A Phase 1b Study Evaluating the Safety and Tolerability of ABT-199 in Combination With Rituximab in Subjects With Relapsed Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

• ClinicalTrials.gov Identifier: NCT01682616
• Recruitment Status: Completed
• First Posted: September 11, 2012
• Last Update Posted: July 12, 2022
• Sponsor: AbbVie
• Collaborator: Genentech, Inc.
• Information provided by (Responsible Party): AbbVie

Tracking Information

• First Submitted Date: June 26, 2012
• First Posted Date: September 11, 2012
• Last Update Posted Date: July 12, 2022
• Actual Study Start Date: July 25, 2012
• Actual Primary Completion Date: June 23, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 2, 2019)

Assess the safety profile, to determine the maximum tolerated dose and Recommended Phase Two Dose of ABT-199 when administered in combination with rituximab (R) in subjects with relapsed chronic lymphocytic leukemia and small lymphocytic lymphoma. [ Time Frame: Continuous dosing at designated dose level up to Month 6. At end of combination treatment, ABT-199 monotherapy may continue up to 8 years following the date of the last subject enrolled. If disease progression occurs, subjects may re-initiate ABT-199. ]

Protocol-defined events, which are attributed as having a reasonable possibility of being related to the administration of ABT-199 and/or rituximab, or can not be attributed by the investigator to a clearly identifiable cause such as tumor progression, concurrent illness, underlying disease or concomitant medication, will be considered a dose limiting toxicity.

Original Primary Outcome Measures (submitted: September 7, 2012)

Assess the safety of ABT-199 when administered in combination with rituximab (R) in subjects with relapsed chronic lymphocytic leukemia. [ Time Frame: Continuous dosing with study drug at the designated cohort dose level up to Week 30. ]

Protocol-defined events, which can not be attributed by the investigator to a clearly identifiable cause such as tumor progression, concurrent illness, or concomitant medication, will be considered a dose limiting toxicity.

Current Secondary Outcome Measures (submitted: May 2, 2019)

• Determination of peak concentration (Cmax) of ABT-199 and/or Rituximab. [ Time Frame: PK samples collected up to Month 6 for ABT-199 and Rituximab ]
  Blood samples for analysis of ABT-199 and rituximab will be collected at designated time points.
• Assess the exploratory efficacy of the combination ABT-199 and rituximab. [ Time Frame: Tumor Assessments will be performed at: Screening, Day 1 on Months 1, 3, 7, and then every 3 months thereafter up to 8 years following the date of the last subject first dose. ]
  Tumor response or clinical disease progression (Objective Response Rate)
• Determination of trough concentration (Ctrough) of ABT-199 and/or Rituximab [ Time Frame: PK samples collected up to Month 6 for ABT-199 and Rituximab ]
  Blood samples for analysis of ABT-199 and rituximab will be collected at designated time points.
• Determination of area under the concentration versus time curve (AUC) of ABT-199 and/or Rituximab [ Time Frame: PK samples collected up to Month 6 for ABT-199 and Rituximab ]
  Blood samples for analysis of ABT-199 and rituximab will be collected at designated time points.
• Assess the exploratory efficacy of the combination ABT-199 and rituximab [ Time Frame: Tumor Assessments will be performed at: Screening, Day 1 on Months 1, 3, 7, and then every 3 months thereafter up to 8 years following the date of the last subject first dose. ]
  Tumor response or clinical disease progression for (Overall Survival)
• Assess the exploratory efficacy of the combination ABT-199 and rituximab [ Time Frame: Tumor Assessments will be performed at: Screening, Day 1 on Months 1, 3, 7, and then every 3 months thereafter up to 8 years following the date of the last subject first dose. ]
  Tumor response or clinical disease progression for (Progression Free Survival)
• Assess the exploratory efficacy of the combination ABT-199 and rituximab [ Time Frame: Tumor Assessments will be performed at: Screening, Day 1 on Months 1, 3, 7, and then every 3 months thereafter up to 8 years following the date of the last subject first dose. ]
  Tumor response or clinical disease progression for (Time to Tumor Progression)
• Assess the exploratory efficacy of the combination ABT-199 and rituximab [ Time Frame: Tumor Assessments will be performed at: Screening, Day 1 on Months 1, 3, 7, and then every 3 months thereafter up to 8 years following the date of the last subject first dose. ]
  Tumor response or clinical disease progression for (Duration Of Response)

Original Secondary Outcome Measures (submitted: September 7, 2012)

• Assess the exploratory efficacy and the pharmacokinetic profile of the combination ABT-199 and rituximab. [ Time Frame: Tumor Assessments will be performed at following timepoints: Screening, Week 30, Week4Day1, Week14 Day 1 and Week 38 Day1, and at least 2 months after Complete Remission or Complete Remission with incomplete bone marrow recovery is first met, ]
  Tumor response or clinical disease progression Time Frame (continued): and at the Final Visit.
• Determination of peak concentration (Cmax), trough concentration (Ctrough) and/or area under the concentration versus time curve (AUC) of ABT-199 and/or Rituximab [ Time Frame: Up to Week 26 for ABT-199 and Rituximab ]
  Blood samples for pharmacokinetic analysis of ABT-199 and rituximab will be collected at designated time points.

