This study has been transitioned to CTIS with ID 2024-514588-24-00 check the CTIS register for the current data. Core Primary Objectives:1. To investigate the safety and tolerability of EP0042 given alone or in combination with anti-cancer…
ID
Source
Brief title
Condition
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Module 1 Primary Endpoints:
1. Incidence of DLT, adverse events (AEs), serious adverse events (SAEs) and
changes in laboratory parameters, physical examination, vital signs and
electrocardiograms (ECGs).
Module 2 Primary Endpoints:
1. Incidence of DLTs, AEs, SAEs and changes in laboratory parameters, physical
examination, vital signs and electrocardiograms.
Secondary outcome
Module 1 Secondary Endpoints:
1. Plasma PK parameters (AUClast, AUCinf, Cmax and/or Cmin, Tmax, t1/2, CL/F,
V/F and/or Vz/F) after single and multiple doses
2. Best overall response (BOR)
3. Duration of response (DOR)
4. Overall survival (OS)
Module 2 Secondary Endpoints:
1. Plasma PK parameters (AUClast, AUCinf, Cmax and/or Cmin, Tmax, t1/2, CL/F,
V/F and/or Vz/F) of EP0042 and combination agents after single and multiple
doses.
2. BOR
3. DOR
4. Event free survival (EFS)
5. Relapse free survival (RFS)
6. OS
Background summary
Acute myeloid leukaemia (AML) is a blood cancer characterised by excessive
production of abnormal white blood cells called blasts, in the blood and bone
marrow. AML is a rare disease with one of the lowest survival rates and can
lead to death within weeks if left untreated. Chemotherapy can be used to treat
newly diagnosed AML, however most patients who achieve complete remission
relapse within 1-3 years.
The study medication, EP0042, has been developed to treat AML by combining the
activities of 2 established cancer treatment pathways called FLT3 inhibitor and
Aurora kinase inhibitor. The FLT3 gene is involved in production and survival
of leukaemia and other cancer cells. Aurora kinase is an enzyme involved in the
division and multiplication of cells in different tumours. Both types of
medicines have been given to patients with AML in other studies as separate
drugs, but this study will investigate the combination of the 2 cancer
treatments in 1 drug.
This is a first time in human study to test the effect of EP0042 alone and in
combination with anti-cancer treatments in patients with advanced cancer.
Study objective
This study has been transitioned to CTIS with ID 2024-514588-24-00 check the CTIS register for the current data.
Core Primary Objectives:
1. To investigate the safety and tolerability of EP0042 given alone or in
combination with anti-cancer treatments.
Module 1 Primary Objectives:
1. To investigate the safety and tolerability of EP0042 given as a monotherapy
in patients with relapsed or refractory (R/R) AML (AML, MDS or CMML).
Module 2 Primary Objectives:
1. Part A: To evaluate the safety, tolerability, of EP0042 + a Bcl-2 inhibitor
(venetoclax) in patients with R/R FLT3 wildtype (WT) AML.
2. Part B: To evaluate the safety, tolerability, of EP0042 in combination with
a Bcl-2 inhibitor (venetoclax) + a hypomethylating agent (azacitidine) in
patients with R/R FLT3 WT or newly diagnosed AML.
Core Secondary Objectives:
1. To characterizse the pharmacokinetics (PK) of EP0042, given alone or in
combination with anti-cancer treatments, after a single dose and at steady
state after multiple dosing.
2. To assess the biological and anti-tumor activity of EP0042, given alone or
in combination with anticancer treatments.
Module 1 Secondary Objectives:
1. To characterizse the (PK) of EP0042, given as a monotherapy, after a single
dose and at steady state after multiple dosing.
2. To assess the efficacy of EP0042, given as a monotherapy in patients with
relapsed or refractory AML (and MDS or CMML).
Module 2 Secondary Objectives:
1. To characterize the PK of EP0042 + combination agent(s), after a single dose
and at steady state after multiple dosing.
2. To assess the efficacy of EP0042 + combination agent(s) in patients with
AML.
