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

• ClinicalTrials.gov Identifier: NCT03181126
• Recruitment Status: Completed
• First Posted: June 8, 2017
• Last Update Posted: January 7, 2021
• Sponsor: AbbVie
• Information provided by (Responsible Party): AbbVie

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Acute Lymphoblastic Leukemia (ALL); Lymphoblastic Lymphoma	Drug: Navitoclax; Drug: Chemotherapy; Drug: Venetoclax	Phase 1

Expanded Access : An investigational treatment associated with this study is available outside the clinical trial.   More info ...

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 69 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: November 27, 2017
• Actual Primary Completion Date: November 11, 2020
• Actual Study Completion Date: November 14, 2020

Arms and Interventions

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 Name: 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 Name: ABT-199 GDC-0199

Outcome Measures

Primary Outcome Measures :

1. Cmax of Venetoclax + Navitoclax [ Time Frame: Up to approximately 9 months ]
   Maximum observed plasma concentration (Cmax) of venetoclax + navitoclax
2. AUC of Venetoclax + Navitoclax [ Time Frame: Up to approximately 9 months ]
   Area under the plasma concentration-time curve (AUC) of venetoclax + navitoclax
3. Tmax of Venetoclax + Navitoclax [ Time Frame: Up to approximately 9 months ]
   Time to Cmax (Tmax) of Venetoclax + Navitoclax
4. CL/F of Venetoclax + Navitoclax [ Time Frame: Up to approximately 9 months ]
   Apparent oral clearance (CL/F) of venetoclax + navitoclax
5. 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.

Secondary Outcome Measures :

1. Progression-free survival (PFS) [ Time Frame: 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.
2. Partial Response (PR) rate [ Time Frame: 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.
3. Number of Participant who Proceed to Stem Cell Transplantation or Chimeric antigen receptor T-cell (CAR-T) Therapy [ Time Frame: 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.
4. Overall survival (OS) [ Time Frame: 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.
5. Objective response rate (ORR) [ Time Frame: 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.
6. Complete Response (CR) rate [ Time Frame: 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.

Eligibility Criteria

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

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)
  • 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.

Contacts and Locations

Locations

United States, California

City of Hope /ID# 169029

Duarte, California, United States, 91010

LPCH Stanford /ID# 163337

Palo Alto, California, United States, 94304

United States, Illinois

University of Chicago /ID# 163369

Chicago, Illinois, United States, 60637

United States, Missouri

Washington University-School of Medicine /ID# 165689

Saint Louis, Missouri, United States, 63110

United States, North Carolina

Univ NC Chapel Hill /ID# 163509

Chapel Hill, North Carolina, United States, 27514-4220

United States, Ohio

Cincinnati Children's Hospital /ID# 164619

Cincinnati, Ohio, United States, 45229

Nationwide Childrens Hospital /ID# 163372

Columbus, Ohio, United States, 43205

United States, Oregon

Oregon Health and Science University /ID# 165690

Portland, Oregon, United States, 97239

United States, Tennessee

St Jude Children's Research Hospital /ID# 163335

Memphis, Tennessee, United States, 38105

United States, Texas

UT Southwestern Medical Center /ID# 163346

Dallas, Texas, United States, 75390-7208

MD Anderson Cancer Center at Texas Medical Center /ID# 163327

Houston, Texas, United States, 77030-4000

United States, Wisconsin

University of Wisconsin-Madiso /ID# 165691

Madison, Wisconsin, United States, 53705

Australia, Victoria

Alfred Hospital /ID# 169576

Melbourne, Victoria, Australia, 3004

Victorian Comprehensive Cancer /ID# 165710

Melbourne, Victoria, Australia, 3050

Royal Children's Hospital /ID# 163322

Melbourne, Victoria, Australia, 3052

Sponsors and Collaborators

AbbVie

Investigators

• Study Director: AbbVie Inc.; AbbVie

More Information

Additional Information:

Related Info 

• Responsible Party: AbbVie
• ClinicalTrials.gov Identifier: NCT03181126
• Other Study ID Numbers: M16-106
• First Posted: June 8, 2017
• Last Update Posted: January 7, 2021
• Last Verified: January 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• 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

Keywords provided by AbbVie:

Relapsed of Refractory Acute Lymphoblastic Leukemia; Cancer; Venetoclax; Navitoclax

Additional relevant MeSH terms:

Lymphoma; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Lymphoma, Non-Hodgkin; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Venetoclax; Navitoclax; Antineoplastic Agents