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Title A Phase II, Single-Arm, Open-Label Study to Evaluate the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of Idasanutlin Monotherapy in Patients with Hydroxyurea-Resistant/Intolerant Polycythemia Vera

IRB ROCH1Z17

CC 17-1239

Hospital Main Campus

Phase Phase 2

Disease Myeloproliferative Neoplasms, Polycythemia Vera (PV/PCV)

Drug Idasanutlin

Description

• To evaluate the efficacy of idasanutlin monotherapy in patients without prior ruxolitinib exposure with HU resistant/intolerant PV:
  • for patients with splenomegaly at baseline using composite response criteria (Hct control without phlebotomy and > 35% decrease in spleen size by imaging) at Week 32 or
  • for patients without splenomegaly at baseline by Hct control without phlebotomy only at Week 32.

• To evaluate the efficacy of idasanutlin monotherapy by using modified ELN hematologic response criteria (complete and partial hematologic response) in patients with baseline splenomegaly, patients without baseline splenomegaly and in total patient population with and without splenomegaly.
• To evaluate the efficacy of idasanutlin monotherapy in patients irrespective of ruxolitinib exposure with HUresistant/intolerant PV:
  • for patients with splenomegaly at baseline using composite response criteria (Hct control without phlebotomy and > 35% decrease in spleen size by imaging) at Week 32 or
  • for patients without splenomegaly at baseline by Hct control without phlebotomy at Week 32.
• To evaluate the safety of idasanutlin monotherapy in patients with HU resistant/intolerant PV
• To characterize the pharmacokinetic (PK) parameters of idasanutlin and M4 metabolite in patients with HU resistant/intolerant PV.
• To evaluate the effect of treatment with idasanutlin on the symptoms of PV, physical function, health-related quality of life (HRQoL), and change in condition in all enrolled patients, as well as in those with and without baseline splenomegaly.

• To assess the relationship between PK exposure and clinical responses, including AEs.
• To assess the pharmacodynamic effects of idasanutlin by serum MIC-1 levels.
• To explore the molecular response to idasanutlin.
• To measure the histologic response (via bone marrow histology).
• To explore the cytogenic response (cytogenetics) to idasanutlin compared to baseline.
• To evaluate potential predictive, pharmacodynamic and response assessment biomarkers for idasanutlin in PV.

Inclusion Criteria

1. Ability to understand and willingness to sign a written informed consent form and comply with the study protocol according to ICH and local regulations.
2. Adults > 18 years of age
3. There must be documentation that the patient has met the revised 2016 WHO criteria for the diagnosis of polycythemia vera (Arber et al 2016; Appendix 4). 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.
   • Major Criteria:
     • 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.
   • Minor Criteria:
     • 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.

4. Hematocrit at initiation of idasanutlin > 40%
5. Phlebotomy-dependent patients with splenomegaly by magnetic resonance imaging (MRI) or computerized tomography (CT) imaging (≥ 450 cm³) or without splenomegaly (< 450 cm³, unpalpable, or prior splenectomy). Phlebotomy dependence is defined as one phlebotomy within 16 weeks before screening and at least one phlebotomy within 16 weeks before screening.
6. Resistance to/intolerance to hydroxyurea according to modified ELN criteria (Barosi et al 2010; Appendix 2):
   • 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 10⁹/L and white blood cell (WBC) count > 10 x 10⁹/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 10⁹/L.
     • PLT count < 100 x 10⁹/L or hemoglobin (Hb) < 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), defined as Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 Grade 3-4 or > one week of CTCAE version 4.0 Grade 2, permanent discontinuation of HU, interruption of HU until toxicity resolved, or hospitalization due to HU toxicity.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
8. Patients must be willing to submit the blood sampling and bone marrow sampling for the PK and pharmacodynamic analyses and exploratory biomarkers.
9. 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.
10. Adequate renal function assessed by serum creatinine within reference lab normal limits OR creatinine clearance ≥ 50 mL/min calculated by the Cockcroft Gault formula.
11. 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.
12. Ability and willingness to comply with the study protocol procedures, including clinical outcome assessment (COA) measures.
13. Male and/or female patients
    • The reliability of sexual abstinence for male and/or female enrollment eligibility needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable methods of contraception (Appendix 11).
      • Male Patient:
        • Agreement to remain abstinent (refrain from heterosexual intercourse) or 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 remain abstinent or use a condom during the treatment period and for at least 90 days after the last dose of idasanutlin to avoid exposing the embryo. Men must refrain from donating sperm during this same period.
      • Female Patients:
        • For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use non-hormonal contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 14 days 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 non-hormonal 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

1. Meets the criteria for post PV MF as defined by the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT).
2. Blast phase disease (> 20% blasts in the marrow or peripheral blood).
3. Clinically-significant thrombosis within 3 months of screening.
4. 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.
5. Patients previously treated with MDM2 antagonist therapies or patients receiving interferon-alpha, anagrelide, or ruxolitinib within 28 days or 5 half-lives, or HU within 1 day, or patients receiving any other cytoreductive or investigational agents within 28 days or 5 half-lives of initial dose. Aspirin is permitted per treatment guidelines for PV unless medically contraindicated.
6. 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.
7. Neutrophil count < 1.5 x 10⁹/L prior to dosing on Cycle 1 Day 1.
8. Platelet count ≤ 150 x 10⁹/L prior to dosing on Cycle 1 Day 1.
9. Women who are pregnant or breastfeeding.
10. Ongoing serious non-healing wound, ulcer, or bone fracture.
11. History of major organ transplant.
12. Uncontrolled intercurrent illness including, but not limited to hepatitis, concurrent malignancy, 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.
13. Patients with active GI conditions (Crohn's disease, ulcerative colitis, diverticulosis associated colitis, and Behcet's disease)