ClinicalTrials.gov
ClinicalTrials.gov Menu
Trial record 1 of 1 for:    NCT03287245 | Recruiting Studies
Previous Study | Return to List | Next Study

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03287245
Recruitment Status : Recruiting
First Posted : September 19, 2017
Last Update Posted : September 10, 2018
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Brief Summary:
This is an open-label, single-arm, study of idasanutlin monotherapy in participants with hydroxyurea (HU)-resistant/intolerant Polycythemia vera (PV).

Condition or disease Intervention/treatment Phase
Polycythemia Vera Drug: Idasanutlin Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : February 21, 2018
Estimated Primary Completion Date : November 8, 2019
Estimated Study Completion Date : March 30, 2021


Arm Intervention/treatment
Experimental: Idasanutlin
150 milligrams (mg), once daily for 5 days, every 28 days, until treatment discontinuation or up to 2 years.
Drug: Idasanutlin
150 milligrams (mg) orally, once daily for 5 days, every 28 days, until treatment discontinuation or up to 2 years.
Other Name: RO5503781




Primary Outcome Measures :
  1. Composite Response at Week 32 for Ruxolitinib-Naïve Participants With Splenomegaly at Baseline [ Time Frame: Week 32 ]
    Composite response is defined as hematocrit (Hct) control without phlebotomy and ≥ 35% decrease in spleen size by imaging at Week 32. Hct control is defined as protocol-specified ineligibility for phlebotomy between Weeks 8 to 32 and ≤ 1 instance of phlebotomy eligibility between first dose and Week 8. Eligibility for phlebotomy is defined as a Hct of ≥ 45% that was ≥ 3% higher than baseline level or a Hct of > 48% at Week 32.

  2. Hematocrit (Hct) Control Without Phlebotomy at Week 32 for Ruxolitinib-Naïve Participants Without Splenomegaly at Baseline [ Time Frame: Week 32 ]
    Hct control is defined as protocol-specified ineligibility for phlebotomy between Weeks 8 to 32 and ≤ 1 instance of phlebotomy eligibility between first dose and Week 8. Eligibility for phlebotomy is defined as a Hct level ≥ 45% that was ≥ 3% higher than baseline level or a Hct level of > 48% at Week 32.

  3. Hct Control Without Phlebotomy at Week 32 for All Ruxolinitib-Naïve Participants (With and Without Splenomegaly) [ Time Frame: Week 32 ]
    Hct control is defined as protocol-specified ineligibility for phlebotomy between Weeks 8 to 32 and ≤ 1 instance of phlebotomy eligibility between first dose and Week 8. Eligibility for phlebotomy is defined as a Hct level ≥ 45% that was ≥ 3% higher than baseline level or a Hct level of > 48% at Week 32.


Secondary Outcome Measures :
  1. Response per Modified European Leukemia Net (ELN) Criteria at Week 32 for Ruxolitinib-Naïve Participants and All Participants Irrespective of Prior Ruxolitinib Exposure [ Time Frame: Week 32 ]
    Complete hematologic response (CHR) includes all of the following: Hct < 45% without phlebotomy; platelet count ≤ 400 × 10^9/liter (L); white blood cell count ≤ 10 × 10^9/L; normal spleen size on imaging; and no disease-related symptoms. Partial hematologic response (PHR): in participants who do not fulfill the criteria for complete response: 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.

  2. Duration of Response, Including Percentage of Participants With Durable Response Lasting at Least 12 Weeks [ Time Frame: Week 32 ]
    Complete hematologic response (CHR) includes all of the following: Hct < 45% without phlebotomy; platelet count ≤ 400 × 10^9/liter (L); white blood cell count ≤ 10 × 10^9/L; normal spleen size on imaging; and no disease-related symptoms. Partial hematologic response (PHR): in participants who do not fulfill the criteria for complete response: 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.

  3. Composite Response at Week 32 for Participants With Splenomegaly at Baseline Irrespective of Prior Ruxolitinib Exposure [ Time Frame: Week 32 ]
    Composite response is defined as hematocrit (Hct) control without phlebotomy and > 35% decrease in spleen size by imaging at Week 32. Hct control is defined as protocol-specified ineligibility for phlebotomy between Weeks 8 to 32 and ≤ 1 instance of phlebotomy eligibility between first dose and Week 8. Eligibility for phlebotomy is defined as a Hct of ≥ 45% that was ≥ 3% higher than baseline level or a Hct of > 48% at Week 32.

  4. Hct Control Without Phlebotomy at Week 32 for Participants Without Splenomegaly at Baseline Irrespective of Prior Ruxolitinib Exposure [ Time Frame: Week 32 ]
    Hct control is defined as protocol-specified ineligibility for phlebotomy between Weeks 8 to 32 and ≤ 1 instance of phlebotomy eligibility between first dose and Week 8. Eligibility for phlebotomy is defined as a Hct level ≥ 45% that was ≥ 3% higher than baseline level or a Hct level of > 48% at Week 32.

