Nucleophosmin 1-mutated Acute Myeloid Leukemia
Conditions
Keywords
Acute Myeloid Leukemia, Nucleophosmin 1-mutated Acute Myeloid Leukemia, Entospletinib, ENTO
Brief summary
The primary objective of this study is to evaluate the efficacy of entospletinib (ENTO) compared to placebo when added to chemotherapy in previously untreated nucleophosmin-1 mutated (NPM1-m) acute myeloid leukemia (AML), as defined by the rate of molecularly defined measurable residual disease (MRD).
Detailed description
This is a multi-center, international, double-blind, placebo-controlled study in previously untreated participants with acute myeloid leukemia (AML) harboring nucleophosmin-1 (NPM1) mutations. Upon fulfillment of all eligibility criteria, participants were randomized 1:1 to receive intensive chemotherapy in combination with either the spleen tyrosine kinase (SYK) inhibitor entospletinib (ENTO), or placebo. The study consisted of Screening, Induction, Consolidation, End-of-Treatment, and Long-term Follow-up phases.
Interventions
DRUGEntospletinib
400 mg, Orally as tablets
DRUGPlacebo
Orally as tablets
DRUGCytarabine
Continuous infusion
DRUGAnthracycline
Either daunorubicin or idarubicin was administered via slow intravenous (IV) push
Sponsors
Kronos Bio
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 74 Years
Healthy volunteers
No
Inclusion criteria
1. Adults 18 to 74 years with previously untreated de novo acute myeloid leukemia (AML), AML with myelodysplastic syndromes (MDS) features, or therapy-related AML, who were candidates for intensive induction therapy. 2. Nucleophosmin-1 (NPM1)-mutated disease documented in a local or the Sponsor's central testing facility. Note: Participants with local test results for nucleophosmin-1 mutated (NPM1-m) (and/or FMS-like tyrosine kinase 3 mutational status) may enroll, provided appropriate samples were sent to the Sponsor's central testing facility for NPM1-m companion diagnostic development. 3. Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0, 1, or 2. 4. Adequate hepatic and renal function defined as: 1. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \< 2.5 times the upper limit of normal (ULN), except those with hepatic involvement by AML, as documented by either computed tomography (CT) or ultrasound, in whom levels of AST and ALT \< 5 times ULN are acceptable; total bilirubin \< 1.5 times ULN unless elevated due to Gilbert's Disease or hemolysis. 2. Calculated creatinine clearance \> 40 mL/min or serum creatinine \< 1.5 times ULN. 5. Prothrombin time (PT), activated partial thromboplastin time (aPTT), and international normalized ratio (INR) ≤ 1.5 x ULN unless receiving therapeutic anticoagulation. 6. Left ventricular ejection fraction ≥ 45% confirmed by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan.
Exclusion criteria
1. Isolated myeloid sarcoma (ie, participants must had peripheral blood and/or bone marrow involvement by AML) or acute promyelocytic leukemia. 2. Concurrent FLT3 mutation (either tyrosine kinase domain or internal tandem duplication). 3. Known central nervous system (CNS) involvement with leukemia. 4. Was a candidate for more intensive treatment than specified in this protocol. 5. Either not a candidate for any anthracycline therapy or a candidate for induction therapy with a higher dose of daunorubicin (eg. 90 mg/m\^2). 6. Was a candidate for daily doses of cytarabine \> 100 mg/m\^2 in Induction Cycle 1. 7. Active infection with hepatitis B, C, or uncontrolled human immunodeficiency virus (HIV). 8. Known active coronavirus disease 2019 (COVID-19) either symptomatic or asymptomatic, as determined by nasopharyngeal swab for severe acute respiratory syndrome (SARS) coronavirus 2 (SARS CoV-2) ribonucleic acid (RNA) or antigen. Note: Participants with a history of SARS-CoV-2 nasopharyngeal carriage (either with or without symptoms), who had subsequently tested negative on follow-up nasopharyngeal swab and were without signs or symptoms of COVID-19 might enroll. Participants who were fully vaccinated against SARS-CoV-2 might enroll. 9. Disseminated intravascular coagulation with active bleeding or signs of thrombosis. 10. History of prior allogeneic hematopoietic stem cell transplant or solid organ transplant. 11. Treatment with proton pump inhibitors (PPIs) from 7 days prior to enrollment until 48 hours after completion of entospletinib (ENTO) or placebo. Note: PPIs were likely to interfere with ENTO absorption, thus requiring a 7-day washout period prior to the initiation of study medication. For management of acute gastrointestinal bleeding during the study treatment period (such as that related to chemotherapy), short term concurrent use of PPIs was permitted for up to 10 consecutive days. If longer durations of PPI exposure were required, participants should discontinue study medication. Histamine (H2) receptor antagonists and antacids were allowed throughout the study treatment period. 