B1761031 MYLOTARG-SINGLE-AGENT REGIMEN FOR RELAPSED CD 33-Positive AML
Research type
Research Study
Full title
A SINGLE ARM, OPEN-LABEL, PHASE 4 STUDY EVALUATING QT INTERVAL, PHARMACOKINETICS, AND SAFETY OF GEMTUZUMAB OZOGAMICIN (MYLOTARG™) AS A SINGLE-AGENT REGIMEN IN PATIENTS WITH RELAPSED OR REFRACTORY CD33-POSITIVE ACUTE MYELOID LEUKEMIA
IRAS ID
253657
Contact name
Amit Patel
Contact email
Sponsor organisation
Pfizer Inc. 235 East 42nd Street, New York, NY 10017
Eudract number
2018-002619-89
Clinicaltrials.gov Identifier
Clinicaltrials.gov Identifier
IND046635, US IND Number
Duration of Study in the UK
1 years, 9 months, 9 days
Research summary
Research Summary
This is a single-arm, open-label, Phase 4 study evaluating the effect of Gemtuzumab Ozogamicin (GO or also Mylotarg™) on the heart and how it is distributed and eliminated in the body (pharmacokinetics, safety, and immunogenicity) as a single-agent monotherapy in adult and pediatric patients with relapsed or refractory CD33-positive AML.
The study drug GO (Mylotarg) is approved in the UK and is available by prescription for newly-diagnosed AML in combination with other drugs for patients aged 15 years and older. The use of GO in this study is investigational since it is being used as a single agent in a younger patient population for relapsed or refractory CD33-positive AML instead of newly diagnosed AML.
This study has two different periods: (1) Treatment Period (one or two cycles that last approximately 1 month each) and (2) Follow-up Period.
About 50 adult patients globally (aged 16 - ≥18 in the UK) and 6 pediatric (aged 12-15 years in the UK) patients globally who satisfy the study eligibility criteria will be enroled and treated with 3 doses of GO 3 mg/m2, as a 2-hour intravenous infusion on Days 1, 4, and 7 in cycle 1. A second cycle 3mg/m² (up to one vial) on Cycle 2 Days 1, 4, and 7 will be allowed at the investigator’s discretion for patients who meet a certain criteria.
The Follow up period will start the day after last treatment received and will last for 12 months.
After GO treatment, subsequent anti-cancer therapy such as consolidation or conditioning regimen and/or HSCT could be considered at the investigator’s discretion. A minimum interval of 2 months is recommended between the last dose of GO and HSCT.
Summary of Results
Subject Disposition and Demography: 52 (51 adults and 1 pediatric) participants were assigned to treatment in this study. 51 of the 66 adult participants screened were assigned to GO of which 50 adult participants received GO treatment and 1 adult participant who did not receive GO treatment (assigned to treatment via Interactive Response Technology [IRT] in error). The 1 pediatric participant received GO treatment but the pediatric participant data is not presented in the results section.
Of the 51 adult participants enrolled, 4 (7.8%) participants permanently discontinued treatment (this includes the 1 adult participant that did not receive GO treatment) and the remaining 47 (92.2%) completed treatment. The 50 treated adult participants were evaluated for pharmacokinetics, immunogenicity and analyzed for safety (QTc and adverse events). 51 adult participants were evaluated for efficacy (based on the full analysis set) and 46 adult participants were evaluated for PD parameters.
Baseline Demographic Characteristic: Median (min, max) age was 67 (22.0, 82.0) years.
32 (62.7%) were ≥65 years of age, 31 (60.8%) were male and 39 (76.5%) participants were White.Efficacy Results:
Response Results
• A best overall response (BOR) based on CR+CRi was achieved in 5 (9.8%, 95% CI:
3.3, 21.4) participants.Overall Survival
• The median overall survival was 2.8 months (95% CI: 1.7, 4.2).
• The percent of participants alive at 12 months was 4.3 (95% CI: 0.8, 12.9).Pharmacokinetics Results:
Following a single infusion of GO at 3 mg/m2 (Cycle 1, Day 1 [C1D1]),
• Peak conjugated calicheamicin (ac-CL-184538), unconjugated calicheamicin (CL-184538) and total HP67.6 (Gemtuzumab) antibody concentrations occurred around the end of the of 2-hour infusion with median time for maximum plasma concentration (Tmax) values of 2.08, 2.17 and 2.08 hours, respectively.
