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Single-Agent Glasdegib In Patients With Myelofibrosis Previously Treated With Ruxolitinib

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ClinicalTrials.gov Identifier: NCT02226172
Recruitment Status : Terminated
First Posted : August 27, 2014
Results First Posted : April 2, 2018
Last Update Posted : July 23, 2018
Sponsor:
Information provided by (Responsible Party):
Pfizer

Brief Summary:
A lead-in cohort of ~20 patients with primary or secondary myelofibrosis previously treated with 1 or more Janus kinase inhibitors enrolled to single-agent glasdegib to evaluate safety and tolerability. Following the lead-in, a phase 2, double blind, 2-arm study, randomized 2:1 to oral single-agent glasdegib versus placebo in 201 patients resistant or intolerant to ruxolitinib.

Condition or disease Intervention/treatment Phase
Primary Myelofibrosis; Post-polycythemia Vera Myelofibrosis; Post-essential Thrombocythemia Myelofibrosis Drug: Glasdegib (PF-04449913) Drug: Placebo Phase 2

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 21 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 2, Double-blind, Randomized Safety And Efficacy Study Of Glasdegib (Pf-04449913) Versus Placebo In Patients With Myelofibrosis Previously Treated With Ruxolitinib
Actual Study Start Date : October 6, 2014
Actual Primary Completion Date : December 14, 2016
Actual Study Completion Date : January 31, 2018


Arm Intervention/treatment
Experimental: Arm A
Oral daily dose of glasdegib (PF-04449913) 100 mg tablet in a continuous regimen of 28-day cycles.
Drug: Glasdegib (PF-04449913)
Oral daily dose of glasdegib (PF-04449913) 100 mg tablet in a continuous regimen of 28-day cycles.

Placebo Comparator: Arm B
Oral daily dose of placebo 100 mg tablet in a continuous regimen of 28-day cycles.
Drug: Placebo
Oral daily dose of placebo 100 mg tablet in a continuous regimen of 28-day cycles.




Primary Outcome Measures :
  1. Percentage of Participants Achieving Spleen Volume Reduction (SVR) ≥35% as Measured by Magnetic Resonance Imaging (MRI)/Computed Tomography (CT) Scan at Week 24 in the Randomized Cohort [ Time Frame: Week 24 ]
    The double blind, randomized, placebo controlled phase of the study was not enrolled after the study was terminated early so no data were collected to assess this endpoint.


Secondary Outcome Measures :
  1. Percentage of Participants Achieving SVR ≥35% as Measured by Magnetic Resonance Imaging/Computed Tomography Scan at Week 24 in the Lead-in Cohort [ Time Frame: Week 24 ]
    MRI (CT scan may have been permitted if MRI was contraindicated) of the spleen and the liver was performed at baseline, then every 12 weeks while the participant was on treatment. The same method of assessment used at baseline was used for the duration of the trial to ensure consistency. Spleen volume was assessed by a central, independent blinded reader.

  2. Percentage of Participants Achieving ≥50% Reduction From Baseline in Total Symptom Score (TSS) as Measured by the Myeloproliferative Neoplasm-Symptom Assessment Diary (MPN-SAD) at Week 24 in the Lead-in Cohort [ Time Frame: Week 24 ]
    The MPN-SAD assessed the impact of 9 myelofibrosis symptoms, at their worst, over the past 7 days and over the past 24 hours on a scale of 0 (absent) to 10 (worst imaginable). The 9 symptoms are early satiety, abdominal discomfort, inactivity, night sweats, pruritus, bone pain, pain below the ribs on the left-hand side, fatigue and shortness of breath. The TSS is the sum of the individual scores, excluding inactivity and shortness of breath. The TSS at Week 24 is the average of the daily total scores from the last 28 days of symptom scores immediately prior to Week 24. A higher score indicates worse symptoms.

  3. Monthly Mean Change From Baseline in Overall Total Symptom Score (TSS) in the Lead-in Cohort [ Time Frame: Weeks 12, 24, 36 and 48 ]
    The MPN-SAD assessed the impact of 9 myelofibrosis symptoms, at their worst, over the past 7 days and over the past 24 hours on a scale of 0 (absent) to 10 (worst imaginable). The 9 symptoms are early satiety, abdominal discomfort, inactivity, night sweats, pruritus, bone pain, pain below the ribs on the left-hand side, fatigue and shortness of breath. The TSS is the sum of the individual scores, excluding inactivity and shortness of breath. The TSS at Week 24 is the average of the daily total scores from the last 28 days of symptom scores immediately prior to Week 24. A higher score indicates worse symptoms.

  4. Percentage of Participants Achieving Anemia Response (Transfusion Dependent Versus Independent) in the Lead-in Cohort [ Time Frame: Baseline to end of treatment ]
    Anemia response was defined as transfusion-independent participants with a ≥20 gram per liter (g/L) increase in hemoglobin (Hb) level where baseline Hb level was <100 g/L, or baseline transfusion-dependent patients becoming transfusion-independent post-baseline. Transfusion dependency before the start of study treatment was defined as transfusions of ≥6 units of packed red blood cells in the 12 weeks prior to start of study treatment, for a final pre-treatment Hb of <85 g/L. In addition, the most recent transfusion episode must have occurred in the 28 days prior to study enrollment. Response in transfusion-dependent patients required absence of any packed red blood cell transfusions during any consecutive rolling 12-week interval during the treatment phase, capped by a Hb level of ≥85 g/L.

  5. Maximum Observed Glasdegib Plasma Concentration (Cmax), Minimum Glasdegib Plasma Concentration Observed Prior to the Next Dose (Cmin), and Average Observed Glasdegib Plasma Concentration (Cavg) in the Lead-in Cohort [ Time Frame: Cycle 1, Day 15 ]
    Cmax was the highest plasma concentration of glasdegib observed directly from the plasma concentration data. Cmin was the lowest plasma concentration of glasdegib observed directly from the plasma concentration data. Cavg was the average concentration at steady state estimated using non-compartmental pharmacokinetic (PK) analysis.

  6. Area Under the Glasdegib Plasma Concentration Versus Time Profile at the End of a Dosing Interval (AUCtau) in the Lead-in Cohort [ Time Frame: Cycle 1, Day 15 ]
    AUCtau was the area under the glasdegib plasma concentration-time profile from time zero to the end of the dosing interval (24 hours) estimated by non-compartmental PK analysis using the linear/log trapezoidal method.

  7. Time to Reach Cmax (Tmax) in the Lead-in Cohort [ Time Frame: Cycle 1, Day 15 ]
    Tmax was the time of the first occurrence of Cmax observed directly from the plasma concentration data.

  8. Percentage of Participants Achieving SVR ≥50% as Measured by MRI/CT Scan at Week 24 in the Randomized Cohort [ Time Frame: Week 24 ]
    The double blind, randomized, placebo controlled phase of the study was not enrolled after the study was terminated early so no data were collected to assess this endpoint.

  9. Monthly Mean Change From Baseline in Overall TSS in the Randomized Cohort [ Time Frame: Weeks 12, 24, 36 and 48 ]
    The double blind, randomized, placebo controlled phase of the study was not enrolled after the study was terminated early so no data were collected to assess this endpoint.

  10. Percentage of Participants Achieving Anemia Response (Transfusion Dependent Versus Independent) in the Randomized Cohort [ Time Frame: Baseline to end of treatment ]
    The double blind, randomized, placebo controlled phase of the study was not enrolled after the study was terminated early so no data were collected to assess this endpoint.

  11. Participant Reported Outcomes of Health Related Quality of Life and Health Status in the Randomised Cohort [ Time Frame: Baseline to end of treatment ]
    The double blind, randomized, placebo controlled phase of the study was not enrolled after the study was terminated early so no data were collected to assess this endpoint.

  12. Median Duration of SVR in the Randomized Cohort [ Time Frame: Baseline to end of treatment ]
    The double blind, randomized, placebo controlled phase of the study was not enrolled after the study was terminated early so no data were collected to assess this endpoint.

  13. Kaplan-Meier Estimate of Overall Survival in the Randomized Cohort [ Time Frame: Baseline to end of treatment ]
    The double blind, randomized, placebo controlled phase of the study was not enrolled after the study was terminated early so no data were collected to assess this endpoint.

  14. Glasdegib PK Parameters in the Randomized Cohort [ Time Frame: Cycle 1, Day 15 ]
    The double blind, randomized, placebo controlled phase of the study was not enrolled after the study was terminated early so no data were collected to assess this endpoint.

  15. Psychometric Validation of the MPN-SAD in the Randomised Cohort [ Time Frame: Baseline to end of treatment ]
    The double blind, randomized, placebo controlled phase of the study was not enrolled after the study was terminated early so no data were collected to assess this endpoint.



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

Inclusion criteria:

  • Diagnosis of primary MF (PMF) or secondary MF (PET-MF and PPV-MF) as per WHO 2008 criteria.
  • Lead-in cohort: resistant or intolerant to 1 or more Janus kinase inhibitors (licensed or experimental).
  • Randomized cohort: resistant or intolerant to prior ruxolitinib therapy. Documentation by the Investigator that the patient has exhausted available treatment options (eg, resistant or intolerant to hydroxyurea, etc).
  • Spleen 5 cm below the inferior left costal margin as measured by manual palpation.
  • Active symptomatic MF as defined by the screening MPN-SAD patient-reported instrument requiring a severity score of at least 5 on one symptom, or a severity score of ≥ 3 on at least two of the symptoms (on a 0 to 10 scale).
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, 2, or 3.
  • Adequate organ function, demonstrated by the following laboratory values:

    1. Absolute Neutrophil Count 75 x 10(9)/L;
    2. Platelet count >50 x 10(9)/L with no evidence of bleeding and not requiring platelet transfusions;
    3. Serum creatinine <1.5 x upper limit of normal (ULN) or estimated creatinine clearance 60 mL/min (as calculated using the standard method of the institution);
    4. Serum amylase or lipase <1.5 x ULN;
    5. Aspartate aminotransferase and alanine aminotransferase values 3.0 x ULN (or 5x ULN in the case of patients with MF accompanied by hepatic extramedullary hematopoiesis, as manifested by any degree of hepatomegaly).
    6. Total bilirubin values <1.5 x ULN unless the bilirubin is principally unconjugated (in the context of hemolysis) or there is documented Gilbert's disease.
    7. Serum electrolyte values < Grade 2 (sodium, potassium, calcium, phosphorous and magnesium), per CTCAE v.4.03.
  • Recovery to Grade 1 from all clinically significant adverse events related to prior MF therapy, including transplant-related toxicities.
  • More than 2 months out from allogenic hematopoietic stem cell transplant prior to randomization.
  • Must be able to undergo MRI of abdomen (spleen and liver). Patients who are contra indicated for MRI may be enrolled and evaluated by CT scan at the discretion of the Sponsor.
  • 18 years of age.
  • Male subjects able to father children and female patients of childbearing potential and at risk for pregnancy must agree to use two highly effective methods of contraception throughout the study and for 90 days after the last dose of assigned treatment.

Exclusion criteria:

  • Prior treatment with a licensed or experimental smoothened inhibitor.
  • Randomized cohort only: Prior treatment with a Janus kinase inhibitor other than ruxolitinib.
  • Other anti-cancer therapy up to 14 days prior to enrollment, with the exception of hydroxyurea, which can be given up to 4 days prior to enrollment.
  • Splenic irradiation 3 months prior to enrollment.
  • History of congenital long QT syndrome, or a baseline >470 msec QTcF abnormality (average of the triplicate reading).
  • Evidence of significant cardiac disease, for example: symptomatic cardiac heart failure (CHF, NYHA class 3), complete bundle branch block, significant atrial or ventricular tachyarrhythmias and any unstable cardiac arrhythmias requiring medication.
  • History of myocardial infarction or unstable angina within 6 months prior to enrollment.
  • Uncontrolled inflammatory bowel disease, peptic ulcer disease or history of significant gastro intestinal bleeding within 6 months of enrollment.
  • Any condition requiring chronic use of moderate/high dose steroids (equivalent to 10 mg QD prednisone).
  • Hematopoietic growth factor receptor agonists (eg, erythropoietin (Epo), granulocyte colony stimulating factor, romiplostim, eltrombopag within 28 days of enrollment.
  • Currently active malignancy (other than MF). Prior malignancies are allowed so long as there is no evidence of disease recurrence within the last 2 years (with the exception of fully excised, non-complicated basal cell carcinoma which can have been active within the prior 2 years, and certain localized, non-invasive fully excised skin, cervical, breast, prostate or bladder tumors).
  • Prior history of chronic liver disease (eg, chronic alcoholic liver disease, autoimmune hepatitis, sclerosing cholangitis, primary biliary cirrhosis, hemachromatosis, non-alcoholic steatohepatitis [NASH]).
  • Active, uncontrolled bacterial, fungal or viral infection, including hepatitis B, hepatitis C, known human immunodeficiency virus or acquired immunodeficiency syndrome related illness.
  • Active graft versus host disease (GVHD) with other than grade 1 skin involvement or GVHD requiring immunosuppressive treatment.
  • Uncontrolled disseminated intravascular coagulation.
  • Current (including their administration within 3 days prior to study entry) use or anticipated need for food or drugs that are strong CYP3A4 inhibitors.
  • Current use or anticipated requirement for drugs that are known strong CYP3A4/5 inducers.

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): NCT02226172


Locations
United States, Arizona
Mayo Clinic Building - Phoenix
Phoenix, Arizona, United States, 85054
Mayo Clinic Hospital
Phoenix, Arizona, United States, 85054
Mayo Clinic
Scottsdale, Arizona, United States, 85259
United States, California
UC San Diego Moores Cancer Center - Investigational Drug Services
La Jolla, California, United States, 92037-0845
UCSD Medical Center Clinical Laboratory - La Jolla
La Jolla, California, United States, 92037
University of California San Diego (UCSD) Moores Cancer Center
La Jolla, California, United States, 92093-0698
UC San Diego Medical Center- Hillcrest
San Diego, California, United States, 92103
United States, Michigan
University of Michigan
Ann Arbor, Michigan, United States, 48109
United States, New York
Weill Cornell Medical College - New York-Presbyterian Hospital
New York, New York, United States, 10021
Herbert Irving Comprehensive Cancer Center-Columbia University Medical Center
New York, New York, United States, 10032
Weill Cornell Medical College-New York Presbyterian Hospital
New York, New York, United States, 10065
United States, Ohio
Cleveland Clinic - Taussig Cancer Institute
Cleveland, Ohio, United States, 44195
United States, Utah
Huntsman Cancer Institute-University of Utah
Salt Lake City, Utah, United States, 84112
University of Utah, Huntsman Cancer Hospital
Salt Lake City, Utah, United States, 84112
United States, Wisconsin
Froedtert Hospital and Medical College of Wisconsin
Milwaukee, Wisconsin, United States, 53226-3522
Japan
Kobe University Hospital
Kobe, Hyogo, Japan, 6500017
Osaka University Hopsital
Suita-Shi, Osaka, Japan, 565-0871
Juntendo University Hospital
Bunkyo-ku, Tokyo, Japan, 113-8431
Tokyo Medical University Hospital
Tokyo, Japan, 160-0023
Sponsors and Collaborators
Pfizer
Investigators
Study Director: Pfizer CT.gov Call Center Pfizer

Additional Information:
Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT02226172     History of Changes
Other Study ID Numbers: B1371013
SMOI ( Other Identifier: Alias Study Number )
2014-000933-21 ( EudraCT Number )
2014-001048-40 ( EudraCT Number )
First Posted: August 27, 2014    Key Record Dates
Results First Posted: April 2, 2018
Last Update Posted: July 23, 2018
Last Verified: July 2018

Keywords provided by Pfizer:
Primary myelofibrosis
Secondary myelofibrosis
PMF
PET-MF
PPV-MF
Ruxolitinib resistant or intolerant
previously treated myelofibrosis
smoothened inhibitor
oral
single agent.

Additional relevant MeSH terms:
Primary Myelofibrosis
Polycythemia
Polycythemia Vera
Thrombocytosis
Thrombocythemia, Essential
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Bone Marrow Neoplasms
Hematologic Neoplasms
Neoplasms by Site
Neoplasms
Blood Platelet Disorders
Blood Coagulation Disorders
Hemorrhagic Disorders