12. Ongoing immunosuppressive therapy, including systemic chemotherapy for treatment of leukemia. Note: Participants may not receive AML-directed therapy prior to enrollment other than hydroxyurea or leukapheresis for acute management of hyperleukocytosis. 13. Clinical signs/symptoms of leukostasis that had failed therapy including hydroxyurea and/or leukapheresis of at least 3 days duration. 14. Clinically significant heart disease defined as: 1. New York Heart Association Class 3 or 4 congestive heart failure, 2. Acute myocardial infarction ≤ 6 months before enrollment, 3. Symptomatic cardiac ischemia/unstable angina ≤ 3 months before enrollment, 4. History of clinically significant arrhythmias (eg, ventricular tachycardia or fibrillation; Torsades de Pointe) including Mobitz type II 2nd degree or 3rd degree heart block without a permanent pacemaker in place. 15. Participants with a corrected congenital long measure between Q wave and T wave in the electrocardiogram (QT) interval (using the Fredericia formula, Fridericia correction of the QT measure \[QTcF\]) \> 480 msec or Long QT Syndrome. 16. Evidence of ongoing, uncontrolled systemic bacterial, fungal, or viral infection at the time of study treatment initiation, including but not limited to persistent fever or positive cultures in the setting of appropriate antimicrobial therapy. 17. Unable to swallow tablets or concurrent disease affecting gastrointestinal function such as, malabsorption syndrome, gastric or small bowel resection, bariatric surgery, inflammatory bowel disease, or bowel obstruction.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Measurable Residual Disease (MRD) Negative Complete Response (CR) Rate | Cycle 1 Day 1, up to Day 42 of chemotherapy cycle 2 (Cycle length = 42 days) | MRD negative CR requires CR as defined by the European Leukemia Network (ELN) 2017 criteria (with minor modification for neutrophil and platelet count thresholds as defined by International Working Group \[IWG\]) as assessed by study site investigators, and MRD negativity (\<0.01%) in bone marrow as measured by a molecular nucleophosmin-1 mutated (NPM1-m) assay (eg, next generation sequencing) in a central laboratory upon recovery of peripheral blood counts following completion of 2 cycles of chemotherapy, no later than Day 42 of Cycle 2. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Event-free Survival (EFS) | Cycle 1 Day 1, up to Day 42 of chemotherapy cycle 2 (Cycle length = 42 days) | EFS is defined as the time from randomization to the earliest occurrence of induction treatment failure, relapse from CR, or death from any cause. Induction treatment failure is failure to achieve morphological CR after completion of the last cycle of induction chemotherapy (no later than Day 42 of the last cycle of induction). |
| Relapse-free Survival (RFS) | Cycle 1 Day 1, up to Day 42 of chemotherapy cycle 2 (Cycle length = 42 days) | RFS is defined as the time from CR until relapse or death from any cause as assessed by study site investigators. |
| Overall Survival (OS) | Cycle 1 Day 1, up to Day 42 of chemotherapy cycle 2 (Cycle length = 42 days) | OS is defined as the time from randomization until death from any cause. |
| Number of Participant With Complete Response (CR) After 2 Cycles of Chemotherapy | Cycle 1 Day 1, up to Day 42 of chemotherapy cycle 2 (Cycle length = 42 days) | CR as defined by ELN 2017 criteria (with minor modification for neutrophil and platelet count thresholds as defined by IWG) as assessed by study site investigators. |
| Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Cycle 1 Day 1 to 30 days following study treatment completion, (Cycle length = 42 days) maximum up to 198 days | A TEAE is any untoward medical occurrence in a clinical study participant, beginning or worsening from Cycle 1, Day 1 through 30 days following study treatment completion, temporarily associated with the use of treatment, whether or not considered related to the study treatment. TEAEs were recorded according to the most current version of the Medical Dictionary for Regulatory Activities (MedDRA). Clinically significant changes in safety laboratory assessments, electrocardiograms, echocardiogram / multi-gated acquisition scans and Eastern Cooperative Oncology Group performance status findings, as assessed by the Investigator, were recorded as TEAEs. |
Countries
Brazil, Canada, Czechia, France, Germany, Hungary, Israel, Italy, Poland, South Korea, Spain, United States
Participant flow
Recruitment details
Participants were enrolled from 5 countries including the Czechia, France, Republic of Korea, Spain, and the United States from 24 November 2021 to 30 March 2023.
Pre-assignment details
In this study participants were randomized 1:1 to receive intensive chemotherapy in combination with either the spleen tyrosine kinase inhibitor, entospletinib (ENTO), or placebo. Randomization was stratified by age (\< 60 vs ≥ 60 years) and anthracycline administered during induction (daunorubicin vs idarubicin). In November 2022, the Sponsor decided to terminate this study prior to full enrollment.
