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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT05183035




Registration number
NCT05183035
Ethics application status
Date submitted
21/12/2021
Date registered
10/01/2022

Titles & IDs
Public title
Venetoclax in Children With Relapsed Acute Myeloid Leukemia (AML)
Scientific title
A Randomized Phase 3 Trial of Fludarabine/Cytarabine/Gemtuzumab Ozogamicin With or Without Venetoclax in Children With Relapsed AML
Secondary ID [1] 0 0
2021-003212-11
Secondary ID [2] 0 0
ITCC-101/APAL2020D
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute Myeloid Leukemia 0 0
Condition category
Condition code
Cancer 0 0 0 0
Leukaemia - Acute leukaemia
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia
Cancer 0 0 0 0
Children's - Leukaemia & Lymphoma

Intervention/exposure
Study type
Interventional
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
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Overall Survival (OS)
Timepoint [1] 0 0
Up to 5 years
Secondary outcome [1] 0 0
Morphology Event Free Survival (EFS)
Timepoint [1] 0 0
Up to 5 years
Secondary outcome [2] 0 0
Flow-based Event Free Survival (EFS)
Timepoint [2] 0 0
Up to 5 years
Secondary outcome [3] 0 0
Morphological Overall Response Rate (ORR)
Timepoint [3] 0 0
Up to Day 84
Secondary outcome [4] 0 0
Flow-based Overall Response Rate (ORR)
Timepoint [4] 0 0
Up to Day 84
Secondary outcome [5] 0 0
Duration of Response (DOR)
Timepoint [5] 0 0
Up to 5 years
Secondary outcome [6] 0 0
Cumulative Incidence of Relapse (CIR)
Timepoint [6] 0 0
Up to 5 years
Secondary outcome [7] 0 0
Number of Participants with Non-relapse Mortality (NRM)
Timepoint [7] 0 0
Up to 5 years
Secondary outcome [8] 0 0
Hematopoietic Stem Cell Transplantation (HSCT) Rate
Timepoint [8] 0 0
Up to 5 years
Secondary outcome [9] 0 0
Number of Participants with Adverse Events (AEs)
Timepoint [9] 0 0
Up to 5 years
Secondary outcome [10] 0 0
Maximum Observed Plasma Concentration (Cmax) of Venetoclax
Timepoint [10] 0 0
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
Secondary outcome [11] 0 0
Time to Maximum Observed Plasma Concentration (Tmax) of Venetoclax
Timepoint [11] 0 0
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
Secondary outcome [12] 0 0
Area Under the Plasma Concentration-time Curve Over a 24-hour Dose Interval (AUC0-24)
Timepoint [12] 0 0
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
Secondary outcome [13] 0 0
Participants That Are Minimal Residual Disease (MRD) Negative with Complete Remission (CR), Partial Complete Remission (CRp), or Complete Remission with Incomplete Hematologic Recovery (CRi)
Timepoint [13] 0 0
Up to 5 years

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.
Minimum age
29 Days
Maximum age
21 Years
Sex
Both males and females
Can healthy volunteers participate?
No
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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
1/10/2022
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/02/2032
Actual
Sample size
Target
98
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD,VIC,WA
Recruitment hospital [1] 0 0
Children's Health Queensland Hospital and Health Service - South Brisbane
Recruitment hospital [2] 0 0
The Royal Children's Hospital - Children's Cancer Centre - Parkville
Recruitment hospital [3] 0 0
Perth Children's Hospital - Nedlands
Recruitment postcode(s) [1] 0 0
4101 - South Brisbane
Recruitment postcode(s) [2] 0 0
3052 - Parkville
Recruitment postcode(s) [3] 0 0
6009 - Nedlands
Recruitment outside Australia
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United States of America
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Arizona
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United States of America
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Arkansas
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California
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Colorado
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Connecticut
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Delaware
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Florida
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Georgia
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Hawaii
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Illinois
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Iowa
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Oregon
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Nova Scotia
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Ontario
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Prague
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France
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France
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France
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France
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Rhône
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Israel
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Genoa
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Monza And Brianza
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Rome
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Italy
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Turin
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Utrecht
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Auckland
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Oslo
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Portugal
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Barcelona
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Madrid
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València
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Sweden
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Stockholms Län
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Switzerland
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Zurich

Funding & Sponsors
Primary sponsor type
Other
Name
LLS PedAL Initiative, LLC
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
Princess Maxima Center for Pediatric Oncology (European Sponsor)
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Commercial sector/industry
Name [2] 0 0
AbbVie
Address [2] 0 0
Country [2] 0 0
Other collaborator category [3] 0 0
Commercial sector/industry
Name [3] 0 0
Roche-Genentech
Address [3] 0 0
Country [3] 0 0
Other collaborator category [4] 0 0
Other
Name [4] 0 0
EuPAL
Address [4] 0 0
Country [4] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Seth Karol, MD
Address 0 0
St. Jude Children's Research Hospital
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Gwen Nichols, MD
Address 0 0
Country 0 0
Phone 0 0
914-821-8217
Fax 0 0
Email 0 0
[email protected]
Contact person for scientific queries

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results not provided in https://clinicaltrials.gov/study/NCT05183035