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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT03287245




Registration number
NCT03287245
Ethics application status
Date submitted
8/09/2017
Date registered
19/09/2017
Date last updated
3/04/2020

Titles & IDs
Public title
A Study to Evaluate the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of Idasanutlin Monotherapy in Participants With Hydroxyurea-Resistant/Intolerant Polycythemia Vera
Scientific 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
Secondary ID [1] 0 0
2017-000861-58
Secondary ID [2] 0 0
NP39761
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Polycythemia Vera 0 0
Condition category
Condition code
Blood 0 0 0 0
Haematological diseases
Blood 0 0 0 0
Other blood disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Idasanutlin

Experimental: 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).


Treatment: Drugs: 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 code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
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%.
Timepoint [1] 0 0
From Baseline to Week 32 (Cycle 8 Day 28)
Primary outcome [2] 0 0
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%.
Timepoint [2] 0 0
From Baseline to Week 32 (Cycle 8 Day 28)
Primary outcome [3] 0 0
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%.
Timepoint [3] 0 0
From Baseline to Week 32 (Cycle 8 Day 28)
Primary outcome [4] 0 0
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%.
Timepoint [4] 0 0
From Baseline to Week 32 (Cycle 8 Day 28)
Secondary outcome [1] 0 0
Percentage of All Ruxolitinib-Naïve and Ruxolitinib-Resistant or Intolerant Participants who Achieved Complete Hematologic Response at Week 32 - Complete hematologic response requires all of the following: Hct control without phlebotomy; White blood cell (WBC) count =10 × 10^9/Liter (L) at Week 32; and Platelet count =400 × 10^9/L 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%.
Timepoint [1] 0 0
From Baseline to Week 32 (Cycle 8 Day 28)
Secondary outcome [2] 0 0
Percentage of All Ruxolitinib-Naïve and Ruxolitinib-Resistant or Intolerant Participants who Achieved Complete Hematologic Remission at Cycle 11 Day 28 - Complete hematologic remission requires all of the following: Hct control without phlebotomy between Weeks 32 and Cycle 11 Day 28; WBC count =10 × 10^9/L at Cycle 11 Day 28; and Platelet count =400 × 10^9/L at Week 32. Hct control is defined as protocol-specified ineligibility for phlebotomy. Eligibility for phlebotomy is defined as a Hct level =45% that was =3% higher than baseline level or a Hct level of >48%.
Timepoint [2] 0 0
Baseline and from Week 32 (Cycle 8 Day 28) to Cycle 11 Day 28 (1 cycle is 28 days)
Secondary outcome [3] 0 0
Duration of Complete Hematologic Remission, with a Durable Responder Defined as a Participant in Remission at Week 32 and Cycle 11 Day 28 - Complete hematologic remission requires all of the following: Hct control without phlebotomy between Week 32 (Cycle 8 Day 28) and Cycle 11 Day 28; WBC count =10 × 10^9/L at Cycle 11 Day 28; and Platelet count =400 × 10^9/L at Week 32. Hct control is defined as protocol-specified ineligibility for phlebotomy. Eligibility for phlebotomy is defined as a Hct level =45% that was =3% higher than baseline level or a Hct level of >48%.
Timepoint [3] 0 0
Baseline, Week 32 (Cycle 8 Day 28), Cycle 11 Day 28, and every 3 cycles thereafter (1 cycle is 28 days) until end of study (up to 2 years)
Secondary outcome [4] 0 0
Percentage of Ruxolitinib-Naïve and Ruxolitinib-Resistant or Intolerant Participants With Splenomegaly at Baseline by Response per Modified European Leukemia Net (ELN) Criteria - Complete response (CR) includes all of the following: Hct <45% without phlebotomy; Platelet count =400 × 10^9/L; WBC count =10 × 10^9/L; Normal spleen size on imaging; and No disease-related symptoms. Partial response (PR): in participants who do not fulfill the criteria for CR: Hct <45% without phlebotomy or response in 3 or more of the other criteria. No response (NR): any response that does not satisfy partial response. Progressive disease (PD): increased bone marrow fibrosis from baseline, and/or transformation to myelofibrosis (MF), myelodysplastic syndrome (MDS) or acute leukemia.
Timepoint [4] 0 0
Baseline, Cycle 3 Day 28, Cycle 5 Day 28, Cycle 8 Day 28 (Week 32), and every 3 cycles thereafter (1 cycle is 28 days) until end of study (up to 2 years)
