Venetoclax in Children With Relapsed Acute Myeloid Leukemia (AML)

Acute Myeloid Leukemia Clinical Trial

Official title:

A Randomized Phase 3 Trial of Fludarabine/Cytarabine/Gemtuzumab Ozogamicin With or Without Venetoclax in Children With Relapsed AML

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05183035
• Other study ID #: ITCC-101/APAL2020D
• Secondary ID: 2021-003212-11
• Status: Recruiting
• Phase: Phase 3
• Start date: October 1, 2022
• Est. completion date: February 2032

Study information

• Verified date: March 2024
• Source: LLS PedAL Initiative, LLC
• Contact: Gwen Nichols, MD
• Phone: 914-821-8217
• Email: gwen.nichols[@]lls.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 98
• Est. completion date: February 2032
• Est. primary completion date: February 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 29 Days to 21 Years

Eligibility

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.

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Drug:
• 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

Locations

Country	Name	City	State
Australia	Perth Children's Hospital	Nedlands	Western Australia
Australia	The Royal Children's Hospital - Children's Cancer Centre	Parkville	Victoria
Australia	Children's Health Queensland Hospital and Health Service	South Brisbane	Queensland
Austria	Sankt Anna-Kinderspital	Vienna
Belgium	Universitair Ziekenhuis Gent	Gent	Oost-Vlaanderen
Canada	Alberta Children's Hospital	Calgary	Alberta
Canada	Izaak Walton Killam (IWK) Health Center	Halifax	Nova Scotia
Canada	Children's Hospital of Eastern Ontario	Ottawa	Ontario
Canada	SickKids - The Hospital for Sick Children	Toronto	Ontario
Canada	British Columbia Children's Hospital	Vancouver	British Columbia
Canada	CancerCare Manitoba	Winnipeg	Manitoba
Czechia	Fakultni nemocnice v Motole	Praha 5	Prague
Denmark	Rigshospitalet	Copenhagen	Hovedstaden
France	Hôpital Jeanne de Flandre	Loos	Hauts-de-France
France	Institut d'Hématologie et d'Oncologie Pédiatrique	Lyon	Rhône
France	CHU de Nantes - Hôpital Femme-Enfant-Adolescent	Nantes Cedex 1	Loire-Atlantique
France	Hôpital Armand-Trousseau	Paris	Ile-de-France
France	Hôpital Universitaire Robert-Debré	Paris	Ile-de-France
France	CHU de Toulouse - Hôpital des Enfants	Toulouse	Haute-Garonne
Israel	Schneider Children's Medical Center of Israel	Petach Tikvah	Central District
Italy	Istituto Giannina Gaslini	Genova	Genoa
Italy	Fondazione IRCCS San Gerardo dei Tintori	Monza	Monza And Brianza
Italy	Ospedale Pediatrico Bambino Gesù	Roma	Rome
Netherlands	Prinses Maxima Centrum Kinderoncologie	Utrecht
New Zealand	Starship Children's Hospital	Grafton	Auckland
Norway	Oslo Universitetssykehus	Oslo
Portugal	Instituto Portugues De Oncologia De Lisboa Francisco Gentil	Lisbon	Lisboa
Spain	Hospital Sant Joan de Déu Barcelona	Barcelona
Spain	Hospital Universitari Vall d'Hebrón	Barcelona
Spain	Hospital Infantil Universitario Niño Jesús	Madrid
Spain	Hospital Universitario La Fe	València
Sweden	Karolinska Universitetssjukhuset Solna	Stockholm	Stockholms Län
Switzerland	Universitaets - Kinderspital Zürich	Zurich
United States	Children's Healthcare of Atlanta	Atlanta	Georgia
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Ann & Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois
United States	Comer Children's Hospital	Chicago	Illinois
United States	Prisma Health Richland Hospital	Columbia	South Carolina
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	Harold C. Simmons Comprehensive Cancer Center	Dallas	Texas
United States	Children's Hospital of Michigan	Detroit	Michigan
United States	Golisano Children's Hospital of Southwest Florida	Fort Myers	Florida
United States	Kapi'olani Medical Center for Women and Children	Honolulu	Hawaii
United States	Texas Children's Hospital	Houston	Texas
United States	University of Iowa Stead Family Children's Hospital	Iowa City	Iowa
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Nemours Children's Specialty Care Jacksonville	Jacksonville	Florida
United States	The Children's Mercy Hospital - Adele Hall Campus	Kansas City	Missouri
United States	Alliance for Childhood Diseases dba Cure 4 The Kids Foundation	Las Vegas	Nevada
United States	Arkansas Children's Hospital	Little Rock	Arkansas
United States	MemorialCare Miller Children's and Women's Hospital Long Beach	Long Beach	California
United States	Norton Children's Hospital	Louisville	Kentucky
United States	St. Jude Children's Research Hospital	Memphis	Tennessee
United States	Masonic Cancer Center	Minneapolis	Minnesota
United States	Morristown Medical Center	Morristown	New Jersey
United States	Monroe Carell Jr. Children's Hospital at Vanderbilt	Nashville	Tennessee
United States	Yale University	New Haven	Connecticut
United States	Columbia University Irving Medical Center	New York	New York
United States	Memorial Sloan Kettering Cancer Center - New York	New York	New York
United States	Children's Hospital of Orange County Main Campus - Orange	Orange	California
United States	Nemours Children's Hospital - Orlando	Orlando	Florida
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Phoenix Children's Hospital	Phoenix	Arizona
United States	Doernbecher Children's Hospital	Portland	Oregon
United States	Cohen Children's Medical Center	Queens	New York
United States	Washington University School of Medicine in St. Louis	Saint Louis	Missouri
United States	Primary Children's Hospital	Salt Lake City	Utah
United States	Benioff Children's Hospital - Mission Bay	San Francisco	California
United States	Seattle Children's Hospital	Seattle	Washington
United States	Saint Joseph's Hospital - Tampa	Tampa	Florida
United States	Nemours Alfred I. Dupont Hospital for Children	Wilmington	Delaware

Sponsors (5)

Lead Sponsor	Collaborator
LLS PedAL Initiative, LLC	AbbVie, EuPAL, Princess Maxima Center for Pediatric Oncology (European Sponsor), Roche-Genentech

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Canada,  Czechia,  Denmark,  France,  Israel,  Italy,  Netherlands,  New Zealand,  Norway,  Portugal,  Spain,  Sweden,  Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival (OS)		Up to 5 years
Secondary	Morphology Event Free Survival (EFS)		Up to 5 years
Secondary	Flow-based Event Free Survival (EFS)		Up to 5 years
Secondary	Morphological Overall Response Rate (ORR)		Up to Day 84
Secondary	Flow-based Overall Response Rate (ORR)		Up to Day 84
Secondary	Duration of Response (DOR)		Up to 5 years
Secondary	Cumulative Incidence of Relapse (CIR)		Up to 5 years
Secondary	Number of Participants with Non-relapse Mortality (NRM)		Up to 5 years
Secondary	Hematopoietic Stem Cell Transplantation (HSCT) Rate		Up to 5 years
Secondary	Number of Participants with Adverse Events (AEs)		Up to 5 years
Secondary	Maximum Observed Plasma Concentration (Cmax) of Venetoclax		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	Time to Maximum Observed Plasma Concentration (Tmax) of Venetoclax		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	Area Under the Plasma Concentration-time Curve Over a 24-hour Dose Interval (AUC0-24)		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	Participants That Are Minimal Residual Disease (MRD) Negative with Complete Remission (CR), Partial Complete Remission (CRp), or Complete Remission with Incomplete Hematologic Recovery (CRi)		Up to 5 years