Single-Agent Glasdegib In Patients With Myelofibrosis Previously Treated With Ruxolitinib
Condition: Primary Myelofibrosis; Post-polycythemia Vera Myelofibrosis; Post-essential Thrombocythemia Myelofibrosis
MeSH terms: Polycythemia Vera; Primary Myelofibrosis; Polycythemia; Thrombocytosis; Thrombocythemia, Essential
Intervention: Glasdegib (PF-04449913); Placebo
Intervention description: Oral daily dose of glasdegib (PF-04449913) 100 mg tablet in a continuous regimen of 28-day cycles.; Oral daily dose of placebo 100 mg tablet in a continuous regimen of 28-day cycles.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 21.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Primary myelofibrosis; Secondary myelofibrosis; PMF; PET-MF; PPV-MF; Ruxolitinib resistant or intolerant; previously treated myelofibrosis; smoothened inhibitor; oral; single agent.

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.