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A RANDOMIZED (1:1), DOUBLE-BLIND, MULTI-CENTER, PLACEBO CONTROLLED STUDY EVALUATING INTENSIVE CHEMOTHERAPY WITH OR WITHOUT GLASDEGIB (PF-04449913) OR AZACITIDINE (AZA) WITH OR WITHOUT GLASDEGIB IN PATIENTS WITH PREVIOUSLY UNTREATED ACUTE MYELOID LEUKEMIA

A Study Evaluating Intensive Chemotherapy With or Without Glasdegib or Azacitidine With or Without Glasdegib In Patients With Previously Untreated Acute Myeloid Leukemia

729

This study consists of 2 independent studies: an intensive chemotherapy study and non intensive chemotherapy study. Within each study, participants will be randomized to chemotherapy with either glasdegib or matching placebo. Intensive Cohort: The external data monitoring committee (E-DMC) reviewed a planned interim analysis and reached conclusion that the study would not meet the primary objective of overall survival (OS). The intensive cohort was terminated for futility and the study achieved last patient last visit on 1 February 2021. Of the 404 participants randomized, 58.4% of the participants were male and 41.6% were female. The majority of the participants were White (57.7%) and 30.4% were Asian. The mean age was 56.55 and 55.38 years in the glasdegib + '7+3' and placebo + '7+3' arms, respectively. Non Intensive Cohort: The E-DMC reviewed a planned interim analysis and reached conclusion that the study would not meet the primary objective of OS. The non-intensive cohort was terminated for futility and achieved primary completion date on 5 June 2020. The data as of 17 January 2022 was determined to be final data for the non-intensive cohort. It was allowed for participants who continue to derive clinical benefit in the non-intensive cohort, to continuously access study medication. Of the 325 randomized participants, 57.2% were male and 42.8% were female; the majority of participants were White (60.3%); mean age was 73.19 and 73.14 years in the glasdegib arm (glasdegib + azacitidine) and the placebo arm (placebo + azacitidine), respectively.

Intensive Cohort: 404 participants were randomized; 399 received treatment (198 in the glasdegib + intensive chemotherapy arm [glasdegib + '7+3'] and 201 in the placebo + intensive chemotherapy [placebo + '7+3'] arm). Non Intensive Cohort: A total of 325 participants were randomized for participation and a total of 322 participants were treated (162 in the glasdegib arm, 160 in the placebo arm). A total of 95.0% of participants discontinued from the study treatment. The most common reason for glasdegib/placebo treatment discontinuations was progressive disease; 23.5% and 25.6% of participants in the glasdegib and placebo arms, respectively, had progressive disease. This was followed by death (22.2% and 18.1% in glasdegib and placebo arms, respectively).