• Exposures as measured by geometric mean area under the plasma concentration-time profile from time zero to 72 hours post-dose (AUC72) and maximum plasma concentration (Cmax) were 93490 pg.hr/mL and 6457 pg/mL; 247.8 pg.hr/mL and 45.69 pg/mL; and 3797 ng.hr/mL and 282.1 ng/mL for ac-CL-184538, CL-184538 and total HP67.6 antibody, respectively.
Following multiple fractionated infusions of GO at 3 mg/m2 (Cycle 1, Day 7 [C1D7]),
• Median Tmax values were 2.13, 3.92 and 2.17 hours for ac-CL-184538, CL-184538 and total HP67.6 antibody, respectively.
• Exposures as measured by geometric mean AUC from time zero to 336 hours postdose (AUC336) and Cmax were 461500 pg.hr/mL and 11740 pg/mL; 1639 pg.hr/Ml and 58.76 pg/mL, and 26820 ng.hr/mL and 585.6 ng/mL for ac-CL-184538, CL-184538 and total HP67.6 antibody, respectively.
In general, both ac-CL-184538 and CL-184538 followed the same time course as total HP67.6 antibody for both C1D1 and C1D7.
Inter-participant variability for geometric mean AUC and Cmax values across both C1D1 and C1D7 for ac-CL-184538, CL-184538 and total HP67.6 antibody were generally high.Immunogenicity Results:
• Among the 50 participants treated with GO, 12 (24%) participants had positive ADA (titer ≥75) against GO at baseline. The presence of positive ADA at baseline was likely due to pre-existing host antibodies that were cross reactive with GO. There was no treatment-boosted ADA response.
• Treatment-induced ADA was detected in 6 (12%) participants with an overall median peak titer of 276 (interquartile range [Q1, Q3]: 182.0, 674.0).
• There were no participants who tested positive for NAb at baseline and therefore no participants had a treatment-boosted response. Treatment-induced NAb was detected in 1 (2.0%) participant.
• The median onset for treatment-induced ADA and NAb was 18 days (Q1, Q3: 15, 21) and 76 days, respectively; while the median duration was 3.5 days (Q1, Q3: 1, 73) and 1 day, respectively. Five of the 6 participants had persistent ADA response.
Other Results:
Metabolic Profiling:
• The calicheamicin-related metabolites of GO were identified in plasma and urine samples from the 6 participants.
• A total of 7 metabolites were detected in urine: N-acetyl-γ-calicheamicin dimethylhydrazide (N-Ac-γ-calicheamicin DMH; PF-06649266; M17; m/z 1516 -corresponding to [M+K]+), N-acetyl-ε-calicheamicin (N-Ac-ε-calicheamicin; PF-06691414; M16, observed as two isomers M16a and M16b; m/z 1372 – corresponding to [M+K]+), N-Ac-ε-calicheamicin with the addition of two hydrogen atoms (M9; m/z 1374 – corresponding to [M+K]+) and three tetrasaccharide products (M5 and M7; m/z 1041 – corresponding to [M+K]+ and M11; m/z 1043 – corresponding to [M+K]+).
• A total of 3 metabolites were detected in plasma: N-Ac-γ-calicheamicin DMH (M17), one isomer of N-Ac-ε-calicheamicin (M16a) and a tetrasaccharide product (M11).
•
Pharmacodynamics Results (CD33 Site Saturation):
• Following 3 mg/m2 GO administration, the highest median percent CD33 site saturation (77.09%) was achieved at end of infusion (2 hour) on C1D1 where Cmax was observed. Similar results were seen at 2-hour post dose on Cycle 1 Day 4 (C1D4) and C1D7.Safety Results:
Extent of Exposure:
• 46 (92.0%) participants received all doses in Cycle 1.
• 9 (18.0%) participants received Cycle 2, of which all 9 participants received all Cycle 2 doses.All-Causality Treatment-Emergent AEs (TEAEs) and Serious AEs (TE-SAEs):
49 (98.0%) and 34 (68.0%) participants experienced TEAEs and TE-SAEs, respectively. The
4 most frequently reported TEAEs were febrile neutropenia in 20 (40.0%), thrombocytopenia in 11 (22.0%) participants, and hypokalemia and pyrexia in 9 (18.0%) participants each. The most frequently reported (≥10%) TE-SAEs were febrile neutropenia in 11 (22.0%), sepsis in 7 (14.0%) , and disease progression in 5 (10.0%) participants.Treatment-Emergent Adverse Events of Special Interest (AESI):
QTc Prolongation (Primary Endpoint):
• The timepoints assessed in primary analysis of QTcF were Day 4 (at 0 hour) and Day 7 (at 0, 2, 4 and 6 hours).
• The upper limit of the 2-sided 90% CIs for least squares (LS)-mean differences was less than the predefined cutoff of 20 msec for the timepoints assessed in primary analysis as defined above. Therefore, the post-baseline dose QTc interval effect is considered “non-inferior” to baseline.
• Highest 90% CI upper limit for QTcF change was 8.06 msec at C1D1 4 hours post dose.Myelosuppression:
• 28 (56.0%) participants had “MYELOSUPPRESSION” TEAEs. The most (≥10%) reported TEAEs were febrile neutropenia occurring in 20 (40.0%), thrombocytopenia in 11 (22.0%), anemia in 6 (12.0%), and neutropenia in 5 (10.0%) participants.
• 26 (52.0%) participants had Grade 3-4 “MYELOSUPPRESSION” TEAEs. The most (≥10%) reported Grade 3-4 TEAEs were febrile neutropenia occurring in 18 (36.0%), thrombocytopenia in 9 (18.0%), and anemia and neutropenia in 5 (10.0%) participants, each.
• No participants had Grade 5 “MYELOSUPPRESSION” TEAEs.
• No “MYELOSUPPRESSION” TEAE resulted in permanent or temporary discontinuation of GO.Infection (Grade >3 [Grade 3-5] and/or serious infection:
• 17 (34.0%) participants had “INFECTIONS” TEAEs. The most (≥10%) reported TEAE was sepsis occurring in 7 (14.0%) participants.
• 10 (20.0%) participants had Grade 3-4 “INFECTIONS” TEAEs. The most (≥5.0%) reported Grade 3-4 TEAEs were sepsis and pneumonia in 3 (6.0%) participants, each.
• 6 (12.0%) participants had Grade 5 “INFECTIONS” TEAEs. The most (≥5.0%) reported Grade 5 TEAE was sepsis in 4 (8.0%) participants.
• 1 (2.0%) participant experienced an infection (Grade 3) that resulted in temporary discontinuation of GO and a Grade 4 sepsis that resulted in permanent discontinuation of GO. Both events were assessed as not related to study intervention by the investigator.Hemorrhage:
• 16 (32.0%) participants had “HAEMORRHAGE” TEAEs. The most (≥10%) reported TEAE was epistaxis in 5 (10.0%) participants.
• 2 (4.0%) participants had Grade 3-4 “HAEMORRHAGE” TEAEs of gastric hemorrhage (Grade 3) and traumatic intracranial hemorrhage (Grade 4) in 1 participant, each.
• No participants had Grade 5 “HAEMORRHAGE” TEAEs.
• No “HAEMORRHAGE” TEAEs resulted in permanent or temporary discontinuation of GO.Infusion-Related Reactions (IRR) (Including Anaphylaxis):
• 9 (18.0%) participants reported “IRR” TEAEs within 24 hours following the GO administration.
• The most frequently (≥10%) reported TEAE was pyrexia in 5 (10.0%) participants.
• 2 (4.0%) participants had Grade 3 “IRR” TEAEs of Pyrexia and urticaria in 1 participant, each.
• No participants had Grade 4 or Grade 5 “IRR” TEAEs.
