A Study to Evaluate the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of Idasanutlin Monotherapy in Participants With Hydroxyurea-Resistant/Intolerant Polycythemia Vera

NCT ID: NCT03287245

Last Updated: 2021-12-08

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 27 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-02-21
• Study Completion Date: 2020-03-03

Brief 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.

Conditions

Polycythemia Vera

Keywords

polycythemia vera; PV; P vera; myeloproliferative diseases; hematologic diseases; myeloproliferative neoplasm; MPN

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Idasanutlin

Two cohorts of ruxolitinib-naïve and ruxolitinib-resitant or intolerant participants will be enrolled to receive idasanutlin once daily for 5 days, every 28 days, until treatment discontinuation or end of study (up to 2 years).

Group Type: EXPERIMENTAL

Idasanutlin

Intervention Type: DRUG

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.

Interventions

Idasanutlin

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.

Intervention Type: DRUG

Other Intervention Names

RO5503781; RG7388

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Hoffmann-La Roche

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clinical Trials

Role: STUDY_DIRECTOR

Hoffmann-La Roche

Locations

Mayo Clinic - Arizona

Phoenix, Arizona, United States

University of Kansas Cancer Center; Westwood Cancer Center/BMT Output Clinic

Kansas City, Kansas, United States

Icahn School of Medicine at Mount Sinai

New York, New York, United States

Cleveland Clinic Cancer Center

Independence, Ohio, United States

University of Texas Health Sciences Center in San Antonio

San Antonio, Texas, United States

Royal Adelaide Hospital; Haematology Clinical Trials

Adelaide, South Australia, Australia

Peter MacCallum Cancer Centre; Department of Haematology

Melbourne, Victoria, Australia

Princess Margaret Cancer Center

Toronto, Ontario, Canada

ASST PAPA GIOVANNI XXIII; Ematologia

Bergamo, Lombardy, Italy

Ospedale Di Circolo E Fondazione Macchi; Ematologia

Varese, Lombardy, Italy

Az. Ospedaliero-Universitaria Careggi; CRIMM

Florence, Tuscany, Italy

Countries

Hungary; United Kingdom; United States; Australia; Canada; Italy

References

Mascarenhas J, Passamonti F, Burbury K, El-Galaly TC, Gerds A, Gupta V, Higgins B, Wonde K, Jamois C, Kovic B, Huw LY, Katakam S, Maffioli M, Mesa R, Palmer J, Bellini M, Ross DM, Vannucchi AM, Yacoub A. The MDM2 antagonist idasanutlin in patients with polycythemia vera: results from a single-arm phase 2 study. Blood Adv. 2022 Feb 22;6(4):1162-1174. doi: 10.1182/bloodadvances.2021006043.

Reference Type: DERIVED

PMID: 34933330 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

https://www.pioneeringhealthcare.com/p-vera

Pioneeringhealthcare.com supports an online community of people impacted by Polycythemia Vera (PV, or P Vera), and provides explanations of medical terms and insights about the purpose of Roche's new clinical trial (NP39761) for patients with P Vera.

Other Identifiers

2017-000861-58

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

NP39761

Identifier Type: -

Identifier Source: org_study_id