Clinical trial NCT03287245: A Study to Evaluate the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of Idasanutlin Monotherapy in Participants With Hydroxyurea-Resistant/Intolerant Polycythemia Vera
Official 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Polycythemia Vera
Keywords: polycythemia vera
PV
P vera
myeloproliferative diseases
hematologic diseases
myeloproliferative neoplasm
MPN
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2017-09-19
Enrollment: 27
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Percentage of Ruxolitinib-Naïve Participants With Splenomegaly at Baseline Who Achieved Composite Response at Week 32
timeFrame: Week 32
measure: Percentage of Ruxolitinib-Naïve Participants Without Splenomegaly at Baseline Who Achieved Hematocrit (Hct) Control Without Phlebotomy at Week 32
timeFrame: Week 32
measure: Percentage of All Ruxolitinib-Naïve Participants (Irrespective of Spleen Size) Who Achieved Hct Control Without Phlebotomy at Week 32
timeFrame: Week 32
measure: Percentage of All Ruxolitinib-Resistant or Intolerant Participants Who Achieved Hct Control Without Phlebotomy at Week 32
timeFrame: From Baseline to Week 32 (Cycle 8 Day 28)
Secondary outcomes:
measure: Percentage of All Ruxolitinib-Naïve and Ruxolitinib-Resistant or Intolerant Participants Who Achieved Complete Hematologic Response at Week 32
timeFrame: Week 32 (Cycle 8 Day 28)
measure: Percentage of All Ruxolitinib-Naïve and Ruxolitinib-Resistant or Intolerant Participants Who Achieved Complete Hematologic Remission at Cycle 11 Day 28
timeFrame: Cycle 11 Day 28
measure: Duration of Complete Hematologic Remission, With a Durable Responder Defined as a Participant in Remission at Week 32 and Cycle 11 Day 28
timeFrame: Week 32 (Cycle 8 Day 28), Cycle 11 Day 28
measure: Percentage of Ruxolitinib-Naïve and Ruxolitinib-Resistant or Intolerant Participants With Splenomegaly at Baseline by Response Per Modified European Leukemia Net (ELN) Criteria
timeFrame: Baseline, Day 28 of Cycles 3, 5, 8, 11, 12, 14, 17, 20 and Final visit (28 days after post-last dose)
measure: Percentage of Ruxolitinib-Naïve and Ruxolitinib-Resistant or Intolerant Participants Without Splenomegaly at Baseline by Response Per Modified ELN Criteria
timeFrame: Baseline, Day 28 of Cycles 3, 5, 8, 11, 12, 14, 17, 20 and Final visit (28 days after post-last dose)
measure: Percentage of All Ruxolitinib-Naïve and Ruxolitinib-Resistant or Intolerant Participants (Irrespective of Spleen Size) by Response Per Modified ELN Criteria
timeFrame: Baseline, Day 28 of Cycles 3, 5, 8, 11, 12, 14, 17, 20 and Final visit (28 days after post-last dose)
measure: 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
timeFrame: From Week 32 (Cycle 8 Day 28) and at least 12 Weeks after until end of study (up to 2 years)
measure: 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
timeFrame: From Week 32 (Cycle 8 Day 28) and at least 12 weeks after until end of study (up to 2 years)
measure: 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
timeFrame: From Week 32 (Cycle 8 Day 28) and at least 12 Weeks after until end of study (up to 2 years)
measure: 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
timeFrame: From Week 32 (Cycle 8 Day 28) and at least 12 weeks after until end of study (up to 2 years)
measure: 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
timeFrame: From Week 32 (Cycle 8 Day 28) and at least 12 Weeks after until end of study (up to 2 years)
measure: 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
timeFrame: From Week 32 (Cycle 8 Day 28) and at least 12 weeks after until end of study (up to 2 years)
measure: Total Number of Participants With Adverse Events by Severity, Graded According to NCI CTCAE v4.0
timeFrame: Baseline to end of study (up to 2 years)
measure: Percentage of Participants With Clinical Laboratory Abnormalities: Hematology Parameters.