• No “IRR” TEAEs resulted in permanent or temporary discontinuation of GO.Cardiac Conduction and Arrhythmias:
• 4 (8.0%) participants had “CARDIAC CONDUCTION” TEAEs reported in 1 (2.0%) participant each, consisting of arrhythmia (Grade 2), QT prolongation (Grade 1), supraventricular extrasystoles (Grade 2), and 1 event each of atrial fibrillation (Grade 3) and supraventricular tachycardia (Grade 3) occurred in the same participant.
• No participants had a QTcF >480 msec or a QTc using a study-specific correction factor (QTcS) >480 msec.
• No events of Torsade de Pointes (TdP), sudden death, ventricular fibrillation, flutter or seizures were reported.
• No Grade 4 or Grade 5 “CARDIAC CONDUCTION” TEAEs were reported.
• No “CARDIAC CONDUCTION” TEAEs resulted in permanent or temporary discontinuation of GO.Hepatotoxicity (Grade ≥3 and/or serious hepatotoxicity including all venoocclusive disease [VOD]/sinusoidal obstruction syndrome [SOS]):
• 4 (8.0%) participants had “HEPATOTOXICITY” TEAEs The most frequently reported “HEPATOTOXICITY” TEAE was gamma-glutamyl transferase (GGT) increased in 2 (4.0%) participants.
• 4 (8.0%) participants had Grade 3 “HEPATOTOXICITY” TEAEs. 1 participant experienced 1 event each of GGT increased, alanine aminotransferase (ALT) increased, and aspartate aminotransferase (AST) increased. The remaining 3 participants reported Grade 3 TEAEs of GGT increased, hypalbuminemia, and transaminases increased (1 [2.0%] each.
• No participant had Grade 4 or Grade 5 “HEPATOTOXICITY” TEAEs.
• 1 participant experienced a Grade 3 “HEPATOTOXICITY” TEAE that resulted in temporary discontinuation of GO. The event was assessed as related to GO treatment by the investigator.Venoocclusive Disease/ Sinusoidal Obstruction Syndrome: No VOD/SOS events were reported as such by any participant during on-treatment and post hematopoietic stem cell transplantation (HSCT). However 1 participant presented with capillary leak syndrome consistent with VOD/SOS. The participant did not receive any HSCT prior to study entry.
Tumor Lysis Syndrome: No “TUMOUR LYSIS SYNDROME” TEAEs were reported by any participant.
Impact of Immunogenicity on Safety:
• Of the 50 participants treated with GO, 44 were ADA negative and 6 had treatment induced ADA.
• 7 of 44 (15.9%) ADA negative participants had an “IRR”.
• 2 of 6 (33.0%) treatment-induced ADA positive participants had an “IRR” of pyrexia.
• None of the participants experienced anaphylaxis, hypersensitivity or other clinical sequelae related to ADA. Therefore, there is no evidence that the presence of ADA had a direct association of immunogenicity or any potential safety issues.
Treatment-induced NAb was detected in 1 (2.0%) participant. This participant did not present any event meeting IRR.GO Permanent Discontinuations due to Adverse Events: TEAEs (all-causality) leading to discontinuation (withdrawal) of GO were reported in 2 (4.0%) participants. 1 (2.0%) participant had Grade 3 sepsis and 1 participant had Grade 4 pyrexia. There were no treatment-related TEAEs leading to permanent discontinuation (withdrawal) of GO reported.
Deaths, Other Serious Adverse Events, and Other Significant Adverse Events:
• 45 (90.0%) participants died. The most common cause of death was reported as disease progression in 35 (77.8%) participants. 1 (2.2%) death was attributed to study treatment toxicity (capillary leak syndrome).
• 6 (12.0%) participants died within 30 days of first dose of GO treatment. 5 (83.3%) participants died due to disease progression.
• 13 (26.0%) participants died within 36 days after last dose of GO treatment. 9 (69.2%) participants died due to disease progression.