Participants by arm
| Arm | Count |
|---|---|
| ENTO Participants received ENTO twice daily (BID), along with intensive chemotherapy (cytarabine and anthracycline) by continuous intravenous (IV) infusion (cytarabine) or slow IV push (anthracycline). | 8 |
| Placebo Participants received placebo BID, along with intensive chemotherapy (cytarabine and anthracycline) by continuous intravenous (IV) infusion (cytarabine) or slow IV push (anthracycline). | 7 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 2 | 1 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Reason not specified | 1 | 0 |
| Overall Study | Study terminated by Sponsor | 5 | 4 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | Total | ENTO |
|---|---|---|---|
| Age, Continuous | 54.6 Years STANDARD_DEVIATION 16.11 | 55.7 Years STANDARD_DEVIATION 12.52 | 56.6 Years STANDARD_DEVIATION 9.41 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 13 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 13 Participants | 7 Participants |
| Sex: Female, Male Female | 2 Participants | 8 Participants | 6 Participants |
| Sex: Female, Male Male | 5 Participants | 7 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 8 | 1 / 7 |
| other Total, other adverse events | 7 / 8 | 7 / 7 |
| serious Total, serious adverse events | 8 / 8 | 2 / 7 |
Outcome results
Primary
Number of Participants With Measurable Residual Disease (MRD) Negative Complete Response (CR) Rate
MRD negative CR requires CR as defined by the European Leukemia Network (ELN) 2017 criteria (with minor modification for neutrophil and platelet count thresholds as defined by International Working Group \[IWG\]) as assessed by study site investigators, and MRD negativity (\<0.01%) in bone marrow as measured by a molecular nucleophosmin-1 mutated (NPM1-m) assay (eg, next generation sequencing) in a central laboratory upon recovery of peripheral blood counts following completion of 2 cycles of chemotherapy, no later than Day 42 of Cycle 2.
Time frame: Cycle 1 Day 1, up to Day 42 of chemotherapy cycle 2 (Cycle length = 42 days)
Population: Data not collected as the study was terminated early.
Secondary
Event-free Survival (EFS)
EFS is defined as the time from randomization to the earliest occurrence of induction treatment failure, relapse from CR, or death from any cause. Induction treatment failure is failure to achieve morphological CR after completion of the last cycle of induction chemotherapy (no later than Day 42 of the last cycle of induction).
Time frame: Cycle 1 Day 1, up to Day 42 of chemotherapy cycle 2 (Cycle length = 42 days)
Population: Data not collected as the study was terminated early.
Secondary
Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs)
A TEAE is any untoward medical occurrence in a clinical study participant, beginning or worsening from Cycle 1, Day 1 through 30 days following study treatment completion, temporarily associated with the use of treatment, whether or not considered related to the study treatment. TEAEs were recorded according to the most current version of the Medical Dictionary for Regulatory Activities (MedDRA). Clinically significant changes in safety laboratory assessments, electrocardiograms, echocardiogram / multi-gated acquisition scans and Eastern Cooperative Oncology Group performance status findings, as assessed by the Investigator, were recorded as TEAEs.
Time frame: Cycle 1 Day 1 to 30 days following study treatment completion, (Cycle length = 42 days) maximum up to 198 days
Population: Safety Analysis Set: All participants randomized who received at least one dose of study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ENTO | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | 8 Participants |
| Placebo | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | 7 Participants |
Secondary
Number of Participant With Complete Response (CR) After 2 Cycles of Chemotherapy
CR as defined by ELN 2017 criteria (with minor modification for neutrophil and platelet count thresholds as defined by IWG) as assessed by study site investigators.
Time frame: Cycle 1 Day 1, up to Day 42 of chemotherapy cycle 2 (Cycle length = 42 days)
Population: Intent-to-Treat (ITT) Analysis Set: All participants who were randomized.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ENTO | Number of Participant With Complete Response (CR) After 2 Cycles of Chemotherapy | 5 Participants |
| Placebo | Number of Participant With Complete Response (CR) After 2 Cycles of Chemotherapy | 5 Participants |
Secondary
Overall Survival (OS)
OS is defined as the time from randomization until death from any cause.
Time frame: Cycle 1 Day 1, up to Day 42 of chemotherapy cycle 2 (Cycle length = 42 days)
Population: Data not collected as the study was terminated early.
Secondary
Relapse-free Survival (RFS)
RFS is defined as the time from CR until relapse or death from any cause as assessed by study site investigators.
Time frame: Cycle 1 Day 1, up to Day 42 of chemotherapy cycle 2 (Cycle length = 42 days)
Population: Data not collected as the study was terminated early.