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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT05183035
Registration number
NCT05183035
Ethics application status
Date submitted
21/12/2021
Date registered
10/01/2022
Date last updated
3/06/2024
Titles & IDs
Public title
Venetoclax in Children With Relapsed Acute Myeloid Leukemia (AML)
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Scientific title
A Randomized Phase 3 Trial of Fludarabine/Cytarabine/Gemtuzumab Ozogamicin With or Without Venetoclax in Children With Relapsed AML
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Secondary ID [1]
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2021-003212-11
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Secondary ID [2]
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ITCC-101/APAL2020D
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Acute Myeloid Leukemia
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Condition category
Condition code
Cancer
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Leukaemia - Acute leukaemia
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Cancer
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Leukaemia - Chronic leukaemia
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Cancer
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Children's - Leukaemia & Lymphoma
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - Fludarabine
Treatment: Drugs - Cytarabine
Treatment: Drugs - Gemtuzumab Ozogamicin
Treatment: Drugs - Azacitidine
Treatment: Drugs - Venetoclax
Active Comparator: Arm A: Control Arm without Venetoclax - During cycle 1 (each cycle is 42 days), participants will receive 30 mg/m^2 of fludarabine followed by 2 g/m^2 of cytarabine on Days 1-5. Gemtuzumab 3 mg/m^2 will be given on Day 6 (only for participants with CD33 expression on leukemia blasts).
During cycle 2 participants will receive 30 mg/m^2 of fludarabine followed by 2 g/m^2 of cytarabine on Days 1-5.
After cycle 2 participants are assessed for hematopoietic stem cell transplantation (HSCT) or azacitidine maintenance therapy.
Experimental: Arm B: Experimental Arm with Venetoclax - During cycle 1 (each cycle is 42 days), participants will receive 300 mg adult dose equivalent of venetoclax once on Day 1 followed by 600 mg adult dose equivalent of venetoclax on Days 2-21. Participants will also receive 30 mg/m^2 of fludarabine followed by 2 g/m^2 of cytarabine on Days 8-12. Gemtuzumab 3 mg/m^2 will be given on Day 13 (only for participants with CD33 expression on leukemia blasts).
During cycle 2, participants will receive 600 mg adult dose equivalent of venetoclax on Days 1-21. Participants will receive 30 mg/m^2 of fludarabine followed by 2 g/m^2 of cytarabine on Days 1-5.
After cycle 2 participants are assessed for HSCT or azacitidine maintenance therapy in combination with venetoclax.
Treatment: Drugs: Fludarabine
Intravenous (IV) infusion
Treatment: Drugs: Cytarabine
Intravenous (IV) infusion
Treatment: Drugs: Gemtuzumab Ozogamicin
Intravenous (IV) infusion
Treatment: Drugs: Azacitidine
Intravenous (IV) infusion or subcutaneous injection
Treatment: Drugs: Venetoclax
Orally via tablet or powder suspension
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Overall Survival (OS)
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Assessment method [1]
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Timepoint [1]
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Up to 5 years
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Secondary outcome [1]
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Morphology Event Free Survival (EFS)
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Assessment method [1]
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Timepoint [1]
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Up to 5 years
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Secondary outcome [2]
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Flow-based Event Free Survival (EFS)
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Assessment method [2]
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Timepoint [2]
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Up to 5 years
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Secondary outcome [3]
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Morphological Overall Response Rate (ORR)
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Assessment method [3]
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Timepoint [3]
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Up to Day 84
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Secondary outcome [4]
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Flow-based Overall Response Rate (ORR)
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Assessment method [4]
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Timepoint [4]
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Up to Day 84
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Secondary outcome [5]
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Duration of Response (DOR)
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Assessment method [5]
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Timepoint [5]
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Up to 5 years
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Secondary outcome [6]
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Cumulative Incidence of Relapse (CIR)
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Assessment method [6]
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Timepoint [6]
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Up to 5 years
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Secondary outcome [7]
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Number of Participants with Non-relapse Mortality (NRM)
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Assessment method [7]
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Timepoint [7]
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Up to 5 years
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Secondary outcome [8]
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Hematopoietic Stem Cell Transplantation (HSCT) Rate
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Assessment method [8]
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Timepoint [8]
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Up to 5 years
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Secondary outcome [9]
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Number of Participants with Adverse Events (AEs)
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Assessment method [9]
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Timepoint [9]
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Up to 5 years
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Secondary outcome [10]
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Maximum Observed Plasma Concentration (Cmax) of Venetoclax
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Assessment method [10]
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Timepoint [10]
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Pre-dose, 2, 4, 6, 8, and 24 hours post-dose on Cycle 1 Day 8 and Day 13 (cycle is 42 days); once on follow-up visits of Cycle 2 between Day 5 and Day 21
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Secondary outcome [11]
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Time to Maximum Observed Plasma Concentration (Tmax) of Venetoclax
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Assessment method [11]
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Timepoint [11]
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Pre-dose, 2, 4, 6, 8, and 24 hours post-dose on Cycle 1 Day 8 and Day 13 (cycle is 42 days); once on follow-up visits of Cycle 2 between Day 5 and Day 21
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Secondary outcome [12]
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Area Under the Plasma Concentration-time Curve Over a 24-hour Dose Interval (AUC0-24)
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Assessment method [12]
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Timepoint [12]
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Pre-dose, 2, 4, 6, 8, and 24 hours post-dose on Cycle 1 Day 8 and Day 13 (cycle is 42 days); once on follow-up visits of Cycle 2 between Day 5 and Day 21
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Secondary outcome [13]
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Participants That Are Minimal Residual Disease (MRD) Negative with Complete Remission (CR), Partial Complete Remission (CRp), or Complete Remission with Incomplete Hematologic Recovery (CRi)
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Assessment method [13]
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Timepoint [13]
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Up to 5 years
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Eligibility
Key inclusion criteria
Inclusion Criteria
- Participants must have enrolled on APAL2020SC, NCT Number: NCT04726241 prior to
enrollment on ITCC-101/APAL2020D. (This is only applicable for participants in
USA/Canada/Australia/New Zealand sites/LLS territory).
- Participants must be = 29 days of age and = 21 years of age at enrollment.
- Participants must have one of the following:
- Children, adolescents, and young adults with acute myeloid leukemia without
FLT3/internal tandem duplication (ITD) mutation in:
1. Second relapse, who are sufficiently fit to undergo another round of
intensive chemotherapy
2. First relapse who per investigator discretion cannot tolerate additional
anthracycline containing chemotherapy.
- Participants must have a performance status corresponding to Eastern Cooperative
Oncology Group (ECOG) scores of 0, 1 or 2 (= 50% Lansky or Karnofsky score)
- Participants must have fully recovered from the acute toxic effects of all prior
anti-cancer therapy and must meet the following minimum duration from prior
anti-cancer directed therapy prior to start of protocol treatment:
1. 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 that can be given up to 24 hours prior to start of
protocol treatment.
2. Intrathecal cytotoxic therapy: No wash-out time is required for participants
having received any combination of intrathecal cytarabine, methotrexate, and/or
hydrocortisone.
3. Antibodies: = 21 days must have elapsed from infusion of last dose of an
antibody-drug conjugate before start of protocol treatment. For unmodified
antibodies or T cell engaging antibodies, 2 half-lives must have elapsed before
start of protocol treatment. Any toxicity related to prior antibody therapy must
be recovered to Grade = 1.
4. Interleukins, Interferons and Cytokines (other than Hematopoietic Growth
Factors): = 21 days after the completion of interleukins, interferon or cytokines
(other than Hematopoietic Growth Factors) before start of protocol treatment.
5. Hematopoietic growth factors: = 14 days after the last dose of a long-acting
growth factor (e.g., pegfilgrastim) or =7 days for short-acting growth factor
before start of protocol treatment.
6. Radiation therapy (RT) (before start of protocol treatment):
- = 14 days have elapsed for local palliative RT (small port);
- = 84 days must have elapsed if prior craniospinal RT or if = 50% radiation
of pelvis;
- = 42 days must have elapsed if other substantial bone marrow (BM) radiation.
7. Stem Cell Infusions (before start of protocol treatment):
- = 84 days since allogeneic (non-autologous) bone marrow or stem cell
transplant (with or without total body irradiation [TBI]) or boost infusion
(any stem cell product; not including donor lymphocyte infusion [DLI])
- No evidence of active graft versus host disease (GVHD).
8. Participants who are receiving cyclosporine, tacrolimus or other agents to treat
or prevent either graft-versus-host disease post bone marrow transplant or organ
rejection post-transplant are not eligible for this trial. Participants must be
off medications to treat or prevent either graft-versus-host disease post bone
marrow transplant or organ rejection post-transplant for at least 14 days prior
to enrollment.
9. Cellular Therapy: = 42 days after the completion of donor lymphocyte infusion
(DLI) or any type of cellular therapy (e.g., modified T cells, natural killer
[NK] cells, dendritic cells, etc.) before start of protocol treatment.
10. Participants with prior exposure to venetoclax are eligible in this trial
- Adequate organ function:
1. Adequate Renal Function defined as:
- Creatinine clearance or radioisotope glomerular filtration rate (GFR) =
60ml/min/1.73 m^2, or
- Normal serum creatinine based on age/sex
2. Adequate Liver Function defined as:
- Direct bilirubin < 1.5 x upper limit of normal (ULN), and
- Alkaline phosphatase = 2.5 x ULN, and
- Serum glutamic pyruvic transaminase (SGPT) alanine aminotransferase (ALT) =
2.5 x ULN. If liver abnormality is due to radiographically identifiable
leukemia infiltrate, the participant will remain eligible.
3. 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
(shortening fraction [SF] < 25% or ejection fraction [EF] < 40%)
- No signs of congestive heart failure at presentation of relapse.
- Participant, parent or 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.
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Minimum age
29
Days
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Maximum age
21
Years
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
Exclusion Criteria
- Participants who in the opinion of the investigator may not be able to comply with the
study requirements of the study, are not eligible.
- Participants with Down syndrome.
- Participants with Acute promyelocytic leukemia (APL) or Juvenile myelomonocytic
leukemia (JMML).
- Participants with isolated CNS3 disease or symptomatic CNS3 disease.
- Participants with malabsorption syndrome or any other condition that precludes enteral
administration of venetoclax.
- Participants who are currently receiving another investigational drug (GO is not
considered investigational in this study).
- Participants with Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other
known congenital bone marrow failure syndrome.
- Participants with known prior allergy to any of the medications used in protocol
therapy.
- Participants with documented active, uncontrolled infection at the time of study
entry.
- No known human immunodeficiency virus (HIV) infection.
- Post menarchal female participants with positive pregnancy test.
- Concomitant Medications
- Participants 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 study treatment.
- Participants who have consumed grapefruit, grapefruit products, Seville oranges
(including marmalade containing Seville oranges) or starfruit within 3 days of
the start of study treatment.
- Participants who have hypersensitivity to the active substance or to any of the
excipients listed in summary of product characteristics (SPC).
- Pregnancy or Breast-Feeding:
- Participants who are pregnant or breast-feeding.
- Participants of reproductive potential may not participate unless they have
agreed to use a highly effective contraceptive method per clinical trials
facilitation group (CTFG) guidelines for the duration of study therapy and for 6
months after the completion of all study therapy.
- Male participants 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
for 4 months after the completion of all study therapy.
Additional criteria to receive a gemtuzumab ozogamicin infusion:
Gemtuzumab ozogamicin should not be given:
- to participants with history of veno-occlusive disease (VOD)/Sinusoidal obstruction
syndrome (SOS) grade 4
- to participants with history of VOD/SOS grade 3
- to participants with CD33 negative leukemic blasts (determined at local lab)
Note that these participants are eligible for the study but will not be treated with
gemtuzumab ozogamicin.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 3
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Recruiting
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
1/10/2022
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
1/02/2032
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Actual
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Sample size
Target
98
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Accrual to date
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Final
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Recruitment in Australia
Recruitment state(s)
QLD,VIC,WA
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Recruitment hospital [1]
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Children's Health Queensland Hospital and Health Service - South Brisbane
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Recruitment hospital [2]
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The Royal Children's Hospital - Children's Cancer Centre - Parkville
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Recruitment hospital [3]
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Perth Children's Hospital - Nedlands
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4101 - South Brisbane
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Recruitment postcode(s) [2]
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3052 - Parkville
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Recruitment postcode(s) [3]
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6009 - Nedlands
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Recruitment outside Australia
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Oslo
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Zurich
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Funding & Sponsors
Primary sponsor type
Other
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Name
LLS PedAL Initiative, LLC
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Address
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Other collaborator category [1]
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Other
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Name [1]
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Princess Maxima Center for Pediatric Oncology (European Sponsor)
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AbbVie
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Roche-Genentech
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Other
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EuPAL
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Ethics approval
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Summary
Brief summary
A study to evaluate if the randomized addition of venetoclax to a chemotherapy backbone
(fludarabine/cytarabine/gemtuzumab ozogamicin [GO]) improves survival of
children/adolescents/young adults with acute myeloid leukemia (AML) in 1st relapse who are
unable to receive additional anthracyclines, or in 2nd relapse.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT05183035
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Seth Karol, MD
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Address
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St. Jude Children's Research Hospital
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Email
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Contact person for public queries
Name
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Gwen Nichols, MD
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Address
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Phone
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914-821-8217
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Email
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[email protected]
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT05183035
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