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Clinical Trials/NCT03287245
NCT03287245TerminatedPhase 2

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

Hoffmann-La Roche11 sites in 4 countries27 target enrollmentStarted: February 21, 2018Last updated:
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Conditions
Interventions
Drugs

Trial Snapshot

Phase
Phase 2
Status
Terminated
Enrollment
27
Locations
11
Primary Endpoint
Percentage of All Ruxolitinib-Resistant or Intolerant Participants Who Achieved Hct Control Without Phlebotomy at Week 32
Study OverviewStudy DesignEligibility CriteriaArms & InterventionsOutcomesInvestigatorsSitesRecords & IdentifiersSimilar Trials

Study Overview

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.

Study Design

Study Type
Interventional
Allocation
Na
Intervention Model
Single Group
Primary Purpose
Treatment
Masking
None

Eligibility Criteria

Ages
18 Years to — (Adult, Older Adult)
Sex
All
Accepts Healthy Volunteers
No

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
  • •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

Arms & Interventions

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).

Intervention: Idasanutlin (Drug)

Outcomes

Primary Outcomes

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

Time Frame: From Baseline to Week 32 (Cycle 8 Day 28)

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%.

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

Time Frame: 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%.

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

Time Frame: 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%.

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

Time Frame: 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.

Secondary Outcomes

  • 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)
  • Percentage of All Ruxolitinib-Naïve and Ruxolitinib-Resistant or Intolerant Participants (Irrespective of Spleen Size) 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))
  • 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))
  • 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 With Splenomegaly at Baseline With Durable Response Lasting at Least 12 Weeks From Week 32(From Week 32 (Cycle 8 Day 28) and at least 12 Weeks after until end of study (up to 2 years))
  • Number of Participants With a Duration Response, in All Ruxolitinib-Naïve and Ruxolitinib-Resistant or Intolerant Participants (Irrespective of Spleen Size) With Durable Response Lasting at Least 12 Weeks From Week 32(From Week 32 (Cycle 8 Day 28) and at least 12 weeks after until end of study (up to 2 years))
  • Number of Participants With a Durable Response, in Ruxolitinib-Naïve and Ruxolitinib-Resistant or Intolerant Participants With Splenomegaly at Baseline With Durable Response Lasting at Least 12 Weeks From Week 32(From Week 32 (Cycle 8 Day 28) and at least 12 weeks after until end of study (up to 2 years))
  • Percentage of Ruxolitinib-Naïve and Ruxolitinib-Resistant or Intolerant Participants Without Splenomegaly at Baseline With Durable Response Lasting at Least 12 Weeks From Week 32(From Week 32 (Cycle 8 Day 28) and at least 12 Weeks after until end of study (up to 2 years))
  • Number of Participants With a Durable Response, in Ruxolitinib-Naïve and Ruxolitinib-Resistant or Intolerant Participants Without Splenomegaly at Baseline With Durable Response Lasting at Least 12 Weeks From Week 32(From Week 32 (Cycle 8 Day 28) and at least 12 weeks after until end of study (up to 2 years))
  • Percentage of All Ruxolitinib-Naïve and Ruxolitinib-Resistant or Intolerant Participants (Irrespective of Spleen Size) With Durable Response Lasting at Least 12 Weeks From Week 32(From Week 32 (Cycle 8 Day 28) and at least 12 Weeks after until end of study (up to 2 years))
