Back to resultsA Study to Evaluate the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of Idasanutlin Monotherapy in Participants With Hydroxyurea-Resistant/Intolerant Polycythemia Vera
Primary Purpose
Polycythemia Vera
Status
Terminated
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Idasanutlin
Sponsored by
About this trial
This is an interventional treatment trial for Polycythemia Vera focused on measuring polycythemia vera, PV, P vera, myeloproliferative diseases, hematologic diseases, myeloproliferative neoplasm, MPN
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
Sites / Locations
- Mayo Clinic - Arizona
- University of Kansas Cancer Center; Westwood Cancer Center/BMT Output Clinic
- Icahn School of Medicine at Mount Sinai
- Cleveland Clinic Cancer Center
- University of Texas Health Sciences Center in San Antonio
- Royal Adelaide Hospital; Haematology Clinical Trials
- Peter MacCallum Cancer Centre; Department of Haematology
- Princess Margaret Cancer Center
- ASST PAPA GIOVANNI XXIII; Ematologia
- Ospedale Di Circolo E Fondazione Macchi; Ematologia
- Az. Ospedaliero-Universitaria Careggi; CRIMM
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Idasanutlin
Arm Description
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).
Outcomes
Primary Outcome Measures
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.
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%.
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%.
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%.
Secondary Outcome Measures
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%.
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%.
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%
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.
All responders of each category grouped per timepoint include all categories mentioned above. There were no PD responses at any timepoint.
The study was pre-maturely terminated by the sponsor's decision due to non-transformative efficacy and poor long-term tolerability of the dosing schedule as well as due to chronic gastrointestinal toxicity, therefore did not reach the end of study.
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.
All responders of each category grouped per timepoint include all categories mentioned above. There were no PD responses at any timepoint.
The study was pre-maturely terminated by the sponsor's decision due to non-transformative efficacy and poor long-term tolerability of the dosing schedule as well as due to chronic gastrointestinal toxicity, therefore did not reach the end of study.
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.
All responders of each category grouped per timepoint include all categories mentioned above. There were no PD responses at any timepoint.
The study was pre-maturely terminated by the sponsor's decision due to non-transformative efficacy and poor long-term tolerability of the dosing schedule as well as due to chronic gastrointestinal toxicity, therefore did not reach the end of study.
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 are analyzed by the type of response achieved: Hct control, complete hematologic response, ELN 2009 response criteria, and composite response, if applicable.
Reported result data start from Cycle 11 Day 28 which is 12 weeks after Week 32 (Cycle 8 Day 28). There was one timepoint for which the participants qualify. The study was pre-maturely terminated by the sponsor decision, therefore did not reach the end of study.
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
The number of participants with a durable response lasting at least 12 weeks from Week 32 is analyzed by the type of response achieved: Hct control, complete hematologic response, ELN 2009 response criteria, and composite response, if applicable.
Reported result data start from Cycle 11 Day 28 which is 12 weeks after Week 32 (Cycle 8 Day 28). There was one timepoint for which the participants qualify.
The study was pre-maturely terminated by the sponsor's decision due to non-transformative efficacy and poor long-term tolerability of the dosing schedule as well as due to chronic gastrointestinal toxicity, therefore did not reach the planned end of study.
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 is analyzed by the type of response achieved: Hct control, complete hematologic response, ELN 2009 response criteria, and composite response, if applicable.
Reported result data start from Cycle 11 Day 28 which is 12 weeks after Week 32 (Cycle 8 Day 28). There was one timepoint for which the participants qualify. The study was pre-maturely terminated by the sponsor decision, therefore did not reach the end of study.
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
The number of participants with a durable response lasting at least 12 weeks from Week 32 is analyzed by the type of response achieved: Hct control, complete hematologic response, ELN 2009 response criteria, and composite response, if applicable.
Reported result data start from Cycle 11 Day 28 which is 12 weeks after Week 32 (Cycle 8 Day 28). There was one timepoint for which the participants qualify.
The study was pre-maturely terminated by the sponsor's decision due to non-transformative efficacy and poor long-term tolerability of the dosing schedule as well as due to chronic gastrointestinal toxicity, therefore did not reach the planned end of study.
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 is analyzed by the type of response achieved: Hct control, complete hematologic response, ELN 2009 response criteria, and composite response, if applicable.
Reported result data start from Cycle 11 Day 28 which is 12 weeks after Week 32 (Cycle 8 Day 28). There was one timepoint for which the participants qualify. The study was pre-maturely terminated by the sponsor decision, therefore did not reach the end of study.
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
The number of participants with a durable response lasting at least 12 weeks from Week 32 is analyzed by the type of response achieved: Hct control, complete hematologic response, ELN 2009 response criteria, and composite response, if applicable.
Reported result data start from Cycle 11 Day 28 which is 12 weeks after Week 32 (Cycle 8 Day 28). There was one timepoint for which the participants qualify.
The study was pre-maturely terminated by the sponsor's decision due to non-transformative efficacy and poor long-term tolerability of the dosing schedule as well as due to chronic gastrointestinal toxicity, therefore did not reach the planned end of study.
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.
During the final analyses, the focus was on the Adverse Events of severity grades >/=3 as shown below. The extensive listings of all grade AEs are available at request.
The study was pre-maturely terminated by the sponsor's decision due to non-transformative efficacy and poor long-term tolerability of the dosing schedule as well as due to chronic gastrointestinal toxicity, therefore did not reach the planned end of study.
Percentage of Participants With Clinical Laboratory Abnormalities: Hematology Parameters.
Hematology parameter laboratory values falling outside the standard reference range were planned to be recorded as either high or low.
There was no clinical laboratory abnormalities identified. The study was pre-maturely terminated by the sponsor's decision, therefore did not reach the end of study.
Percentage of Participants With Clinical Laboratory Abnormalities: Clinical Chemistry Parameters
Clinical chemistry parameter laboratory values falling outside the standard reference range were to be recorded as either high or low.
There was no clinical chemistry abnormalities identified. The study was pre-maturely terminated by the sponsor's decision, therefore did not reach the end of study.
Percentage of Participants With Clinical Laboratory Abnormalities: Urinalysis Parameters
Urinalysis parameter laboratory values falling outside the standard reference range were planned to be recorded as either high or low.
There was no clinical laboratory (urinalysis) abnormalities identified. The study was pre-maturely terminated by the sponsor's decision, therefore did not reach the end of study.
Change From Baseline in Electrocardiogram Parameters: PQ(PR), QRS, QT, QTcB, QTcF, and RR Durations
Single 12-lead ECGs was obtained using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
The study was pre-maturely terminated by the sponsor's decision due to non-transformative efficacy and poor long-term tolerability of the dosing schedule as well as due to chronic gastrointestinal toxicity, therefore did not reach the planned end of study.
Change From Baseline in Heart Rate, as Measured by Electrocardiogram
Single 12-lead ECGs was obtained using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
The study was pre-maturely terminated by the sponsor's decision due to non-transformative efficacy and poor long-term tolerability of the dosing schedule as well as due to chronic gastrointestinal toxicity, therefore did not reach the planned end of study.
Change From Baseline in Oral Temperature
Vital signs were measured prior to the infusion while the participant was in a seated position. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value. The study was pre-maturely terminated by the sponsor's decision, therefore did not reach the end of study.
Change From Baseline in Pulse Rate
Vital signs were measured prior to the infusion while the participant was in a seated position. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
The study was pre-maturely terminated by the sponsor's decision due to non-transformative efficacy and poor long-term tolerability of the dosing schedule as well as due to chronic gastrointestinal toxicity, therefore did not reach the planned end of study.
Change From Baseline in Respiratory Rate
Vital signs were measured prior to the infusion while the participant was in a seated position. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
The study was pre-maturely terminated by the sponsor's decision due to non-transformative efficacy and poor long-term tolerability of the dosing schedule as well as due to chronic gastrointestinal toxicity, therefore did not reach the planned end of study.
