NIPH Clinical Trials Search

A randomized phase 3 trial of fludarabine/cytarabine/gemtuzumab ozogamicin with or without venetoclax in children with relapsed AML

Basic Information

Recruitment status	Recruiting
Health condition(s) or Problem(s) studied	Acute myeloid leukemia
Date of first enrollment	27/02/2025
Target sample size	10
Countries of recruitment	Netherlands,Japan,Austria,Japan,Belgium,Japan,Czech Republic,Japan,Denmark,Japan,Finland,Japan,France,Japan,Germany,Japan,Ireland,Japan,Israel,Japan,Italy,Japan,Norway,Japan,Portugal,Japan,Spain,Japan,Sweden,Japan,Switzerland,Japan,United States,Japan,Canada,Japan,New Zealand,Japan,Australia,Japan
Study type	Interventional
Intervention(s)	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. 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.

Outcome(s)

Primary Outcome

Overall Survival

Secondary Outcome

(1)Morphology Event Free Survival (EFS) (2)Flow-based Event Free Survival (EFS) (3)Morphological Overall Response Rate (ORR) (4)Flow-based Overall Response Rate (ORR) (5)Duration of Response (DOR) (6)Cumulative Incidence of Relapse (CIR) (7)Disease-related mortality and Non-disease-related mortality (8)Hematopoietic Stem Cell Transplantation (HSCT) Rate (9)Number of Participants with Adverse Events (AEs) (10)Maximum Observed Plasma Concentration (Cmax) of Venetoclax (11)Time to Maximum Observed Plasma Concentration (Tmax) of Venetoclax (12)Area Under the Plasma Concentration-time Curve Over a 24-hour Dose Interval (AUC0-24) (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)

Key inclusion & exclusion criteria

Age minimum	> 4weeks old
Age maximum	< 22age old
Gender	Both
Include criteria	(1)Patients must be >28 days of age and < 22 years of age at enrolment. (2)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. And patients must have AML which is either: -Untreated second relapse, who are sufficiently fit to undergo another round of intensive chemotherapy,or -Untreated first relapse who per investigator discretion cannot tolerate additional anthracycline containing chemotherapy. (3)Patients must have a performance status corresponding to ECOG scores of 0, 1 or 2 ( >=50% Lansky or Karnofsky score). (4)Patients 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 to treatment. a.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. b.Intrathecal cytotoxic therapy: No wash-out time is required for patients having received any combination of intrathecal cytarabine, methotrexate, and/or hydrocortisone. c.Antibodies: >= 21 days must have elapsed from infusion of last dose of an antibody-drug conjugate prior to start of protocol treatment. For unmodified antibodies or T cell engaging antibodies, 2 half-lives must have elapsed prior to start of protocol treatment. Any toxicity related to prior antibody therapy must be recovered to Grade =< 1. d.Interleukins, Interferons and Cytokines (other than Hematopoietic Growth Factors): >= 21 days after the completion of interleukins, interferon or cytokines (other than Hematopoietic Growth Factors) prior to start of protocol treatment. e.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 prior to start of protocol treatment. f.Radiation therapy (RT) prior to 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 BM radiation. g.Stem Cell Infusions: ->= 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)) prior to start of protocol treatment. -No evidence of active graft versus host disease (GVHD). h.Patients 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. Patients 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 start of protocol treatment. i.Cellular Therapy: >= 42 days after the completion of DLI (donor lymphocyte infusion) or any type of cellular therapy (e.g., modified T cells, NK cells, dendritic cells, etc.) prior to start of protocol treatment. j.Patients with prior exposure to venetoclax are eligible in this trial (5)Adequate Renal Function Defined as: -Calculated eGFR (based on Schwartz formul) or radioisotope GFR >= 60ml/min/1.73 m2, OR -A serum creatinine based on age/sex. (6)Adequate Liver Function Defined as: -Total or direct (conjugated) bilirubin =< 1.5xULN, AND -Alkaline phosphatase =< 2.5xULN, AND -SGPT (ALT) =< 2.5xULN If higher transaminases outside these ranges (up to 5xULN) are due to a radiographically identifiable leukemia infiltrate, the patient will remain eligible. Transaminase elevation up to 5xULN is also allowed in case of steatosis on echography. (7)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 (8)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.
Exclude criteria	(1) Patients who in the opinion of the investigator, may not be able to comply with the study requirements of the study, are not eligible. (2) Patients with Down syndrome. (3) Patients with Acute promyelocytic leukemia (APL) or Juvenile myelomonocytic leukemia (JMML). (4) Patients with isolated CNS3 disease or symptomatic CNS3 disease. (5) Patients with malabsorption syndrome or any other condition that precludes enteral administration of venetoclax. (6) Patients who are currently receiving another investigational drug . (7) Patients with Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known congenital bone marrow failure syndrome. (8) Patients with known prior allergy to any of the medications used in protocol therapy. (9) Patients with documented active, uncontrolled infection at the time of study entry. (10) Known hepatitis C virus (HCV), hepatitis B virus (HBV) (known positive hepatitis B virus (HBV) surface antigen (HBsAg) results), or human immunodeficiency virus (HIV) infection. (11) 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. (12) 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. (13) 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. (14) Patients who are pregnant or breast-feeding. (15) 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 and 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. (16) 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. (17) Additional criteria to receive a Gemtuzumab ozogamicin infusion: Gemtuzumab ozogamicin should not be given: -to patients with history of veno-occlusive disease (VOD)/Sinusoidal obstruction syndrome (SOS) grade3 or4 -to patients with CD33 negative leukemic blasts Note that these patients are eligible for the study but will not be treated with Gemtuzumab ozogamicin.