A Study of Venetoclax in Combination With Navitoclax and Chemotherapy in Subjects With Relapsed/Refractory Acute Lymphoblastic Leukemia or Relapsed/Refractory Lymphoblastic Lymphoma

• Navitoclax (Drug), also known as ABT-263: tablet
• Chemotherapy (Drug): peg-asparaginase (or other form of asparaginase, per local standard of care (intravenous) + vincristine (intravenous) + dexamethasone (oral) + tyrosine kinase inhibitor (TKI) (if applicable, oral)
• Venetoclax (Drug), also known as ABT-199 GDC-0199: tablet

Primary outcomes

• Cmax of Venetoclax + Navitoclax [Up to approximately 9 months]: Maximum observed plasma concentration (Cmax) of venetoclax + navitoclax
• AUC of Venetoclax + Navitoclax [Up to approximately 9 months]: Area under the plasma concentration-time curve (AUC) of venetoclax + navitoclax
• Tmax of Venetoclax + Navitoclax [Up to approximately 9 months]: Time to Cmax (Tmax) of Venetoclax + Navitoclax
• CL/F of Venetoclax + Navitoclax [Up to approximately 9 months]: Apparent oral clearance (CL/F) of venetoclax + navitoclax
• Number of participants with dose-limiting toxicities (DLT) [Up to approximately 28 days after initial dose of study drug]: A DLT is any Grade 3 or higher non-hematologic adverse event (AE) with exceptions outlined in the protocol. AEs and toxicities that occur beyond the DLT assessment period will also be evaluated by the investigator and AbbVie and may be considered as dose-limiting.

Secondary outcomes

• Progression-free survival (PFS) [Up to 9 months after the last subject has enrolled into the study]: PFS is defined as the number of days from the date of enrollment to the date of earliest disease progression or death.
• Partial Response (PR) rate [Up to 9 months after the last subject has enrolled into the study]: PR defined as no peripheral blasts or peripheral blood absolute blast count decreased by ≥ 50% from baseline, bone marrow with 5 - 25% blasts and at least a 50% decrease in bone marrow blast percent from baseline, no evidence of extramedullary disease.
• Number of Participant who Proceed to Stem Cell Transplantation or Chimeric antigen receptor T-cell (CAR-T) Therapy [Up to 9 months after the last subject has enrolled into the study]: Determine the number of participants who proceed to stem cell transplantation or CAR-T therapy.
• Overall survival (OS) [Up to 9 months after the last subject has enrolled into the study]: OS is defined as the number of days from the date of enrollment to the date of death.
• Objective response rate (ORR) [Up to 9 months after the last subject has enrolled into the study]: The proportion of subjects with objective response rate (complete response \[CR\] + CR incomplete recovery \[CRi\] + CR without platelet recovery \[CRp\]) for ALL subjects and (CR+PR) for LL subjects.
• Complete Response (CR) rate [Up to 9 months after the last subject has enrolled into the study]: CR defined as hematologic recovery (absolute neutrophil count \[ANC\] greater than or equal to 500/μL; platelet counts greater than or equal to 75,000/μL), evidence of trilineage hematopoiesis in the bone marrow and less than 5% blasts in the bone marrow, absence of circulating blasts, and no evidence of extramedullary disease.

Sex: All, ages: 4 Years to any

Inclusion Criteria:

* Must have relapsed or refractory acute lymphoblastic leukemia (ALL) or relapsed or refractory lymphoblastic lymphoma (LL). Refractory is defined as persistent disease after at least 2 courses of chemotherapy.

  * Participants with ALL with Philadelphia chromosome or with an ABL class targetable fusion are eligible.
  * Participants with LL must have radiographic evidence of disease
* Participants <= 18 years of age who do not have a standard of care treatment option available.
* Must weigh greater than or equal to 20 kg.
* Must be able to swallow pills.
* Must have adequate hepatic and kidney function.
* Must have adequate performance status:

  * Participants less than or equal to 16 years of age: Lansky greater than or equal to 50
  * Participants greater than 16 years of age: Karnofsky greater than or equal to 50 or Eastern Cooperative Oncology Group (ECOG) less than 3.

Exclusion Criteria:

* Participant has central nervous system (CNS) disease with cranial involvement that requires radiation.
* Participants who are less than 100 days post-transplant, or greater than 100 days post-transplant with active graft versus host disease (GVHD), or are still continuing post-transplant immunosuppressant therapy within 7 days prior to the first dose of study drug.
* Participants who have received any of the following prior to the first dose of study drug:

  * Inotuzumab within 30 days (if participant received inotuzumab > 30 days prior to Day 1, must have ALT, AST and bilirubin < ULN).
  * A biologic agent (i.e., monoclonal antibodies) for anti-neoplastic intent within 30 days
  * CAR-T infusion or other cellular therapy within 30 days
  * Any anti-cancer therapy including blinatumomab, chemotherapy, radiation therapy targeted small molecule agents or investigational agents within 14 days, or 5 half-lives, whichever is shorter

    * Exception: Philadelphia Chromosome (Ph)+ ALL subjects on TKIs at Screening may enroll and remain on Tyrosine Kinase Inhibitor (TKI) therapy to control disease. Participants on venetoclax at screening may enroll and remain on venetoclax.
  * Steroid therapy for anti-neoplastic intent within 5 days
  * Hydroxyurea that is ongoing (hydroxyurea is permitted up to the first dose)
  * A strong or moderate CYP3A inhibitor or inducer within 7 days
  * Aspirin within 7 days, or 5 half-lives, whichever is longer
  * An excluded antiplatelet/anticoagulant drug or a herbal supplement that affects platelet function within 7 days, or 5 half-lives, whichever is longer
* Participants with malabsorption syndrome or any other condition that precludes enteral administration.

• Results publication: Badawi M, Gopalakrishnan S, Engelhardt B, Palenski T, Karol SE, Rubnitz JE, Menon R, Salem AH. Dosing of Venetoclax in Pediatric Patients with Relapsed Acute Myeloid Leukemia: Analysis of Developmental Pharmacokinetics and Exposure-Response Relationships. Clin Ther. 2024 Oct;46(10):759-767. doi: 10.1016/j.clinthera.2024.09.008. Epub 2024 Oct 5. PMID 39368878

• AbbVie Inc., Study director, AbbVie