- Diagnosis of primary MF (PMF) or secondary MF (PET-MF and PPV-MF) as per WHO 2008
- 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
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
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
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
- 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
- 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
- Prior treatment with a licensed or experimental smoothened inhibitor.
- Randomized cohort only: Prior treatment with a Janus kinase inhibitor other than
- 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
- History of myocardial infarction or unstable angina within 6 months prior to
- 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
- 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