| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
| A bone marrow disorder that disrupts a body's normal production of blood cells. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10028537 |
| E.1.2 | Term | Myelofibrosis |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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.
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| E.2.2 | Secondary objectives of the trial |
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. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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) performance status of 0, 1, 2 or 3.
8. The following laboratory values:
a. Absolute Neutrophil Count (ANC) >.75 x 109/L;
b. Platelet count >50 x 109/L with no evidence of bleeding and not requiring platelet transfusions;
c. Serum creatinine <1.5 x upper limit of normal (ULN) or estimated creatinine clearance ≥-60mL/min (as calculated using the standard method of institution);
d. Serum amylase or lipase <1.5 x ULN;
e. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 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).
f. 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.
g. Serum electrolyte values < Grade 2 (sodium, potassium, calcium, phosphorous and magnesium), .per CTCAE v.4.03.
9. Recovery to ≤ Grade 1 from all clinically significant adverse events related to prior MF therapy, including transplant related toxicities.
10. More than 2 months out from allogenic hematopoietic stem cell transplant prior to randomization.
11. 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.
12. ≥18 years of age.
13. Male subjects able to father children and female patients of childbearing potential and at risk for pregnancy must agree to use two highly effective method of contraception throughout the study and for 90 days after the last dose of assigned treatment.
14. Serum or urine pregnancy test (for females of childbearing potential) negative at screening .
15. Evidence of a personally signed and dated informed consent document indicating that the patient (or a legally acceptable representative) has been informed of all pertinent aspects of the study.
16. Patients who are willing and able to comply with the scheduled visits, treatment plan, laboratory tests, and other study procedures.
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| E.4 | Principal 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 supervised by the Investigator, or patients who are Pfizer employees directly involved in the conduct of the trial.
19. Participation in other clinical trials with investigational agents (Phases 1-4) within 28 days prior to first dose of study treatment.
20. Other severe acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior as judged by the treating physician or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
21. Pregnant female patients; breastfeeding female patients; male subjects able to father children and female patients of childbearing potential who are unwilling or unable to use two highly effective methods of contraception as outlined in this protocol for the duration of the study and for 90 days after the last dose of investigational product or longer, based upon the compound’s half-life characteristics. |
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| E.5 End points |
| E.5.1 | 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
by MRI (or CT, in patients unable to tolerate an MRI). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Primary endpoint will be reached at Week 24 |
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| E.5.2 | 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. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Primary endpoint will be reached at Week 24 |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 56 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Austria |
| Belgium |
| France |
| Germany |
| Israel |
| Italy |
| Japan |
| Netherlands |
| Spain |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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End of Study in a Member State of the EU is defined as the time at which it is deemed that sufficient patients have been recruited and completed the study as stated in the regulatory application and ethics application in the Member State. Poor recruitment by a Member State is not a reason for premature termination but is considered a normal conclusion to the study in that Member State.
End of Study in all other participating countries is defined as Last Patient Last Visit. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 3 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
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