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

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

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.

Study Overview

• Status: Completed
• Conditions: Lymphoblastic Lymphoma; Acute Lymphoblastic Leukemia (ALL)
• Intervention / Treatment: Drug: Navitoclax; Drug: Chemotherapy; Drug: Venetoclax

• Study Type: Interventional
• Enrollment (Actual): 69
• Phase: Phase 1

Expanded Access

Available outside the clinical trial. See expanded access record.

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Melbourne, Victoria, Australia, 3004
      • Alfred Hospital /ID# 169576
    • Melbourne, Victoria, Australia, 3050
      • Victorian Comprehensive Cancer /ID# 165710
    • Melbourne, Victoria, Australia, 3052
      • Royal Children's Hospital /ID# 163322
• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope /ID# 169029
    • Palo Alto, California, United States, 94304
      • LPCH Stanford /ID# 163337
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago /ID# 163369
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University-School of Medicine /ID# 165689
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514-4220
      • Univ NC Chapel Hill /ID# 163509
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital /ID# 164619
    • Columbus, Ohio, United States, 43205
      • Nationwide Childrens Hospital /ID# 163372
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University /ID# 165690
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • St Jude Children's Research Hospital /ID# 163335
  • Texas
    • Dallas, Texas, United States, 75390-7208
      • UT Southwestern Medical Center /ID# 163346
    • Houston, Texas, United States, 77030-4000
      • MD Anderson Cancer Center at Texas Medical Center /ID# 163327
  • Wisconsin
    • Madison, Wisconsin, United States, 53705
      • University of Wisconsin-Madiso /ID# 165691

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 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.

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cmax of Venetoclax + Navitoclax	Maximum observed plasma concentration (Cmax) of venetoclax + navitoclax	Up to approximately 9 months
AUC of Venetoclax + Navitoclax	Area under the plasma concentration-time curve (AUC) of venetoclax + navitoclax	Up to approximately 9 months
Tmax of Venetoclax + Navitoclax	Time to Cmax (Tmax) of Venetoclax + Navitoclax	Up to approximately 9 months
CL/F of Venetoclax + Navitoclax	Apparent oral clearance (CL/F) of venetoclax + navitoclax	Up to approximately 9 months
Number of participants with dose-limiting toxicities (DLT)	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.	Up to approximately 28 days after initial dose of study drug

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival (PFS)	PFS is defined as the number of days from the date of enrollment to the date of earliest disease progression or death.	Up to 9 months after the last subject has enrolled into the study
Partial Response (PR) rate	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.	Up to 9 months after the last subject has enrolled into the study
Number of Participant who Proceed to Stem Cell Transplantation or Chimeric antigen receptor T-cell (CAR-T) Therapy	Determine the number of participants who proceed to stem cell transplantation or CAR-T therapy.	Up to 9 months after the last subject has enrolled into the study
Overall survival (OS)	OS is defined as the number of days from the date of enrollment to the date of death.	Up to 9 months after the last subject has enrolled into the study
Objective response rate (ORR)	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.	Up to 9 months after the last subject has enrolled into the study
Complete Response (CR) rate	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.	Up to 9 months after the last subject has enrolled into the study

Collaborators and Investigators

• Sponsor: AbbVie

Publications and helpful links

Helpful Links

• clinical study report synopsis

Study record dates

Study Major Dates

• Study Start (Actual): November 27, 2017
• Primary Completion (Actual): November 11, 2020
• Study Completion (Actual): November 14, 2020

Study Registration Dates

• First Submitted: June 5, 2017
• First Submitted That Met QC Criteria: June 7, 2017
• First Posted (Actual): June 8, 2017

Study Record Updates

• Last Update Posted (Actual): October 14, 2021
• Last Update Submitted That Met QC Criteria: October 7, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: Cancer; Venetoclax; Navitoclax; Relapsed of Refractory Acute Lymphoblastic Leukemia
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Leukemia; Lymphoma, Non-Hodgkin; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Antineoplastic Agents; Venetoclax; Navitoclax
• Other Study ID Numbers: M16-106

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No