Secondary outcome [5] 0 0
Percentage of Ruxolitinib-Naïve and Ruxolitinib-Resistant or Intolerant Participants Without Splenomegaly at Baseline by Response per Modified ELN Criteria - Complete response (CR) includes all of the following: Hct <45% without phlebotomy; Platelet count =400 × 10^9/L; WBC count =10 × 10^9/L; Normal spleen size on imaging; and No disease-related symptoms. Partial response (PR): in participants who do not fulfill the criteria for CR: Hct <45% without phlebotomy or response in 3 or more of the other criteria. No response (NR): any response that does not satisfy partial response. Progressive disease (PD): increased bone marrow fibrosis from baseline, and/or transformation to myelofibrosis (MF), myelodysplastic syndrome (MDS) or acute leukemia.
Timepoint [5] 0 0
Baseline, Cycle 3 Day 28, Cycle 5 Day 28, Cycle 8 Day 28 (Week 32), and every 3 cycles thereafter (1 cycle is 28 days) until end of study (up to 2 years)
Secondary outcome [6] 0 0
Percentage of All Ruxolitinib-Naïve and Ruxolitinib-Resistant or Intolerant Participants (Irrespective of Spleen Size) by Response per Modified ELN Criteria - Complete response (CR) includes all of the following: Hct <45% without phlebotomy; Platelet count =400 × 10^9/L; WBC count =10 × 10^9/L; Normal spleen size on imaging; and No disease-related symptoms. Partial response (PR): in participants who do not fulfill the criteria for CR: Hct <45% without phlebotomy or response in 3 or more of the other criteria. No response (NR): any response that does not satisfy partial response. Progressive disease (PD): increased bone marrow fibrosis from baseline, and/or transformation to myelofibrosis (MF), myelodysplastic syndrome (MDS) or acute leukemia.
Timepoint [6] 0 0
Baseline, Cycle 3 Day 28, Cycle 5 Day 28, Cycle 8 Day 28 (Week 32), and every 3 cycles thereafter (1 cycle is 28 days) until end of study (up to 2 years)
Secondary outcome [7] 0 0
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 - The percentage of participants with a durable response lasting at least 12 weeks from Week 32 will be analyzed by the type of response achieved: Hct control, complete hematologic response, ELN 2009 response criteria, and composite response, if applicable.
Timepoint [7] 0 0
Baseline, Cycle 3 Day 28, Cycle 5 Day 28, Week 32 (Cycle 8 Day 28), Cycle 11 Day 28, and every 3 cycles thereafter (1 cycle is 28 days) until end of study (up to 2 years)
Secondary outcome [8] 0 0
Duration of 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 - The duration of response in participants with a durable response lasting at least 12 weeks from Week 32 will be analyzed by the type of response achieved: Hct control, complete hematologic response, ELN 2009 response criteria, and composite response, if applicable.
Timepoint [8] 0 0
Baseline, Cycle 3 Day 28, Cycle 5 Day 28, Week 32 (Cycle 8 Day 28), Cycle 11 Day 28, and every 3 cycles thereafter (1 cycle is 28 days) until end of study (up to 2 years)
Secondary outcome [9] 0 0
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 - The percentage of participants with a durable response lasting at least 12 weeks from Week 32 will be analyzed by the type of response achieved: Hct control, complete hematologic response, ELN 2009 response criteria, and composite response, if applicable.
Timepoint [9] 0 0
Baseline, Cycle 3 Day 28, Cycle 5 Day 28, Week 32 (Cycle 8 Day 28), Cycle 11 Day 28, and every 3 cycles thereafter (1 cycle is 28 days) until end of study (up to 2 years)
Secondary outcome [10] 0 0
Duration of 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 - The duration of response in participants with a durable response lasting at least 12 weeks from Week 32 will be analyzed by the type of response achieved: Hct control, complete hematologic response, ELN 2009 response criteria, and composite response, if applicable.
Timepoint [10] 0 0
Baseline, Cycle 3 Day 28, Cycle 5 Day 28, Week 32 (Cycle 8 Day 28), Cycle 11 Day 28, and every 3 cycles thereafter (1 cycle is 28 days) until end of study (up to 2 years)
Secondary outcome [11] 0 0
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 - The percentage of participants with a durable response lasting at least 12 weeks from Week 32 will be analyzed by the type of response achieved: Hct control, complete hematologic response, ELN 2009 response criteria, and composite response, if applicable.
Timepoint [11] 0 0