Change From Baseline in Systolic Blood Pressure
Vital signs were measured prior to the infusion while the participant was in a seated position. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
The study was pre-maturely terminated by the sponsor's decision due to non-transformative efficacy and poor long-term tolerability of the dosing schedule as well as due to chronic gastrointestinal toxicity, therefore did not reach the planned end of study.
Change From Baseline in Diastolic Blood Pressure
Vital signs were measured prior to the infusion while the participant was in a seated position. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
The study was pre-maturely terminated by the sponsor's decision due to non-transformative efficacy and poor long-term tolerability of the dosing schedule as well as due to chronic gastrointestinal toxicity, therefore did not reach the planned end of study.
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, 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.
Only baseline data were collectable. The study was pre-maturely terminated by the sponsor's decision, therefore did not reach the planned end of study.
Percentage of Participants With Concomitant Medications
Participants with Concomitant Medications used from 28 days prior to screening until the final visit or end of study (EOS) were reported.
The result data not derived due to early termination of the study by the sponsor's decision and did not reach the end of study.
Maximum Serum Concentration Observed (Cmax) of Idasanutlin
Cmax is the maximum observed concentration of drug in blood. The result data not derived due to early termination of the study by the sponsor's decision and did not reach the end of study.
Trough Concentration (Ctrough) of Idasanutlin
Ctrough is the measured concentration of a drug at the end of a dosing interval at steady state.
The result data not derived due to early termination of the study by the sponsor's decision and did not reach the end of study.
Time of Maximum Concentration Observed (Tmax) of Idasanutlin
Tmax is the time elapsed from the time of drug administration to maximum plasma concentration.
The result data not derived due to early termination of the study by the sponsor's decision and did not reach the end of study.
Clearance (CL) of Idasanutlin
CL is a measure of the body's elimination of a drug from plasma over time. The result data not derived due to early termination of the study by the sponsor's decision and did not reach the end of study.
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.
The result data not derived due to early termination of the study by the sponsor's decision and did not reach the end of study.
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.
The result data not derived due to early termination of the study by the sponsor's decision and did not reach the end of study.
Area Under the Concentration-Time Curve (AUC) of Idasanutlin
AUC (from zero to infinity) represents the total drug exposure over time. The result data not derived due to early termination of the study by the sponsor's decision and did not reach the end of study.
Half-life (t1/2) of Idasanutlin
t1/2 is defined as the time required for the drug plasma concentration to be reduced to half.
The result data not derived due to early termination of the study by the sponsor's decision and did not reach the end of study.
Baseline and Mean Change From Baseline Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Over Time
MPN-SAF Total Symptom Score is the sum of the following 10 items: early satiety, abdominal discomfort, inactivity, concentration issues, night sweats, Itching, Bone pain, Fever and Unintentional weight loss last 6 months and fatigue. The participant provides a severity score for each symptom on a scale of 0 as a minimum score (none/absent) to 10 (worst imaginable) as a maximum score.
Baseline (Cycle 1, Day 1) MPN-SAF total symptom score and the mean change from baseline score at each timepoint are reported. The change from baseline score was calculated by subtracting the post-baseline score from the baseline score.
The study was pre-maturely terminated by the sponsor's decision due to non-transformative efficacy and poor long-term tolerability of the dosing schedule as well as due to chronic gastrointestinal toxicity, therefore did not reach the end of study.
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
Reported EORTC QLQ-C30 Scores include: Cognitive function, Diarrhea Emotional functioning, Nausea and vomiting, Social functioning, Physical functioning, Global health status/QoL and Role functioning. The 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.
The study was pre-maturely terminated by the sponsor's decision due to non-transformative efficacy and poor long-term tolerability of the dosing schedule as well as due to chronic gastrointestinal toxicity, therefore did not reach the end of study.
