Clinical Trials List
Protocol NumberB1371012
2014-12-30 - 2019-06-03
Phase I/II
Terminated2
Study ended1
ICD-10D46.9
Myelodysplastic syndrome, unspecified
ICD-10 C92.0
Acute myeloblastic leukemia
ICD-10 C93.1
Chronic myelomonocytic leukemia
ICD-9238.7
Neoplasm of uncertain behavior of other lymphatic and hematopoietic tissues
A RANDOMIZED, DOUBLE-BLIND PHASE 1B/2 STUDY OF PF-04449913 IN COMBINATION WITH AZACITIDINE IN PATIENTS WITH PREVIOUSLY UNTREATED INTERMEDIATE-2 OR HIGH-RISK MYELODYSPLASTIC SYNDROME, ACUTE MYELOID LEUKEMIA WITH 20-30% BLASTS AND MULTI-LINEAGE DYSPLASIA, OR CHRONIC MYELOMONOCYTIC LEUKEMIA
-
Sponsor
Pfizer Inc.
-
Trial scale
Multi-Regional Multi-Center
-
Update
2025/08/19
Investigators and Locations
Co-Principal Investigator
- Huey-En Tzeng Division of Hematology & Oncology
- 韓紹民 Division of Hematology & Oncology
- 楊陽生 Division of Hematology & Oncology
- Chieh-Lin Teng Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Stop recruiting
The Actual Total Number of Participants Enrolled
0 Stop recruiting
Co-Principal Investigator
- Ching Yun Hsieh Division of Hematology & Oncology
- Ching-Chan Lin Division of Hematology & Oncology
- Ming-Yu Lien Division of Hematology & Oncology
- Chang-Fang Chiu Division of Hematology & Oncology
- Yu-Min Liao Division of Hematology & Oncology
- Li-Yuan Bai Division of Hematology & Oncology
- Chen-Yuan Lin Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Study ended
Condition/Disease
PREVIOUSLY UNTREATED INTERMEDIATE-2 OR HIGH-RISK MYELODYSPLASTIC SYNDROME, ACUTE MYELOID LEUKEMIA WITH 20-30% BLASTS AND MULTI-LINEAGE DYSPLASIA, OR CHRONIC MYELOMONOCYTIC LEUKEMIA
Objectives
Objectives for the Phase 1b (Safety Lead-In)
Primary Objective
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, and CMML.
Objectives for the Randomized Phase 2
Primary Objective
To demonstrate superior ORR 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.
Test Drug
PF-04449913
Active Ingredient
PF-04449913
Dosage Form
Tablet
Dosage
25 mg/tab及100 mg/tab
Endpoints
Endpoints for the Phase 1b (Safety Lead-In)
Primary Endpoint
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.
Secondary Endpoints
Objective response (Complete Remission (CR) + Partial Remission (PR)) as defined by
modified International Working Group (IWG) criteria (2006) Appendix 2;
Other efficacy measures of HI, marrow CR (mCR), Cytogenetic Response, and Stable
Disease (SD) as defined by modified IWG criteria (2006) Appendix 2;
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.
Endpoints for the Randomized Phase 2
Primary Endpoint
Objective response (CR + PR) as defined by modified IWG criteria (2006) Appendix 2.
Secondary Endpoints
OS;
Survival probabilities at 12, 18, and 24 months;
EFS;
Efficacy measures of HI, mCR, Cytogenetic Response, and SD as defined by modified
IWG criteria (2006) Appendix 2;
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 (graded by NCI CTCAE
v.4.03, timing, seriousness and relationship to study therapy;
Laboratory abnormalities as characterized by type, frequency, severity (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.
Primary Endpoint
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.
Secondary Endpoints
Objective response (Complete Remission (CR) + Partial Remission (PR)) as defined by
modified International Working Group (IWG) criteria (2006) Appendix 2;
Other efficacy measures of HI, marrow CR (mCR), Cytogenetic Response, and Stable
Disease (SD) as defined by modified IWG criteria (2006) Appendix 2;
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.
Endpoints for the Randomized Phase 2
Primary Endpoint
Objective response (CR + PR) as defined by modified IWG criteria (2006) Appendix 2.
Secondary Endpoints
OS;
Survival probabilities at 12, 18, and 24 months;
EFS;
Efficacy measures of HI, mCR, Cytogenetic Response, and SD as defined by modified
IWG criteria (2006) Appendix 2;
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 (graded by NCI CTCAE
v.4.03, timing, seriousness and relationship to study therapy;
Laboratory abnormalities as characterized by type, frequency, severity (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.
Inclution Criteria
1. Morphologically confirmed diagnosis of:
a. MDS according to the WHO 2008 classification (Appendix 1), and bone
marrow blasts 5%;
b. AML with 20-30 % BM blasts and multi-lineage dysplasia, according to
WHO 2008 classification(Appendix 1) and WBC <20x109
/L;
c. CMML according to the WHO 2008 classification (Appendix 1) 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 1997 (IPSS).
3. MDS patients must have normal levels of vitamin B12 within the institutional range
of normal as determined within 28 days of study entry.
4. AML patients with 20-30% BM blasts and multi-lineage dysplasia, must have stable
blast counts per Investigator’s judgment.
5. Clinical indication for treatment with azacitidine for MDS, AML or CMML
6. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤2. See
Appendix 11.
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 chorionic gonadotropin
(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 ovarian 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).
a. MDS according to the WHO 2008 classification (Appendix 1), and bone
marrow blasts 5%;
b. AML with 20-30 % BM blasts and multi-lineage dysplasia, according to
WHO 2008 classification(Appendix 1) and WBC <20x109
/L;
c. CMML according to the WHO 2008 classification (Appendix 1) 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 1997 (IPSS).
3. MDS patients must have normal levels of vitamin B12 within the institutional range
of normal as determined within 28 days of study entry.
4. AML patients with 20-30% BM blasts and multi-lineage dysplasia, must have stable
blast counts per Investigator’s judgment.
5. Clinical indication for treatment with azacitidine for MDS, AML or CMML
6. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤2. See
Appendix 11.
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 chorionic gonadotropin
(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 ovarian 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).
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.
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 high 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 (Appendix 4).
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) non-melanoma 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.
1. Patients with AML who are candidates for standard induction chemotherapy.
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 high 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 (Appendix 4).
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) non-melanoma 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.
The Estimated Number of Participants
-
Taiwan
17 participants
-
Global
170 participants