Baseline, Cycle 3 Day 28, Cycle 5 Day 28, Week 32 (Cycle 8 Day 28), Cycle 11 Day 28, and every 3 cycles thereafter (1 cycle is 28 days) until end of study (up to 2 years)
Secondary outcome [12] 0 0
Duration of 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 - The duration of response in participants with a durable response lasting at least 12 weeks from Week 32 will be analyzed by the type of response achieved: Hct control, complete hematologic response, ELN 2009 response criteria, and composite response, if applicable.
Timepoint [12] 0 0
Baseline, Cycle 3 Day 28, Cycle 5 Day 28, Week 32 (Cycle 8 Day 28), Cycle 11 Day 28, and every 3 cycles thereafter (1 cycle is 28 days) until end of study (up to 2 years)
Secondary outcome [13] 0 0
Total Number of Participants With Adverse Events by Severity, Graded According to NCI CTCAE v4.0 - An adverse event is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a study drug, whether or not considered related to the study drug. The adverse event severity grading scale for the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI CTCAE v4.0) will be used for assessing adverse event severity.
Timepoint [13] 0 0
From Baseline to end of study (up to 2 years)
Secondary outcome [14] 0 0
Percentage of Participants With Clinical Laboratory Abnormalities: Hematology Parameters - Hematology parameter laboratory values falling outside the standard reference range will be recorded as either high or low.
Timepoint [14] 0 0
From Baseline to end of study (up to 2 years)
Secondary outcome [15] 0 0
Percentage of Participants With Clinical Laboratory Abnormalities: Clinical Chemistry Parameters - Clinical chemistry parameter laboratory values falling outside the standard reference range will be recorded as either high or low.
Timepoint [15] 0 0
From Baseline to end of study (up to 2 years)
Secondary outcome [16] 0 0
Percentage of Participants With Clinical Laboratory Abnormalities: Urinalysis Parameters - Urinalysis parameter laboratory values falling outside the standard reference range will be recorded as either high or low.
Timepoint [16] 0 0
From Baseline to end of study (up to 2 years)
Secondary outcome [17] 0 0
Change from Baseline in Electrocardiogram Parameters: PQ(PR), QRS, QT, QTcB, QTcF, and RR Durations
Timepoint [17] 0 0
Baseline, Cycle 1 Days 1, 2, and 5, Cycle 2 Day 1, Cycle 3 Day 1, and Day 1 of each cycle thereafter (1 cycle is 28 days) until end of study (up to 2 years)
Secondary outcome [18] 0 0
Change from Baseline in Heart Rate, as Measured by Electrocardiogram
Timepoint [18] 0 0
Baseline, Cycle 1 Days 1, 2, and 5, Cycle 2 Day 1, Cycle 3 Day 1, and Day 1 of each cycle thereafter (1 cycle is 28 days) until end of study (up to 2 years)
Secondary outcome [19] 0 0
Change from Baseline in Oral Temperature
Timepoint [19] 0 0
Baseline, Cycle 1 Days 1, 15, and 22, Days 1 and 15 of Cycles 2 and 3, and Day 1 of Cycle 4 and each cycle thereafter (1 cycle is 28 days) until end of study (up to 2 years)
Secondary outcome [20] 0 0
Change from Baseline in Pulse Rate
Timepoint [20] 0 0
Baseline, Cycle 1 Days 1, 15, and 22, Days 1 and 15 of Cycles 2 and 3, and Day 1 of Cycle 4 and each cycle thereafter (1 cycle is 28 days) until end of study (up to 2 years)
Secondary outcome [21] 0 0
Change from Baseline in Respiratory Rate
Timepoint [21] 0 0
Baseline, Cycle 1 Days 1, 15, and 22, Days 1 and 15 of Cycles 2 and 3, and Day 1 of Cycle 4 and each cycle thereafter (1 cycle is 28 days) until end of study (up to 2 years)
Secondary outcome [22] 0 0
Change from Baseline in Systolic Blood Pressure
Timepoint [22] 0 0
Baseline, Cycle 1 Days 1, 15, and 22, Days 1 and 15 of Cycles 2 and 3, and Day 1 of Cycle 4 and each cycle thereafter (1 cycle is 28 days) until end of study (up to 2 years)
Secondary outcome [23] 0 0
Change from Baseline in Diastolic Blood Pressure
Timepoint [23] 0 0
Baseline, Cycle 1 Days 1, 15, and 22, Days 1 and 15 of Cycles 2 and 3, and Day 1 of Cycle 4 and each cycle thereafter (1 cycle is 28 days) until end of study (up to 2 years)
Secondary outcome [24] 0 0
Eastern Cooperative Oncology Group (ECOG) Performance Status Over Time - The ECOG performance status is a scale used to quantify cancer patients' general well-being and activities of daily life. The scale ranges from 0 to 5, with 0 denoting perfect health and 5 indicating death. The 6 categories are 0=Asymptomatic (Fully active, able to carry on all pre-disease activities without restriction), 1=Symptomatic but completely ambulatory (Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature), 2=Symptomatic, < 50% in bed during the day (Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours), 3=Symptomatic, > 50% in bed, but not bedbound (Capable of only limited self-care, confined to bed or chair 50% or more of waking hours), 4=Bedbound (Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair), 5=Death.
Timepoint [24] 0 0
From Baseline to end of study (up to 2 years)
Secondary outcome [25] 0 0
Percentage of Participants With Concomitant Medications
Timepoint [25] 0 0
From Baseline to end of study (up to 2 years)
Secondary outcome [26] 0 0
Maximum Serum Concentration Observed (Cmax) of Idasanutlin - Cmax is the maximum observed concentration of drug in blood.
Timepoint [26] 0 0
Days 1, 2, and 5 of Cycles 1 and 4
Secondary outcome [27] 0 0
Trough Concentration (Ctrough) of Idasanutlin - Ctrough is the measured concentration of a drug at the end of a dosing interval at steady state.
Timepoint [27] 0 0
Days 1, 2, and 5 of Cycles 1 and 4
Secondary outcome [28] 0 0
Time of Maximum Concentration Observed (tmax) of Idasanutlin - Tmax is the time elapsed from the time of drug administration to maximum plasma concentration.
Timepoint [28] 0 0
Days 1, 2, and 5 of Cycles 1 and 4
Secondary outcome [29] 0 0
Clearance (CL) of Idasanutlin - CL is a measure of the body's elimination of a drug from plasma over time.
Timepoint [29] 0 0
Days 1, 2, and 5 of Cycles 1 and 4
Secondary outcome [30] 0 0
Apparent Clearance (CL/F) of Idasanutlin - CL/F is a measure of the body's elimination of a drug from plasma over time, after oral administration.
Timepoint [30] 0 0
Days 1, 2, and 5 of Cycles 1 and 4
Secondary outcome [31] 0 0
Volume or Apparent Volume of Distribution (Vdss/F) of Idasanutlin - Vdss/F is the theoretical volume that would be necessary to contain the total amount of an administered drug at the same concentration that it is observed in the plasma.
Timepoint [31] 0 0
Days 1, 2, and 5 of Cycles 1 and 4
Secondary outcome [32] 0 0
Area Under the Concentration-Time Curve (AUC) of Idasanutlin - AUC (from zero to infinity) represents the total drug exposure over time.
Timepoint [32] 0 0
Days 1, 2, and 5 of Cycles 1 and 4
Secondary outcome [33] 0 0
Half-life (t1/2) of Idasanutlin - t1/2 is defined as the time required for the drug plasma concentration to be reduced to half.
Timepoint [33] 0 0
Days 1, 2, and 5 of Cycles 1 and 4
Secondary outcome [34] 0 0
Baseline and Mean Change from Baseline Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Over Time - The MPN-SAF TSS is an assessment form to measure the severity of 9 clinically important symptoms of polycythemia vera. These include: early satiety, abdominal discomfort, inactivity, concentration issues, night sweats, itching, bone pain, fever, and weight loss. The participant provides a severity score for each additional symptom on a scale of 0 (none/absent) to 10 (worst imaginable). A tenth symptom, fatigue, is assessed using the "worst" fatigue item from the Brief Fatigue Inventory (BFI).
Timepoint [34] 0 0
Baseline (Cycle 1 Day 1), 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)
Secondary outcome [35] 0 0
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 - EORTC QLQ-C30: includes functional scales (physical, role, cognitive, emotional, and social), global health status, symptom scales (fatigue, pain, nausea/vomiting) and single items (dyspnoea, appetite loss, insomnia, constipation/diarrhea and financial difficulties). Most questions use a 4-point scale (1 'Not at all' to 4 'Very much'; 2 questions used 7-point scale [1 'very poor' to 7 'Excellent']). Scores are averaged and transformed to 0-100 scale; higher score=better level of functioning or greater degree of symptoms.
Timepoint [35] 0 0
Baseline (Cycle 1 Day 1), 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)
Secondary outcome [36] 0 0
Frequency Count of Participant Responses to the Patient Global Impression of Change (PGIC) Question Over Time - The PGIC is a one-item measure used to assess perceived treatment benefit. Participants will be asked "Since the start of the treatment you've received in this study, your polycythemia vera (PV) symptoms are: 'very much improved', 'much improved', 'minimally improved', 'no change', 'minimally worse', 'much worse', and 'very much worse'.
Timepoint [36] 0 0
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)

