A Phase 1 Study Evaluating the Safety and Pharmacokinetics of ABT-199 in Subjects With Relapsed or Refractory Chronic Lymphocytic Leukemia and Non-Hodgkin Lymphoma

Chronic Lymphocytic Leukemia Clinical Trial

Official title:

A Phase 1 Study Evaluating the Safety and Pharmacokinetics of ABT-199 in Subjects With Relapsed or Refractory Chronic Lymphocytic Leukemia and Non-Hodgkin Lymphoma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01328626
• Other study ID #: M12-175
• Status: Completed
• Phase: Phase 1
• Start date: May 23, 2011
• Est. completion date: May 8, 2020

Study information

• Verified date: February 2022
• Source: AbbVie
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a Phase 1, open-label, multicenter study evaluating the safety and PK profile of ABT-199 under a once daily dosing schedule. Two arms will be implemented for dose escalation: Arm A, CLL/SLL subjects and Arm B, NHL subjects. Arm A is designed to enroll approximately 116 subjects with relapsed or refractory CLL or SLL and Arm B is designed to enroll approximately 95 subjects with relapsed or refractory NHL. Fifty-six subjects were enrolled in Arm A and approximately 55 subjects will be enrolled in Arm B during the dose escalation portion of the study, with the objective of defining dose limiting toxicities (DLTs) and the MTD. Once the MTD is declared for the arm, approximately 60 additional CLL/SLL subjects in Arm A and approximately 20 additional DLBCL subjects and 20 additional follicular lymphoma subjects in Arm B will be enrolled in an expanded safety portion of the study at the recommended phase 2 dose (RPTD) and schedule.

Description:

Interventional Study Design - Primary Purpose: Determination of safety and tolerability.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 222
• Est. completion date: May 8, 2020
• Est. primary completion date: May 8, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 99 Years

Eligibility

Inclusion Criteria:

• Subject must have either:

• (Arm A) relapsed or refractory CLL/SLL and require treatment in the opinion of the Investigator. Subject must have relapsed following or be refractory to standard treatments such as fludarabine based regimens (F, FC, FR, FCR) or alkylator (chlorambucil, bendamustine) based regimens. In addition, there are no other curative options, and the subject has exhausted options that would be considered standard of care, or

• (Arm B) relapsed or refractory NHL and require treatment in the opinion of the Investigator. Subject must have histologically documented diagnosis of NHL as defined in the World Health Organization classification scheme, except as noted in the exclusion criteria. Subject must have relapsed following or be refractory to standard treatments such as R-CHOP, R-CVP, or fludarabine based regimens. In addition, there are no other curative options, and the subject has exhausted options that would be considered standard of care. Subjects with other lymphoproliferative diseases can be considered in consultation with the Abbott medical monitor.

• Subject has an Eastern Cooperative Oncology Group (ECOG) performance score less than or equal to 1.

• Subject must have adequate bone marrow independent of growth factor support per local laboratory reference range at Screening.

• Subject must have adequate coagulation, renal, and hepatic function, per laboratory reference range at Screening.

Exclusion Criteria:

• CLL subject has undergone an allogeneic or autologous stem cell transplant or NHL subject has undergone an allogeneic stem cell transplant or has been diagnosed with Post-Transplant Lymphoproliferative Disease, Burkitt's lymphoma, Burkitt-like lymphoma, or lymphoblastic lymphoma/leukemia.

• Subject has tested positive for HIV.

• Subject has a cardiovascular disability status of New York Heart Association Class greater or equal to 2. Class 2 is defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity, results in fatigue, palpitations, dyspnea or anginal pain.

• Subject has a significant history of renal, neurologic, psychiatric, pulmonary, endocrinologic, metabolic, immunologic, cardiovascular, or hepatic disease that in the opinion of the Investigator would adversely affect his/her participating in this study.

• Subject has received a monoclonal antibody for anti-neoplastic intent within 8 weeks prior to the first dose of study drug.

Related Conditions & MeSH terms

• Chronic Lymphocytic Leukemia
• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid
• Lymphoma
• Lymphoma, Non-Hodgkin
• Non-Hodgkin Lymphoma

Intervention

Drug:
• ABT-199
Arm A (Cohorts 1-8) and Arm B (Cohort 1-6): Subjects in dose escalation phase will receive 1 dose of ABT-199, followed by 6 days off drug, followed by continuous once daily dosing with ABT-199. Arm B (Cohorts 7+): Subjects in dose escalation phase will receive continuous once daily dosing with ABT-199. Arm A and Arm B: Subjects in expanded safety cohort will receive continuous once daily dosing with ABT-199.

