Clinical trial NCT01328626: 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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Chronic Lymphocytic Leukemia
Non-Hodgkin Lymphoma
Keywords: Safety
Maximum Tolerated Dose
Pharmacokinetics
ABT-199
Preliminary Efficacy
Cancer
Non-Hodgkin Lymphoma
Chronic Lymphocytic Leukemia
Lead sponsor: AbbVie
Sponsor class: INDUSTRY
Collaborators: name: Genentech, Inc.
First posted: 2011-04-05
Enrollment: 222
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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

Eligibility criteria: 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.

Primary outcomes:
measure: Determination of dose limiting toxicity (DLT), maximum tolerated dose (MTD), recommended phase two dose (RPTD), and lead-in period regimen
timeFrame: Lead-in period (2-5 weeks) plus 3 weeks of study drug administration at the designated cohort dose (continuous dosing)
measure: Number of subjects with adverse events
timeFrame: First 16 weeks of study drug administration and every 4 weeks thereafter (continuous dosing for an anticipated maximum duration of 9 months)
measure: Determination of plasma peak concentration (Cmax) of ABT-199
timeFrame: Up to Week 24 for ABT-199
measure: Determination of trough concentration (Ctrough) of ABT-199
timeFrame: Up to Week 24 for ABT-199
measure: Determination of area under the concentration versus time curve (AUC) of ABT-199
timeFrame: Up to Week 24 for ABT-199
Secondary outcomes:
measure: Food Effect - Cmax
timeFrame: Approximately 3 days
measure: Preliminary efficacy assessment
timeFrame: 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)
measure: Minimal residual disease collection (MRD)
timeFrame: 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).
measure: Food Effect - Tmax
timeFrame: Approximately 3 days
measure: Food Effect - AUC
timeFrame: Approximately 3 days
Other outcomes:
Locations:
city: Tucson
country: United States
facility: University of Arizona Cancer Center - North Campus /ID# 52902
state: Arizona
city: La Jolla
country: United States
facility: Ucsd /Id# 48325
state: California
city: Boston
country: United States
facility: Dana-Farber Cancer Institute /ID# 48324
state: Massachusetts
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center /ID# 56810
state: New York
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center /ID# 48326
state: Texas
city: Seattle
country: United States
facility: Swedish Medical Center /ID# 135853
state: Washington
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research /ID# 52882
state: Washington
city: Madison
country: United States
facility: Univ of Wisconsin Hosp/Clinics /ID# 56811
state: Wisconsin
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Ctr /ID# 48323
state: Victoria
city: Parkville
country: Australia
facility: Royal Melbourne Hospital /ID# 48322
state: Victoria
Study officials:
affiliation: AbbVie
name: AbbVie Inc.
role: STUDY_DIRECTOR
References:
citation: 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.
citation: Davids MS, Roberts AW, Kenkre VP, Wierda WG, Kumar A, Kipps TJ, Boyer M, Salem AH, Pesko JC, Arzt JA, Mantas M, Kim SY, Seymour JF. Long-term Follow-up of Patients with Relapsed or Refractory Non-Hodgkin Lymphoma Treated with Venetoclax in a Phase I, First-in-Human Study. Clin Cancer Res. 2021 Sep 1;27(17):4690-4695. doi: 10.1158/1078-0432.CCR-20-4842. Epub 2021 Jun 3.
citation: Roberts AW, Ma S, Kipps TJ, Coutre SE, Davids MS, Eichhorst B, Hallek M, Byrd JC, Humphrey K, Zhou L, Chyla B, Nielsen J, Potluri J, Kim SY, Verdugo M, Stilgenbauer S, Wierda WG, Seymour JF. Efficacy of venetoclax in relapsed chronic lymphocytic leukemia is influenced by disease and response variables. Blood. 2019 Jul 11;134(2):111-122. doi: 10.1182/blood.2018882555. Epub 2019 Apr 25.
citation: Roberts AW, Davids MS, Pagel JM, Kahl BS, Puvvada SD, Gerecitano JF, Kipps TJ, Anderson MA, Brown JR, Gressick L, Wong S, Dunbar M, Zhu M, Desai MB, Cerri E, Heitner Enschede S, Humerickhouse RA, Wierda WG, Seymour JF. Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 2016 Jan 28;374(4):311-22. doi: 10.1056/NEJMoa1513257. Epub 2015 Dec 6.