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 were 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'.
The study was pre-maturely terminated by the sponsor's decision, therefore did not reach the end of study.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03287245
Brief Title
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
2. Study Status
Record Verification Date
December 2021
Overall Recruitment Status
Terminated
Why Stopped
The Sponsor decided to discontinue the development of idasanutlin in the polycythemia vera indication.
Study Start Date
February 21, 2018 (Actual)
Primary Completion Date
March 3, 2020 (Actual)
Study Completion Date
March 3, 2020 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Hoffmann-La Roche
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Polycythemia Vera
Keywords
polycythemia vera, PV, P vera, myeloproliferative diseases, hematologic diseases, myeloproliferative neoplasm, MPN
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
27 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Idasanutlin
Arm Type
Experimental
Arm Description
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 Type
Drug
Intervention Name(s)
Idasanutlin
Other Intervention Name(s)
RO5503781, RG7388
Intervention Description
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.
Primary Outcome Measure Information:
Title
Percentage of Ruxolitinib-Naïve Participants With Splenomegaly at Baseline Who Achieved Composite Response at Week 32
Description
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.
Time Frame
Week 32
Title
Percentage of Ruxolitinib-Naïve Participants Without Splenomegaly at Baseline Who Achieved Hematocrit (Hct) Control Without Phlebotomy at Week 32
Description
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%.
Time Frame
Week 32
Title
Percentage of All Ruxolitinib-Naïve Participants (Irrespective of Spleen Size) Who Achieved Hct Control Without Phlebotomy at Week 32
Description
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%.
Time Frame
Week 32
Title
Percentage of All Ruxolitinib-Resistant or Intolerant Participants Who Achieved Hct Control Without Phlebotomy at Week 32
Description
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%.
Time Frame
From Baseline to Week 32 (Cycle 8 Day 28)
Secondary Outcome Measure Information:
Title
Percentage of All Ruxolitinib-Naïve and Ruxolitinib-Resistant or Intolerant Participants Who Achieved Complete Hematologic Response at Week 32
Description
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%.
Time Frame
Week 32 (Cycle 8 Day 28)
Title
Percentage of All Ruxolitinib-Naïve and Ruxolitinib-Resistant or Intolerant Participants Who Achieved Complete Hematologic Remission at Cycle 11 Day 28
Description
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%.
Time Frame
Cycle 11 Day 28
Title
Duration of Complete Hematologic Remission, With a Durable Responder Defined as a Participant in Remission at Week 32 and Cycle 11 Day 28
Description
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%
Time Frame
Week 32 (Cycle 8 Day 28), Cycle 11 Day 28
Title
Percentage of Ruxolitinib-Naïve and Ruxolitinib-Resistant or Intolerant Participants With Splenomegaly at Baseline by Response Per Modified European Leukemia Net (ELN) Criteria
Description
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.
All responders of each category grouped per timepoint include all categories mentioned above. There were no PD responses at any timepoint.
The study was pre-maturely terminated by the sponsor's decision due to non-transformative efficacy and poor long-term tolerability of the dosing schedule as well as due to chronic gastrointestinal toxicity, therefore did not reach the end of study.
Time Frame
Baseline, Day 28 of Cycles 3, 5, 8, 11, 12, 14, 17, 20 and Final visit (28 days after post-last dose)
Title
Percentage of Ruxolitinib-Naïve and Ruxolitinib-Resistant or Intolerant Participants Without Splenomegaly at Baseline by Response Per Modified ELN Criteria
Description
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.
All responders of each category grouped per timepoint include all categories mentioned above. There were no PD responses at any timepoint.
The study was pre-maturely terminated by the sponsor's decision due to non-transformative efficacy and poor long-term tolerability of the dosing schedule as well as due to chronic gastrointestinal toxicity, therefore did not reach the end of study.
