Blood and Lymph Conditions

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Neoplasms

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Myeloproliferative Disorders

Polycythemia Vera

Polycythemia

Hematologic Diseases

Bone Marrow Neoplasms

Hematologic Neoplasms

Bone Marrow Diseases

Chronic Myeloproliferative Disorders

Antineoplastic Agents

Antisickling Agents

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Hydroxyurea

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).

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.

Idasanutlin

Clinical Trials

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.

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

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

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.

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%.

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%.

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%.

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%

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Hoffmann-La Roche

Reported: Safety Population. During the Safety Follow-up Period, non-Serious Adverse Events occurred at the 5% frequency threshold.

Participants received 150 milligrams (mg) idasanutlin orally, once daily for 5 days, every 28 days, until treatment discontinuation or end of study (up to 2 years).

Ruxolitinib Naive-With Splenomegaly

Ruxolitinib Naive-Without Splenomegaly

Ruxolitinib-Resistant or Intolerant Participants With Splenomegaly

Ruxolitinib-Resistant or Intolerant Participants Without Splenomegaly

Ruxolitinib-naïve Participants With Splenomegaly

Ruxolitinib-naïve Participants Without Splenomegaly

Participants received 150 milligrams (mg) idasanutlin orally, once daily for 5 days, every 28 days, until treatment discontinuation or end of study (up to 2 years)

Total

Age, Continuous

Sex: Female, Male

Race/Ethnicity, Customized

Asian

White

Medical Communications

Ruxolitinib-Naïve Participants With Splenomegaly

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

Ruxolitinib-Naïve Participants Without Splenomegaly

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

Total Ruxolitinib-Naïve Participants

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

Total Ruxolitinib-Resistant or Intolerant Participants

ITT population. The number analyzed includes participants who were evaluable at each timepoint.

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

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

ITT Population. The number analyzed includes participants who were evaluable at each timepoint.

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

Cycle 11, Day 28

Week 32

ITT population. The "number of participants analyzed" is the number of patients (total n) per arm. "The number analyzed" was the number of patients evaluable at that specific timepoint. Not all participants of each arm were evaluable at each time point.

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

Baseline Complete Response

Baseline Partial Response

Baseline Progressive Disease

Baseline No Response

Cycle 3, Day 28 Complete Response

Cycle 3, Day 28 Partial Response

Cycle 3, Day 28 Progressive Disease

Cycle 3, Day 28 No Response

Cycle 5, Day 28 Complete Response

Cycle 5, Day 28 Partial Response

Cycle 5, Day 28 Progressive Disease

Cycle 5, Day 28 No Response

Cycle 8, Day 28 (Week 32) Complete Response

Cycle 8, Day 28 (Week 32) Partial Response

Cycle 8, Day 28 (Week 32) Progressive Disease

Cycle 8, Day 28 (Week 32) No Response

Cycle 11, Day 28 Complete Response

Cycle 11, Day 28 Partial Response

Cycle 11, Day 28 Progressive Disease

Cycle 11, Day 28 No Response

Cycle 12, Day 28 Complete Response

Cycle 12, Day 28 Partial Response

Cycle 12, Day 28 Progressive Disease

Cycle 12, Day 28 No Response

Cycle 14, Day 28 Complete Response

Cycle 14, Day 28 Partial Response

Cycle 14, Day 28 Progressive Disease

Cycle 14, Day 28 No Response

Cycle 17, Day 28 Complete Response

Cycle 17, Day 28 Partial Response

Cycle 17, Day 28 Progressive Disease

Cycle 17, Day 28 No Response

Cycle 20, Day 28 Complete Response

Cycle 20, Day 28 Partial Response

Cycle 20, Day 28 Progressive Disease

Cycle 20, Day 28 No Response

Final Visit (28 Days post-last dose) Complete Response

Final Visit (28 Days post-last dose) Partial Response

Final Visit (28 Days post-last dose) Progressive Disease

Final Visit (28 Days post-last dose) No Response

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

Cycle 5 Day 28 Complete Response

Cycle 5 Day 28 Partial Response

Cycle 5 Day 28 Progressive Disease

Cycle 5 Day 28 No Response

Cycle 11, day 28 Complete Response

Cycle 11, day 28 Partial Response

Cycle 11, day 28 Progressive Disease

Cycle 11, day 28 No Response

Final (28 Days post-last dose) Complete Response

Final (28 Days post-last dose) Partial Response

Final (28 Days post-last dose) Progressive Disease

Final (28 Days post-last dose) No Response

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

Cycle 11 Day 28 Complete Response

Cycle 11 Day 28 Partial Response

Cycle 11 Day 28 Progressive Disease

Cycle 11 Day 28 No Response

Cycle 12 Day 28 Complete Response

Cycle 12 Day 28 Partial Response

Cycle 12 Day 28 Progressive Disease

Cycle 12 Day 28 No Response

Final Visit Complete Response

Final Visit Partial Response

Final Visit Progressive Disease

Final Visit No Response

All Ruxolitinib-Naïve Participants

All Ruxolitinib-Resistant or Intolerant Participants

Percentage of All Ruxolitinib-Naïve and Ruxolitinib-Resistant or Intolerant Participants (Irrespective of Spleen Size) by Response Per Modified ELN Criteria

HCT Control

Composite Response

ELN Response

Complete Hematologic Response

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

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

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

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

After 12 Weeks from Week 32 HCT Control

After 12 Weeks from Week 32 Composite Response

After 12 Weeks from Week 32 ELN Response

After 12 Weeks from Week 32 Complete Hematologic Response

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

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

Baseline

Grade 3-5 AE

Total Number of Participants With Adverse Events by Severity, Graded According to NCI CTCAE v4.0

Percentage of Participants With Clinical Laboratory Abnormalities: Hematology Parameters.

Percentage of Participants With Clinical Laboratory Abnormalities: Clinical Chemistry Parameters

Percentage of Participants With Clinical Laboratory Abnormalities: Urinalysis Parameters

PR Duration Baseline

PQ(PR) Durations Cycle 1, Day 1, 4 hour

PQ(PR) Durations Cycle 1, Day 1, 6 hour

PQ(PR) Durations Cycle 1, Day 2, pre-dose

PQ(PR) Durations Cycle 1, Day 2, 24 hour

PQ(PR) Durations Cycle ,1 Day 5, pre-dose

PQ(PR) Durations Cycle 1, Day 5, 4 hour

PQ(PR) Durations Cycle 1, Day 5, 6 hour

PQ(PR) Durations Cycle 2, Day1, pre-dose

PQ(PR) Durations Cycle 3, Day 1, pre-dose

PQ(PR) Durations Cycle 3, Day 1, 4 hour

PQ(PR) Durations Cycle 3, Day 1, 6 hour

PQ(PR) Durations Cycle 4, Day 1, pre-dose

PQ(PR) Durations Cycle 4, Day 1, 4 hour

QRS Duration Baseline

QRS Cycle 1 Day 1 (4 H)

QRS Cycle 1 Day 1 (6 H)

QRS Cycle 1 Day 2 (PREDOSE)

QRS Cycle 1 Day 2 (24 H)

QRS Cycle 1 Day 5 (PREDOSE)

QRS Cycle 1 Day 5 (4 H)

QRS Cycle 1 Day 5 (6 H)

QRS Cycle 2 Day 1 (PREDOSE)

QRS Cycle 3 Day 1 (PREDOSE)

QRS Cycle 3 Day 1 (4 H)

QRS Cycle 3 Day 1 (6 H)

QRS Cycle 4 Day 1 (PREDOSE)

Safety-Evaluable population. The number analyzed includes participants who were evaluable at each timepoint.

Change From Baseline in Electrocardiogram Parameters: PQ(PR), QRS, QT, QTcB, QTcF, and RR Durations

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

Trial Identification

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Study Description

Keywords

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