B1371019 - Chemo with or without Glasdegib for Acute Myeloid Leukemia
Research type
Research Study
Full title
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
IRAS ID
235161
Contact name
Christine G. DiRienzo
Contact email
Sponsor organisation
Pfizer Inc., 235 East 42nd Street, New York, NY 10017
Eudract number
2017-002822-19
Clinicaltrials.gov Identifier
AML1019, Bright
Duration of Study in the UK
6 years, 8 months, 28 days
Research summary
Research Summary
This is a Phase 3, randomised, double blind, placebo controlled study of chemotherapy given with or without the investigational drug Glasdegib to patients with previously untreated acute myeloid leukaemia.
There will be 2 separate registration studies conducted under this one protocol (B1371019) to evaluate the addition of glasdegib (PF-04449913) in (1)intensive- and (2)non-intensive chemotherapy population. Both studies will have a placebo (fake drug) as a control, and as it is double blind, the participant and their study doctor, will NOT know if they are receiving glasdegib or the placebo with the relevant chemotherapy treatment.
(1) Glasdegib is being studied in combination with cytarabine and daunorubicin for the treatment of adult patients (18 years and above) with previously untreated acute myeloid leukemia (Intensive AML population).
(2)Glasdegib is also being studied in combination with azacitidine for the treatment of adult patients (18 years and above) with previously untreated acute myeloid leukemia who are NOT candidates for intensive induction chemotherapy (Non-intensive AML population).
Azacitidine (Vidaza®) is a UK Approved chemotherapy drug used to treat conditions that affect the blood and the bone marrow, known as myelodysplastic syndromes (MDS).
Cytarabine is a UK approved chemotherapy drug used to treat acute myeloid leukaemia (AML). It may also be used to treat other types of leukaemia and lymphomas.
Daunorubicin is a UK approved chemotherapy drug used to treat acute myeloid leukaemia (AML) and acute lymphocytic leukaemia (ALL).
Time spend in these studies will depend on the study doctor's decision on how long the participant will receive study treatment and on how many treatment cycles will be received, depending on how well the participant responds to treatment. There will be a 5 year long-term-follow-up-phase on both studies after the end-of-study treatment.
Summary of Results
"Number of Study Center(s) and Investigator(s):
A total of 14 participants were enrolled in the continuation study at 11 sites in 11 countries.
Study Period:
Study Initiation Date (First Participant First Visit [FPFV]) – Continuation Study:
17 May 2021
Study Completion (Last Participant Last Visit [LPLV]) Date: 02 December 2022
Objectives, Endpoints, and Statistical Methods:
Methodology:
This was an open-label, continuation study for eligible non-intensive cohort participants enrolled in Study B1371019 or eligible participants originating from Study B1371012 continuing on study intervention with azacitidine with or without glasdegib to derive clinical benefit.
The participants moving on to the continuation study were in the same treatment arm as assigned in the original Study B1371019. The glasdegib+azacitidine arm is used throughout this report, and the placebo+azacitidine arm will be referred to as the azacitidine alone arm.
Number of Participants (planned and analyzed):
A maximum of 34 participants from Study B1371019 and 3 participants from Study B1371012 were planned to continue to receive access to study intervention in the continuation study.
A total of 14 participants continued in the study (all from Study B1371019) and received study intervention. No participant from Study B1371012 met the enrollment criteria to enter this continuation study.
Among the 14 participants in the continuation study, 9 participants were treated in the glasdegib+azacitidine arm (6 participants received glasdegib+azacitidine and 3 participants received azacitidine only), and 5 participants were treated in the azacitidine alone arm.
Diagnosis and Main Criteria for Inclusion and Exclusion:
Participants were eligible to be included in the continuation study only if they continued to demonstrate clinical benefit (as determined by the principal investigator) from study treatment with azacitidine with or without glasdegib in Study B1371019 or from Study B1371012 and were capable of giving signed informed consent. Participants were excluded from the study if they had recent or active suicidal ideation/behavior or laboratory abnormality that could increase the risk of study participation or, in the investigators judgment, make the participant inappropriate for the study; if female, the participant was pregnant or breastfeeding; or if the participant had been withdrawn from Study B1371019 or Study B1371012 for any reason.
Study Interventions, Dose, Mode of Administration:
The study intervention in the continuation study was open-label azacitidine with or without glasdegib, and no placebo was to be administered.
Duration of Study Intervention:
The median (range) duration of treatment of the 14 participants in the continuation study was28.8 (1.0, 72.0) weeks.
Summary of Results:
Demographic and Other Baseline Characteristics:
Of the 14 participants who continued in the study, 8 (57.1%) were male and 6 (42.9%) werefemale; the majority of participants were White (64.3%); all 14 participants were ≥65 years with the mean (standard deviation [SD]) age of 73.93 (4.80) years.
Exposure:
Exposure to Glasdegib
• The median (range) treatment exposure time of glasdegib was 30.0 (2.3, 72.0) weeks for the glasdegib+azacitidine arm.
• The median (range) cumulative dose was 19700.0 (1200.0, 44900.0) mg in the glasdegib+azacitidine arm.
• The median relative dose intensity for glasdegib was 78.8% in the glasdegib+azacitidine arm.
Exposure to Azacitidine
• The median treatment duration of azacitidine was 21.7 weeks in the glasdegib+azacitidine
arm and was 34.7 weeks in the azacitidine alone arm.
• The median cumulative dose of azacitidine was 3200 mg/m2 in the glasdegib+azacitidine arm and 3900 mg/m2 in the azacitidine alone arm.
• The median relative dose intensity of azacitidine was 514.3% in the glasdegib+azacytidine arm and 671.4% in the azacitidine alone arm.
Safety Results:
AEs
In the glasdegib+azacitidine arm:
• Seven (77.8%) participants experienced 24 all-causality treatment-emergent adverse events (TEAEs), among whom 5 (55.6%) participants experienced 9 treatment-related TEAEs. A total of 2 (22.2%) participants experienced SAEs, among whom
1 (11.1%) participant experienced a treatment-related SAE. One (11.1%) participant discontinued from study due to non-treatment-related TEAEs.
• Two (22.2%), 3 (33.3%), 1 (11.1%) and 1 (11.1%) participants had TEAEs at maximum
Common Terminology Criteria for Adverse Events (CTCAE) Grades 2, 3, 4 and 5, respectively.
• A total of 5 (55.6%) participants had treatment-related TEAEs, most of which were at maximum CTCAE Grades 3-4 (4 [44.4%] participants) or Grades 3-5 (4 [44.4%] participants).
• All TEAEs were reported in single participant in the glasdegib+azacitidine arm except for neutropenia reported in 4 (44.4%) participants.
In the azacitidine alone arm:
• Four (80.0%) participants experienced 6 all-causality TEAEs, and these 4 (80.0%) participants experienced 5 treatment-related TEAEs. One (20.0%) participant experienced a treatment-related SAE. One (20.0%) participant discontinued from study due to a treatment-related TEAE.
• One (20.0%), 2 (40.0%) and 1 (20.0%) participants had TEAEs at maximum CTCAE Grades 2, 3 and 4, respectively.
• All TEAEs in the azacitidine alone arm were related to the study intervention except for back pain.
• Neutropenia was reported in 2 (40.0%) participants, and febrile neutropenia, back pain, oedema peripheral, and platelet count decreased were reported in single participant.Death
One participant in the glasdegib+azacitidine arm died due to a non-treatment-related TEAE of cardiopulmonary failure within 28 days after the last dose of study intervention. No death was reported in the azacitidine alone arm.SAEs
Two (22.2%) participants in the glasdegib+azacitidine arm had SAEs:• One participant experienced SAEs of coronavirus disease 2019 (COVID-19) pneumonia and cardiopulmonary failure, neither of which was related to the study intervention (the COVID-19 pneumonia was related to COVID-19 infection and the cardiopulmonary failure was related to COVID-19 pneumonia). This participant discontinued the study intervention due to COVID-19 pneumonia and then died due to cardiopulmonary failure.
• One participant experienced an SAE of febrile neutropenia, which was related to the study intervention of glasdegib and azacitidine as assessed by the investigator.
One (20.0%) participant in the azacitidine alone arm experienced an SAE of febrile neutropenia, which was related to the study intervention of azacitidine as assessed by the investigator. The participant permanently discontinued the azacitidine and discontinued from study due to the SAE of febrile neutropenia.
Permanent Discontinuations of Study Intervention Due to Adverse Events
In the glasdegib+azacitidine arm, 1 participant discontinued the study intervention of glasdegib and azacitidine due to the SAE of COVID-19 pneumonia and then died due to cardiopulmonary failure.In the azacitidine alone arm, 2 participants discontinued the study intervention of azacitidine due to TEAEs; 1 participant discontinued due to febrile neutropenia and the other discontinued due to neutropenia.
Dose Interruptions Due to Adverse Events
One (11.1%) participant in the glasdegib+azacitidine arm had glasdegib interruption due to a TEAE of neutropenia. Two (22.2%) participants in the glasdegib+azacitidine arm and 1 (20.0%) participant in the azacitidine alone arm had any dose interruptions (either glasdegib or azacitidine) due to TEAEs of neutropenia. No other TEAEs leading to dose interruptions.No dose reductions due to TEAEs were reported in the continuation study.
Adverse Events of Special Interest
No glasdegib-specific AEs of dysgeusia or muscle spasms were reported in this continuation study.
Other AEs of special interest are summarized as follows:
• Four (44.4%) participants in the glasdegib+azacitidine arm and 2 (40.0%) participants in the azacitidine alone arm experienced TEAEs of neutropenia.
• One (11.1%) participant in the glasdegib+azacitidine arm experienced a TEAE of anaemia.
• One (11.1%) participant in the glasdegib+azacitidine arm and 1 (20.0%) participant in the azacitidine alone arm experienced TEAEs of febrile neutropenia, and both of these febrile neutropenia were reported as SAEs.
• One (11.1%) participant in the glasdegib+azacitidine arm experienced a TEAE of thrombocytopenia.
Conclusions:
• The evaluation of the safety of glasdegib plus azacitidine or azacitidine alone demonstrated a manageable safety profile in adult participants with previously untreated acute myeloid leukemia, and no new safety signal was identified in the continuation study.• There were no unexpected AEs reported in the continuation study. Febrile neutropenia was the only treatment-related SAE reported in the glasdegib+azacitidine arm and azacitidine alone arm in the continuation study.
• There were no treatment-related deaths among the 14 participants in the continuation study."
Summary of Results:
Number of Study Center(s) and Investigator(s):
A total of 14 participants were enrolled in the continuation study at 11 sites in 11 countries.
Study Period:
Study Initiation Date (First Participant First Visit [FPFV]) – Continuation Study:
17 May 2021
Study Completion (Last Participant Last Visit [LPLV]) Date: 02 December 2022 Objectives, Endpoints, and Statistical Methods:
Methodology:
This was an open-label, continuation study for eligible non-intensive cohort participants enrolled in Study B1371019 or eligible participants originating from Study B1371012 continuing on study intervention with azacitidine with or without glasdegib to derive clinical benefit.
The participants moving on to the continuation study were in the same treatment arm as assigned in the original Study B1371019. The glasdegib+azacitidine arm is used throughout this report, and the placebo+azacitidine arm will be referred to as the azacitidine alone arm.
Number of Participants (planned and analyzed):
A maximum of 34 participants from Study B1371019 and 3 participants from Study B1371012 were planned to continue to receive access to study intervention in the continuation study.
A total of 14 participants continued in the study (all from Study B1371019) and received study intervention. No participant from Study B1371012 met the enrollment criteria to enter this continuation study.
Among the 14 participants in the continuation study, 9 participants were treated in the glasdegib+azacitidine arm (6 participants received glasdegib+azacitidine and 3 participants received azacitidine only), and 5 participants were treated in the azacitidine alone arm.
Diagnosis and Main Criteria for Inclusion and Exclusion:
Participants were eligible to be included in the continuation study only if they continued to demonstrate clinical benefit (as determined by the principal investigator) from study treatment with azacitidine with or without glasdegib in Study B1371019 or from Study B1371012 and were capable of giving signed informed consent. Participants were excluded from the study if they had recent or active suicidal ideation/behavior or laboratory abnormality that could increase the risk of study participation or, in the investigator’s judgment, make the participant inappropriate for the study; if female, the participant was pregnant or breastfeeding; or if the participant had been withdrawn from Study B1371019 or Study B1371012 for any reason.
Study Interventions, Dose, Mode of Administration:
The study intervention in the continuation study was open-label azacitidine with or without glasdegib, and no placebo was to be administered.
Duration of Study Intervention:
The median (range) duration of treatment of the 14 participants in the continuation study was
28.8 (1.0, 72.0) weeks.
Summary of Results:
Demographic and Other Baseline Characteristics:
Of the 14 participants who continued in the study, 8 (57.1%) were male and 6 (42.9%) were female; the majority of participants were White (64.3%); all 14 participants were ≥65 years with the mean (standard deviation [SD]) age of 73.93 (4.80) years.
Exposure:
Exposure to Glasdegib
• The median (range) treatment exposure time of glasdegib was 30.0 (2.3, 72.0) weeks for
the glasdegib+azacitidine arm.
• The median (range) cumulative dose was 19700.0 (1200.0, 44900.0) mg in the
glasdegib+azacitidine arm.
• The median relative dose intensity for glasdegib was 78.8% in the glasdegib+azacitidine
arm.
Exposure to Azacitidine
• The median treatment duration of azacitidine was 21.7 weeks in the glasdegib+azacitidine
arm and was 34.7 weeks in the azacitidine alone arm.
• The median cumulative dose of azacitidine was 3200 mg/m2 in the glasdegib+azacitidine
arm and 3900 mg/m2 in the azacitidine alone arm.
• The median relative dose intensity of azacitidine was 514.3% in the glasdegib+azacytidine arm and 671.4% in the azacitidine alone arm.
Safety Results:
AEs
In the glasdegib+azacitidine arm:
• Seven (77.8%) participants experienced 24 all-causality treatment-emergent adverse
events (TEAEs), among whom 5 (55.6%) participants experienced 9 treatment-related TEAEs. A total of 2 (22.2%) participants experienced SAEs, among whom
1 (11.1%) participant experienced a treatment-related SAE. One (11.1%) participant discontinued from study due to non-treatment-related TEAEs.
• Two (22.2%), 3 (33.3%), 1 (11.1%) and 1 (11.1%) participants had TEAEs at maximum
Common Terminology Criteria for Adverse Events (CTCAE) Grades 2, 3, 4 and 5, respectively.
• A total of 5 (55.6%) participants had treatment-related TEAEs, most of which were at
maximum CTCAE Grades 3-4 (4 [44.4%] participants) or Grades 3-5 (4 [44.4%] participants).
• All TEAEs were reported in single participant in the glasdegib+azacitidine arm except for neutropenia reported in 4 (44.4%) participants.
In the azacitidine alone arm:
• Four (80.0%) participants experienced 6 all-causality TEAEs, and these 4 (80.0%)
participants experienced 5 treatment-related TEAEs. One (20.0%) participant experienced a treatment-related SAE. One (20.0%) participant discontinued from study due to a treatment-related TEAE.
• One (20.0%), 2 (40.0%) and 1 (20.0%) participants had TEAEs at maximum CTCAE Grades 2, 3 and 4, respectively.
• All TEAEs in the azacitidine alone arm were related to the study intervention except for
back pain.
• Neutropenia was reported in 2 (40.0%) participants, and febrile neutropenia, back pain,
oedema peripheral, and platelet count decreased were reported in single participant.Death
One participant in the glasdegib+azacitidine arm died due to a non-treatment-related TEAE of cardiopulmonary failure within 28 days after the last dose of study intervention. No death was reported in the azacitidine alone arm.SAEs
Two (22.2%) participants in the glasdegib+azacitidine arm had SAEs:• One participant experienced SAEs of coronavirus disease 2019 (COVID-19) pneumonia and cardiopulmonary failure, neither of which was related to the study intervention (the COVID-19 pneumonia was related to COVID-19 infection and the cardiopulmonary failure was related to COVID-19 pneumonia). This participant discontinued the study intervention due to COVID-19 pneumonia and then died due to cardiopulmonary failure.
• One participant experienced an SAE of febrile neutropenia, which was related to the study intervention of glasdegib and azacitidine as assessed by the investigator.
One (20.0%) participant in the azacitidine alone arm experienced an SAE of febrile neutropenia, which was related to the study intervention of azacitidine as assessed by the investigator. The participant permanently discontinued the azacitidine and discontinued from study due to the SAE of febrile neutropenia.
Permanent Discontinuations of Study Intervention Due to Adverse Events In the glasdegib+azacitidine arm, 1 participant discontinued the study intervention of glasdegib and azacitidine due to the SAE of COVID-19 pneumonia and then died due to cardiopulmonary failure.
In the azacitidine alone arm, 2 participants discontinued the study intervention of azacitidine due to TEAEs; 1 participant discontinued due to febrile neutropenia and the other discontinued due to neutropenia.
Dose Interruptions Due to Adverse Events One (11.1%) participant in the glasdegib+azacitidine arm had glasdegib interruption due to a TEAE of neutropenia. Two (22.2%) participants in the glasdegib+azacitidine arm and
1 (20.0%) participant in the azacitidine alone arm had any dose interruptions (either glasdegib or
azacitidine) due to TEAEs of neutropenia. No other TEAEs leading to dose interruptions.No dose reductions due to TEAEs were reported in the continuation study.
Adverse Events of Special Interest
No glasdegib-specific AEs of dysgeusia or muscle spasms were reported in this continuation study.
Other AEs of special interest are summarized as follows:
• Four (44.4%) participants in the glasdegib+azacitidine arm and 2 (40.0%) participants in the azacitidine alone arm experienced TEAEs of neutropenia.
• One (11.1%) participant in the glasdegib+azacitidine arm experienced a TEAE of anaemia.
• One (11.1%) participant in the glasdegib+azacitidine arm and 1 (20.0%) participant in the azacitidine alone arm experienced TEAEs of febrile neutropenia, and both of these febrile neutropenia were reported as SAEs.
• One (11.1%) participant in the glasdegib+azacitidine arm experienced a TEAE of thrombocytopenia.
Conclusions:
• The evaluation of the safety of glasdegib plus azacitidine or azacitidine alone demonstrated a manageable safety profile in adult participants with previously untreated acute myeloid leukemia, and no new safety signal was identified in the continuation study.• There were no unexpected AEs reported in the continuation study. Febrile neutropenia was the only treatment-related SAE reported in the glasdegib+azacitidine arm and azacitidine alone arm in the continuation study.
• There were no treatment-related deaths among the 14 participants in the continuation study.
REC name
London - Surrey Borders Research Ethics Committee
REC reference
18/LO/0779
Date of REC Opinion
23 May 2018
REC opinion
Favourable Opinion