Time Frame
Baseline, Day 28 of Cycles 3, 5, 8, 11, 12, 14, 17, 20 and Final visit (28 days after post-last dose)
Title
Percentage of All Ruxolitinib-Naïve and Ruxolitinib-Resistant or Intolerant Participants (Irrespective of Spleen Size) by Response Per Modified ELN Criteria
Description
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.
All responders of each category grouped per timepoint include all categories mentioned above. There were no PD responses at any timepoint.
The study was pre-maturely terminated by the sponsor's decision due to non-transformative efficacy and poor long-term tolerability of the dosing schedule as well as due to chronic gastrointestinal toxicity, therefore did not reach the end of study.
Time Frame
Baseline, Day 28 of Cycles 3, 5, 8, 11, 12, 14, 17, 20 and Final visit (28 days after post-last dose)
Title
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
Description
The percentage of participants with a durable response lasting at least 12 weeks from Week 32 are analyzed by the type of response achieved: Hct control, complete hematologic response, ELN 2009 response criteria, and composite response, if applicable.
Reported result data start from Cycle 11 Day 28 which is 12 weeks after Week 32 (Cycle 8 Day 28). There was one timepoint for which the participants qualify. The study was pre-maturely terminated by the sponsor decision, therefore did not reach the end of study.
Time Frame
From Week 32 (Cycle 8 Day 28) and at least 12 Weeks after until end of study (up to 2 years)
Title
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
Description
The number of participants with a durable response lasting at least 12 weeks from Week 32 is analyzed by the type of response achieved: Hct control, complete hematologic response, ELN 2009 response criteria, and composite response, if applicable.
Reported result data start from Cycle 11 Day 28 which is 12 weeks after Week 32 (Cycle 8 Day 28). There was one timepoint for which the participants qualify.
The study was pre-maturely terminated by the sponsor's decision due to non-transformative efficacy and poor long-term tolerability of the dosing schedule as well as due to chronic gastrointestinal toxicity, therefore did not reach the planned end of study.
Time Frame
From Week 32 (Cycle 8 Day 28) and at least 12 weeks after until end of study (up to 2 years)
Title
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
Description
The percentage of participants with a durable response lasting at least 12 weeks from Week 32 is analyzed by the type of response achieved: Hct control, complete hematologic response, ELN 2009 response criteria, and composite response, if applicable.
Reported result data start from Cycle 11 Day 28 which is 12 weeks after Week 32 (Cycle 8 Day 28). There was one timepoint for which the participants qualify. The study was pre-maturely terminated by the sponsor decision, therefore did not reach the end of study.
Time Frame
From Week 32 (Cycle 8 Day 28) and at least 12 Weeks after until end of study (up to 2 years)
Title
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
Description
The number of participants with a durable response lasting at least 12 weeks from Week 32 is analyzed by the type of response achieved: Hct control, complete hematologic response, ELN 2009 response criteria, and composite response, if applicable.
Reported result data start from Cycle 11 Day 28 which is 12 weeks after Week 32 (Cycle 8 Day 28). There was one timepoint for which the participants qualify.
The study was pre-maturely terminated by the sponsor's decision due to non-transformative efficacy and poor long-term tolerability of the dosing schedule as well as due to chronic gastrointestinal toxicity, therefore did not reach the planned end of study.
Time Frame
From Week 32 (Cycle 8 Day 28) and at least 12 weeks after until end of study (up to 2 years)
Title
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
Description
The percentage of participants with a durable response lasting at least 12 weeks from Week 32 is analyzed by the type of response achieved: Hct control, complete hematologic response, ELN 2009 response criteria, and composite response, if applicable.
Reported result data start from Cycle 11 Day 28 which is 12 weeks after Week 32 (Cycle 8 Day 28). There was one timepoint for which the participants qualify. The study was pre-maturely terminated by the sponsor decision, therefore did not reach the end of study.
Time Frame
From Week 32 (Cycle 8 Day 28) and at least 12 Weeks after until end of study (up to 2 years)
Title
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
Description
The number of participants with a durable response lasting at least 12 weeks from Week 32 is analyzed by the type of response achieved: Hct control, complete hematologic response, ELN 2009 response criteria, and composite response, if applicable.
Reported result data start from Cycle 11 Day 28 which is 12 weeks after Week 32 (Cycle 8 Day 28). There was one timepoint for which the participants qualify.
The study was pre-maturely terminated by the sponsor's decision due to non-transformative efficacy and poor long-term tolerability of the dosing schedule as well as due to chronic gastrointestinal toxicity, therefore did not reach the planned end of study.
Time Frame
From Week 32 (Cycle 8 Day 28) and at least 12 weeks after until end of study (up to 2 years)
Title
Total Number of Participants With Adverse Events by Severity, Graded According to NCI CTCAE v4.0
Description
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.
During the final analyses, the focus was on the Adverse Events of severity grades >/=3 as shown below. The extensive listings of all grade AEs are available at request.
The study was pre-maturely terminated by the sponsor's decision due to non-transformative efficacy and poor long-term tolerability of the dosing schedule as well as due to chronic gastrointestinal toxicity, therefore did not reach the planned end of study.
Time Frame
Baseline to end of study (up to 2 years)
Title
Percentage of Participants With Clinical Laboratory Abnormalities: Hematology Parameters.
Description
Hematology parameter laboratory values falling outside the standard reference range were planned to be recorded as either high or low.
There was no clinical laboratory abnormalities identified. The study was pre-maturely terminated by the sponsor's decision, therefore did not reach the end of study.
Time Frame
Baseline to end of study (up to 2 years)
Title
Percentage of Participants With Clinical Laboratory Abnormalities: Clinical Chemistry Parameters
Description
Clinical chemistry parameter laboratory values falling outside the standard reference range were to be recorded as either high or low.
There was no clinical chemistry abnormalities identified. The study was pre-maturely terminated by the sponsor's decision, therefore did not reach the end of study.
Time Frame
Baseline to end of study (up to 2 years)
Title
Percentage of Participants With Clinical Laboratory Abnormalities: Urinalysis Parameters
Description
Urinalysis parameter laboratory values falling outside the standard reference range were planned to be recorded as either high or low.
There was no clinical laboratory (urinalysis) abnormalities identified. The study was pre-maturely terminated by the sponsor's decision, therefore did not reach the end of study.
Time Frame
Baseline to end of study (up to 2 years)
Title
Change From Baseline in Electrocardiogram Parameters: PQ(PR), QRS, QT, QTcB, QTcF, and RR Durations
Description
Single 12-lead ECGs was obtained using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
The study was pre-maturely terminated by the sponsor's decision due to non-transformative efficacy and poor long-term tolerability of the dosing schedule as well as due to chronic gastrointestinal toxicity, therefore did not reach the planned end of study.
Time Frame
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)
Title
Change From Baseline in Heart Rate, as Measured by Electrocardiogram
Description
Single 12-lead ECGs was obtained using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
The study was pre-maturely terminated by the sponsor's decision due to non-transformative efficacy and poor long-term tolerability of the dosing schedule as well as due to chronic gastrointestinal toxicity, therefore did not reach the planned end of study.
Time Frame
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)
Title
Change From Baseline in Oral Temperature
Description
Vital signs were measured prior to the infusion while the participant was in a seated position. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value. The study was pre-maturely terminated by the sponsor's decision, therefore did not reach the end of study.
Time Frame
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
Title
Change From Baseline in Pulse Rate
Description
Vital signs were measured prior to the infusion while the participant was in a seated position. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
The study was pre-maturely terminated by the sponsor's decision due to non-transformative efficacy and poor long-term tolerability of the dosing schedule as well as due to chronic gastrointestinal toxicity, therefore did not reach the planned end of study.
Time Frame
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
Title
Change From Baseline in Respiratory Rate
Description
Vital signs were measured prior to the infusion while the participant was in a seated position. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
The study was pre-maturely terminated by the sponsor's decision due to non-transformative efficacy and poor long-term tolerability of the dosing schedule as well as due to chronic gastrointestinal toxicity, therefore did not reach the planned end of study.
