Intermediate-2, High-Risk Myelodysplastic Syndrome, Acute Myeloid Leukemia with 20-30% Blasts and Multi-Lineage Dysplasia, or Chronic Myelomonocytic Leukemia. MedDRA version: 18.0 Level: PT Classification code 10028537 Term: Myelofibrosis System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: PF-04449913
Product Code: PF-04449913
Pharmaceutical Form: Tablet
INN or Proposed INN: N/A
Current Sponsor code: B1371012
Other descriptive name: PF-04449913
Concentration unit: mg milli
Sponsors
Pfizer Inc. 235 East 42nd Street, New York, NY 10017
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Patient must meet all of the following inclusion criteria to be eligible for enrollment into the study: 1. Morphologically confirmed diagnosis of one of the following: a. MDS according to WHO 2008 classification (See Appendix 1 of the protocol), and bone marrow blasts = 5% b. AML with 20-30 % BM or PB blasts and multi-lineage dysplasia, according to WHO 2008 classification(Appendix 1 of the protocol) and WBC =65 years) yes F.1.3.1 Number of subjects for this age range 114
Exclusion criteria
Exclusion criteria: Patients with any of the following may not be included in the study: 1. Patients with AML who are candidates for standard induction chemotherapy as first line treatment. 2. Therapy-related (secondary to radiation or chemotherapy) MDS or AML. 3. Prior hypomethylating agents or cytotoxic chemotherapy for MDS, AML or CMML (prior immunosuppressive therapy and hydroxyurea are permitted provided that treatment is stopped within 8 and 2 weeks from study entry, respectively). 4. Previous hematopoietic stem cell transplant. 5. Prior treatment with a licensed or experimental smoothened inhibitor (SMOi) and/or hypomethylating agent (HMA). 6. Participation in a clinical study involving an investigational drug(s) (Phases 1-4) within 4 weeks prior to study entry. 7. Major surgery or radiation within 12 weeks prior to study entry. 8. Patients known to be refractory to platelet or packed red cell transfusions as per institutional guidelines, or who are known to refuse or who are likely to refuse blood product support. 9. Treatment with hematopoietic growth factors including: erythropoietin, granulocyte colony stimulating factor (G-CSF), and granulocyte macrophage colony stimulating factor (GM-CSF), or thrombopoietin receptor agonists within 3 weeks prior to study entry. 10. Any ongoing medical condition requiring chronic use of moderate to igh dose steroids (defined as =10 mg/day of prednisone or equipotent dose of another corticosteroid). 11. Any anti-cancer treatment within 2 weeks prior to study entry. 12. Current use or anticipated requirement for drugs that are known strong CYP3A4/5 inducers. 13. Diagnosis of any malignant disease other than MDS, AML or CMML within the prior 12 months, with the exception of adequately treated: (i) in-situ carcinomas, (ii) basal or squamous cell carcinoma, or (iii) nonmelanoma skin cancer. 14. Known malabsorption syndrome or other condition that may impair the absorption of the study drug (eg, gastrectomy, lap band, Crohn's disease) and inability or unwillingness to swallow tables or capsules. 15. Patients with 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. 16. Known uncontrolled central nervous system (CNS) involvement. 17. Known moderate to severe chronic obstructive pulmonary disease, interstitial lung disease, or pulmonary fibrosis. 18. Prior history of chronic liver disease (eg, chronic alcoholic liver disease, autoimmune hepatitis, sclerosing cholangitis, primary biliary cirrhosis, hemachromatosis, hepatic tumors, non-alcoholic steatohepatitis [NASH]). 19. Any one of the following ongoing or in the previous 6 months: myocardial infarction, congenital long QT syndrome, Torsades de pointes, arrhythmias (including sustained ventricular tachyarrhythmia), right bundle branch block and left anterior hemiblock (bifascicular block), unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure (CHF New York Heart Association class III or IV), cerebrovascular accident, transient ischemic attack or symptomatic pulmonary embolism; as well as bradycardia defined as 470 msec. 21. Pregnant or breastfeeding female patients. 22. Patients who are investigational site staff members directly involved in t
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Primary Objectives for the Phase 1b (Safety Lead-In) •To assess the safety and tolerability of PF 04449913 when administered in combination with azacitidine in patients with previously untreated Intermediate-2 or High-Risk MDS, AML with 20%-30% blasts and multi-lineage dysplasia or CMML. Primary Objectives for the Randomized Phase 2 Component •To demonstrate superior response rate (RR) of azacitidine and PF-04449913 versus azacitidine and placebo in the treatment of patients with previously untreated Intermediate-2 or High-Risk MDS, AML with 20-30% blasts and multi-lineage dysplasia and CMML.;Secondary Objective: Secondary Objectives for the Phase 1b (Safety Lead-In) • To assess the response rate (RR); • To assess other clinical efficacy measures; • To assess the rate of treatment emergent transfusion independence in patients who were transfusion dependent at study entry; • To characterize the PK of PF 04449913 and azacitidine alone and in combination; • To characterize any effects of PF 04449913 alone and in combination with azacitidine on QTc interval. Secondary Objectives for the Randomized Phase 2 Component • To compare the OS between treatment arms; • To compare the survival probabilities at 12, 18, and 24 months between treatment arms; • To compare the EFS between treatment arms; • To compare other clinical efficacy measures between treatment arms; • To compare the rate of treatment-emergent transfusion independence between treatment arms in patients who were transfusion dependent at study entry; Refer to Section 2.3 of the Protocol for further information;Primary end point(s): Primary Endpoints for the Phase 1b (Safety Lead-In) • Adverse events 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 and laboratory abnormalities as characterized by type, frequency, severity (as graded by N | — |
Secondary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: 12, 18 and 24 months.;Secondary end point(s): Secondary Endpoints for the Phase 1b (Safety Lead-In) • Response rate (Percentage of Patients achieving Complete Remission CR) + Partial Remission (PR)) as defined by modified IWG criteria (2006); • Other efficacy measures HI, mCR, Cytogenetic Response, and SD as defined by modified IWG criteria (2006); • Proportion of patients becoming transfusion independent on-study in patients who were transfusion dependent at the time of study entry; • PK parameters of PF-04449913 and azacitidine, including but not limited to Cmax, Tmax and AUC; • QTc interval. Secondary Endpoints for the Randomized Phase 2 • OS; • Survival probabilities at 12, 18, and 24 months; • lEFS; • Efficacy measures of HI, mCR, Cytogenetic Response, and SD as defined by modified IWG criteria (2006); •Proportion of patients becoming transfusion independent on-study in patients who were transfusion dependent at the time of study entry; • Duration of response; • Duration of HI; • Time to first response or any HI; • Time to best response or any HI; • Time to reaching >30% bone marrow blasts; • 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; • PROs of HRQOL as measured by the European Organization for Research and Treatment of Cancer (EORTC QLQ-C30) questionnaire and health status as measured by the EuroQol EQ-5D-5L self-report questionnaire Appendix 9 and Appendix 10; • Ctrough for PF-04449913; • QTc interval. | — |
Countries
Australia, Austria, Belgium, Canada, France, Hungary, Italy, Korea, Republic of, Netherlands, Spain, Taiwan, United Kingdom, United States
Contacts
Public ContactClinical Trials.gov Call Center
Pfizer Inc
Outcome results
None listed