  • Percentage of Participants With Clinical Laboratory Abnormalities: Hematology Parameters.(Baseline to end of study (up to 2 years))
  • Percentage of Participants With Clinical Laboratory Abnormalities: Clinical Chemistry Parameters(Baseline to end of study (up to 2 years))
  • Total Number of Participants With Adverse Events by Severity, Graded According to NCI CTCAE v4.0(Baseline to end of study (up to 2 years))
  • Percentage of Participants With Clinical Laboratory Abnormalities: Urinalysis Parameters(Baseline to end of study (up to 2 years))
  • Change From Baseline in Electrocardiogram Parameters: PQ(PR), QRS, QT, QTcB, QTcF, and RR Durations(Baseline, Cycle 1 (Day 1, hours 4 and 6, Day 2 pre-dose and 24 Hour, Day 5 pre-dose, 4 and 6 Hour), Cycle 2 (Day 1 pre-dose only), Cycle 3 (Day 1 pre-dose, 4 and 6 Hour), Cycle 4 (Day 1 pre-dose and 4 Hour))
  • Change From Baseline in Heart Rate, as Measured by Electrocardiogram(Baseline, Cycle 1 (Day 1, hours 4 and 6, Day 2 pre-dose and 24 Hour, Day 5 pre-dose, 4 and 6 Hour), Cycle 2 (Day 1 pre-dose only), Cycle 3 (Day 1 pre-dose, 4 and 6 Hour), Cycle 4 (Day 1 pre-dose and 4 Hour))
  • Percentage of Participants With Concomitant Medications(Overall Study Period)
  • Change From Baseline in Diastolic Blood Pressure(Baseline, Cycle 1 (Days 15 and 22), Cycle 2 and 3 (Days 1 and 15), Each Cycle 4-23 (Day 1 only) and Final Visit)
  • Maximum Serum Concentration Observed (Cmax) of Idasanutlin(Days 1, 2, and 5 of Cycles 1 and 4)
  • Apparent Clearance (CL/F) of Idasanutlin(Days 1, 2, and 5 of Cycles 1 and 4)
  • Change From Baseline in Oral Temperature(Baseline, Cycle 1 (Days 15 and 22), Cycle 2 and 3 (Days 1 and 15), Each Cycle 4-23 (Day 1 only) and Final Visit)
  • Change From Baseline in Systolic Blood Pressure(Baseline, Cycle 1 (Days 15 and 22), Cycle 2 and 3 (Days 1 and 15), Each Cycle 4-23 (Day 1 only) and Final Visit)
  • Eastern Cooperative Oncology Group (ECOG) Performance Status Over Time(Baseline)
  • Time of Maximum Concentration Observed (Tmax) of Idasanutlin(Days 1, 2, and 5 of Cycles 1 and 4)
  • Baseline and Mean Change From Baseline Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Over Time(Baseline (Cycle 1 Day 1), Cycle 2 Day 1, Days 28 of Cycles 3, 5, 8 (Week 32), 11, 14, 17 ) Day 28, Cycle 5 Day 28, End of Cycle 8 (Week 32), and Final Visit)
  • Frequency Count of Participant Responses to the Patient Global Impression of Change (PGIC) Question Over Time(Cycle 2 Day 1, Cycle 3 Day 28, Cycle 5 Day 28, End of Cycle 8 (Week 32), and every 3 cycles thereafter (1 cycle is 28 days) until end of study (up to 2 years))
  • Change From Baseline in Pulse Rate(Baseline, Cycle 1 (Days 15 and 22), Cycle 2 and 3 (Days 1 and 15), Each Cycle 4-23 (Day 1 only) and Final Visit)
  • Change From Baseline in Respiratory Rate(Baseline, Cycle 1 (Days 15 and 22), Cycle 2 and 3 (Days 1 and 15), Each Cycle 4-23 (Day 1 only) and Final Visit)
  • Trough Concentration (Ctrough) of Idasanutlin(Days 1, 2, and 5 of Cycles 1 and 4)
  • Clearance (CL) of Idasanutlin(Days 1, 2, and 5 of Cycles 1 and 4)
  • Volume or Apparent Volume of Distribution (Vdss/F) of Idasanutlin(Days 1, 2, and 5 of Cycles 1 and 4)
  • Area Under the Concentration-Time Curve (AUC) of Idasanutlin(Days 1, 2, and 5 of Cycles 1 and 4)
  • Half-life (t1/2) of Idasanutlin(Days 1, 2, and 5 of Cycles 1 and 4)
  • Baseline and Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Scores Over Time(Baseline (Cycle 1 Day 1), Cycle 2 Day 1, Cycles 3, 5, 8, 11, 14, 17, 20 Day 28 and Final Visit)

Investigators

Sponsor Class
Industry
Responsible Party
Sponsor

Study Sites (11)

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