  5. Hct Control Without Phlebotomy at Week 32 for All Participants (With and Without Splenomegaly) Irrespective of Prior Ruxolitinib Exposure [ Time Frame: Week 32 ]
    Hct control is defined as protocol-specified ineligibility for phlebotomy between Weeks 8 to 32 and ≤ 1 instance of phlebotomy eligibility between first dose and Week 8. Eligibility for phlebotomy is defined as a Hct level ≥ 45% that was ≥ 3% higher than baseline level or a Hct level of > 48% at Week 32.

  6. Hct Control Without Phlebotomy at Week 32 for All Participants (With and Without Splenomegaly) Who Had Prior Ruxolitinib Exposure [ Time Frame: Week 32 ]
    Hct control is defined as protocol-specified ineligibility for phlebotomy between Weeks 8 to 32 and ≤ 1 instance of phlebotomy eligibility between first dose and Week 8. Eligibility for phlebotomy is defined as a Hct level ≥ 45% that was ≥ 3% higher than baseline level or a Hct level of > 48% at Week 32.

  7. Percentage of Participants With Abnormal Clinical Laboratory Findings [ Time Frame: Up to 2 years ]
  8. Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to 2 years ]
    An AE 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. A SAE is any experience that: results in death, is life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is medically significant.

  9. Eastern Cooperative Oncology Group (ECOG) Performance Status [ Time Frame: Up to 2 years ]
    The ECOG performance status is a scale used to quantify cancer patients' general well-being and activities of daily life. The scale ranges from 0 to 5, with 0 denoting perfect health and 5 indicating death. The 6 categories are 0=Asymptomatic (Fully active, able to carry on all pre-disease activities without restriction), 1=Symptomatic but completely ambulatory (Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature), 2=Symptomatic, < 50% in bed during the day (Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours), 3=Symptomatic, > 50% in bed, but not bedbound (Capable of only limited self-care, confined to bed or chair 50% or more of waking hours), 4=Bedbound (Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair), 5=Death.

  10. Percentage of Participants With Abnormal Electrocardiogram (ECG) Findings, Vital Signs, and Physical Findings [ Time Frame: Up to 2 years ]
  11. Percentage of Participants With Concomitant Medications [ Time Frame: Up to 2 years ]
  12. Maximum Serum Concentration Observed (Cmax) [ Time Frame: Day 1, Day 2, Day 5 of Cycle 1 ]
    Cmax is the maximum observed concentration of drug in blood plasma.

  13. Trough Concentration (Ctrough) [ Time Frame: Day 1, Day 2, Day 5 of Cycle 1 ]
    Ctrough is the measured concentration of a drug at the end of a dosing interval at steady state.

  14. Time of Maximum Concentration Observed (tmax) [ Time Frame: Day 1, Day 2, Day 5 of Cycle 1 ]
    Tmax is the time elapsed from the time of drug administration to maximum plasma concentration.

  15. Clearance (CL) [ Time Frame: Day 1, Day 2, Day 5 of Cycle 1 ]
    CL is a measure of the body's elimination of a drug from plasma over time.

  16. Apparent clearance (CL/F) [ Time Frame: Day 1, Day 2, Day 5 of Cycle 1 ]
    CL/F is a measure of the body's elimination of a drug from plasma over time, after oral administration.

  17. Volume or Apparent Volume of Distribution (Vdss/F) [ Time Frame: Day 1, Day 2, Day 5 of Cycle 1 ]
    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.

  18. Area under the curve (AUC) [ Time Frame: Day 1, Day 2, Day 5 of Cycle 1 ]
    AUC (from zero to infinity) represents the total drug exposure over time.

  19. Half-life (t1/2) [ Time Frame: Day 1, Day 2, Day 5 of Cycle 1 ]
    t1/2 is defined as the time required for the drug plasma concentration to be reduced to half.

  20. Baseline and Mean Change from Baseline Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) [ Time Frame: Day 1 of Cycle 1, Cycle 2, Cycle 3, Day 28 of Cycle 5, Week 32, every 3 cycles beyond Week 32, end of study (2 years) or 28 days post last dose ]
    The MPN-SAF TSS is an assessment form to measure the severity of 9 clinically important symptoms of polycythemia vera. These include: early satiety, abdominal discomfort, inactivity, concentration issues, night sweats, itching, bone pain, fever, and weight loss. The participant provides a severity score for each additional symptom on a scale of 0 (none/absent) to 10 (worst imaginable). A tenth symptom, fatigue, is assessed using the "worst" fatigue item from the Brief Fatigue Inventory (BFI).

