| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Intermediate-2, High-Risk Myelodysplastic Syndrome, Acute Myeloid Leukemia with 20-30% Blasts and Multi-Lineage Dysplasia, or Chronic Myelomonocytic Leukemia. |
|
| E.1.1.1 | Medical condition in easily understood language |
| A bone marrow disorder that disrupts a body's normal production of blood cells |
|
| 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 | 18.0 |
| 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) |
|
| 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 |
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. |
|
| E.2.2 | Secondary objectives of the trial |
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 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 < 20x109/L
c. CMML according to the WHO 2008 classification (Appendix 1 of the protocol) and BM blasts between 10% - 19% and WBC < 13x109/L
2. MDS patients must have intermediate-2 (1.5 to 2.0 points) or High-Risk (≥2.5 points) disease according to the International Prognostic Scoring System (IPSS).
3. MDS patients must have normal levels of vitimin B12 within the institutional range of normal as determined within 28 days of study entry.
4. AML pateients with 20-30% BM blasts and multi-linage dysplasia, must have stable blast counts per Investigator's judgment.
5. Clinical indication for treatment with azacitidine for MDS, AML or CMML.
6. Eastern Cooperatve Oncology Group (ECOG) Performance Status ≤2. See Appendix 11 of the protocol.
7. ≥18 years of age.
8. Adequate Renal Function:
a. Serum creatinine ≤1.5 x upper limit of normal (ULN);
OR
b. Estimated creatinine clearance ≥60 ml/min (calculated using the standard method for the institution).
9. Adequate Liver Function:
a. Total serum bilirubin ≤1.5 x ULN (unless the bilirubin is principally unconjugated and there is strong suspicion of sub-clinical hemolysis or the patient has documented Gilbert's disease);
b. Aspartate transaminase (AST) and Alanine transaminase ( ALT) ≤2.5 x ULN;
c. Alkaline phosphatase ≤2.5 x ULN.
10. Serum amylase or lipase <1.5 x ULN.
11. Serum or urine pregnancy test (for female patients of childbearing potential) with a minimum sensitivity of 25 IU/L or equivalent units of human chorinic gonadotropom (HCG) negative at screening.
12. Male and female patients of childbearing potential and at risk for pregnancy must agree to use two highly effective method(s) of contraception throughout the study and for 90 days after the last dose of azacitidine and the last dose of PF-04449913 or placebo, whichever occurs later.
13. Female patients who are not of childbearing potential (ie, meet at least 1 of the following criteria):
a. Have undergone a documented hysterectomy and/or bilateral oophorectomy;
b. Have medically confirmed overian failure; or
c. Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; status may be confirmed by having a serum follicle stimulating hormone (FSH) level within the laboratory's reference range for postmenopausal women.
14. 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.
15. Patients who are willing and able to comply with scheduled visits, treatment plans, laboratory tests and other procedures (including BM assessments).
|
|
| E.4 | Principal 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 <50 bpms .
20. Active cardiac dysrhythmias of NCI CTCAE Grade ≥2 (eg, atrial fibrillation) or
QTcF interval >470 msec.
21. Pregnant or breastfeeding female patients.
22. Patients who are investigational site staff members directly involved in the conduct of the study 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 study.
23. Documented or suspected hypersensitivity to azacitidine or mannitol.
24. Other severe acute or chronic medical or psychiatric conditions, including recent (within the past year) or active/ongoing suicidal ideation or behavior, or laboratory abnormalities that may increase the risk associated with study participation or investigational product
administration or may interfere with the interpretation of study results and that in the judgment of the investigator, would make the patient inappropriate for entry into the study. |
|
| E.5 End points |
| E.5.1 | 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 NCI CTCAE v.4.03) and timing.
Primary Endpoints for the Randomized Phase 2
• Response rate (Percentage of Patients achieving CR + PR) as defined by modified IWG criteria (2006) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | 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. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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) | Yes |
| 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 | 46 |
| 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 |
| Australia |
| Austria |
| Belgium |
| Canada |
| France |
| Hungary |
| Italy |
| Korea, Republic of |
| Netherlands |
| Spain |
| Taiwan |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
| End of trial in a Member State of the EU is defined as the time at which it is deemed that a sufficient number of patients have been recruited and completed the study as stated in the regulatory application (ie, clinical trial application [CTA]) and ethics application in the Member State. Poor recruitment (recruiting less than the anticipated number in the CTA) by a Member State is not a reason for premature termination but is considered a normal conclusion to the study in that Member State. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
Print
