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JOURNAL ONKOLOGIE – STUDIE

Venetoclax in Children With Relapsed Acute Myeloid Leukemia (AML)

Rekrutierend

NCT-Nummer:
NCT05183035

Studienbeginn:
Oktober 2022

Letztes Update:
25.03.2024

Wirkstoff:
Fludarabine, Cytarabine, Gemtuzumab Ozogamicin, azacitidine, Venetoclax

Indikation (Clinical Trials):
Leukemia, Leukemia, Myeloid, Leukemia, Myeloid, Acute

Geschlecht:
Alle

Altersgruppe:
Alle

Phase:
Phase 3

Sponsor:
LLS PedAL Initiative, LLC

Collaborator:
Princess Maxima Center for Pediatric Oncology (European Sponsor), AbbVie, Roche-Genentech, EuPAL,

Studienleiter

Seth Karol, MD
Principal Investigator
St. Jude Children's Research Hospital
Marlous Bakker
Study Director
Princess Maxima Center for Pediatric Oncology

Kontakt

Studienlocations
(3 von 72)

Phoenix Children's Hospital
85016 Phoenix
United StatesRekrutierend» Google-Maps
Arkansas Children's Hospital
72202 Little Rock
United StatesRekrutierend» Google-Maps
MemorialCare Miller Children's and Women's Hospital Long Beach
90806 Long Beach
United StatesRekrutierend» Google-Maps
Children's Hospital of Orange County Main Campus - Orange
92868 Orange
United StatesRekrutierend» Google-Maps
Benioff Children's Hospital - Mission Bay
94158 San Francisco
United StatesRekrutierend» Google-Maps
Children's Hospital Colorado
80045 Aurora
United StatesRekrutierend» Google-Maps
Nemours Alfred I. Dupont Hospital for Children
19803 Wilmington
United StatesRekrutierend» Google-Maps
Golisano Children's Hospital of Southwest Florida
33908 Fort Myers
United StatesRekrutierend» Google-Maps
Nemours Children's Specialty Care Jacksonville
32207 Jacksonville
United StatesRekrutierend» Google-Maps
Nemours Children's Hospital - Orlando
32827 Orlando
United StatesRekrutierend» Google-Maps
Saint Joseph's Hospital - Tampa
33607 Tampa
United StatesRekrutierend» Google-Maps
Children's Healthcare of Atlanta
30322 Atlanta
United StatesRekrutierend» Google-Maps
Kapi'olani Medical Center for Women and Children
96826 Honolulu
United StatesRekrutierend» Google-Maps
Ann & Robert H. Lurie Children's Hospital of Chicago
60611 Chicago
United StatesRekrutierend» Google-Maps
Comer Children's Hospital
60637 Chicago
United StatesRekrutierend» Google-Maps
University of Iowa Stead Family Children's Hospital
52242 Iowa City
United StatesRekrutierend» Google-Maps
Norton Children's Hospital
40202 Louisville
United StatesRekrutierend» Google-Maps
Dana-Farber Cancer Institute
02215 Boston
United StatesRekrutierend» Google-Maps
Children's Hospital of Michigan
48201 Detroit
United StatesRekrutierend» Google-Maps
Masonic Cancer Center
55455 Minneapolis
United StatesRekrutierend» Google-Maps
University of Mississippi Medical Center
39216 Jackson
United StatesRekrutierend» Google-Maps
The Children's Mercy Hospital - Adele Hall Campus
64108 Kansas City
United StatesRekrutierend» Google-Maps
Washington University School of Medicine in St. Louis
63110 Saint Louis
United StatesRekrutierend» Google-Maps
Alliance for Childhood Diseases dba Cure 4 The Kids Foundation
89135 Las Vegas
United StatesRekrutierend» Google-Maps
Morristown Medical Center
07960 Morristown
United StatesRekrutierend» Google-Maps
Columbia University Irving Medical Center
10032 New York
United StatesRekrutierend» Google-Maps
Memorial Sloan Kettering Cancer Center - New York
10065 New York
United StatesRekrutierend» Google-Maps
Cohen Children's Medical Center
11040 Queens
United StatesRekrutierend» Google-Maps
Nationwide Children's Hospital
43205 Columbus
United StatesRekrutierend» Google-Maps
Doernbecher Children's Hospital
97239 Portland
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Children's Hospital of Philadelphia
19104 Philadelphia
United StatesRekrutierend» Google-Maps
Prisma Health Richland Hospital
29203 Columbia
United StatesRekrutierend» Google-Maps
St. Jude Children's Research Hospital
38105-3678 Memphis
United StatesRekrutierend» Google-Maps
Monroe Carell Jr. Children's Hospital at Vanderbilt
37232 Nashville
United StatesRekrutierend» Google-Maps
Harold C. Simmons Comprehensive Cancer Center
75235 Dallas
United StatesRekrutierend» Google-Maps
Texas Children's Hospital
77030 Houston
United StatesRekrutierend» Google-Maps
Primary Children's Hospital
84113 Salt Lake City
United StatesRekrutierend» Google-Maps
Seattle Children's Hospital
98105 Seattle
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Children's Health Queensland Hospital and Health Service
4101 South Brisbane
AustraliaRekrutierend» Google-Maps
The Royal Children's Hospital - Children's Cancer Centre
3052 Parkville
AustraliaRekrutierend» Google-Maps
Alberta Children's Hospital
T3B 6A8 Calgary
CanadaRekrutierend» Google-Maps
British Columbia Children's Hospital
V6H 3N1 Vancouver
CanadaRekrutierend» Google-Maps
Izaak Walton Killam (IWK) Health Center
B3K 6R8 Halifax
CanadaRekrutierend» Google-Maps
Children's Hospital of Eastern Ontario
K1H 8L1 Ottawa
CanadaRekrutierend» Google-Maps
SickKids - The Hospital for Sick Children
M5G 1X8 Toronto
CanadaRekrutierend» Google-Maps
Fakultni nemocnice v Motole
150 06 Praha 5
CzechiaRekrutierend» Google-Maps
CHU de Toulouse - Hôpital des Enfants
31059 Toulouse
FranceRekrutierend» Google-Maps
Hôpital Jeanne de Flandre
59120 Loos
FranceAktiv, nicht rekrutierend» Google-Maps
Hôpital Universitaire Robert-Debré
75019 Paris
FranceRekrutierend» Google-Maps
CHU de Nantes - Hôpital Femme-Enfant-Adolescent
44093 Nantes Cedex 1
FranceRekrutierend» Google-Maps
Institut d'Hématologie et d'Oncologie Pédiatrique
69008 Lyon
FranceRekrutierend» Google-Maps
Schneider Children's Medical Center of Israel
4920235 Petach Tikvah
IsraelRekrutierend» Google-Maps
Fondazione IRCCS San Gerardo dei Tintori
20900 Monza
ItalyRekrutierend» Google-Maps
Ospedale Pediatrico Bambino Gesù
00165 Roma
ItalyRekrutierend» Google-Maps
Prinses Maxima Centrum Kinderoncologie
3584 CS Utrecht
NetherlandsRekrutierend» Google-Maps
Starship Children's Hospital
1023 Grafton
New ZealandRekrutierend» Google-Maps
Instituto Portugues De Oncologia De Lisboa Francisco Gentil
1099-023 Lisbon
PortugalRekrutierend» Google-Maps
Hospital Universitari Vall d'Hebrón
08035 Barcelona
SpainRekrutierend» Google-Maps
Hospital Sant Joan de Déu Barcelona
08950 Barcelona
SpainRekrutierend» Google-Maps
Hospital Infantil Universitario Niño Jesús
28009 Madrid
SpainRekrutierend» Google-Maps
Hospital Universitario La Fe
46026 València
SpainRekrutierend» Google-Maps
Karolinska Universitetssjukhuset Solna
171 76 Stockholm
SwedenRekrutierend» Google-Maps
Universitaets - Kinderspital Zürich
8032 Zurich
SwitzerlandRekrutierend» Google-Maps
Alle anzeigen

Studien-Informationen

Detailed Description:

Relapse of AML is driven by chemotherapy resistant stem cells. One mechanism of

chemotherapeutic resistance in AML is the overexpression of the protein B-cell lymphoma 2

(BCL-2), an anti-apoptotic protein which sequesters intracellular activators of apoptosis.

Venetoclax is a selective, potent, orally bioavailable, small molecule inhibitor of B-cell

lymphoma (BCL)-2 that restores programmed cell death in cancer cells.

This is a trial for children, adolescents and young adults with 2nd relapsed AML or 1st

relapsed AML unable to receive additional anthracycline.

This is randomized trial of venetoclax in combination with intensive chemotherapy

(fludarabine/cytarabine/gemtuzumab ozogamicin) for the first two cycles that would inform and

evaluate if this agent is an effective option for this population to improve its poor

prognosis. Participants can receive up to two cycles of induction chemotherapy before

hematopoietic stem cell transplantation (HSCT). Participants benefiting from treatment and

who are not able to proceed to HSCT have the possibility to continue to receive azacitidine

in monotherapy (Arm A, control arm) or in combination with venetoclax (Arm B, experimental

arm).

Ein-/Ausschlusskriterien

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.

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.

Studien-Rationale

Primary outcome:

1. Overall Survival (OS) (Time Frame - Up to 5 years)



Secondary outcome:

1. Morphology Event Free Survival (EFS) (Time Frame - Up to 5 years)

2. Flow-based Event Free Survival (EFS) (Time Frame - Up to 5 years)

3. Morphological Overall Response Rate (ORR) (Time Frame - Up to Day 84)

4. Flow-based Overall Response Rate (ORR) (Time Frame - Up to Day 84)

5. Duration of Response (DOR) (Time Frame - Up to 5 years)

6. Cumulative Incidence of Relapse (CIR) (Time Frame - Up to 5 years)

7. Number of Participants with Non-relapse Mortality (NRM) (Time Frame - Up to 5 years)

8. Hematopoietic Stem Cell Transplantation (HSCT) Rate (Time Frame - Up to 5 years)

9. Number of Participants with Adverse Events (AEs) (Time Frame - Up to 5 years)

10. Maximum Observed Plasma Concentration (Cmax) of Venetoclax (Time Frame - 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)

11. Time to Maximum Observed Plasma Concentration (Tmax) of Venetoclax (Time Frame - 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)

12. Area Under the Plasma Concentration-time Curve Over a 24-hour Dose Interval (AUC0-24) (Time Frame - 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)

13. Participants That Are Minimal Residual Disease (MRD) Negative with Complete Remission (CR), Partial Complete Remission (CRp), or Complete Remission with Incomplete Hematologic Recovery (CRi) (Time Frame - Up to 5 years)

Studien-Arme

  • 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.

Geprüfte Regime

  • Fludarabine:
    Intravenous (IV) infusion
  • Cytarabine:
    Intravenous (IV) infusion
  • Gemtuzumab Ozogamicin:
    Intravenous (IV) infusion
  • Azacitidine:
    Intravenous (IV) infusion or subcutaneous injection
  • Venetoclax:
    Orally via tablet or powder suspension

Quelle: ClinicalTrials.gov


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