Study design
Module 1, in patients with AML, will be performed initially and include
intensive safety monitoring to ensure the safety of study patients. Module 2
will explore the combination of EP0042 with other approved anti-cancer
treatments. Further modules may be added later as substantial protocol
amendments.
The EP0042 starting dose and schedule of EP0042 in Module 1 was selected using
the pre-clinical data and the Food and Drug Administration (FDA) and ICHS9
guidance for industry for selection of a starting dose in cancer patients. The
starting dose in subsequent modules will be determined by the Safety Monitoring
Committee (SMC) based on emerging clinical data. In each module, the frequency
of dosing and washout (off-treatment period) may change based upon emerging
data, as reviewed and agreed by the SMC, without the requirement to submit a
substantial amendment to the protocol. The frequency of PK sampling may also be
modified based on SMC review and may include up to three additional PK samples
of 4 ml within any given cycle, in order to better characterize the PK profile,
based upon emerging PK data. Only patients who provide written informed consent
and meet all inclusion and no exclusion criteria will be enrolled into the
respective study module.
Once the maximum tolerated dose (MTD) has been identified in Module 1,
recruitment of approximately 9-18 additional patients may be initiated in order
to obtain further safety and efficacy data for identification of the optimal
dose and schedule to take forward into Module 2.
In all treatment combinations (e.g. Module 2, EP0042 + venetoclax +
azacitidine) the dose of each approved standard of care combination agent will
not exceed its approved dose.
Intervention
This is a modular, Phase I/IIa study to investigate the optimal dose of EP0042
when used as monotherapy dose or in combination with other anti-cancer
treatments.
The design consists of a core study protocol and individual modules, as follows:
1. Module 1: EP0042 Monotherapy dosing in patients with relapsed/refractory
(R/R) acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML) or
myelodysplastic syndrome (MDS): dose escalation and dose optimization.
2. Module 2: EP0042 Combinations in R/R AML patients.
This protocol includes Modules 1 and 2. Additional modules may be added in the
future. Initiation of further modules will occur only following approval of a
substantial protocol amendment.
Study burden and risks
Risks, burdens and benefit:
Module 1 of the study is a first in human Phase I dose escalation study with
EP004, a dual FLT-3 and Aurora Kinase A/B inhibitor, in patients with AML.Both
FLT-3 and Aurora Kinase A/B inhibitors have individually shown levels of
clinical efficacy, with the dual combination, as EP0042,
demonstrating evidence of anti-tumour activity in both in vitro and in vivo
preclinical experiments. The safety profile of both Aurora kinase inhibitors
and various FLT-3 inhibitors have been well profiled in clinical trials. The
study design aims to minimize potential risks and is being conducted with
several parameters identified to maximize the benefit of and minimize the risks
to patients enrolled in the study. Measures taken to minimize the risks to
patients participating in the study include: a Cycle 0 for patients in cohort 1
(to determine the half-life of EP0042 after a single dose of EP0042, before
entering repeat dosing in Cycle 1, to assess and reduce the risk of
accumulation with appropriate dose/schedule adjustment), staggered dosing (7
days apart) of the first 2 patients in each cohort, regular monitoring of
peripheral blood counts, vital signs, ECGs, physical examinations, laboratory
safety tests and dose escalation adjustment pending safety signals.
There may be risks, discomforts and inconveniences associated with study
procedures. Participants will be required to visit the research site and
undergo tests and procedures more frequently than they would if they were not
in the study. This may be seen as a potential burden to the participant.
However, participants will be assured that these visits and procedures are very
important and are required to ensure their safety by close monitoring of their
health. Related study procedures will be performed by a qualified study nurse,
a doctor or phlebotomy trained health care professional within the hospital.
Some of the procedures that will be performed in the study are described below:
- Bone marrow aspirate samples are collected using a needle and syringe which
removes liquid bone marrow.
- Bone marrow trephine samples involve the collection of a 1 or 2 cm sample of
bone marrow (these are optional and will only be requested if a bone marrow
aspirate is not able to be obtained.')
