A Study To Evaluate PF-04449913 With Chemotherapy In Patients With Acute Myeloid Leukemia or Myelodysplastic Syndrome.

Phase 1

• Conditions: Acute myeloid leukemia or myelodysplastic syndrome; MedDRA version: 20.0 Level: LLT Classification code 10000886 Term: Acute myeloid leukemia System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 20.0 Level: PT Classification code 10028533 Term: Myelodysplastic syndrome System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2012-000684-24-PL
• Lead Sponsor: Pfizer Inc. 235 East 42nd Street, New York, NY 10017

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2013-02-05
• Last Update Posted: 30 June 2019

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: Not specified
• Target Recruitment: 255

Inclusion Criteria

Patients must meet all of the following inclusion criteria to be eligible for enrollment into the study:

1. Patients with AML or RAEB-2 High-Risk MDS who are newly diagnosed according to the WHO 2008 Classification and previously untreated. Eligible patients with MDS, as well as eligible patients with AML arising from an antecedent hematologic disease (AHD) or MDS may have had one prior regimen with commercially-available agent(s) (eg, azacytadine or decitabine) for the treatment of their prior hematologic disease. The patients may not have had a prior therapy for their AML.
Patients enrolling in the P2 Unfit Arms must have a known cytogenetic profile at study entry.
2. AML patients include de-novo AML, AML evolving from MDS or other AHD and AML after previous cytotoxic therapy or radiation (secondary AML).
• For a diagnosis of AML, a bone marrow blast count of 20% or more is required.
• For AML defined by cytogenetic aberrations t(8;21), inv(16) or t(16;16) and some cases of erythroleukemia the proportion of bone marrow blasts may be <20%.
• In AML FAB M6a (erythroid leukemia) =20% of non erythroid cells in the bone marrow must be leukemic blasts and =50% of the cells are erythroid precursors.
• In AML with monocytic or myelomonocytic differentiation, monoblasts and promonocytes, but not abnormal monocytes, are counted as blast equivalents.
3. For a diagnosis of high-risk Myelodysplastic Syndrome RAEB-2 the patient must have 10-19% bone marrow blasts (See Appendix 3 of the protocol).
4. Age:
• =18 years old for patients enrolled in Phase 1B and P2 Fit Arm
• =55 years old for patients enrolled in the P2 Unfit Arms.
5. ECOG Performance Status 0, 1, or 2.
6. Patients with AML or High-Risk MDS who have one or more of the criteria below are considered unfit for intensive chemotherapy (Kantarjian et al, 2006) and are eligible for Phase 1B Arms A and B or P2 Unfit Arms:
• Age =75 years.
• ECOG of 2.
• Serum creatinine >1.3 mg/dL.
• Severe cardiac disease (eg, LVEF <45% by multigated
acquisition [MUGA] or echocardiography [ECHO] at screening).
7. Patients with AML or high risk MDS and have none of the following criteria are considered fit for more intensive chemotherapy and are only eligible for Phase 1B Arm C or P2 Fit Arm:
• ECOG of 2.
• Serum creatinine >1.3 mg/dL.
• Severe cardiac disease (eg, LVEF <45% by MUGA or ECHO at screening).
8. Adequate Organ Function as defined by the following:
• Serum aspartate aminotransferase (AST) and serum alanine aminotransferase (ALT) =3 x upper limit of normal (ULN), or AST and ALT =5 x ULN if liver function abnormalities are due to underlying malignancy.
• Total serum bilirubin =2 x ULN (except patients with documented Gilbert’s syndrome).
• Serum creatinine =1.5 x ULN or estimated creatinine clearance =60 mL/min as calculated using the method standard for the institution.
9. All anti-cancer treatments (unless specified) should be discontinued =2 weeks from study entry (defined in Section 6 of the protocol), for

Exclusion Criteria

Patients presenting with any of the following will not be included in the study:
1. AML M3 Acute Promyelocytic Leukemia (APL) or patients with a t(15:17) or patients with a t(9:22) cytogenetic translocation for any component of the study.
2. Hyperleukocytosis (leukocytes =30 x 109/L) at study entry. These patients may be treated with hydroxyurea or receive leukopheresis treatment according to routine practice, and enrolled in the study when the leukocyte count falls below 30 x 109/L.
3. Patients known to be refractory to platelet or packed red cell transfusions per Institutional Guidelines, or a patient who refuses blood product support.
4. Patients with active malignancy with the exception of basal cell carcinoma, non melanoma skin cancer, cervical carcinoma in situ. Other prior or concurrent malignancies will be considered on a case-by-case basis.
5. For fit patients (Phase IB Arm C or P2 Fit Arm):
• LVEF <45% by ECHO or MUGA scan.
• Cumulative anthracyline dose equivalent of =250 mg/m^2 of daunorubicin or =125 mg/m^2 of idarubicin.
6. Any one of the following currently or in the previous 6 months: myocardial infarction, congenital long QT syndrome, torsades de pointes or clinically significant ventricular arrhythmias.
7. QTc interval >470 msec using the Fridericia (QTcF).
8. Patients with an active, life threatening or clinically significant uncontrolled systemic infection.
9. Patients with known active uncontrolled central nervous system (CNS) leukemia.
10. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness or active Hepatitis B or C infection.
11. Known malabsorption syndrome or other condition that may impair absorption of study medication (eg, gastrectomy or lap band).
12. Major surgery or radiation within 4 weeks of starting study treatment.
13. Prior treatment with
• a Hedgehog inhibitor at any time
• an investigational agent for the treatment of an antecedent hematologic disease (AHD).
14. Prior treatment of primary diagnosis or AHD with decitabine or azacitidine (Phase 1B Arm B only), or cytarabine (Phase 1B Arm A and P2 Unfit only).
15. The presence of any one of the following hypersensitivities:
• For patients receiving cytarabine on study (Phase 1B Arm A, P2 Fit and P2 Unfit Arms only): Hypersensitivity to cytarabine (not including drug fever or exanthema).
• For patients receiving decitabine on study (Phase 1B Arm B): hypersensitivity to decitabine.
• For patients receiving daunorubicin on study (Phase 1B Arm C and P2 Fit Arm): hypersensitivity to daunorubicin.
16. Concurrent treatment with any investigational or approved oncology agents (unless specified in the protocol).
17. Concurrent administration of herbal preparations.
18. Current use at time of study entry (defined in Section 6).
19. Or anticipated need for drugs that are known strong CYP3A4/5 inducers. Please refer to section 5.5 of the protocol for list of prohibited inducers.
20. Current drug or alcohol abuse.
21. Othe

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified