| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Acute myeloid leukemia or myelodysplastic syndrome |
|
| E.1.1.1 | Medical condition in easily understood language |
| Acute myeloid leukemia or myelodysplastic syndrome |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10000886 |
| E.1.2 | Term | Acute myeloid leukemia |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10028533 |
| E.1.2 | Term | Myelodysplastic syndrome |
| 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 |
Phase 1B Portion:
• To determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of PF-04449913 in combination with low dose ARA-C (LDAC; Arm A), decitabine (Arm B) or cytarabine/daunorubicin (Arm C) when administered to adults with previously untreated AML or high-risk MDS.
Phase 2 Portion:
Single Arm Component in Fit Patients:
• To determine the rate of complete remission (CR) of PF-04449913 when administered in combination with cytarabine/daunorubicin to fit patients with previously untreated AML or high-risk MDS.
Randomized Component in Unfit Patients:
• To compare the overall survival (OS) for PF-04449913 + LDAC versus LDAC alone in unfit patients with previously untreated AML or high risk MDS. |
|
| E.2.2 | Secondary objectives of the trial |
For the secondary objectives of the Phase 1B Portion, please refer to the protocol.
Phase 2 Portion:
Single Arm Component in Fit Patients:
• Efficacy of PF-04449913 in combination with cytarabine/daunorubicin
• Safety & tolerability of PF-04449913 in combination with cytarabine/daunorubicin
• PD of PF-04449913 in combination with cytarabine/daunorubicin
• PK of PF-04449913
• Characterize the effects of PF-04449913 on QTc interval
Randomized Component in Unfit Patients
• Efficacy of PF 04449913 in combination with LDAC versus LDAC alone
• Safety and tolerability of PF 04449913 when administered in combination with LDAC versus LDAC alone
• PD of PF 04449913 when administered in combination with LDAC versus LDAC alone
• PK of PF 04449913 |
|
| 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. 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 example: targeted chemotherapy, radiotherapy, investigational agents, hormones, anagrelide or cytokines.
• For control of rapidly progressing leukemia, hydroxyurea or leukapheresis may be used before and for up to 1 week after first dose of PF-04449913.
• Patients with controlled CNS leukemia (documented by two consecutive assessments of zero blast count in cerebrospinal fluid), and who are still receiving intrathecal (IT) therapy at study entry are considered eligible, and will continue to receive IT therapy.
10. Resolved acute effects of any prior therapy to baseline severity or Grade ≤1 CTCAE except for AEs not constituting a safety risk by investigator judgement.
11. Serum/urine pregnancy test (for females of childbearing potential) that is negative at screening and immediately prior to initiation of treatment (first dose).
Male and female patients of childbearing potential must agree to use a highly effective method of contraception throughout the study and for at least 180 days after the last dose of assigned treatment. A patient is of childbearing potential if, in the opinion of the investigator, he/she is biologically capable of having children and is sexually active.
12. Evidence of a personally signed and dated informed consent document indicating that the patient (or a legal representative) has been informed of all pertinent aspects of the study.
13. Willingness and ability to comply with the study scheduled visits, treatment plans, laboratory tests and other procedures. |
|
| E.4 | Principal 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. Other severe acute or chronic medical or psychiatric condition 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.
22. Patients who are investigational site staff members or relatives of those site staff members or patients who are Pfizer employees directly involved in the conduct of the trial.
23. Pregnant females; breastfeeding females; males and females of childbearing potential not using highly effective contraception or not agreeing to continue highly effective contraception for at least 180 days after last dose of investigational product; males and females of childbearing potential not using two (2) methods of highly effective contraception or not agreeing to continue two (2) methods of highly effective contraception for at least 180 days after last dose of investigational product.
24. Recent or active suicidal ideation or behavior. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1B Portion Primary Endpoint:
• First cycle dose limiting toxicities (DLTs).
Phase 2 Portion Primary Endpoints:
Single Arm Component in Fit Patients (P2 Fit)
• Complete response (CR).
Randomized component in Unfit Patients (P2 Unfit)
• Overall survivial (OS). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Due to the complexity of the study and the character limit in this section, please refer to the protocol for details of the timepoints of evaluation of the various primary endpoints. |
|
| E.5.2 | Secondary end point(s) |
Phase 1B Portion Secondary Endpoints
• Type, incidence, severity (graded by the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE], Version 4.0), timing, seriousness, and relatedness of adverse events.
• Pharmacodynamic biomarkers.
• Pharmacokinetic parameters of PF-04449913, LDAC, decitabine and cytarabine/daunorubicin.
• CR/CRi
• Overall survival (OS).
• QTc interval.
Phase 2 Portion Secondary Endpoints
• OS for Phase 2 single arm component in fit patients (P2 Fit only).
• CR for Phase 2 randomized component in unfit patients (P2 Unfit only).
• For all AML patients: disease-specific efficacy endpoints, such as CRi, Morphologic Leukemia-Free State, Partial Remission (PR), Partial Remission with incomplete blood count recovery (PRi), Minor Response (MR), Stable Disease (SD), Cytogenetic Complete Response (CRc), and Molecular Complete Response (CRm).
• For all MDS patients: disease-specific efficacy endpoints, such as marrow CR, partial remission (PR), Stable Disease (SD), Partial or Complete Cytogenetic Response, and CRi.
• Type, incidence, severity (graded by the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE], Version 4.0), timing, seriousness, and relatedness of adverse events.
• Pharmacodynamic biomarkers.
• Pharmacokinetic parameters of PF-04449913.
• QTc interval. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Due to the complexity of the study and the character limit in this section, please refer to the protocol for details of the timepoints of evaluation of the various secondary endpoints. |
|
| 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 | No |
| 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 | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Phase 1B: MTD & RP2D of PF-04449913 in combination with three other treatments |
|
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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 | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| 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 |
| Canada |
| Germany |
| Italy |
| Poland |
| Spain |
| 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 all participating countries is defined as date upon which enrolment is completed according to protocol planned sample size and the assessments and requirements are completed according to protocol (including the follow up period). |
|
| 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 | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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