Clinical trial NCT05183035: Venetoclax in Children With Relapsed Acute Myeloid Leukemia (AML)
Official title: A Randomized Phase 3 Trial of Fludarabine/Cytarabine/Gemtuzumab Ozogamicin With or Without Venetoclax in Children With Relapsed AML
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Acute Myeloid Leukemia
Keywords: Venetoclax
Gemtuzumab Ozogamicin
Fludarabine
Cytarabine
Relapsed refractory
Azacitidine
Lead sponsor: LLS PedAL Initiative, LLC
Sponsor class: OTHER
Collaborators: name: Princess Maxima Center for Pediatric Oncology (European Sponsor)
name: AbbVie
name: Roche-Genentech
name: EuPAL
First posted: 2022-01-10
Enrollment: 98
Sex: ALL
Minimum age (years): 29
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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 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 (42-day-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). If participants who have perceived clinical benefit cannot be transplanted after the 2 cycles, maintenance treatment may be given at the discretion of the investigator. In Arm B (experimental arm), participants can continue venetoclax if they have perceived clinical benefit, and maintenance therapy will combine venetoclax with azacitidine for a maximum of 24 cycles. In Arm A (control arm), participants will receive azacitidine in monotherapy. Maintenance is continued until clinical progression or unacceptable toxicity with a maximum of 24 cycles.

Eligibility 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:

  1. Children, adolescents, and young adults with AML without demonstrated FLT3/internal tandem duplication (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.
  2. And participants must have AML which is either:

     * Untreated second relapse, in participants who are sufficiently fit to undergo another round of intensive chemotherapy, or
     * Untreated first relapse, in participants who cannot tolerate additional anthracycline containing chemotherapy per investigator discretion.
* 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 higher transaminases outside these ranges (up to 5x ULN) are due to a radiographically identifiable leukemia infiltrate, the participant will remain eligible. Transaminase elevation up to 5x ULN is also allowed in case of steatosis on echography.
  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 an investigational drug other than those specified for 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.
* 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.
* 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 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.
  * 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 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.

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 3 or 4
* 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.

Primary outcomes:
measure: Overall Survival (OS)
timeFrame: Up to 5 years
Secondary outcomes:
measure: Morphology Event Free Survival (EFS)
timeFrame: Up to 5 years
measure: Flow-based Event Free Survival (EFS)
timeFrame: Up to 5 years
measure: Flow-based Overall Response Rate (ORR)
timeFrame: Up to Day 84
measure: Morphological Overall Response Rate (ORR)
timeFrame: Up to Day 84
measure: Duration of Response (DOR)
timeFrame: Up to 5 years
measure: Cumulative Incidence of Relapse (CIR)
timeFrame: Up to 5 years
measure: Disease-related Mortality
timeFrame: Up to 5 years
measure: Non-disease-related Mortality
timeFrame: Up to 5 years
measure: Hematopoietic Stem Cell Transplantation (HSCT) Rate
timeFrame: Up to 5 years
measure: Number of Participants with Adverse Events (AEs)
timeFrame: Up to 5 years
measure: Maximum Observed Plasma Concentration (Cmax) of Venetoclax
timeFrame: 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
measure: Time to Maximum Observed Plasma Concentration (Tmax) of Venetoclax
timeFrame: 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
measure: Area Under the Plasma Concentration-time Curve Over a 24-hour Dose Interval (AUC0-24)
timeFrame: 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
measure: Number of Participants That Are Pediatric Minimal Residual Disease (Ped-MRD) Negative with Complete Remission (CR), Partial Complete Remission (CRp), or Complete Remission with Incomplete Hematologic Recovery (CRi)
timeFrame: Up to 5 years
measure: Number of Participants with International Working Group Complete Response (IWG-CR)
timeFrame: Up to 5 years
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Phoenix Children's Hospital
state: Arizona
city: Little Rock
country: United States
facility: Arkansas Children's Hospital
state: Arkansas
city: Long Beach
country: United States
facility: MemorialCare Miller Children's and Women's Hospital Long Beach
state: California
city: Orange
country: United States
facility: Children's Hospital of Orange County Main Campus - Orange
state: California
city: San Francisco
country: United States
facility: Benioff Children's Hospital - Mission Bay
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Wilmington
country: United States
facility: Nemours Alfred I. Dupont Hospital for Children
state: Delaware
city: Fort Myers
country: United States
facility: Golisano Children's Hospital of Southwest Florida
state: Florida
city: Jacksonville
country: United States
facility: Nemours Children's Specialty Care Jacksonville
state: Florida
city: Orlando
country: United States
facility: Nemours Children's Hospital - Orlando
state: Florida
city: Tampa
country: United States
facility: Saint Joseph's Hospital - Tampa
state: Florida
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta
state: Georgia
city: Honolulu
country: United States
facility: Kapi'olani Medical Center for Women and Children
state: Hawaii
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's Hospital of Chicago
state: Illinois
city: Chicago
country: United States
facility: Comer Children's Hospital
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa Stead Family Children's Hospital
state: Iowa
city: Louisville
country: United States
facility: Norton Children's Hospital
state: Kentucky
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Children's Hospital of Michigan
state: Michigan
city: Minneapolis
country: United States
facility: Masonic Cancer Center
state: Minnesota
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Kansas City
country: United States
facility: The Children's Mercy Hospital - Adele Hall Campus
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine in St. Louis
state: Missouri
city: Las Vegas
country: United States
facility: Alliance for Childhood Diseases dba Cure 4 The Kids Foundation
state: Nevada
city: Morristown
country: United States
facility: Morristown Medical Center
state: New Jersey
city: New York
country: United States
facility: Columbia University Irving Medical Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center - New York
state: New York
city: Queens
country: United States
facility: Cohen Children's Medical Center
state: New York
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Portland
country: United States
facility: Doernbecher Children's Hospital
state: Oregon
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Columbia
country: United States
facility: Prisma Health Richland Hospital
state: South Carolina
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
city: Nashville
country: United States
facility: Monroe Carell Jr. Children's Hospital at Vanderbilt
state: Tennessee
city: Dallas
country: United States
facility: Harold C. Simmons Comprehensive Cancer Center
state: Texas
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Salt Lake City
country: United States
facility: Primary Children's Hospital
state: Utah
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: South Brisbane
country: Australia
facility: Children's Health Queensland Hospital and Health Service
state: Queensland
city: Parkville
country: Australia
facility: The Royal Children's Hospital - Children's Cancer Centre
state: Victoria
city: Nedlands
country: Australia
facility: Perth Children's Hospital
state: Western Australia
city: Vienna
country: Austria
facility: Sankt Anna-Kinderspital
city: Gent
country: Belgium
facility: Universitair Ziekenhuis Gent
state: Oost-Vlaanderen
city: Calgary
country: Canada
facility: Alberta Children's Hospital
state: Alberta
city: Vancouver
country: Canada
facility: British Columbia Children's Hospital
state: British Columbia
city: Winnipeg
country: Canada
facility: CancerCare Manitoba
state: Manitoba
city: Halifax
country: Canada
facility: Izaak Walton Killam (IWK) Health Center
state: Nova Scotia
city: Ottawa
country: Canada
facility: Children's Hospital of Eastern Ontario
state: Ontario
city: Toronto
country: Canada
facility: SickKids - The Hospital for Sick Children
state: Ontario
city: Praha 5
country: Czechia
facility: Fakultni nemocnice v Motole
state: Prague
city: Copenhagen
country: Denmark
facility: Rigshospitalet
state: Hovedstaden
city: Helsinki
country: Finland
facility: Uusi Lastensairaala
state: Etelä-Suomen Lääni
city: Toulouse
country: France
facility: CHU de Toulouse - Hôpital des Enfants
state: Haute-Garonne
city: Loos
country: France
facility: Hôpital Jeanne de Flandre
state: Hauts-de-France
city: Paris
country: France
facility: Hôpital Armand-Trousseau
state: Ile-de-France
city: Paris
country: France
facility: Hôpital Universitaire Robert-Debré
state: Ile-de-France
city: Nantes Cedex 1
country: France
facility: CHU de Nantes - Hôpital Femme-Enfant-Adolescent
state: Loire-Atlantique
city: Lyon
country: France
facility: Institut d'Hématologie et d'Oncologie Pédiatrique
state: Rhône
city: Petach Tikvah
country: Israel
facility: Schneider Children's Medical Center of Israel
state: Central District
city: Genova
country: Italy
facility: Istituto Giannina Gaslini
state: Genoa
city: Monza
country: Italy
facility: Fondazione IRCCS San Gerardo dei Tintori
state: Monza And Brianza
city: Roma
country: Italy
facility: Ospedale Pediatrico Bambino Gesù
state: Rome
city: Torino
country: Italy
facility: Ospedale Infantile Regina Margherita
state: Turin
city: Nagoya-shi
country: Japan
facility: Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital
state: Aiti
city: Kobe-Shi
country: Japan
facility: Hyogo Prefectural Kobe Children's Hospital
state: Hyogo
city: Saitama-Shi
country: Japan
facility: Saitama Prefectural Children's Medical Center
state: Saitama
city: Setagaya-Ku
country: Japan
facility: National Center for Child Health and Development
state: Tokyo
city: Osaka
country: Japan
facility: Osaka City General Hospital
city: Utrecht
country: Netherlands
facility: Prinses Maxima Centrum Kinderoncologie
city: Grafton
country: New Zealand
facility: Starship Children's Hospital
state: Auckland
city: Oslo
country: Norway
facility: Oslo Universitetssykehus
city: Lisbon
country: Portugal
facility: Instituto Portugues De Oncologia De Lisboa Francisco Gentil
state: Lisboa
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebrón
city: Barcelona
country: Spain
facility: Hospital Sant Joan de Déu Barcelona
city: Madrid
country: Spain
facility: Hospital Infantil Universitario Niño Jesús
city: València
country: Spain
facility: Hospital Universitario La Fe
city: Stockholm
country: Sweden
facility: Karolinska Universitetssjukhuset Solna
state: Stockholms Län
city: Zurich
country: Switzerland
facility: Universitaets - Kinderspital Zürich
Study officials:
affiliation: St. Jude Children's Research Hospital
name: Seth Karol, MD
role: PRINCIPAL_INVESTIGATOR
References: