Trial Title:
Dose Escalation and Expansion Study to Evaluate the Safety, PK, PD and Efficacy of ZE46-0134 in Adults With FLT3 Mutated Relapsed or Refractory Acute Myeloid Leukemia
NCT ID:
NCT06366789
Condition:
AML With Gene Mutations
Conditions: Official terms:
Leukemia, Myeloid, Acute
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Not yet recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Sequential Assignment
Intervention model description:
dose escalation and dose optimization study
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
ZE46-0134
Description:
oral capsules QD
Arm group label:
ZE46-0134 Dose Level -1
Arm group label:
ZE46-0134 Dose Level 1
Arm group label:
ZE46-0134 Dose Level 2
Arm group label:
ZE46-0134 Dose Level 3
Arm group label:
ZE46-0134 Dose Level 4
Arm group label:
ZE46-0134 Dose Level 5
Arm group label:
ZE46-0134 Selected dose 1
Arm group label:
ZE46-0134 Selected dose 2
Summary:
This is a clinical study aiming to assess pharmacokinetics, pharmacodynamics and
preliminary efficacy of ZE46-0134 in patients with FLT3 mutated Relapsed or Refractory
Acute Myeloid Leukemia
Detailed description:
This is a Phase 1, open-label, multicenter, dose escalation, and dose optimization study
to evaluate the safety, tolerability, PK, PD, and preliminary efficacy of ZE46-0134 in
adult patients with relapsed or refractory AML with FLT3-ITD and/or FLT3-TKD mutations.
Patients with AML that are out-patients or hospitalized due to their AML can be enrolled
in the study..
The study will be run in 2 parts: Part 1 will be dose escalation and determination of
MTD, and Part 2 will be dose expansion.
In Part 1 of the study 3 to 6 eligible patients will be sequentially enrolled into each
of 5 planned dose level cohorts. Patients will receive up to 24 cycles (28 days each) of
study treatment. For patients that continued to derive benefit after 24 cycles of
treatment, continuation of ZE46-0134 therapy will be considered.
In Part 2, the dose expansion phase will involve enrolling up to 30 patients across 2
dose cohorts (i.e., 15 patients per cohort). ZE46-0134 will be dosed as described for
Part 1 of the study. The doses used in Part 2 of the study will be determined based on
the data from Part 1 of the study.
Indication background information:
Acute myeloid leukemia (AML) comprises a heterogeneous group of aggressive blood cell
cancers that arise from clonal expansion of malignant hematopoietic precursor cells in
the bone marrow (BM) and is the most commonly diagnosed adult leukemia with a median age
at diagnosis is 68 years, with an overall survival (OS) rate of 29.8%. As patients age,
there is a 10% decrease in 5-year OS for every additional decade of life, with a 5-year
OS of 0.4% in patients age >85 years1. Furthermore, remission rates and OS depend on a
number of other factors, including cytogenetics, previous BM disorders, and
comorbidities.
FMS-like tyrosine kinase-3 (FLT3) is a receptor tyrosine kinase (RTK) primarily expressed
on immature hematopoietic progenitors and hematopoietic stem cells. FLT3 signaling is
initiated when FLT3 ligand binds to FLT3, inducing the dimerization and activation of
FLT3 via autophosphorylation. This then activates downstream signaling of
phosphoinositide 3-kinase/protein kinase B (PI3K/PKB), mitogen-activated protein kinase
(MAPK), and JAK2/STAT5 which leads to cell proliferation and suppression of apoptosis2.
FLT3 kinase is directly implicated in the pathogenesis of hematologic malignancies,
particularly AML. FLT3 mutations are the most frequently identified mutations in AML
patients. Activating mutations in FLT3, which are FLT3-internal tandom duplication (ITD)
and FLT3 tyrosine kinase domain (TKD) mutations, account for 30% of all AML cases2. As a
result of these mutations, the FLT3 receptor is continuously activated leading to the
continuous activation of downstream signaling pathways, PI3K/AKT, MAPK, and signal
transducer and activator of transcription (STAT5), resulting in increased cell
proliferation and decreased apoptosis.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
-
1. Written Informed Consent must be obtained from the patient or legally
authorized representative prior to any study-related procedures (including
withdrawal of prohibited medication, if applicable).
2. Patient is ≥18 years of age at the time of obtaining informed consent. 3.
Patient is refractory to or relapsed after first-line AML therapy (with or
without HSCT).
4. Patient must have a confirmed FLT3 ITD, TKD or ITD-F691L mutation documented
within the past 90 days in absence of therapy or within the Screening period 28
days) prior to study drug administration on C1D1 if therapy has been given.
5. Patients must have previously been treated with Gilteritinib with failure to
stop disease progression, or not met the criteria for treatment with
Gilteritinib in the opinion of the Investigator, or chosen not to have
treatment with Gilteritinib for social reasons.
6. Patients have a life expectancy of at least 3 months in the opinion of the
Investigator.
7. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
8. Patient must meet the following criteria as indicated on the clinical
laboratory tests:
a. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 ×
upper limit of normal (ULN) b. Serum total bilirubin ≤1.5 × ULN unless due to
Gilbert's disease c. Estimated glomerular filtration (eGFR) rate of >50 mL/min as
calculated by the Modification of Diet in Renal Disease equation.
9. Female patients:
a. If of non-childbearing potential i.e., surgically sterilized (hysterectomy,
bilateral salpingectomy, bilateral oophorectomy) at least 6 weeks before the
Screening visit or postmenopausal (where postmenopausal is defined as no menses for
12 months without an alternative medical cause and a follicle-stimulating hormone
(FSH) level consistent with postmenopausal status, per local laboratory guidelines),
or b. If of childbearing potential, must: i. Have a negative serum pregnancy test at
the Screening visit and urine pregnancy test on admission to the clinic on Day-1.
ii. Agree not to attempt to become pregnant or donate ova from signing the consent form
until at least 45 days after the last dose of study drug.
iii. Agree to use adequate contraception (defined as use of a condom by the male partner
combined with use of a highly effective method of contraception from Screening until at
least 45 days after the last dose of study drug, if not exclusively in a same-sex
relationship or abstinent as a committed lifestyle).