  21. Baseline and Mean Change from Baseline European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) [ Time Frame: Day 1 of Cycle 1, Cycle 2, Cycle 3, Day 28 of Cycle 5, Week 32, every 3 cycles beyond Week 32, end of study (2 years) or 28 days post last dose ]
    EORTC QLQ-C30: includes functional scales (physical, role, cognitive, emotional, and social), global health status, symptom scales (fatigue, pain, nausea/vomiting) and single items (dyspnoea, appetite loss, insomnia, constipation/diarrhea and financial difficulties). Most questions use a 4-point scale (1 'Not at all' to 4 'Very much'; 2 questions used 7-point scale [1 'very poor' to 7 'Excellent']). Scores are averaged and transformed to 0-100 scale; higher score=better level of functioning or greater degree of symptoms.

  22. Baseline and Mean Change from Baseline Patient Global Impression of Change (PGIC) [ Time Frame: Day 1 of Cycle 2, Cycle 3, Day 28 of Cycle 5, Week 32, every 3 cycles beyond Week 32, end of study (2 years) or 28 days post last dose ]
    The PGIC is a one-item measure used to assess perceived treatment benefit. Participants will be asked "Since the start of the treatment you've received in this study, your polycythemia vera (PV) symptoms are: 'very much improved', 'much improved', 'minimally improved', 'no change', 'minimally worse', 'much worse', and 'very much worse'.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Adults > 18 years of age
  • 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 > 40%
  • Phlebotomy-dependent participants with splenomegaly by magnetic resonance imaging (MRI) or computerized tomography (CT) imaging (≥ 450 cubic centimeters [cm^3]) or without splenomegaly (< 450 cm^3, unpalpable, or prior splenectomy)
  • Resistance to/intolerance to hydroxyurea according to modified European Leukemia Net (ELN) criteria
  • 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
  • For women of childbearing potential: agreement to use contraceptive methods that result in a failure rate of < 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
  • Participants previously treated with murine double minute 2 (MDM2) antagonist therapies or participants receiving interferon-alpha, anagrelide, or ruxolitinib within 28 days or 5 half-lives, or hydroxyurea within 1 day, or participants receiving any other cytoreductive or investigational agents within 28 days or 5 half-lives of initial dose. Aspirin is permitted per treatment guidelines for PV unless medically contraindicated
  • Participants 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 ≤ 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
  • Participants 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03287245


Contacts
Contact: Reference Study ID: NP39761 www.roche.com/about_roche/roche_worldwide.htm 888-662-6728 (U.S. only) global-roche-genentech-trials@gene.com

Locations
United States, Arizona
Mayo Clinic - Arizona Not yet recruiting
Phoenix, Arizona, United States, 85054
United States, Kansas
University of Kansas Cancer Center; Westwood Cancer Center/BMT Output Clinic Recruiting
Kansas City, Kansas, United States, 66205
United States, New York
Icahn School of Medicine at Mount Sinai Recruiting
New York, New York, United States, 10029
Columbia Univ Med Ctr Recruiting
New York, New York, United States, 10032
MSKCC Withdrawn
New York, New York, United States, 10065
Weill Cornell Medical College Recruiting
New York, New York, United States, 10065
United States, Ohio
Cleveland Clinic Cancer Center Recruiting
Independence, Ohio, United States, 44131
United States, Texas
University of Texas Health Sciences Center in San Antonio Recruiting
San Antonio, Texas, United States, 78229
Australia, Victoria
Peter MacCallum Cancer Centre; Department of Haematology Recruiting
Melbourne, Victoria, Australia, 3002
Canada, Ontario
Princess Margaret Hospital; Department of Med Oncology Recruiting
Toronto, Ontario, Canada, M5G 2M9
Italy
ASST PAPA GIOVANNI XXIII; Ematologia Recruiting
Bergamo, Lombardia, Italy, 24127
Ospedale Di Circolo E Fondazione Macchi; Ematologia Recruiting
Varese, Lombardia, Italy, 21100
Az. Ospedaliero-Universitaria Careggi; CRIMM Recruiting
Firenze, Toscana, Italy, 50134
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Study Director: Clinical Trials Hoffmann-La Roche

Additional Information:
Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT03287245     History of Changes
Other Study ID Numbers: NP39761
2017-000861-58 ( EudraCT Number )
First Posted: September 19, 2017    Key Record Dates
Last Update Posted: September 10, 2018
Last Verified: September 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Hoffmann-La Roche:
polycythemia vera
PV
P vera
myeloproliferative diseases
hematologic diseases
myeloproliferative neoplasm
MPN

Additional relevant MeSH terms:
Polycythemia
Polycythemia Vera
Hematologic Diseases
Bone Marrow Neoplasms
Hematologic Neoplasms
Neoplasms by Site
Neoplasms
Bone Marrow Diseases
Myeloproliferative Disorders
Hydroxyurea
Antineoplastic Agents
Antisickling Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors