This study has been transitioned to CTIS with ID 2023-510160-12-00 check the CTIS register for the current data. To assess if venetoclax combined with FLA+GO (fludarabine, high-dose cytarabine, and gemtuzumab ozogamicin) will improve overall…
ID
Source
Brief title
Condition
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint of the study is overall survival (OS). OS is defined as
time from randomization until death of any cause. Patients still alive at the
time of clinical cutoff date will be censored at their last known alive date.
Secondary outcome
Morphology and flow-based event-free survival (EFS): days from date of
randomization to the first event (subsequent relapse after ped-flow and
ped-morph CR, death of any cause, failure to achieve remission (ped-flow and
ped-morph CR, CRp or CRi) after 2 cycles of treatment, or secondary
malignancy). Patients who are event-free will be censored at date of last
adequate disease assessment. Pediatric flow and morphologic treatment failure
(defined by morphology and flow as not achieving remission after two cycles in
separate analyses) is calculated as an event at day 1.
Flow-based overall response rate (ORR)
Morphological ORR
Duration of response (DOR): Time from documentation of disease response
(ped-flow CR/CRp/CRri or ped-morph CR/CRp/CRi) to disease progression or death
of disease, whichever occurs earlier.
Cumulative incidence of relapse (CIR): Estimate of the risk that a patient will
develop a relapse during a specified period of time.
Non-relapse mortality (NRM): Death without recurrence or progression of disease
during treatment.
Hematopoietic stem cell transplantation (HSCT) rate: The rate of those
proceeding to subsequent hematopoietic stem cell transplantation as
consolidation therapy is calculated as the number of patients who receive a
hematopoietic stem cell infusion divided by the total number of patients
enrolled.
Safety
Pharmacokinetics (PK) of venetoclax in blood in combination with intensive
chemotherapy and GO.
Pediatric Minimal Residual Disease (Ped-MRD) negative ped-flow is defined as
patients obtaining ORR (CR/CRp/CRri: ) CR/CRp/CRi with no detectable residual
disease defines asand <0.1% leukemic blasts in a cellular BM by central flow
cytometry.
To compare the morphological International Working Group complete response
(IWG-CR) rate in patients receiving FLA+GO with and without venetoclax.
Background summary
Although the prognosis of children with acute myeloid leukemia (AML) has
improved over the last decades, with overall survival (OS) rates approaching
70% as a result of intensive frontline treatment, aggressive salvage therapy
following relapse and improvements in supportive care, outcome after relapse
remains poor. The 4-year probability of survival (pOS) of children with AML in
1st relapse is 38% and the recommended treatment approach for first relapse
includes an anthracycline-based re-induction followed by a second cycle of
chemotherapy and HSCT, based on the results of the iBFM AML 2001/01 using
FLAG-liposomal daunorubicin in 1st cycle, and FLAG in second cycle, followed by
allogenic transplantation. In the iBFM AML 2001/01 study, one-year OS of early
first relapse was 52% and late relapse of 66%. However, options for patients
unable to tolerate anthracyclines in first relapse are limited.
For patients beyond first relapse, limited data exist. The AML-BFM study group
reported that survival of children with AML in 2nd relapse was poor, with a
5-year pOS of approximately 15% and 31 following HSCT (n=25/73). Early second
relapse (within one year after first relapse) was associated with dismal
outcome (pOS 2%, n=44 vs. 33%, n=29; p<0.0001). There is no consensus on the
therapy recommended in the 2nd relapses of AML in children. Additional
therapeutic options for children in 2nd relapsed AML, and children in 1st
relapse unable to tolerate anthracycline, are needed.
Based on the promising results of the phase I/II VENAML trial shown below,
off-label use of venetoclax in children with relapsed AML in the United States
is more and more frequent. A randomized trial of venetoclax in combination with
intensive chemotherapy in children with 2nd relapsed AML and 1st relapsed AML
unable to receive additional anthracycline would inform and evaluate if this
agent is an effective option for this population to improve its poor prognosis.
Study objective
This study has been transitioned to CTIS with ID 2023-510160-12-00 check the CTIS register for the current data.
To assess if venetoclax combined with FLA+GO (fludarabine, high-dose
cytarabine, and gemtuzumab ozogamicin) will improve overall survival of
children with relapsed acute myeloid leukemia (AML) compared to FLA+GO .
Study design
This is an open-label phase 3 randomized multicenter international trial in
children with relapsed acute myeloid leukemia (AML), to assess if venetoclax
combined with FLA+GO (fludarabine, high-dose cytarabine, and gemtuzumab
ozogamicin) will improve overall survival compared to FLA+GO.
Intervention
This is an open-label randomized phase 3 study. Patients receiving venetoclax
will receive adult equivalent dosages, either based on age (less than 2 years)
or weight (2 years and older), unless dose reductions are required for toxicity
management. Patients will take venetoclax for 21 days in two cycles. In the
first cycle, a dose ramp-up is applied for venetoclax, and in
bridging/maintenance courses the venetoclax dose is adapted when used in
combination with azacitidine.
Venetoclax will be provided by AbbVie as 10 mg, 50 mg, and 100 mg tablets, and
3 mg, 10 mg, 25 mg, 100 mg and 600 mg powder sachets for oral suspension that
will be used to administer PO 300 mg adult equivalent dose on Cycle 1 Day 1 and
600 mg adult equivalent dose on subsequent days. Note that in maintenance a
lower dose of venetoclax is applied in combination with azacitidine, i.e., 400
mg adult equivalent dose.
A 2-day ramp-up is proposed in this study, based on the observed low rates of
TLS in both the M13-833 and VENAML studies, and the use of a 2-day ramp up in
the VENAML trial, in which the ramp up was well-tolerated. Additionally, the
shorter ramp up enables patients to benefit from the target dose of Venetoclax
more rapidly by minimizing the time during which AML can progress.
FLA/GO will be given at regular doses, therefore there is no undertreatment in
terms of chemotherapy, and Venetoclax may be added to this.
Study burden and risks
Participation in this trial can induce regular AML chemotherapy side effects,
including added side effects from venetoclax, including potentially unknown
side effects. Since there is no validated biomarker that can predict response,
we opted for a randomized study without applying a selection biomarker. Dosing
of venetoclax was tested and considered safe in a prior pediatric study in
combination with high-dose chemotherapy in a similar population of relapsed
pediatric AML patients.
Given the poor outcome of 2nd relapse patients and the improvements in stem
cell transplantation (with the option to provide for example a 2nd or even 3rd
HSCT where needed) it offers novel option for patients who desire treatment
with curative intent, who would otherwise probably be offered chemotherapy such
as FLA or FLA/GO as regular care. The study will assess whether venetoclax has
added value on top of background chemotherapy, and will be the largest second
relapse study performed to date, and hence will be an important point of
reference for future studies as well, in a similar fashion as the study AML
2001/01 by Kaspers et al in 1st relapse. Some patients may opt out or it may
not be feasible to offer them another round of intensive treatment due to
existing organ-toxicity, and such patients will be treated according to patient
and physician preference, including the possibility of palliative care or
*palliative chemotherapy* only.
Patients will undergo some additional tests as required per protocol, i.e.,
pregnancy tests (if applicable). Moreover patient and/or parents or legal
guardians will be asked to participate in ancillary studies, especially PK and
some PD studies. This will require additional blood sampling, which is
performed either through the available central line, already in place for all
patients, or via venipuncture only in case there is no available central line,
and only in the venetoclax arm. Given the intensity of AML treatment and the
requirement for regular transfusions the burden regarding the additional blood
volume is considered limited, and within keeping with EMA guidelines on blood
sampling volumes.
Most of the hospital stays and outpatient visits and monitoring of treatment
response are according to standard of care in this population and would also
have occurred outside this study. Nevertheless, investigators at the sites are
encouraged to perform the invasive procedures (e.g., bone marrow aspirate,
lumbar puncture, blood sampling, nasogatric tube insertion) in a way to
minimize the discomfort and pain to the patients.
In this study, next-generation sequencing (NGS) will be performed using bone
marrow samples to identify AML genetic variation. When there is suspicion of
germline variants this will be communicated to the treating physician, and
patients and/or parents or legal guardians(s) can decide if they want further
testing after consultation with a clinical geneticist.
Considering the SARS-CoV-2 or COVID-19 pandemic, the benefit and risk to
patients participating in this study has been considered. Based on the
population and disease being studied, it is anticipated that COVID-19 related
risks are not expected to differ substantially between study participants and
the broader population of pediatric patients receiving treatment for AML.
Therefore, no change to the benefit/risk balance for study participants in this
study is expected, section 1.4.3 of the protocol.
A stopping rule is included in the study, based on toxic mortality and the
incidence of grade 3-4 or higher targeted toxicities (e.g., renal failure,
hepatotoxicity). An external Data Safety Monitoring Board (DSMB) will be
installed for this study, consisting of an adult hematologist, a pediatric
oncologist and an independent statistician, to monitor safety.
Taken together, we feel that the benefit-risk ratio for patients participating
in this study is favorable for patients seeking treatment with a curative
approach.
Heidelberglaan 25
Utrecht 3584 CS
NL
Heidelberglaan 25
Utrecht 3584 CS
NL
Listed location countries
Age
Inclusion criteria
Patient must have the following:
a. Children, adolescents, and young adults with acute myeloid leukemia without
demonstrated FLT3/ITD mutation. Ideally, the status of the mutation needs to be
proven in the current relapse. Nevertheless, patients with previous FLT3/ITD
negative test from prior lines can be included based on local results in order
to not delay the start of treatment.
b. And patients must have AML which is either:
- untreated second relapse, in patients who are sufficiently fit to undergo
another round of intensive chemotherapy, or
- untreated first relapse, in patients who cannot tolerate additional
anthracycline containing chemotherapy per investigator discretion.
Patients must have a performance status corresponding to ECOG scores of 0, 1 or
2 (>= 50% Lansky or Karnofsky score)
Patients must have fully recovered from the acute toxic effects of all prior
anti-cancer therapy and must meet the minimum duration from prior anti-cancer
directed therapy prior to enrolment (more details in the
protocol).
Cytotoxic chemotherapy: Must not have received cytotoxic chemotherapy within 14
days prior to start of protocol treatment, except for corticosteroids, low dose
cytarabine or hydroxyurea (see below) that can be given up to 24 hours prior to
start of protocol treatment.
Antibodies: >= 21 days must have elapsed from infusion of last dose of an
antibody-drug conjugate prior to start of protocol treatment.
Interleukins, Interferons and Cytokines : >= 21 days after the completion of
interleukins, interferon or cytokines
Hematopoietic growth factors: >= 14 days after the last dose of a longacting
growth factor or >=7 days for short-acting growth factor prior to start of
protocol treatment.
Radiation therapy (RT): Between 14 and 84 days depeding on the extent of
radiation fields
Stem Cell Infusions: >= 84 days since allogeneic bone marrow or stem cell
transplant or boost infusion. No evidence of active graft versus host disease
Patients must be off medications to treat or prevent either graft-versushost
disease post bone marrow transplant or organ rejection posttransplant for at
least 14 days
Cellular Therapy: >= 42 days after the completion of any type of cellular Therapy
Adequate organ function.
a. Adequate Renal Function defined as:
• Calculated eGFR (based on Schwartz formula) or radioisotope GFR >=
60ml/min/1.73 m2, OR •A serum creatinine based on age/sex
b. Adequate Liver Function defined as:
•Total or direct (conjugated) bilirubin <= 1.5xULN, AND •Alkaline phosphatase <=
2.5xULN, AND
•SGPT (ALT) <= 2.5xULN oIf liver abnormality is due to radiographically
identifiable leukemia infiltrate, the patient will remain eligible.
c. Cardiac performance: Minimum cardiac function defined as:
•No history of congestive heart failure in need of medical treatment
•No pre-treatment diminished left ventricular function on echocardiography (FS
<25% or EF <40%)
•No signs of congestive heart failure at presentation of relapse.
Patient, parent or legal guardian must sign and date informed consent and
pediatric assent (when required), prior to the initiation of screening or study
specific procedures, according to local law and legislation
Exclusion criteria
D5a. In het Engels
1) General exclusion criteria
a. Patients who in the opinion of the investigator, may not be able to comply
with the study requirements of the study, are not eligible.
b. Patients with Down syndrome.
c. Patients with Acute promyelocytic leukemia (APL) or Juvenile myelomonocytic
leukemia (JMML).
d. Patients with isolated CNS3 disease or symptomatic CNS3 disease.
e. Patients with malabsorption syndrome or any other condition that precludes
enteral administration of venetoclax.
f. Patients who are currently receiving another investigational drug other than
those specified for this study (venetoclax and GO are considered
investigational in this study).
g. Patients with Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any
other known congenital bone marrow failure syndrome.
h. Patients with known prior allergy to any of the medications used in protocol
therapy.
i. Patients with documented active, uncontrolled infection at the time of study
entry.
j. Known hepatitis C virus (HCV), hepatitis B virus (HBV) (known positive
hepatitis B virus (HBV) surface antigen (HBsAg) result) or human
immunodeficiency virus (HIV) infection. Note: For the countries under EU CTR,
these tests are required at screening. For other countries, HCV, HBV, and HIV
testing does not need to be conducted at screening unless it is required per
local guidelines or local regulations.
2) Concomitant Medications
a. Patients who have received strong and moderate CYP3A inducers such as
rifampin, carbamazepine, phenytoin, and St. John*s wort within 7 days of the
start of protocol treatment.
b. Patients who have consumed grapefruit, grapefruit products, Seville oranges
(including marmalade containing Seville oranges) or starfruit within 3 days of
the start of protocol treatment.
c. Patients who are hypersensitive to the active substance or to any of the
excipients listed in the summary of products characteristics (SPC) or US
prescribing information per local label.
3) Pregnancy or Breast-Feeding:
a. Patients who are pregnant or breast-feeding.
b. Patients of reproductive potential may not participate unless they have
agreed to use a highly effective contraceptive method per Clinical Trial
Facilitation Group (CTFG) guidelines for the duration of study therapy at least
30 days after last dose of venetoclax, or 7 months after gemtuzumab ozogamicin
treatment, or for 6 months after the completion of all study therapy, whichever
is longer
c. Male patients must use a condom during intercourse and agree not to father a
child or donate sperm during therapy and for the duration of study therapy and
at least 30 days after last dose of venetoclax or 4 months after last dose of
gemtuzumab ozogamicin, 6 months from the last dose of cytarabine, or 90 days
after last exposure to any other chemotherapy, whichever is longer.
Gemtuzumab ozogamicin should not be given:
• to patients with history of veno-occlusive disease (VOD)/Sinusoidal
obstruction syndrome (SOS) grade 3 or 4
• to patients with CD33 negative leukemic blasts (determined at local lab)
These patients are eligible for the study but will not be treated with
gemtuzumab ozogamicin.
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 | CTIS2023-510160-12-00 |
| EudraCT | EUCTR2021-003212-11-NL |
| ClinicalTrials.gov | NCT05183035 |
| CCMO | NL79147.041.21 |