Trial Treating Relapsed Acute Lymphoblastic Leukemia With Venetoclax and Navitoclax

NCT05192889 | Active Not Recruiting Phase 1 Results FDA Drug

• 2 other identifiers: RAVENNCI-2022-00304
• Study Type: interventional
• Target: 35
• Locations: 1 country
• Sites: 2

Brief Summary

This is a phase I/II clinical trial evaluating the activity of combination chemotherapy with venetoclax and navitoclax in children with relapsed or refractory acute lymphoblastic leukemia or lymphoma (rALL) and assessing the combination dose of venetoclax combinations with either blinatumomab for CD19-positive patients or navitoclax and high-dose cytarabine for CD19-negative patients. Primary Objectives

• To compare Minimal Residual Disease (MRD)-negative CR/CRi rate in children with relapsed or refractory acute lymphoblastic leukemia or lymphoma (rALL) following Block 1 therapy with venetoclax and navitoclax based reinduction to historical controls.
• To identify the recommended phase 2 combination dose (RP2D) of venetoclax based consolidation in novel combinations with a) high-dose cytarabine and navitoclax or b) blinatumomab. Secondary Objectives
• To estimate the tolerability and activity of venetoclax based consolidation in novel combinations with a) high-dose cytarabine and navitoclax or b) blinatumomab.
• To describe event-free and overall survival in patients treated with this regimen. Exploratory Objectives
• To evaluate MRD-negative CR/CRi rates in each prespecified groups: late first relapse B-ALL; early first relapse and second or greater relapse B-ALL; and relapsed T-ALL.
• To identify drug sensitivity patterns in patient samples prior to and after receiving combination therapy and evaluate mechanisms of disease resistance/ escape.
• To explore immune subsets during and after this regimen.
• Evaluate response to therapy in rare relapse patient subsets.
• Explore breakthrough infections in children and young adults with relapsed or refractory ALL

Conditions

Refractory Acute Lymphoblastic Leukemia; Relapsed Acute Lymphoblastic Leukemia

Keywords

Recurrent Acute Lymphoblastic Leukemia; Refractory Acute Lymphoblastic Leukemia; Children; Young Adults

Outcome Measures

Primary Outcomes (3)

• Number of Participants With Minimal Residual Disease (MRD)-Negative Response

  The number of participants with end Block 1 minimal residual disease \<0.01% by flow cytometry

  4 weeks from start of therapy

• Recommended Phase 2 Dose of Venetoclax in Combination With a) High-dose Cytarabine and Navitoclax

  The recommended Phase 2 dose (RP2D) of venetoclax in combination with a) high-dose cytarabine and navitoclax will be the dose at which 0 or 1 of 6 treated patients experience a dose limiting toxicity.

  6 weeks from the start of block 2a

• Recommended Phase 2 Dose of Venetoclax in Combination With b) Blinatumomab

  The recommended Phase 2 dose (RP2D) of venetoclax in combination with b) blinatumomab will be the dose at which 0 or 1 of 6 treated patients experience a dose limiting toxicity. RP2D is 240mg/m2 which was delivered for 21 days.

  4 weeks from the start of block 2b

Secondary Outcomes (4)

• Number of Participants With Grade 3 or Higher CTCAE Events in Block 2a

  6 weeks from start of block 2a

• Number of Participants With Grade 3 or Higher CTCAE Events in Block 2b

  4 weeks from start of block 2b

• Event Free Survival (EFS)

  1, 3 and 5 years from study entry

• Overall Survival (OS)

  1, 3 and 5 years from study entry

Study Arms (2)

Block 1

EXPERIMENTAL

All eligible patients receive intervention according to the Detailed Description section with the following: Venetoclax, Navitoclax, Dexamethasone, Vincristine, Calaspargase Pegol, Pegaspargase, Erwinia asparaginase, Dasatinib, Leucovorin, Intrathecal (IT) MHA (methotrexate/hydrocortisone/cytarabine)

Drug: Venetoclax; Drug: Navitoclax; Drug: Dexamethasone; Drug: Vincristine; Drug: Calaspargase Pegol; Drug: Dasatinib; Drug: Leucovorin; Drug: Intrathecal Triples; Drug: Pegaspargase; Drug: Erwinia asparaginase