Locations

Country	Name	City	State
Australia	Peter MacCallum Cancer Ctr /ID# 48323	Melbourne	Victoria
Australia	Royal Melbourne Hospital /ID# 48322	Parkville	Victoria
United States	Dana-Farber Cancer Institute /ID# 48324	Boston	Massachusetts
United States	University of Texas MD Anderson Cancer Center /ID# 48326	Houston	Texas
United States	Ucsd /Id# 48325	La Jolla	California
United States	Univ of Wisconsin Hosp/Clinics /ID# 56811	Madison	Wisconsin
United States	Memorial Sloan Kettering Cancer Center /ID# 56810	New York	New York
United States	Fred Hutchinson Cancer Research /ID# 52882	Seattle	Washington
United States	Swedish Medical Center /ID# 135853	Seattle	Washington
United States	University of Arizona Cancer Center - North Campus /ID# 52902	Tucson	Arizona

Sponsors (2)

Lead Sponsor	Collaborator
AbbVie	Genentech, Inc.

Countries where clinical trial is conducted

United States,  Australia, 

References & Publications (1)

Davids MS, Roberts AW, Seymour JF, Pagel JM, Kahl BS, Wierda WG, Puvvada S, Kipps TJ, Anderson MA, Salem AH, Dunbar M, Zhu M, Peale F, Ross JA, Gressick L, Desai M, Kim SY, Verdugo M, Humerickhouse RA, Gordon GB, Gerecitano JF. Phase I First-in-Human Study of Venetoclax in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma. J Clin Oncol. 2017 Mar 10;35(8):826-833. doi: 10.1200/JCO.2016.70.4320. Epub 2017 Jan 17. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Determination of dose limiting toxicity (DLT), maximum tolerated dose (MTD), recommended phase two dose (RPTD), and lead-in period regimen	Protocol-defined events, which can not be attributed by the investigator to a clearly identifiable cause such as tumor progression, underlying illness, concurrent illness, or concomitant medication, will be considered a DLT. Dose limiting toxicities of tumor lysis syndrome observed during the lead-in period will be attributed to the lead-in period.	Lead-in period (2-5 weeks) plus 3 weeks of study drug administration at the designated cohort dose (continuous dosing)
Primary	Number of subjects with adverse events		First 16 weeks of study drug administration and every 4 weeks thereafter (continuous dosing for an anticipated maximum duration of 9 months)
Primary	Determination of plasma peak concentration (Cmax) of ABT-199	Blood and urine samples for pharmacokinetic analysis of ABT-199 will be collected at designated time points	Up to Week 24 for ABT-199
Primary	Determination of trough concentration (Ctrough) of ABT-199	Blood and urine samples for pharmacokinetic analysis of ABT-199 will be collected at designated time points	Up to Week 24 for ABT-199
Primary	Determination of area under the concentration versus time curve (AUC) of ABT-199	Blood and urine samples for pharmacokinetic analysis of ABT-199 will be collected at designated time points	Up to Week 24 for ABT-199
Secondary	Food Effect - Cmax	Pharmacokinetic (PK) parameter Cmax (maximum plasma concentration of ABT-199) between each diet (ABT-199 under fasting versus low-fat, and fasting versus high-fat conditions (Cohorts 1-6 in Arm B subjects only)	Approximately 3 days
Secondary	Preliminary efficacy assessment	Tumor response or clinical disease progression	Starting Week 4 for clinical disease progression and Week 6 for tumor response; and every 4 weeks thereafter (continuous dosing for an anticipated maximum duration of 9 months)
Secondary	Minimal residual disease collection (MRD)	MRD assessed in the peripheral blood and/or bone marrow (BM) either by four color flow cytometry or ASO-PCR, will be measured in CLL subjects achieving CR/CRi.	At least 2 months after the CR, CRi criteria for tumor response are first met. Every 12 weeks thereafter, until MRD negativity has been achieved (in peripheral blood).
Secondary	Food Effect - Tmax	Pharmacokinetic (PK) parameter Tmax (time to reach maximum plasma concentration of ABT-199) between each diet (ABT-199 under fasting versus low-fat, and fasting versus high-fat conditions (Cohorts 1-6 in Arm B subjects only)	Approximately 3 days
Secondary	Food Effect - AUC	Pharmacokinetic (PK) parameter AUC (area under the concentration-time curve from time zero to hour 24 of ABT-199) between each diet (ABT-199 under fasting versus low-fat, and fasting versus high-fat conditions (Cohorts 1-6 in Arm B subjects only)	Approximately 3 days

External Links

•   clinical study report synopsis