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

Lymphoblastic Lymphoma Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03181126
• Other study ID #: M16-106
• Status: Completed
• Phase: Phase 1
• Start date: November 27, 2017
• Est. completion date: November 14, 2020

Study information

• Verified date: October 2021
• Source: AbbVie
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 69
• Est. completion date: November 14, 2020
• Est. primary completion date: November 11, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 4 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Acute Lymphoblastic Leukemia (ALL)
• Leukemia
• Leukemia, Lymphoid
• Lymphoblastic Lymphoma
• Lymphoma
• Lymphoma, Non-Hodgkin
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

Drug:
• Navitoclax
tablet
• 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)
• Venetoclax
tablet

Locations

Country	Name	City	State
Australia	Alfred Hospital /ID# 169576	Melbourne	Victoria
Australia	Royal Children's Hospital /ID# 163322	Melbourne	Victoria
Australia	Victorian Comprehensive Cancer /ID# 165710	Melbourne	Victoria
United States	Univ NC Chapel Hill /ID# 163509	Chapel Hill	North Carolina
United States	University of Chicago /ID# 163369	Chicago	Illinois
United States	Cincinnati Children's Hospital /ID# 164619	Cincinnati	Ohio
United States	Nationwide Childrens Hospital /ID# 163372	Columbus	Ohio
United States	UT Southwestern Medical Center /ID# 163346	Dallas	Texas
United States	City of Hope /ID# 169029	Duarte	California
United States	MD Anderson Cancer Center at Texas Medical Center /ID# 163327	Houston	Texas
United States	University of Wisconsin-Madiso /ID# 165691	Madison	Wisconsin
United States	St Jude Children's Research Hospital /ID# 163335	Memphis	Tennessee
United States	LPCH Stanford /ID# 163337	Palo Alto	California
United States	Oregon Health and Science University /ID# 165690	Portland	Oregon
United States	Washington University-School of Medicine /ID# 165689	Saint Louis	Missouri

Sponsors (1)

Lead Sponsor	Collaborator
AbbVie

Countries where clinical trial is conducted

United States,  Australia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Cmax of Venetoclax + Navitoclax	Maximum observed plasma concentration (Cmax) of venetoclax + navitoclax	Up to approximately 9 months
Primary	AUC of Venetoclax + Navitoclax	Area under the plasma concentration-time curve (AUC) of venetoclax + navitoclax	Up to approximately 9 months
Primary	Tmax of Venetoclax + Navitoclax	Time to Cmax (Tmax) of Venetoclax + Navitoclax	Up to approximately 9 months
Primary	CL/F of Venetoclax + Navitoclax	Apparent oral clearance (CL/F) of venetoclax + navitoclax	Up to approximately 9 months
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

External Links

•   clinical study report synopsis