10. Male patients and their female spouse/partners who are of childbearing potential
must agree to use highly effective contraception consisting of 2 forms of birth
control (at least 1of which must be a barrier method) starting at Screening and
continue throughout the study period and for 45 days after the final study drug
administration. Male patient must not donate sperm starting at Screening and
throughout the study period and for 45 days after the final study drug
administration.
Exclusion Criteria:
1. Written Informed Consent must be obtained from the patient or legally authorized
representative prior to any study-related procedures (including withdrawal of
prohibited medication, if applicable).
2. Patient is ≥18 years of age at the time of obtaining informed consent.
3. Patient is refractory to or relapsed after first-line AML therapy (with or without
HSCT).
4. Patient must have a confirmed FLT3 ITD, TKD or ITD-F691L mutation documented within
the past 90 days in absence of therapy or within the Screening period 28 days) prior
to study drug administration on C1D1 if therapy has been given.
5. Patients must have previously been treated with Gilteritinib with failure to stop
disease progression, or not met the criteria for treatment with Gilteritinib in the
opinion of the Investigator, or chosen not to have treatment with Gilteritinib for
social reasons.
6. Patients have a life expectancy of at least 3 months in the opinion of the
Investigator.
7. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
8. Patient must meet the following criteria as indicated on the clinical laboratory
tests:
1. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5
× upper limit of normal (ULN)
2. Serum total bilirubin ≤1.5 × ULN unless due to Gilbert's disease
3. Estimated glomerular filtration (eGFR) rate of >50 mL/min as calculated by the
Modification of Diet in Renal Disease equation.
9. Female patients:
1. If of non-childbearing potential i.e., surgically sterilized (hysterectomy,
bilateral salpingectomy, bilateral oophorectomy) at least 6 weeks before the
Screening visit or postmenopausal (where postmenopausal is defined as no menses
for 12 months without an alternative medical cause and a follicle-stimulating
hormone (FSH) level consistent with postmenopausal status, per local laboratory
guidelines), or
2. If of childbearing potential, must:
i. Have a negative serum pregnancy test at the Screening visit and urine pregnancy
test on admission to the clinic on Day-1.
ii. Agree not to attempt to become pregnant or donate ova from signing the consent
form until at least 45 days after the last dose of study drug.
iii. Agree to use adequate contraception (defined as use of a condom by the male
partner combined with use of a highly effective method of contraception from
Screening until at least 45 days after the last dose of study drug, if not
exclusively in a same-sex relationship or abstinent as a committed lifestyle).
10. Male patients and their female spouse/partners who are of childbearing potential
must agree to use highly effective contraception consisting of 2 forms of birth
control (at least 1of which must be a barrier method) starting at Screening and
continue throughout the study period and for 45 days after the final study drug
administration. Male patient must not donate sperm starting at Screening and
throughout the study period and for 45 days after the final study drug
administration.
Exclusion criteria
1. Diagnosis of isolated myeloid sarcoma (meaning, patients must have blood or marrow
involvement with AML)
2. Acute promyelocytic leukemia (FAB M3)
3. Active central nervous system (CNS) involvement by AML
4. Clinical signs/symptoms of leukostasis requiring urgent therapy
5. Known active infection with Human Immunodeficiency Virus (HIV), hepatitis B or
hepatitis C. Patients with a history of positive serology for hepatitis B or C
require a negative Polymerase chain reaction (PCR) test for virus to go onto therapy
6. Disseminated intravascular coagulopathy with active, unmanageable bleeding or signs
of thrombosis.
7. Patients who have received an investigational agent (for any indication) within 5
half-lives of the agent; if the half-life of the agent is unknown, patients must
wait 1 week prior to first dose of study treatment. An investigational agent is one
for which there is no approved indication by the local regulatory authority.
8. Systemic antineoplastic therapy within 5 half-lives or radiation therapy within 1
week prior to starting protocol with the exception of hydroxyurea, which is allowed
to control white blood cell counts.
9. Female patients who are pregnant or lactating
10. Patients with psychological, familial, social, or geographic factors, other
significant medical condition, laboratory abnormality that otherwise preclude them
from giving informed consent, following the protocol, potentially hamper compliance
with study treatment and follow-up or would confound the interpretation of the
results of the study.
11. Patients with the following will be excluded: uncontrolled intercurrent illness
including, but not limited to, symptomatic congestive heart failure, unstable angina
pectoris, serious cardiac arrhythmia, myocardial infarction with evidence of
residual abnormalities within 6 months prior to enrollment (Troponin (regular or
high sensitivity) leak alone not included if no residual dysfunction), New York
Heart Association (NYHA) Class III or IV heart failure, severe uncontrolled
ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or
active conduction system abnormalities. Patients with medical comorbidities that
will preclude safety evaluation of the combination should not be enrolled.
12. Infection is a common feature of AML, patients with active infection are permitted
to enroll provided that the infection is under control in the opinion of the
Investigator. Patients with uncontrolled infection shall not be enrolled until
infection is treated and brought under control.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Linear Clinical Research Ltd
Address:
City:
Perth
Zip:
6009
Country:
Australia
Contact:
Last name:
Carolyn Grove, Prof
Start date:
April 2024
Completion date:
December 2027
Lead sponsor:
Agency:
Eilean Therapeutics
Agency class:
Industry
Source:
Eilean Therapeutics
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06366789