Eligibility
Key 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
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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

Study design
Purpose of the study
Treatment
Allocation to intervention
N/A
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Terminated
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA,VIC
Recruitment hospital [1] 0 0
Royal Adelaide Hospital; Haematology Clinical Trials - Adelaide
Recruitment hospital [2] 0 0
Peter MacCallum Cancer Centre; Department of Haematology - Melbourne
Recruitment postcode(s) [1] 0 0
5000 - Adelaide
Recruitment postcode(s) [2] 0 0
3002 - Melbourne
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Arizona
Country [2] 0 0
United States of America
State/province [2] 0 0
Kansas
Country [3] 0 0
United States of America
State/province [3] 0 0
New York
Country [4] 0 0
United States of America
State/province [4] 0 0
Ohio
Country [5] 0 0
United States of America
State/province [5] 0 0
Texas
Country [6] 0 0
Canada
State/province [6] 0 0
Ontario
Country [7] 0 0
Italy
State/province [7] 0 0
Lombardia
Country [8] 0 0
Italy
State/province [8] 0 0
Toscana

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Hoffmann-La Roche
Address
Country

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/show/NCT03287245
Trial related presentations / publications
Public notes

Contacts
Principal investigator
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Clinical Trials
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Hoffmann-La Roche
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Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT03287245