Clinical trial NCT02226172: Single-Agent Glasdegib In Patients With Myelofibrosis Previously Treated With Ruxolitinib
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Primary Myelofibrosis; Post-polycythemia Vera Myelofibrosis; Post-essential Thrombocythemia Myelofibrosis
Keywords: Primary myelofibrosis
Secondary myelofibrosis
PMF
PET-MF
PPV-MF
Ruxolitinib resistant or intolerant
previously treated myelofibrosis
smoothened inhibitor
oral
single agent.
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2014-08-27
Enrollment: 21
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.


Eligibility 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.

Primary outcomes:
measure: 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
timeFrame: Week 24
measure: Number of Participants With Treatment -Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs): Lead-in Cohort
timeFrame: Baseline up to Week 131
measure: Number of Participants With Treatment Emergent Treatment -Related Adverse Events (AEs) and Serious Adverse Events (SAEs): Lead-in Cohort
timeFrame: Baseline up to Week 131
measure: Number of Participants With Treatment Emergent Adverse Events (AEs) According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03: Lead-in Cohort
timeFrame: Baseline up to Week 131
measure: Number of Participants With Laboratory Abnormalities: Lead-in Cohort
timeFrame: Baseline up to Week 131
measure: Number of Participants With Laboratory Test Abnormalities According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03 Grade 3 and Above Hematological Test Abnormalities: Lead-in Cohort
timeFrame: Baseline up to Week 131
measure: Number of Participants With Laboratory Test Abnormalities According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03 Grade 3 and Above Chemistry Test Abnormalities: Lead-in Cohort
timeFrame: Baseline up to Week 131
Secondary outcomes:
measure: Percentage of Participants Achieving SVR ≥35% as Measured by Magnetic Resonance Imaging/Computed Tomography Scan at Week 24 in the Lead-in Cohort
timeFrame: Week 24
measure: 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
timeFrame: Week 24
measure: Monthly Mean Change From Baseline in Overall Total Symptom Score (TSS) in the Lead-in Cohort
timeFrame: Weeks 12, 24, 36 and 48
measure: Percentage of Participants Achieving Anemia Response (Transfusion Dependent Versus Independent) in the Lead-in Cohort
timeFrame: Baseline to end of treatment
measure: 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
timeFrame: Cycle 1, Day 15
measure: Area Under the Glasdegib Plasma Concentration Versus Time Profile at the End of a Dosing Interval (AUCtau) in the Lead-in Cohort
timeFrame: Cycle 1, Day 15
measure: Time to Reach Cmax (Tmax) in the Lead-in Cohort
timeFrame: Cycle 1, Day 15
measure: Percentage of Participants Achieving SVR ≥50% as Measured by MRI/CT Scan at Week 24 in the Randomized Cohort
timeFrame: Week 24
measure: Monthly Mean Change From Baseline in Overall TSS in the Randomized Cohort
timeFrame: Weeks 12, 24, 36 and 48
measure: Percentage of Participants Achieving Anemia Response (Transfusion Dependent Versus Independent) in the Randomized Cohort
timeFrame: Baseline to end of treatment
measure: Participant Reported Outcomes of Health Related Quality of Life and Health Status in the Randomised Cohort
timeFrame: Baseline to end of treatment
measure: Median Duration of SVR in the Randomized Cohort
timeFrame: Baseline to end of treatment
measure: Kaplan-Meier Estimate of Overall Survival in the Randomized Cohort
timeFrame: Baseline to end of treatment
measure: Glasdegib PK Parameters in the Randomized Cohort
timeFrame: Cycle 1, Day 15
measure: Psychometric Validation of the MPN-SAD in the Randomised Cohort
timeFrame: Baseline to end of treatment
measure: Number of Participants With Treatment -Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs): Randomized Cohort
timeFrame: Baseline up to Week 131
measure: Number of Participants With Treatment Emergent Treatment -Related Adverse Events (AEs) and Serious Adverse Events (SAEs): Randomized Cohort
timeFrame: Baseline up to Week 131
measure: Number of Participants With Treatment Emergent Adverse Events (AEs) According to Maximum Severity: Randomized Cohort
timeFrame: Baseline up to Week 131
measure: Number of Participants With Laboratory Abnormalities: Randomized Cohort
timeFrame: Baseline up to Week 131
measure: Number of Participants With Laboratory Test Abnormalities By Maximum Severity: National Cancer Institute Common Terminology Criteria for Adverse Event (Version 4.0) Grade 3 and Above Hematological Test Abnormalities: Randomized Cohort
timeFrame: Baseline up to Week 131
measure: Number of Participants With Laboratory Test Abnormalities By Maximum Severity: National Cancer Institute Common Terminology Criteria for Adverse Event (Version 4.0) Grade 3 and Above Chemistry Test Abnormalities: Randomized Cohort
timeFrame: Baseline up to Week 131
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic Building - Phoenix
state: Arizona
city: Phoenix
country: United States
facility: Mayo Clinic Hospital
state: Arizona
city: Scottsdale
country: United States
facility: Mayo Clinic
state: Arizona
city: La Jolla
country: United States
facility: UC San Diego Moores Cancer Center - Investigational Drug Services
state: California
city: La Jolla
country: United States
facility: UCSD Medical Center Clinical Laboratory - La Jolla
state: California
city: La Jolla
country: United States
facility: University of California San Diego (UCSD) Moores Cancer Center
state: California
city: San Diego
country: United States
facility: UC San Diego Medical Center- Hillcrest
state: California
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: New York
country: United States
facility: Weill Cornell Medical College - New York-Presbyterian Hospital
state: New York
city: New York
country: United States
facility: Herbert Irving Comprehensive Cancer Center-Columbia University Medical Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College-New York Presbyterian Hospital
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic - Taussig Cancer Institute
state: Ohio
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute-University of Utah
state: Utah
city: Salt Lake City
country: United States
facility: University of Utah, Huntsman Cancer Hospital
state: Utah
city: Milwaukee
country: United States
facility: Froedtert Hospital and Medical College of Wisconsin
state: Wisconsin
city: Kobe
country: Japan
facility: Kobe University Hospital
state: Hyogo
city: Suita-Shi
country: Japan
facility: Osaka University Hopsital
state: Osaka
city: Bunkyo-ku
country: Japan
facility: Juntendo University Hospital
state: Tokyo
city: Tokyo
country: Japan
facility: Tokyo Medical University Hospital
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References: