| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Polycythemia Vera is a blood disorder in which your bone marrow makes too many red blood cells. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10036061 |
| E.1.2 | Term | Polycythemia vera |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Ruxolitinib Naive Patients:
• To evaluate the efficacy of idasanutlin monotherapy in patients with HU resistant/intolerant PV and without prior ruxolitinib exposure
o For patients with splenomegaly at baseline using composite response criteria
o For patients without splenomegaly at baseline by hematocrit (Hct) control without phlebotomy
o For all patients (with and without splenomegaly) by Hct control without phlebotomy.
Ruxolitinib Resistant or Intolerant Patients
• To evaluate the efficacy of idasanutlin monotherapy by Hct control without phlebotomy. |
|
| E.2.2 | Secondary objectives of the trial |
Ruxolitinib Naive and -Resistant or Intolerant Patients:
• To evaluate the efficacy of idasanutlin monotherapy in all patients (with and without splenomegaly) by complete hematologic response
• To evaluate the efficacy of idasanutlin monotherapy by using modified ELN hematologic response criteria (complete and partial response) in patients with baseline splenomegaly, patients without baseline splenomegaly and in all patients irrespective of spleen size
• To evaluate the safety of idasanutlin in HU resistant/intolerant PV patients for all patients
• To characterize the PK parameters of idasanutlin and M4 metabolite in PV patients
• To evaluate the effect of treatment with idasanutlin on the symptoms of PV, physical functioning, general health status/ Health-related quality of life (HRQoL), and change in condition in all enrolled patients, as well as in those with and without baseline splenomegaly. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Adults > 18 years of age.
- PV according to the 2016 WHO criteria for the diagnosis of polycythemia vera.
- Hematocrit at screening and initiation of idasanutlin > 40%.
- Phlebotomy-dependent patients with splenomegaly by magnetic resonance imaging (MRI) or computerized tomography (CT) imaging (>= 450 cm3) or without splenomegaly (< 450 cm3, or prior splenectomy).
- Resistance to/intolerance to hydroxyurea according to modified ELN criteria.
- For patients in the ruxolitinib intolerant or resistant group, documentation of adverse events likely caused by ruxolitinib inadequate disease control on ruxolitinib in addition to previous hydroxyurea intolerance/resistance.
- 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 and renal function.
- For women of childbearing potential: agreement to or use non-hormonal 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.
- 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. |
|
| E.4 | Principal 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.
- Patients previously treated with MDM2 antagonist therapies
- 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 of initial dose (whichever is shorter). 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 × 10^9/L prior to dosing on Cycle 1 Day 1.
- Platelet count <= 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 GI 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 Day 1 Cycle 1. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Ruxolitinib Naive Patients:
1. Composite response at Week 32 (Hct control without phlebotomy and > 35% decrease in spleen size by imaging at Week 32) for patients with splenomegaly at baseline.
2. Hct control with freedom from phlebotomy at Week 32 in patients without splenomegaly at baseline and in all patients (with and without splenomegaly).
Ruxolitinib-Resistant or Intolerant Patients:
3. Hct control without phlebotomy at Week 32 in patients with and without splenomegaly at baseline and in all patients |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Ruxolitinib- Naive Patients and Resistant or Intolerant Patients:
1. Complete hematologic response criteria at Week 32 for ruxolitinib naïve patients and all patients irrespective of prior ruxolitinib exposure
2. Complete hematologic remission at response Cycle 11 Day 28, including proportion of patients with durable response lasting at least 12 week from Week 32
3. Response by using modified ELN hematologic response at Week 32 for patients with splenomegaly at baseline and Hct control at Week 32 in patients without splenomegaly and in all patients (with and without splenomegaly) at baseline irrespective of prior ruxolitinib exposure.
4. Duration of response, including proportion of patients with durable response lasting at least 12 weeks
5. Clinical safety laboratory tests (hematology, clinical chemistry, urinalysis, pregnancy testing)
6. Incidence, nature and severity of AEs graded according to the NCI CTCAE v4.0
7. Incidence and severity of AEs, including targeted AEs.
8. Incidence of ECOG PS, ECG, vital signs abnormalities
9. Concomitant medication
10. Maximum serum concentration of idasanutlin observed (Cmax)
11. Trough concentration of idasanutlin (Ctrough)
12. Time of maximum concentration observed for is idasanutlin (tmax)
13. Clearance (CL) of idasanutlin
14. Apparent clearance (CL/F) of idasanutlin
15. Volume or apparent volume of distribution (Vdss/F) of idasanutlin
16. Area under the curve (AUC) of idasanutlin
17. Half-life (t1/2) of idasanutlin
18. Mean and mean change from baseline in MPN symptom assessment form total symptom score (MPN-SAF TSS)
19. Mean and mean change from baseline in European Organization for Research and Treatment of Cancer
Quality of Life Questionnaire–Core 30 (EORTC QLQ-C30)
20. Distribution of responses at each assessment and across time of Patient Global Impression of Change (PGIC) scale.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. At Week 32
2. Day 28 of Cycle 11
3-9. Up to 2 years
10-17. Day 1, Day 2, Day 5 of Cycle 1
18-19. Day 1 of Cycle 1, Cycle 2, Cycle 3, Day 28 of Cycle 5, Week 32, end of study (2 years) or 28 days post last dose
20. Day 1 of Cycle 2, Cycle 3, Day 28 of Cycle 5, Week 32, end of study (2 years) or 28 days post last dose. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Brazil |
| Canada |
| Czech Republic |
| France |
| Hungary |
| Italy |
| Russian Federation |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The end of the study is defined as the date when the last data point from the last patient is received, up to 28 days post final dose.
The end of study for each patient is defined as 2 years post initial dose.
Due to the exploratory nature of this clinical study, its conduct can be discontinued at any time at the discretion of the Sponsor. This will not constitute a premature termination of the study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
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