Time Frame
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
Title
Change From Baseline in Systolic Blood Pressure
Description
Vital signs were measured prior to the infusion while the participant was in a seated position. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
The study was pre-maturely terminated by the sponsor's decision due to non-transformative efficacy and poor long-term tolerability of the dosing schedule as well as due to chronic gastrointestinal toxicity, therefore did not reach the planned end of study.
Time Frame
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
Title
Change From Baseline in Diastolic Blood Pressure
Description
Vital signs were measured prior to the infusion while the participant was in a seated position. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
The study was pre-maturely terminated by the sponsor's decision due to non-transformative efficacy and poor long-term tolerability of the dosing schedule as well as due to chronic gastrointestinal toxicity, therefore did not reach the planned end of study.
Time Frame
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
Title
Eastern Cooperative Oncology Group (ECOG) Performance Status Over Time
Description
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, 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.
Only baseline data were collectable. The study was pre-maturely terminated by the sponsor's decision, therefore did not reach the planned end of study.
Time Frame
Baseline
Title
Percentage of Participants With Concomitant Medications
Description
Participants with Concomitant Medications used from 28 days prior to screening until the final visit or end of study (EOS) were reported.
The result data not derived due to early termination of the study by the sponsor's decision and did not reach the end of study.
Time Frame
Overall Study Period
Title
Maximum Serum Concentration Observed (Cmax) of Idasanutlin
Description
Cmax is the maximum observed concentration of drug in blood. The result data not derived due to early termination of the study by the sponsor's decision and did not reach the end of study.
Time Frame
Days 1, 2, and 5 of Cycles 1 and 4
Title
Trough Concentration (Ctrough) of Idasanutlin
Description
Ctrough is the measured concentration of a drug at the end of a dosing interval at steady state.
The result data not derived due to early termination of the study by the sponsor's decision and did not reach the end of study.
Time Frame
Days 1, 2, and 5 of Cycles 1 and 4
Title
Time of Maximum Concentration Observed (Tmax) of Idasanutlin
Description
Tmax is the time elapsed from the time of drug administration to maximum plasma concentration.
The result data not derived due to early termination of the study by the sponsor's decision and did not reach the end of study.
Time Frame
Days 1, 2, and 5 of Cycles 1 and 4
Title
Clearance (CL) of Idasanutlin
Description
CL is a measure of the body's elimination of a drug from plasma over time. The result data not derived due to early termination of the study by the sponsor's decision and did not reach the end of study.
Time Frame
Days 1, 2, and 5 of Cycles 1 and 4
Title
Apparent Clearance (CL/F) of Idasanutlin
Description
CL/F is a measure of the body's elimination of a drug from plasma over time, after oral administration.
The result data not derived due to early termination of the study by the sponsor's decision and did not reach the end of study.
Time Frame
Days 1, 2, and 5 of Cycles 1 and 4
Title
Volume or Apparent Volume of Distribution (Vdss/F) of Idasanutlin
Description
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.
The result data not derived due to early termination of the study by the sponsor's decision and did not reach the end of study.
Time Frame
Days 1, 2, and 5 of Cycles 1 and 4
Title
Area Under the Concentration-Time Curve (AUC) of Idasanutlin
Description
AUC (from zero to infinity) represents the total drug exposure over time. The result data not derived due to early termination of the study by the sponsor's decision and did not reach the end of study.
Time Frame
Days 1, 2, and 5 of Cycles 1 and 4
Title
Half-life (t1/2) of Idasanutlin
Description
t1/2 is defined as the time required for the drug plasma concentration to be reduced to half.
The result data not derived due to early termination of the study by the sponsor's decision and did not reach the end of study.
Time Frame
Days 1, 2, and 5 of Cycles 1 and 4
Title
Baseline and Mean Change From Baseline Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Over Time
Description
MPN-SAF Total Symptom Score is the sum of the following 10 items: early satiety, abdominal discomfort, inactivity, concentration issues, night sweats, Itching, Bone pain, Fever and Unintentional weight loss last 6 months and fatigue. The participant provides a severity score for each symptom on a scale of 0 as a minimum score (none/absent) to 10 (worst imaginable) as a maximum score.
Baseline (Cycle 1, Day 1) MPN-SAF total symptom score and the mean change from baseline score at each timepoint are reported. The change from baseline score was calculated by subtracting the post-baseline score from the baseline score.
The study was pre-maturely terminated by the sponsor's decision due to non-transformative efficacy and poor long-term tolerability of the dosing schedule as well as due to chronic gastrointestinal toxicity, therefore did not reach the end of study.
Time Frame
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
Title
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
Description
Reported EORTC QLQ-C30 Scores include: Cognitive function, Diarrhea Emotional functioning, Nausea and vomiting, Social functioning, Physical functioning, Global health status/QoL and Role functioning. The 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.
The study was pre-maturely terminated by the sponsor's decision due to non-transformative efficacy and poor long-term tolerability of the dosing schedule as well as due to chronic gastrointestinal toxicity, therefore did not reach the end of study.
Time Frame
Baseline (Cycle 1 Day 1), Cycle 2 Day 1, Cycles 3, 5, 8, 11, 14, 17, 20 Day 28 and Final Visit
Title
Frequency Count of Participant Responses to the Patient Global Impression of Change (PGIC) Question Over Time
Description
The PGIC is a one-item measure used to assess perceived treatment benefit. Participants were 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'.
The study was pre-maturely terminated by the sponsor's decision, therefore did not reach the end of study.
Time Frame
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)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Clinical Trials
Organizational Affiliation
Hoffmann-La Roche
Official's Role
Study Director
Facility Information:
Facility Name
Mayo Clinic - Arizona
City
Phoenix
State/Province
Arizona
ZIP/Postal Code
85054
Country
United States
Facility Name
University of Kansas Cancer Center; Westwood Cancer Center/BMT Output Clinic
City
Kansas City
State/Province
Kansas
ZIP/Postal Code
66205
Country
United States
Facility Name
Icahn School of Medicine at Mount Sinai
City
New York
State/Province
New York
ZIP/Postal Code
10029
Country
United States
Facility Name
Cleveland Clinic Cancer Center
City
Independence
State/Province
Ohio
ZIP/Postal Code
44131
Country
United States
Facility Name
University of Texas Health Sciences Center in San Antonio
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78229
Country
United States
Facility Name
Royal Adelaide Hospital; Haematology Clinical Trials
City
Adelaide
State/Province
South Australia
ZIP/Postal Code
5000
Country
Australia
Facility Name
Peter MacCallum Cancer Centre; Department of Haematology
City
Melbourne
State/Province
Victoria
ZIP/Postal Code
3002
Country
Australia
Facility Name
Princess Margaret Cancer Center
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 1Z5
Country
Canada
Facility Name
ASST PAPA GIOVANNI XXIII; Ematologia
City
Bergamo
State/Province
Lombardia
ZIP/Postal Code
24127
Country
Italy
Facility Name
Ospedale Di Circolo E Fondazione Macchi; Ematologia
City
Varese
State/Province
Lombardia
ZIP/Postal Code
21100
Country
Italy
Facility Name
Az. Ospedaliero-Universitaria Careggi; CRIMM
City
Firenze
State/Province
Toscana
ZIP/Postal Code
50134
Country
Italy
12. IPD Sharing Statement
Citations:
PubMed Identifier
34933330
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.
Results Reference
derived
Links:
URL
https://www.pioneeringhealthcare.com/p-vera
Description
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.
Learn more about this trial
A Study to Evaluate the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of Idasanutlin Monotherapy in Participants With Hydroxyurea-Resistant/Intolerant Polycythemia Vera
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