| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10000886 |
| E.1.2 | Term | Acute myeloid leukemia |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To demonstrate that glasdegib is superior to placebo in combination with azacitidine (non-intensive study) or cytarabine and daunorubicin (intensive study) in prolonging OS in subjects with untreated AML. |
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| E.2.2 | Secondary objectives of the trial |
To compare fatigue score post-baseline as measured by MDASI-AML/MDS in both treatment arms;
To compare glasdegib versus placebo in combination with azacitidine (non-intensive study) or ‘7+3’ (cytarabine and daunorubicin) in improving other clinical efficacy measures;
To estimate the duration of response in both treatment arms;
To estimate the time to response in both treatment arms in the Non-intensive study only;
To compare Event-free Survival (EFS) in both treatment arms;
To compare PRO measurements in both treatment arms;
To evaluate the overall safety profile in both treatment arms;
To evaluate laboratory abnormalities in both treatment arms;
To characterize the PK of glasdegib;
To characterize treatment effects on the QTc interval |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Banked biospecimens will be collected from subjects for exploratory research relating to the drug and AML. Protocol version is Amendment 5 dated on 12 April 2019.
The primary purpose is to examine DNA; however, the biospecimen may also be used to study other molecules (eg, RNA, proteins, and metabolites). |
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| E.3 | Principal inclusion criteria |
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the Intensive and Non-Intensive study (unless where indicated):
1. Subjects with untreated AML according to the World Health Organization (WHO) 2016 Classification, including those with:
AML arising from MDS or another antecedent hematologic disease (AHD).
AML after previous cytotoxic therapy or radiation (secondary AML).
FLT3+ AML, assuming the patient is not receiving and is not intend to receive FLT3 inhibitor therapy during study participation.
2. ≥18 years of age (In Japan, ≥20 years of age).
3. Adequate Organ Function as defined by the following:
Serum aspartate aminotransferase (AST) and serum alanine aminotransferase (ALT) ≤ 3 x upper limit of normal (ULN), excluding subjects with liver function abnormalities due to underlying malignancy.
Total serum bilirubin ≤2 x ULN (except subjects with documented Gilbert’s syndrome).
Estimated creatinine clearance ≥30 mL/min as calculated using the standard method for the institution.
4. QTc interval ≤470 msec using the Fridericia correction (QTcF).
QTc criteria for eligibility does not apply to subjects with a functioning
pacemaker, whether the rhythm is paced or not.
5. All anti-cancer treatments (unless specified) should be discontinued ≥ 2 weeks from study entry, for example: targeted chemotherapy, radiotherapy, investigational anti-cancer agents, hormones, or cytokines.
For control of rapidly progressing leukemia, hydroxyurea, and/or leukopheresis
may be used before and for up to 1 week after the first dose of glasdegib.
Continuation or resumption of hydroxyurea or leukopheresis after that time period must be approved by the Sponsor.
6. Serum or urine pregnancy test (for female subjects of childbearing potential) with a minimum sensitivity of 25 IU/L or equivalent units of human chorionic gonadotropin (hCG) negative at screening.
7. Male and female subjects of childbearing potential and at risk for pregnancy must agree to use at least one highly effective method of contraception throughout the study and for 180 days after the last dose of azacitidine, cytarabine, or daunorubicin; and the last dose
of glasdegib or placebo, whichever occurs later.
8. Female subjects of non-childbearing potential must 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 confirming the postmenopausal state.
All other female subjects (including female subjects with tubal ligations) are considered to be of childbearing potential.
9. Consent to a saliva sample collection for a germline comparator, unless prohibited by local regulations or ethics committee (EC) decision.
10. Evidence of a personally signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the study.
11. Subjects who are willing and able to comply with the study scheduled visits, treatment plans, laboratory tests and other procedures (including bone marrow [BM] assessments). |
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| E.4 | Principal exclusion criteria |
Subjects with any of the following characteristics/conditions will not be included in the study:
1. Acute Promyelocytic Leukemia (APL) and APLwith PML-RARA, subjects (WHO 2016 classification). This disease is associated with t(15;17).
2. AML with known BCR-ABL1 mutation or known t(9;22)(q34;q11.2) as a sole abnormality.
Complex genetics may include t(9;22) cytogenetic translocation.
3. Subjects with known active CNS leukemia.
4. Participation in other clinical studies involving investigational drug(s) other than anti-cancer agents (Phases 1-4) within 4 weeks prior study entry and/or during study participation.
5. Subjects known to be refractory to platelet or packed blood red cell transfusions per Institutional Guidelines, or a patient who refuses blood product support.
6. Subjects with another active malignancy on treatment 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.
7. Any one of the following ongoing or in the previous 6 months: myocardial infarction, congenital long QT syndrome, Torsades de pointes, symptomatic arrhythmias
(including sustained ventricular tachyarrhythmia), left bundle branch block or 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.
8. Subjects with an active, life threatening or clinically significant uncontrolled systemic infection not related to AML.
9. Subjects with left ventricular ejection fraction (LVEF) <50% are excluded from the Intensive Chemotherapy Study only.
10. Cumulative anthracycline dose equivalent of ≥550 mg/m2 of daunorubicin for the Intensive Chemotherapy Study only.
11. Known malabsorption syndrome or other condition that may significantly impair absorption of study medication in the investigator’s judgment (eg, gastrectomy, lap band, Crohn’s disease) and inability or unwillingness to swallow tablets or capsules.
12. Current use or anticipated requirement for drugs that are known strong CYP3A4/5 inducers (Appendix 5).
13. Concurrent administration of herbal preparations.
14. Major surgery within 4 weeks of starting study treatment.
15. Documented or suspected hypersensitivity to any one of the following:
For subjects assigned to intensive chemotherapy, documented or suspected hypersensitivity to cytarabine (not including drug fever or exanthema, including known cerebellar side-effects) or daunorubicin.
For subjects assigned to non-intensive chemotherapy, documented or suspected hypersensitivity to azacitidine or mannitol.
16. Known active drug or alcohol abuse.
17. Other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior 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 subject inappropriate for entry into this study.
18. Pregnant females or breastfeeding female subjects.
19. Known recent or active suicidal ideation or behavior.
20. Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or subjects who are Pfizer employees, including their family members, directly involved in the conduct of the study. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
For the intensive chemotherapy population a first interim analysis for efficacy and futility is planned when 50% of death events have occurred.A second interim analysis for efficacy and futility is planned when 70% of death events have occurred or upon completion of enrollment of intensive chemotherapy subjects, whichever is later.
For the non-intensive chemotherapy population an interim analysis for efficacy and futility is planned when 60% of death events have
occurred or upon completion of enrollment of non-intensive chemotherapy subjects, whichever is later. |
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| E.5.2 | Secondary end point(s) |
Fatigue score measured by the MDASI-AML/MDS questionnaire;
Rate of CR (including CRMRD-negative as assessed by multiparametric flow cytometry), CRi as defined by the ELN recommendations (2017), MLFS, PR and CR with partial hematologic recovery (CRh) for the Non-intensive study only;
Duration of response (defined as CRi or better or CRh or better if applicable)*;
Time to response (CRi or better -or CRh or better)* in the non-intensive study only;
Event-free Survival
PROs as measured by the M.D. Anderson Symptom Inventory AML/MDS Module (MDASI-AML/MDS), EuroQoL 5 Dimension questionnaire 5-Level version (EQ-5D-5L), Patient Global Impression of Symptoms (PGIS) and Patient Global Impression of Change (PGIC);
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;
PK of glasdegib;
QTc interval |
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| 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 | Yes |
| E.6.13 | Others | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | Yes |
| 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 | 4 |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 74 |
| 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 |
| Canada |
| Israel |
| Japan |
| Korea, Republic of |
| Mexico |
| Russian Federation |
| Taiwan |
| United States |
| Austria |
| Belgium |
| France |
| Germany |
| Greece |
| Hungary |
| Italy |
| Poland |
| Romania |
| Spain |
| Sweden |
| United Kingdom |
| Czechia |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
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| End of Study in all participating countries is defined as Last Subject Last Visit. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 13 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 6 |
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