Block 2

EXPERIMENTAL

Block 2a Therapy: Patients receive intervention according to the Detailed Description section with the following: Venetoclax, Navitoclax, Dexamethasone, Cytarabine, Calaspargase Pegol, Pegaspargase, Erwinia asparaginase, Dasatinib, IT MHA, Radiation Block 2b Therapy: Patients receive intervention according to the Detailed Description section with the following: Venetoclax, Blinatumomab, Dexamethasone, Dasatinib, IT MHA Following Block 2 of therapy, late (≥36 months from diagnosis) first relapse B-ALL who are MRD negative after Block 1 will continue chemotherapy using adapted R3 intensification, interim, and continuation therapies. Patients receive intervention according to the Detailed Description section with the following: Methotrexate, Mercaptopurine, IT MHA, Leucovorin, Dexamethasone, Vincristine, Cyclophosphamide, Etoposide, Cytarabine, Dasatinib, Calaspargase Pegol, Pegaspargase, Erwinia asparaginase, Radiation

Drug: Venetoclax; Drug: Navitoclax; Drug: Dexamethasone; Drug: Vincristine; Drug: Calaspargase Pegol; Drug: Dasatinib; Drug: Cytarabine; Biological: Blinatumomab; Drug: Methotrexate; Drug: Mercaptopurine; Drug: Cyclophosphamide; Drug: Etoposide; Drug: Leucovorin; Drug: Intrathecal Triples; Drug: Pegaspargase; Drug: Erwinia asparaginase; Radiation: Radiation

Interventions

Venetoclax DRUG

Given oral (PO).

Also known as: Venclextra®, ABT-199

Block 1; Block 2

Navitoclax DRUG

Given oral (PO).

Also known as: ABT-263

Block 1; Block 2

Dexamethasone DRUG

Given orally (PO) or intravenously (IV).

Also known as: Decadron®, Hexadrol®, Dexameth®

Block 1; Block 2

Vincristine DRUG

Given intravenously (IV).

Also known as: Vincristine sulfate, Oncovin®

Block 1; Block 2

Calaspargase Pegol DRUG

Given intravenously (IV).

Also known as: Asparlas

Block 1; Block 2

Dasatinib DRUG

Given oral (PO).

Also known as: Sprycel®

Block 1; Block 2

Cytarabine DRUG

Given intravenously (IV) or Intrathecal (IT).

Also known as: Ara-C, Cytosar-U®

Block 2

Blinatumomab BIOLOGICAL

Given intravenously (IV).

Also known as: Blincyto®

Block 2

Methotrexate DRUG

Given intravenously (IV), oral (PO), or Intrathecal (IT).

Also known as: MTX, Trexall®, amethopterin

Block 2

Mercaptopurine DRUG

Given oral (PO).

Also known as: 6-MP, Purinethol®

Block 2

Cyclophosphamide DRUG

Given intravenously (IV).

Also known as: Cytoxan®

Block 2

Etoposide DRUG

Given intravenously (IV).

Also known as: VP-16, Vepesid®

Block 2

Leucovorin DRUG

Given oral (PO) or intravenously (IV).

Also known as: Folinic acid

Block 1; Block 2

Intrathecal Triples DRUG

Given Intrathecal (IT).

Also known as: ITMHA, methotrexate/hydrocortisone/cytarabine

Block 1; Block 2

Pegaspargase DRUG

May be used in place of Calaspargase Pegol where available. Given intravenously (IV) or intramuscularly (IM).

Also known as: Oncaspar®, PEG-asparaginase, PEG-L-asparaginase

Block 1; Block 2

Erwinia asparaginase DRUG

To be used in case of hypersensitivity or intolerance to Calaspargase Pegol or Pegaspargase. Given intravenously (IV) or intramuscularly (IM).

Also known as: Erwinase®

Block 1; Block 2

Radiation RADIATION

See detailed description section.

Also known as: Irradiation

Block 2

Eligibility Criteria

• Age: 4 Years - 30 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Diagnosis:
• Relapsed or refractory acute lymphoblastic leukemia or lymphoma with ≥1% bone marrow disease as measured by flow cytometry, PCR, or next generation sequencing. However, if an adequate bone marrow sample cannot be obtained, patients may be enrolled if there is unequivocal evidence of leukemia with ≥ 5% blasts in the peripheral blood.
• Patients with 1-4.99% bone marrow involvement must have disease confirmed in one of the following ways: an alternative minimal residual disease assay (e.g. flow cytometry and PCR or NGS), cytogenetic abnormality consistent with patient's leukemia, FISH abnormality, or a second bone marrow with MRD ≥1% separated by 1-4 weeks.
• Patients with ≥5% bone marrow disease by a single measurement as measured by flow cytometry, PCR, or next generation sequencing do not require a second confirmatory test.
• Refractory disease is defined as residual leukemia ≥1% after at least 2 prior lines of frontline therapy with curative intent.
• Patients in exploratory cohort I must have measurable extramedullary disease but may have \<1% bone marrow disease.
• Patients in exploratory cohort M must have ≥1% bone marrow disease as measured by flow cytometry of mixed phenotype acute leukemia (MPAL)/ acute leukemia of ambiguous lineage (ALAL).
• Age ≥4 to \< 30 years. Patients ≥ 22 years old are only eligible for exploratory cohort O. Sites may have different (lower) maximum ages based on institutional guidelines but may not exceed 30 years.
• Patient weighs ≥ 20 kg.
• Patient is able to swallow pills.
• Lansky/Karnofsky score is ≥ 60%. The Lansky performance score should be used for participants \< 16 years and the Karnofsky performance score for participants ≥ 16 years.
• Participant has adequate organ function as defined by the following:
• Direct bilirubin ≤ 1.5x the institutional upper limit of normal (ULN) unless attributable to leukemic involvement. At institutions which do not obtain a direct bilirubin in patients with a normal total bilirubin, a normal total bilirubin may be used as evidence that the direct bilirubin is not \> 1.5x the ULN. Patients with a direct bilirubin ≥ 2 mg/dl may not enroll regardless of attribution.
• Aspartate transaminase (AST) and alanine transaminase (ALT) \< 3.0 x the ULN unless increase is attributable to leukemic involvement.
• Normal creatinine for age or a calculated creatinine clearance ≥ 60 mL/min/1.73 m\^2.

You may not qualify if:

• Known HIV infection or active hepatitis B (defined as hepatitis B surface antigen-positive) or C (defined as hepatitis C antibody-positive).
• Pregnant or lactating (female participant of childbearing potential must have negative serum or urine pregnancy test required within 7 days prior to start of treatment).
• Concomitant medications and food:
• Treatment with moderate or strong cytochrome P450 3A (CYP3A) inhibitors within 3 days of starting protocol therapy.
• Treatment with moderate or strong CYP3A inducers within 7 days of starting protocol therapy.
• Administration or consumption within 3 days prior to the first dose of study drug or grapefruit or grapefruit products, Seville oranges (including marmalade containing Seville oranges), or star fruit.
• Inability or unwillingness of research participant or legal guardian/representative to give written informed consent.

Sponsors & Collaborators

• St. Jude Children's Research Hospital: lead
• AbbVie: collaborator

Study Sites (2)

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

Location

Related Links

• St. Jude Children's Research Hospital
• ClinicalTrials Open at St. Jude

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Interventions

venetoclax; navitoclax; Dexamethasone; Calcium Dobesilate; Vincristine; calaspargase pegol; Dasatinib; Cytarabine; blinatumomab; Methotrexate; Mercaptopurine; Cyclophosphamide; Etoposide; Leucovorin; pegaspargase; asparaginase erwinia chrysanthemi recombinant; Asparaginase; Radiation

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Benzenesulfonates; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Arylsulfonates; Arylsulfonic Acids; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Thiazoles; Azoles; Heterocyclic Compounds, 1-Ring; Pyrimidines; Cytidine; Pyrimidine Nucleosides; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Aminopterin; Pterins; Pteridines; Sulfhydryl Compounds; Purines; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Glucosides; Glycosides; Carbohydrates; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Coenzymes; Enzymes and Coenzymes; Amidohydrolases; Hydrolases; Enzymes; Physical Phenomena

Results Point of Contact

• Title: Seth Karol, MD
• Organization: St. Jude Children's Research Hospital

seth.karol@stjude.org

(901) 595-1716

Study Officials

• Seth E. Karol, MD

  St. Jude Children's Research Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: All eligible patients receive a common first block of therapy and therapy in the 2nd block being determined by CD19 expression on leukemic blasts.

Study Record Dates

• First Submitted: January 11, 2022
• First Posted: January 14, 2022
• Study Start: August 25, 2022
• Primary Completion: June 13, 2024
• Study Completion (Estimated): February 1, 2027
• Last Updated: September 22, 2025
• Results First Posted: September 22, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Data will be made available at the time of article publication.
• Access Criteria: Data will be provided to researchers following a formal request with the following information: full name of requestor, affiliation, data set requested, and timing of when data is needed. As an informational point, the lead statistician and study principal investigator will be informed that primary results datasets have been requested.

Locations

US (2)