence of or multiple) at any time during study treatment.
• Adverse events likely caused by ruxolitinib (assessment of attending physician) and that is of a severity that precludes 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.
• Patients must be willing to submit the blood sampling and bone marrow sampling for the PK and pharmacodynamic analyses and exploratory biomarkers.
• Adequate hepatic function assessed by:
  • Serum total bilirubin < 2 mg/dL, unless resulting from hemolysis or known Gilbert’s disease.
    • AST/ALT < 2.5 x institutional ULN.
• Adequate renal function assessed by serum creatinine within reference lab normal limits OR creatinine clearance ≥ 50 mL/min calculated by the Cockcroft Gault.
• Patients must meet all of the general inclusion criteria listed above prior to dosing on Cycle 1, Day 1 (including ECOG and labs checked following initial screening eligibility verification) when screening performed > 72 hours from start of treatment.
• Ability and willingness to comply with the study protocol procedures, including clinical outcome assessment (COA) measures.
• Male and/or female patients
  • Male Patient:
    • Agreement to use contraceptive measures, and agreement to refrain from donating sperm, as defined below:
    • With female partners of childbearing potential or pregnant female partners, men must use a condom during the treatment period and for at least 90 days after the last dose of idasanutlin. Men must refrain from donating sperm during this same period.
  • Female Patients:
    • For women of childbearing potential: agreement to use contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 6 weeks after the last dose of idasanutlin.
    • A woman is considered to be of childbearing potential if she is post-menarcheal, has not reached a post-menopausal state (at least 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus).
    • Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation; male sterilization; established, proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices; and copper intrauterine devices.

Exclusion Criteria:

• Meets the criteria for post PV MF 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.
• Patients 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.
• Treatment with the following agents within 7 days prior to the first dose of idasanutlin:
  • CYP2C8 inhibitors such as gemfibrozil (also a UGT1A3 inhibitor);
  • CYP2C8 substrates such as repaglinide;
  • OATP1B1/3 substrates such as statin drugs.
• Treatment with the following agents within 14 days prior to the first dose of idasanutlin:
  • Strong CYP3A inducers such as rifampin (also a CYP2C8 inducer) and carbamazepine.
• Chronic use of CYP2C8 or OATP1B1/3 substrates during treatment with idasanutlin is prohibited.
• Patients previously treated with MDM2 antagonist therapies or patients receiving interferon-alpha, anagrelide, or ruxolitinib within 28 days or 5 half-lives (whichever is shorter), or HU within 1 day, or patients 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 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 x 10^9/L prior to dosing on Cycle 1 Day 1.
• PLT count ≤ 150 x 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, 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 GI conditions (Crohn’s disease, ulcerative colitis, diverticulosis associated colitis, and Behçt'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 Day 1 Cycle 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
• If the structural abnormality is not found to be clinically significant by the investigator, the patient may still be eligible for the study, after Medical Monitor confirmation has been obtained.
• Unstable angina pectoris
• Presence or history of any type of supraventricular and ventricular arrhythmias, including lone atrial fibrillation or flutter.