Myelofibrosis MedDRA version: 19.0 Level: PT Classification code 10028537 Term: Myelofibrosis System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: Glasdegib
Product Code: PF-04449913
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Glasdegib
Current Sponsor
Sponsors
Pfizer Inc. 235 East 42nd Street, New York, 10017
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Patients must meet all of the following inclusion criteria to be eligible for enrollment into the study: 1. Diagnosis of primary MF (PMF) or secondary MF (PET-MF and PPV-MF) as per WHO 2008 criteria. 2. Lead-in cohort only: Prior treatment with =1 JAKi (must meet one of the following criteria): a. Previous treatment with =1 JAKi (licensed or experimental) for a minimum duration of =4 weeks and failure to achieve or sustain adequate symptomatic control and/or achieve or sustain an adequate reduction of splenomegaly (Investigator’s judgment); b. JAKi therapy discontinuation for unacceptable toxicity irrespective of the duration of therapy. 3. Randomized cohort: At least one of the following criteria for prior ruxolitinib resistance OR intolerance must be met: a. Primary Resistance i. No reduction in spleen volume (MRI/CT) or size (manual palpation from below left inferior costal margin) following treatment with ruxolitinib for at least 12 weeks. b. Secondary Resistance: i. Increase in spleen volume (assessed by MRI/CT) from nadir by =25% at any time following the start of ruxolitinib therapy; OR ii. Appearance for new splenomegaly palpable at least 5cm below the left inferior costal margin; OR iii. Increase in spleen size (manual palpation from below the left inferior costal margin) by =50% from nadir (or =100% if nadir is <5 cm) in the context of worsening splenomegaly-related abdominal pain or other disease-related signs/symptoms at any time following the start of ruxolitinib therapy. c. Intolerance i. Anaphylaxis or Grade 3/4 allergic reactions following any duration of ruxolitinib therapy; OR ii. In accordance with the dose modification guidelines in the ruxolitinib prescribing information, documentation in the medical record of the presence of ruxolitinib-related toxicity/toxicities that resulted in ruxolitinib discontinuation. 4. Documentation by the Investigator that the patient has exhausted available treatment options (eg, resistant or intolerant to hydroxyurea, etc). 5. Spleen =5 cm below the inferior left costal margin (LCM) as measured by manual palpation. 6. 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) (Appendix 1): a. Early satiety; b. Abdominal discomfort (pressure or bloating); c. Inactivity (including work, home and social activities); d. Nights sweats; e. Pruritus; f. Bone pain (other than arthritis or joint pains); g. Pain below the ribs on the left-hand side; h. Fatigue; i. Shortness of breath. 7. Eastern Cooperative Oncology Group (ECOG) performanc
Exclusion criteria
Exclusion criteria: Patients presenting with any of the following will not be included in the study: 1. Prior treatment with a licensed or experimental smoothened inhibitor (SMOi). 2. Randomized cohort only: Prior treatment with a Janus Kinase (JAK) inhibitor other than ruxolitinib. 3. 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. 4. Splenic irradiation =3 months prior to enrollment. 5. History of congenital long QT syndrome, or a baseline >470 msec QTcF abnormality (average of the triplicate reading), 6. Evidence of significant cardiac disease, for example: symptomatic cardiac heart failure (CHF, NYHA = class 3), complete bundle branch block, significant atrial or ventricular tachyarrythmias and any unstable cardiac arrhythmias requiring medication. 7. History of myocardial infarction or unstable angina within 6 months prior to enrollment. 8. Uncontrolled inflammatory bowel disease, peptic ulcer disease or history of significant gastro-intestinal bleeding within 6 months of enrollment. 9. Any condition requiring chronic use of moderate/high dose steroids (equivalent to =10 mg QD prednisone). 10. Hematopoietic growth factor receptor agonists (eg, erythropoietin (Epo)), granulocyte colony stimulating factor (GCSF), romiplostim, eltrombopag within 28 days of enrollment. 11. 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). 12. Prior history of chronic liver disease (eg, chronic alcoholic liver disease, autoimmune hepatitis, sclerosing cholangitis, primary biliary cirrhosis, hemachromatosis, non-alcoholic steatohepatitis [NASH]). 13. Active, uncontrolled bacterial, fungal or viral infection, including hepatitis B (HBV), hepatitis C (HCV), known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness. 14. Active graft versus host disease (GVHD) with other than grade 1 skin involvement or GVHD requiring immunosuppressive treatment. 15. Uncontrolled disseminated intravascular coagulation. 16. Current (including their administration within 3-days prior to study entry) use or anticipated need for food or drugs that are strong CYP3A4 inhibitors. Please refer to Appendix 8 for a list of strong inhibitors. 17. Current use or anticipated requirement for drugs that are known strong CYP3A4/5 inducers. 18. Patients who are investigational site staff members directly involved in the conduct of the trial and their family members, site staff members otherwise supervis
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Lead-in Cohort • To assess the safety and tolerability of PF-04449913 in patients with primary or secondary MF who have been previously treated with =1 JAKi. Randomized Cohort • To compare the effect of PF-04449913 vs. placebo on SVR in patients with primary or secondary MF who have been previously treated with ruxolitinib. ; Secondary Objective: Lead-in Cohort • To assess the effect of PF-04449913 on spleen volume reduction (SVR) in patients with primary or secondary MF who have been previously treated with =1 JAKi. • To assess the effect of PF-04449913 on patient reported MF symptoms in patients with primary or secondary MF who have been previously treated with =1 JAKi. • To assess the effect of PF-04449913 on hematologic improvement (peripheral blood) in patients with primary or secondary MF who have been previously treated with = 1 JAKi. • To characterize the pharmacokinetics (PK) of PF-04449913. Randomized Cohort • To compare the symptomatic efficacy of PF-04449913 vs. placebo on patient reported MF symptoms in patients with primary or secondary MF who have been previously treated with ruxolitinib; Please refer to Section 2.2.2 of the Protocol for the additional Randomized Cohort Secondary objectives. ; Primary end point(s): Lead-in Cohort: Adverse events (AEs) as characterized by: type, frequency, severity (as graded by National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] v.4.03), timing, seriousness and relationship to study therapy. Laboratory abnormalities as characterized by: type, frequency, severity (as graded by NCI CTCAE v.4.03) and timing. Randomized Cohort Proportion of patients achieving SVR =35% at Week 24 as measured | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Lead-in Cohort • Proportion of patients achieving SVR =35% at Week 24 as measured by MRI (or computed tomography (CT) in patients unable to tolerate an MRI); • Proportion of patients achieving =50% reduction in total symptom score (TSS) at Week 24, as measured by the Myeloproliferative Neoplasms Symptom Assessment Diary (MPN-SAD); • Overall total symptom score (TSS) as measured by MPN-SAD; • Proportion of patients with improvement in peripheral blood counts, as defined by the Revised IWG-MRT Response Criteria13 (Appendix 6); • Pharmacokinetic parameters of PF-04449913, including but not limited to Cmax, Tmax, AUC and Cavg. Randomized Cohort • Proportion of patients achieving =50% reduction in TSS at Week 24, as measured by the MPN-SAD; • Overall TSS at Week 24, as measured by MPN-SAD; • Proportion of patients with improvement in peripheral blood counts, as defined by the Revised IWG-MRT Response Criteria13 (Appendix 6); • Patient Reported Outcome (PRO) of health-related quality of life as measured by the European Organisation for Research and Treatment of Cancer (EORTC QLQ-30), Health status as measured by the EuroQol EQ-5D Self-Report Questionnaire (EQ-5D-5L) and Patient Global Impression of Change (PGIC); • Duration of spleen volume reduction; • OS; • Adverse Events as characterized by: type, frequency, severity (as graded by NCI CTCAE v.4.03), timing , seriousness and relationship to study therapy; • Laboratory abnormalities as characterized by: type, frequency, severity (as graded by NCI CTCAE v.4.03) and timing; • Pharmacokinetic parameters of PF-04449913, including but not limited to Cmax, Tmax, AUC and Cavg; • Psychometric validation of the MPN-SAD. ;Time | — |
Countries
Austria, Belgium, France, Germany, Israel, Italy, Japan, Netherlands, Spain, United Kingdom, United States
Contacts
Public ContactClinical Trials.gov Call Center
Pfizer Inc
Outcome results
None listed