- Blood draws for routine clinical haematology, biochemistry and biomarkers.
Informed Consent
All patients will be fully informed of all study assessments and what is
required of them to take part in the study, each patient will be asked to
complete a consent form in order to participate in the study.
Laboratory tests
Lab tests performed could be uncomfortable or painful but are necessary to
monitor the patient's health status.
The Investigator must ensure that all participants* confidentiality will be
maintained and that their identities are protected from unauthorized parties.
On eCRFs or other documents that are submitted to the sponsor, participants
should be identified by an identification code and not by their names. The
sponsor will control all data collected during the study, and will abide by the
General Data Protection Regulation (GDPR).
Receiving treatment could result in a positive AML / MDS / CMML disease
response but there is no guarantee that the patients will receive a direct
medical benefit by participating in this research study. However, it is hoped
that the information gathered as part of this research study may help those
with advanced cancers in the future.
Stratton Street 10
London W1J 8LG
NL
Stratton Street 10
London W1J 8LG
NL
Listed location countries
Age
Inclusion criteria
Core Inclusion Criteria:
1. Male or female patients aged >= 18 years of age, at the time of informed
consent, with histological or cytological confirmation of leukemia.
2. Ability to understand and provide written informed consent before any
study-specific procedures, sampling, or analyses, including access to archival
tumor tissue.
3. Ability to swallow and retain oral medication.
Exclusion criteria
Core Exclusion Criteria:
1. Suspected brain and/or leptomeningeal metastases that are symptomatic or
untreated or that require current therapy.
2. Ongoing toxic manifestations of previous treatments that have not reduced to
at least Common Terminology Criteria for Adverse Events (CTCAE) Grade 1.
Exceptions to this are alopecia or certain Grade 2 treatment related
toxicities, which in the opinion of the Investigator should not exclude the
patient.
3. Creatinine clearance (calculated using Cockcroft-Gault formula, or measured)
< 50 mL/min.
4. Receiving an investigational anti-cancer treatment concurrently or within 14
days or five half-lives of either the parent drug or any active metabolite
prior to the start of treatment with EP0042. Patients with AML may receive
hydroxyurea throughout the screening period and during the first 2 cycles of
study treatment in the first module (FIH study).
5. Current refractory nausea and vomiting, malabsorption syndrome, disease
significantly affecting gastrointestinal (GI) function, resection of the
stomach, extensive small bowel resection that is likely to affect absorption,
symptomatic inflammatory bowel disease, partial or complete bowel obstruction,
or gastric restrictions and bariatric surgery such as gastric bypass.
6. Known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection
per institutional protocol. Testing for HBV or HCV status is not necessary
unless clinically indicated or the patient has a history of HBV or HCV
infection.
7. Patients with active human immunodeficiency virus infection (HIV) infection
(testing is not required). Patients living with HIV will be eligible if they
have CD4+ T-cell count >= 350 cells/µL, no history of AIDS-defining
opportunistic infections in the past 12 months, and can be managed on a regimen
consistent with this protocol's permitted concomitant medications.
8. Malignant disease other than that being treated in this study, with the
following exceptions:
a. Malignancies that were treated curatively and have not recurred within 2
years prior to study treatment.
b. Completely resected basal cell and squamous cell skin cancers.
c. Any malignancy considered to be indolent and that has never required therapy.
d. Completely resected carcinoma in situ of any type.
9. Any medical condition that would, in the investigator's judgment, prevent
the patient's participation in the clinical study due to safety concerns,
compliance with clinical study procedures, or interpretation of study results.
10. Any major surgical procedure (in the investigator's judgement) within 2
weeks of the first dose of study drug.
11. Pregnant, likely to become pregnant, or lactating women (where pregnancy is
defined as the state of a female after conception and until the termination of
gestation).
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-514588-24-00 |
| EudraCT | EUCTR2020-000168-53-NL |
| ClinicalTrials.gov | NCT04581512 |
| CCMO | NL74204.078.20 |