• Grade 5 AEs were reported in 16 (32.0%) participants, of which 5 (10.0%) died of disease progression, 4 (8.0%) died of sepsis, and multiple organ dysfunction, pyrexia, atypical pneumonia, Coronavirus Disease 2019 (COVID-19) pneumonia, AML (consistent with disease progression), respiratory failure, and capillary leak syndrome accounted for the deaths of the remaining participants.Clinical Laboratory Results:
• A total of 43/50 (86.0%) participants experienced a hematology and coagulation parameter shift to Grade 3 or 4 postbaseline. The 3 most reported hematology and coagulation parameter postbaseline shifts to Grade 3 or 4 reported were white blood cell (WBC) decreased in 25/49 (51.0%), decreased lymphocyte count in 24/49 (49.0%) and anemia in 21/50 (42.0%) participants.
• No prolonged cytopenia was experienced by any of the participants with CR/CRi in Cycle 1. Prolonged neutropenia (neutrophils <500/μL lasting past Day 42) was reported in 1/3 (33.3%) participants with CR/CRi in Cycle 2.
• Among the 3 responders in Cycle 1, the median time to recovery of platelets to 50,000/μL was 32.0 days. Among all 3 responders in Cycle 2, the median time to recovery of platelets to 50,000/μL was 11.0 days. Among the 3 responders in Cycle 1, the median time to recovery of neutrophils to 500/μL was 32.0 days. Among all 3 responders in Cycle 2, the median time to recovery of neutrophils to 500/μL was 35.0 days.
• A total of 18/50 (36.0%) participants experienced a chemistry laboratory shift to Grade 3 or 4 postbaseline. The 3 most reported chemistry laboratory shifts to Grade 3 or 4 postbaseline were hyperglycemia in 7/50 (14.0%), hyponatremia in 5/50 (10.0%), and hypokalemia in 4/50 (8.0%) participants.
• No participants met the criteria for a potential Hy’s Law case (ie, concurrent ALT or AST ≥3 × upper limit of normal (ULN) and total bilirubin ≥2 × ULN and alkaline phosphatase (ALP) <2 × ULN or missing). The overall incidence of ALT or AST values ≥3 × ULN was 6 participants, with 5 participants experiencing ALT ≥3 × ULN and 3 participants experiencing AST ≥3 × ULN).Electrocardiogram Results:
• There were no participants who had a QTcF >480 msec or a QTcS >480 msec.
• There were no participants with a maximum increase from baseline of QTcF or QTcS>60 msec. A maximum change in QTcF and QTcS between 30 and ≤60 msec was reported in 3 (6.1%) participants, each.
• 11 (22.0%) participants exhibited a Grade 0 to Grade 1 shift in QTcF.
11 22.0%) participants exhibited a Grade 0 to Grade 1 shift in QTcS.
• No participants exhibited a Grade 3 or 4 event related to QTcF or QTcS (shift from Grade ≤2 at baseline to Grade 3 or 4 on study).CONCLUSIONS
Safety:
The study met its primary endpoint demonstrating no evidence implicating the role of GO in prolongation of the of the change from baseline in QTc. The safety data were consistent with the known safety profile of fractionated regimen of GO. There were no direct evidences that the presence of ADA had a direct association with any potential safety issues following GO treatment.Efficacy:
The BOR based on CR+CRi was achieved in 5 (9.8%, 95% CI: 3.3, 21.4) participants.
This result is lower than the OR of published data (MyloFrance 1, 33.3%), likely due to differences in the baseline characteristics in the study participants. Participants in this Study B1761031 included participants with prior HSCT and with multiple lines of prior therapy while the MyloFrance 1 included only participants in initial (first) relapse and excluded those participants with prior HSCT.Pharmacokinetics:
In general, the PK profiles of both ac-CL-184538 and CL-184538 mirror that of total hP67.6 antibody following fractionated dosing regimen of GO.Pharmacodynamics:
Following 3 mg/m2 GO administration, the highest median percent CD33 site saturation
(77.09%) was achieved at end of infusion (2 hour) on C1D1 where Cmax was observed.
Similar results were seen at 2-hour post dose on C1D4 and C1D7.Immunogenicity:
The incidence of ADA and NAb is 12% and 2.0%, respectively. None of the participants experienced anaphylaxis, hypersensitivity or other clinical sequelae related to ADA.REC name
South Central - Hampshire B Research Ethics Committee
REC reference
19/SC/0131
Date of REC Opinion
13 Jun 2019
REC opinion
Further Information Favourable Opinion