Intensive Cohort: 99.0% and 98.5% of participants in the glasdegib + '7+3' and placebo + '7+3' arms, respectively, experienced all-causality treatment-emergent adverse events (TEAEs), and 43.4% and 45.8% of participants, respectively, experienced all-causality serious adverse events (SAEs). The most frequently reported all-causality TEAEs (>=30% of participants in any treatment arm) in the 2 arms, respectively, were: nausea (55.6%, 53.7%), febrile neutropenia (53.5%, 53.2%), anaemia (53.5%, 50.2%), diarrhoea (49.5%, 43.8%), pyrexia (41.9%, 43.3%), hypokalaemia (38.4%, 41.8%), platelet count decreased (40.4%, 37.8%), constipation (35.9%, 30.3%), and white blood cell count decreased (32.8%, 26.9%). The most frequently reported all-causality SAEs (>=5% of participants in any treatment arm) in the 2 arms, respectively, were febrile neutropenia (9.1%, 8.5%), sepsis (7.6%, 6.5%), pneumonia (7.6%, 5.5%), and electrocardiogram (ECG) QT prolonged (6.6%, 4.0%). 91.4% and 93.5% of participants in the glasdegib + '7+3' and placebo + '7+3' arms, respectively, experienced treatment-related TEAEs, and 24.2% and 29.9% of participants, respectively, experienced treatment-related SAEs. The most frequently reported treatment-related TEAEs (>=30% of participants in any treatment arm) in the 2 arms, respectively, were anaemia (46.5%, 43.8%), febrile neutropenia (35.4%, 37.8%), nausea (46.0%, 45.3%), diarrhoea (31.8%, 26.4%), platelet count decreased (38.4%, 32.3%), and white blood cell count decreased (32.3%, 25.9%). The most frequently reported treatment-related SAEs (>=3% of participants in any treatment arm) in the 2 arms, respectively, were: febrile neutropenia (6.6%, 8.0%), sepsis (4.5%, 4.5%), and ECG QT prolonged (4.5%, 4.0%). A total of 44.8% and 43.3% of participants in the glasdegib + '7+3' and placebo + '7+3' arms, respectively, in the intensive cohort died. The primary reason for death was disease progression, with 25.9% and 24.1% of participants in the 2 arms, respectively. A total of 10.6% and 10.0% of participants in the glasdegib + '7+3' and placebo + '7+3' arms, respectively, discontinued from study due to all-causality TEAEs. A total of 6.6% and 4.5% of participants in the 2 arms, respectively, discontinued from study due to treatment-related adverse events (AEs). A total of 13.1% and 14.4% of participants in the glasdegib '7+3' and placebo + '7+3' arms, respectively, discontinued any study intervention due to all causality TEAEs. A total of 31.3% and 27.9% of participants in the 2 arms, respectively, had TEAEs leading to any study intervention dose interruptions. A total of 14.6% and 11.9% of participants in the 2 arms, respectively, had TEAEs leading to any study intervention dose reductions. Non Intensive Cohort: 99.4% and 98.8% of participants in the glasdegib arm and placebo arm, respectively, experienced all-causality TEAEs. A total of 82.1% and 76.9% of participants in the 2 arms, respectively, had treatment-related TEAEs. The most frequently reported all-causality TEAEs (in the glasdegib arm and placebo arm) were anaemia (46.3% and 45.6% of participants), constipation (36.4% and 32.5% of participants), nausea (35.8% and 27.5% of participants), pneumonia (26.5% and 30.0% of participants), and pyrexia (29.6% and 26.3% of participants). The most frequently reported treatment-related TEAEs (in the glasdegib arm and placebo arm) were anaemia (27.8% and 30.0% of participants) and nausea (27.2% and 23.1% of participants). There were more participants with treatment-related TEAEs of dysgeusia (21.0% vs 4.4%) and muscle spasms (18.5% vs 1.3%) in the glasdegib arm vs placebo arm. These TEAEs were expected as part of the glasdegib-specific AEs. A total of 71.8% and 69.8% of participants in the glasdegib and placebo arms, respectively, died in this non-intensive study. The most common cause of death was disease progression, which was reported in 42.3% and 42.0% of participants in the glasdegib and placebo arms, respectively. The incidence of serious TEAEs was 72.2% in the glasdegib arm and 77.5% in the placebo arm. The most frequently reported all-causality serious TEAEs in the glasdegib and placebo arms were pneumonia (17.9% and 22.5% of participants, respectively) and febrile neutropenia (14.8% and 12.5% of participants, respectively). The most frequently reported treatment-related serious TEAEs in the glasdegib and placebo arms were febrile neutropenia (7.4% and 3.8% of participants, respectively) and pneumonia (5.6% and 5.0% of participants, respectively). The percentages of participants discontinued any study drug due to AEs were 41.4% in the glasdegib arm and 39.4% in the placebo arm. The incidence of TEAEs leading to any dose interruptions was 64.2% and 63.8% in the glasdegib and placebo arms, respectively. The incidence of TEAEs leading to any dose reductions was 15.4% in the glasdegib arm and 8.1% in the placebo arm.

Intensive Cohort: Primary Endpoint Analysis: OS The intensive study did not meet its primary objective of demonstrating that glasdegib + '7+3' is superior to placebo + '7+3' in prolonging OS in all randomized participants with untreated acute myelogenous leukemia (AML). A total of 90 (44.8%) and 88 (43.3%) events were observed in the 2 arms, respectively. The median OS estimated by Kaplan-Meier method was 17.2 (95% confidence interval [CI]: 15.3, 18.5) and 20.0 (95% CI: 14.0, Not Estimable) months in the 2 arms, respectively. The observed stratified hazard ratio comparing the 2 arms was 0.97 (95% CI: 0.725, 1.309) with 1-sided p-value of 0.4321. The median time of follow-up for OS was 12.65 and 12.19 months in the 2 arms, respectively. An analysis of OS by baseline characteristics showed the control arm (placebo + '7+3') had an OS survival advantage in participants with intermediate European Leukemia Net (ELN) risk, and in the Asian population. The experimental arm (glasdegib + '7+3') performed better than the control arm in the Favorable ELN risk category, and in the White population. Non Intensive Cohort: Primary Endpoint: OS The non-intensive study did not meet its primary objective of demonstrating that glasdegib + azacitidine was superior to placebo + azacitidine in prolonging OS in all randomized participants with untreated AML. A total of 117 (71.8%) and 113 (69.8%) participants died in the glasdegib and placebo arms, respectively. The estimated median OS for the glasdegib arm was 10.3 (95% CI: 7.6, 12.2) months while for the placebo arm was 10.9 (95% CI: 7.9, 12.9) months. Glasdegib did not extend OS [hazard ratio = 1.02 (95% CI: 0.787, 1.326), 1-sided p-value = 0.5622]. An analysis of OS by baseline characteristics showed that the glasdegib arm performed better than the placebo arm in subgroups of Favorable and Intermediate ELN risk categories, females, Eastern Cooperative Oncology Group performance status (ECOG PS) >=2, de novo hematological disease history, and participants with baseline WBC >=10 * 109/L, but the OS benefit was not statistically significant. In contrast, the placebo arm performed better in subgroups of adverse ELN risk category, males, Asian population, ECOG PS 0 and 1, and Secondary hematological disease history.

Intensive Cohort: Because the intensive cohort was terminated for futility, data for several secondary and exploratory endpoints in the protocol were not collected and analysis was not done for these endpoints. Key Secondary Endpoint Analysis: Fatigue by M.D. Anderson Symptom Inventory AML/MDS Module (MDASI-AML/MDS) A total of 17.41% and 17.24% of participants in the 2 arms, respectively, had improvement in fatigue. Other Secondary Endpoints: The proportion of participants achieving complete remission with negative minimal residual disease (CRMRD-), complete remission (CR), partial remission (PR), morphologic leukemia-free state (MLFS) was similar between the 2 arms (CRMRD-: 5.0%, 5.4%, CR: 49.3%, 47.3%, PR: 5.0%, 4.4%, MLFS: 1.5%, 2.0%). The proportion of CR with incomplete count recovery (CRi) responders was 3 (1.5%) and 11 (5.4%) in the 2 arms, respectively. Non Intensive Cohort: Because the non-intensive cohort was terminated for futility, data for several secondary and exploratory endpoints in the protocol were not collected, and analysis was not done for these endpoints. Key Secondary Endpoint: Fatigue by MDASI-AML/MDS At Week 12, the percentage of participants with improvement in fatigue was numerically lower in the glasdegib arm compared to that in the placebo arm (11.66% vs 15.43%) with the Cochran-Mantel-Haenszel (CMH) unstratified 1-sided p-value of 0.8397 and CMH stratified 1-sided p-value of 0.8359. Other Secondary Endpoints: * Rate of CR, CRi, MLFS, PR and CR with partial hematologic recovery (CRh) The percentages of participants achieving CR (including CRMRD-), CRi and MLFS were numerically greater in the glasdegib arm as compared to the placebo arm. A total of 32 (19.6%) participants in the glasdegib arm and 21 (13.0%) participants in the placebo arm had CR. A total of 4 (2.5%) participants in the glasdegib arm and 1 (0.6%) participant in the placebo arm had CRi. A total of 5 (3.1%) participants in the glasdegib arm and 1 (0.6%) participant in the placebo arm had MLFS. The percentage of participants achieving PR was numerically lower in the glasdegib arm (4 [2.5%] participants) as compared to the placebo arm (8 [4.9%] participants). The number of participants achieving CRh was same between the 2 treatment arms (5 [3.1%] participants each). * Time to Response For participants who responded, the time to response was comparable between the 2 treatment arms {median TTRi [time to response (response is defined as CRi or better)] of 3.76 months in both treatment arms; median TTRh [time to response (response is defined as CRh or better)] of 3.88 months in the glasdegib arm, and 3.75 months in the placebo arm}.