timeFrame: Baseline to end of study (up to 2 years)
measure: Percentage of Participants With Clinical Laboratory Abnormalities: Clinical Chemistry Parameters
timeFrame: Baseline to end of study (up to 2 years)
measure: Percentage of Participants With Clinical Laboratory Abnormalities: Urinalysis Parameters
timeFrame: Baseline to end of study (up to 2 years)
measure: Change From Baseline in Electrocardiogram Parameters: PQ(PR), QRS, QT, QTcB, QTcF, and RR Durations
timeFrame: 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)
measure: Change From Baseline in Heart Rate, as Measured by Electrocardiogram
timeFrame: 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)
measure: Change From Baseline in Oral Temperature
timeFrame: 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
measure: Change From Baseline in Pulse Rate
timeFrame: 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
measure: Change From Baseline in Respiratory Rate
timeFrame: 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
measure: Change From Baseline in Systolic Blood Pressure
timeFrame: 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
measure: Change From Baseline in Diastolic Blood Pressure
timeFrame: 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
measure: Eastern Cooperative Oncology Group (ECOG) Performance Status Over Time
timeFrame: Baseline
measure: Percentage of Participants With Concomitant Medications
timeFrame: Overall Study Period
measure: Maximum Serum Concentration Observed (Cmax) of Idasanutlin
timeFrame: Days 1, 2, and 5 of Cycles 1 and 4
measure: Trough Concentration (Ctrough) of Idasanutlin
timeFrame: Days 1, 2, and 5 of Cycles 1 and 4
measure: Time of Maximum Concentration Observed (Tmax) of Idasanutlin
timeFrame: Days 1, 2, and 5 of Cycles 1 and 4
measure: Clearance (CL) of Idasanutlin
timeFrame: Days 1, 2, and 5 of Cycles 1 and 4
measure: Apparent Clearance (CL/F) of Idasanutlin
timeFrame: Days 1, 2, and 5 of Cycles 1 and 4
measure: Volume or Apparent Volume of Distribution (Vdss/F) of Idasanutlin
timeFrame: Days 1, 2, and 5 of Cycles 1 and 4
measure: Area Under the Concentration-Time Curve (AUC) of Idasanutlin
timeFrame: Days 1, 2, and 5 of Cycles 1 and 4
measure: Half-life (t1/2) of Idasanutlin
timeFrame: Days 1, 2, and 5 of Cycles 1 and 4
measure: Baseline and Mean Change From Baseline Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Over Time
timeFrame: 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
measure: 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
timeFrame: Baseline (Cycle 1 Day 1), Cycle 2 Day 1, Cycles 3, 5, 8, 11, 14, 17, 20 Day 28 and Final Visit
measure: Frequency Count of Participant Responses to the Patient Global Impression of Change (PGIC) Question Over Time
timeFrame: 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)
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic - Arizona
state: Arizona
city: Kansas City
country: United States
facility: University of Kansas Cancer Center; Westwood Cancer Center/BMT Output Clinic
state: Kansas
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: Independence
country: United States
facility: Cleveland Clinic Cancer Center
state: Ohio
city: San Antonio
country: United States
facility: University of Texas Health Sciences Center in San Antonio
state: Texas
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital; Haematology Clinical Trials
state: South Australia
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre; Department of Haematology
state: Victoria
city: Toronto
country: Canada
facility: Princess Margaret Cancer Center
state: Ontario
city: Bergamo
country: Italy
facility: ASST PAPA GIOVANNI XXIII; Ematologia
state: Lombardia
city: Varese
country: Italy
facility: Ospedale Di Circolo E Fondazione Macchi; Ematologia
state: Lombardia
city: Firenze
country: Italy
facility: Az. Ospedaliero-Universitaria Careggi; CRIMM
state: Toscana
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.