A Phase 1 Dose Escalation, Open-Label Study of Venetoclax in Combination With Navitoclax and Chemotherapy in Subjects With Relapsed/Refractory Acute Lymphoblastic Leukemia or Relapsed/Refractory Lymphoblastic Lymphoma
Overview
- Phase
- Phase 1
- Intervention
- Navitoclax
- Conditions
- Acute Lymphoblastic Leukemia (ALL)
- Sponsor
- AbbVie
- Enrollment
- 69
- Locations
- 15
- Primary Endpoint
- Tmax of Venetoclax + Navitoclax
- Status
- Completed
- Last Updated
- 4 years ago
Overview
Brief Summary
This dose-escalating study is to determine the safety, pharmacokinetics, and preliminary efficacy of venetoclax in combination with navitoclax and chemotherapy in adult and pediatric participants with relapsed/refractory acute lymphoblastic leukemia (ALL) or relapsed/refractory lymphoblastic lymphoma. A safety expansion cohort of approximately 20 patients may be enrolled in addition to the 50 participants in dose-escalation cohort.
Investigators
Eligibility Criteria
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)
Arms & Interventions
Venetoclax + Navitoclax + Chemotherapy
Venetoclax weight-adjusted doses administered orally every day (QD) starting on Day 1 + navitoclax various, weight-adjusted doses administered orally QD starting on Day 3 + chemotherapy (peg-asparaginase \[or any other forms of asparaginase\], vincristine, dexamethasone) and tyrosine kinase inhibitor \[TKI, if applicable\]). This regimen and any of its components may be delayed, reduced or omitted at the discretion of the Investigator.
Intervention: Navitoclax
Venetoclax + Navitoclax + Chemotherapy
Venetoclax weight-adjusted doses administered orally every day (QD) starting on Day 1 + navitoclax various, weight-adjusted doses administered orally QD starting on Day 3 + chemotherapy (peg-asparaginase \[or any other forms of asparaginase\], vincristine, dexamethasone) and tyrosine kinase inhibitor \[TKI, if applicable\]). This regimen and any of its components may be delayed, reduced or omitted at the discretion of the Investigator.
Intervention: Chemotherapy
Venetoclax + Navitoclax + Chemotherapy
Venetoclax weight-adjusted doses administered orally every day (QD) starting on Day 1 + navitoclax various, weight-adjusted doses administered orally QD starting on Day 3 + chemotherapy (peg-asparaginase \[or any other forms of asparaginase\], vincristine, dexamethasone) and tyrosine kinase inhibitor \[TKI, if applicable\]). This regimen and any of its components may be delayed, reduced or omitted at the discretion of the Investigator.
Intervention: Venetoclax
Outcomes
Primary Outcomes
Tmax of Venetoclax + Navitoclax
Time Frame: Up to approximately 9 months
Time to Cmax (Tmax) of Venetoclax + Navitoclax
Cmax of Venetoclax + Navitoclax
Time Frame: Up to approximately 9 months
Maximum observed plasma concentration (Cmax) of venetoclax + navitoclax
CL/F of Venetoclax + Navitoclax
Time Frame: Up to approximately 9 months
Apparent oral clearance (CL/F) of venetoclax + navitoclax
Number of participants with dose-limiting toxicities (DLT)
Time Frame: 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.
AUC of Venetoclax + Navitoclax
Time Frame: Up to approximately 9 months
Area under the plasma concentration-time curve (AUC) of venetoclax + navitoclax
Secondary Outcomes
- 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)
- Progression-free survival (PFS)(Up to 9 months after the last subject has enrolled into the study)
- Partial Response (PR) rate(Up to 9 months after the last subject has enrolled into the study)
- Overall survival (OS)(Up to 9 months after the last subject has enrolled into the study)
- Objective response rate (ORR)(Up to 9 months after the last subject has enrolled into the study)
- Complete Response (CR) rate(Up to 9 months after the last subject has enrolled into the study)