Neither intensive nor non-intensive cohort did not meet the primary objective of demonstrating that glasdegib is superior to placebo in combination with '7+3' azacitidine (intensive) or '7+3' (non-intensive) in prolonging OS in untreated AML patients. The safety profile of glasdegib + '7+3' was consistent with these known safety profiles. The safety profile of glasdegib + azacitidine was manageable and consistent with the known safety profiles of glasdegib.

April. 26, 2024

Aug. 21, 2023

https://www.nature.com/articles/s41375-023-02001-z

Yes

Pfizer provides an environment which enables researchers to access de-identified individual subject data and related documents (protocol, statistical analysis plan, clinical study report, etc.). Details of our clinical trial data sharing standards and access requests are available at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

Kawai Norisuke

Pfizer R&D Japan G.K.

Shinjuku Bunka Quint Bldg., 3-22-7 Yoyogi, Shibuya-ku, Tokyo

clinical-trials@pfizer.com

Clinical Trials Information Desk

Pfizer R&D Japan G.K.

Shinjuku Bunka Quint Bldg., 3-22-7 Yoyogi, Shibuya-ku, Tokyo

+81-3-5309-7000

clinical-trials@pfizer.com

completed

April. 20, 2018

Interventional

Randomized, double blind, multicenter, placebo control study

treatment purpose

3

Inclusion Criteria:
1.Subjects with untreated AML inclusing
* AML arising from MDS or another antecedent hematologic disease (AHD).
* AML after previous cytotoxic therapy or radiation (secondary AML).
2.Adequate Organ Function as defined by the following:
3.QTc interval 470 msec using the Fridericia correction (QTcF).
4.All anti cancer treatments (unless specified) should be discontinued 2 weeks from study entry, for example: targeted chemotherapy, radiotherapy, investigational agents, hormones, anagrelide or cytokines.
*For control of rapidly progressing leukemia, all trans retinoic acid (ATRA), hydroxyurea, and/or leukopheresis may be used before and for up to 1 week after the first dose of glasdegib.
etc.

Exclusion Criteria:
1.Acute Promyelocytic Leukemia (APL) and APLwith PML RARA, subjects (WHO 2016 classification).
2.AML with BCR ABL1 or 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 other investigational drug(s) within 4 weeks prior study entry and/or during study participation.
5.Subjects known to be refractory to platelet or packed red cell transfusions per Institutional Guidelines, or a patient who refuses blood product support.
6.Subjects with another active malignancy on treatment.
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), right or left bundle branch block and 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.Current use or anticipated requirement for drugs that are known strong CYP3A4/5 inducers.
11.Major surgery or radiation within 4 weeks of starting study treatment.
12.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.
etc.

Both

Acute myeloid leukemia

investigational material(s)
Generic name etc : Glasdegib (PF-04449913)
INN of investigational material : Glasdegib
Therapeutic category code : 429 Other antitumor agents
Dosage and Administration for Investigational material :
Drug: glasdegib

Daily Glasdegib (100 mg, PO) or matching placebo will continue throughout Induction(s) and Consolidation therapies regardless of dose modifications/delays in the chemotherapy.

Drug: daunorubicin + cytarabine
'7+3' (cytarabine 100 mg/m2, IV for 7 days by continuous infusion and daunorubicin 60 mg/m2 for 3 days). Or a 5 day cytarabine continuous infusion plus daunorubicin for 2 days ('5+2');

Drug: cytarabine
Consolidation with single agent cytarabine 3 g/m2 IV for adults <60 years and 1 g/m2 for adults 60 years over 3 BID on Days 1, 3, and 5, every 28 days for up to 4 cycles or alternative single agent cytarabine consolidation schedules may be used.

Drug: azacitidine
Azacitidine (75 mg/m2, SC or IV) daily for 7 days, in 28 day cycles.


control material(s)
Generic name etc : Placebo
INN of investigational material : -
Therapeutic category code : --- Other
Dosage and Administration for Investigational material : -

Efficacy
Overall Survival

Safety
Efficacy
Pharmacokinetics
Pharmacogenomics
* 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
* Time to response in the non-intensive study only
* Event-free Survival
* Patient-Reported Outcomes
* Adverse events, Laboratory abnormalities
* Pharmacokinetics
* QTc interval

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