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

NCT03287245 | Terminated Phase 2 Results FDA Drug

• 2 other identifiers: NP397612017-000861-58
• Study Type: interventional
• Target: 27
• Locations: 4 countries
• Sites: 11

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

Outcome Measures

Primary Outcomes (4)

• Percentage of Ruxolitinib-Naïve Participants With Splenomegaly at Baseline Who Achieved Composite Response at Week 32

  Composite response is defined as hematocrit (Hct) control without phlebotomy and ≥35% decrease in spleen size by imaging at Week 32. Hct control is defined as protocol-specified ineligibility for phlebotomy between Weeks 8 to 32 and ≤1 instance of phlebotomy eligibility between first dose and Week 8. Eligibility for phlebotomy is defined as a Hct of ≥45% that was ≥3% higher than baseline level or a Hct of \>48%. One Cycle is 28 Days.

  Week 32

• Percentage of Ruxolitinib-Naïve Participants Without Splenomegaly at Baseline Who Achieved Hematocrit (Hct) Control Without Phlebotomy at Week 32

  Hct control is defined as protocol-specified ineligibility for phlebotomy between Weeks 8 to 32 and ≤1 instance of phlebotomy eligibility between first dose and Week 8. Eligibility for phlebotomy is defined as a Hct level ≥45% that was ≥3% higher than baseline level or a Hct level of \>48%.

  Week 32

• Percentage of All Ruxolitinib-Naïve Participants (Irrespective of Spleen Size) Who Achieved Hct Control Without Phlebotomy at Week 32

  Hct control is defined as protocol-specified ineligibility for phlebotomy between Weeks 8 to 32 and ≤1 instance of phlebotomy eligibility between first dose and Week 8. Eligibility for phlebotomy is defined as a Hct level ≥45% that was ≥3% higher than baseline level or a Hct level of \>48%.

  Week 32

• Percentage of All Ruxolitinib-Resistant or Intolerant Participants Who Achieved Hct Control Without Phlebotomy at Week 32

  Hct control is defined as protocol-specified ineligibility for phlebotomy between Weeks 8 to 32 and ≤1 instance of phlebotomy eligibility between first dose and Week 8. Eligibility for phlebotomy is defined as a Hct level ≥45% that was ≥3% higher than baseline level or a Hct level of \>48%.

  From Baseline to Week 32 (Cycle 8 Day 28)

Secondary Outcomes (36)

• Percentage of All Ruxolitinib-Naïve and Ruxolitinib-Resistant or Intolerant Participants Who Achieved Complete Hematologic Response at Week 32

  Week 32 (Cycle 8 Day 28)

• Percentage of All Ruxolitinib-Naïve and Ruxolitinib-Resistant or Intolerant Participants Who Achieved Complete Hematologic Remission at Cycle 11 Day 28

  Cycle 11 Day 28

• Duration of Complete Hematologic Remission, With a Durable Responder Defined as a Participant in Remission at Week 32 and Cycle 11 Day 28

  Week 32 (Cycle 8 Day 28), Cycle 11 Day 28

• Percentage of Ruxolitinib-Naïve and Ruxolitinib-Resistant or Intolerant Participants With Splenomegaly at Baseline by Response Per Modified European Leukemia Net (ELN) Criteria

  Baseline, Day 28 of Cycles 3, 5, 8, 11, 12, 14, 17, 20 and Final visit (28 days after post-last dose)

• Percentage of Ruxolitinib-Naïve and Ruxolitinib-Resistant or Intolerant Participants Without Splenomegaly at Baseline by Response Per Modified ELN Criteria

  Baseline, Day 28 of Cycles 3, 5, 8, 11, 12, 14, 17, 20 and Final visit (28 days after post-last dose)

Study Arms (1)

Idasanutlin

EXPERIMENTAL

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).

Drug: Idasanutlin

Interventions

Idasanutlin 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.

Also known as: RO5503781, RG7388

Idasanutlin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (11)

Mayo Clinic - Arizona

Phoenix, Arizona, 85054, United States

Location

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

Kansas City, Kansas, 66205, United States

Location

Icahn School of Medicine at Mount Sinai

New York, New York, 10029, United States

Location

Cleveland Clinic Cancer Center

Independence, Ohio, 44131, United States

Location

University of Texas Health Sciences Center in San Antonio

San Antonio, Texas, 78229, United States

Location

Royal Adelaide Hospital; Haematology Clinical Trials

Adelaide, South Australia, 5000, Australia

Location

Peter MacCallum Cancer Centre; Department of Haematology

Melbourne, Victoria, 3002, Australia

Location

Princess Margaret Cancer Center

Toronto, Ontario, M5G 1Z5, Canada

Location

ASST PAPA GIOVANNI XXIII; Ematologia

Bergamo, Lombardy, 24127, Italy

Location

Ospedale Di Circolo E Fondazione Macchi; Ematologia

Varese, Lombardy, 21100, Italy

Location

Az. Ospedaliero-Universitaria Careggi; CRIMM

Florence, Tuscany, 50134, Italy

Location

Related Publications (1)

• 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.

  PMID: 34933330 DERIVED

Related Links

• 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.

MeSH Terms

Conditions

Polycythemia Vera; Hematologic Diseases; Myeloproliferative Disorders

Interventions

RG7388

Condition Hierarchy (Ancestors)

Bone Marrow Neoplasms; Hematologic Neoplasms; Neoplasms by Site; Neoplasms; Bone Marrow Diseases; Hemic and Lymphatic Diseases

Results Point of Contact

• Title: Medical Communications
• Organization: Hoffmann-La Roche

genentech@druginfo.com

800 821-8590

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 8, 2017
• First Posted: September 19, 2017
• Study Start: February 21, 2018
• Primary Completion: March 3, 2020
• Study Completion: March 3, 2020
• Last Updated: December 8, 2021
• Results First Posted: May 27, 2021

Record last verified: 2021-12

Locations

IT (3); US (5); CA (1); AU (2)