Current Other Pre-specified Outcome Measures (submitted: August 20, 2013)

Assess the exploratory pharmacodynamics and pharmacogenetics of the combination of ABT-199 and rituximab. [ Time Frame: MRD Assessments will be performed at following timepoints: At least 2 months after CR/CRi criteria for tumor response first met, every 12 weeks thereafter until MRD negativity is achieved, and as needed. ]

Minimal residual disease (MRD) will be assessed in the peripheral blood and bone marrow (BM) either by flow cytometry or real-time PCR.

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Phase 1b Study Evaluating the Safety and Tolerability of ABT-199 in Combination With Rituximab in Subjects With Relapsed Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma
• Official Title: A Phase 1b Study Evaluating the Safety and Tolerability of ABT-199 in Combination With Rituximab in Subjects With Relapsed Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma
• Brief Summary: This is a Phase 1b, open-label, multicenter study evaluating the safety and tolerability of ABT-199 in combination with rituximab in up to 50 subjects with Relapsed Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma. The primary objectives of this study are to assess the safety profile, to determine the maximum tolerated dose and establish the Recommended Phase Two Dose of ABT-199 when administered in combination with rituximab. The dose escalation portion of the study will include approximately 30 subjects. Once the recommended phase two dose and schedule have been determined, up to 20 additional subjects will be enrolled in an expanded safety portion of the study. Subjects who meet criteria for CR, CRi, or MRD-negative PR during the study may discontinue ABT 199. If disease progression occurs, as defined by iwCLL NCI/WG criteria for tumor response, or MRD progression, subjects may re-initiate ABT-199.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Small Lymphocytic Lymphoma
• Chronic Lymphocytic Leukemia

Intervention

• Drug: ABT-199
  ABT-199 is taken continuously once daily. This is a dose escalation study, therefore the dose of ABT-199 will change throughout the study.
  Other Name: venetoclax
• Drug: Rituximab
  Rituximab will be given by intravenous infusion on day 1 of Months 1, 2, 3, 4, 5, and 6. May be reinitiated for an additional 6 months.

Study Arms

Experimental: Arm 1

Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL)

Interventions:

• Drug: ABT-199
• Drug: Rituximab

Publications *

• Badawi M, Chen X, Marroum P, Suleiman AA, Mensing S, Koenigsdorfer A, Schiele JT, Palenski T, Samineni D, Hoffman D, Menon R, Salem AH. Bioavailability Evaluation of Venetoclax Lower-Strength Tablets and Oral Powder Formulations to Establish Interchangeability with the 100 mg Tablet. Clin Drug Investig. 2022 Aug;42(8):657-668. doi: 10.1007/s40261-022-01172-4. Epub 2022 Jul 13.
• 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.
• Seymour JF, Ma S, Brander DM, Choi MY, Barrientos J, Davids MS, Anderson MA, Beaven AW, Rosen ST, Tam CS, Prine B, Agarwal SK, Munasinghe W, Zhu M, Lash LL, Desai M, Cerri E, Verdugo M, Kim SY, Humerickhouse RA, Gordon GB, Kipps TJ, Roberts AW. Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study. Lancet Oncol. 2017 Feb;18(2):230-240. doi: 10.1016/S1470-2045(17)30012-8. Epub 2017 Jan 13.

Recruitment Information

• Recruitment Status: Completed
• Estimated Enrollment (submitted: September 7, 2012): 50
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: June 23, 2022
• Actual Primary Completion Date: June 23, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Subject must be greater then or equal to 18 years of age.
• Subject must have relapsed Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma.
• Subject has an Eastern Cooperative Oncology Group performance score of 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:

• Chronic lymphocytic leukemia or Small Lymphocytic Lymphoma subject has undergone an allogeneic or autologous stem cell transplant.
• Subject has uncontrolled autoimmune hemolytic anemia or thrombocytopenia.
• Subject has tested positive for human immunodeficiency virus.
• Seropositivity for hepatitis B surface antigen or hepatitis C virus antibody or ribonucleic acid.
• History of severe allergic or anaphylactic reactions to rituximab.
• Subject has received a live viral vaccine within 6 months prior to the first dose of study drug.
• Subject has received a monoclonal antibody for anti-neoplastic intent within 8 weeks prior to the first dose of study drug.

• Subject has received any of the following within 14 days prior to the first dose of study drug, or has not recovered to less than grade 2 clinically significant adverse effect(s)/toxicity(s) of the previous therapy:

  • Any anti-cancer therapy including chemotherapy, immunotherapy, or radiotherapy;
  • Investigational therapy, including targeted small molecule agents.
• Subject has a cardiovascular disability status of New York Heart Association Class greater then or equal to 2. Class 2 is defined as cardiac disease in which subjects 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 a history of other active malignancies other than CLL/SLL within the past 2 years prior to study entry, with the exception of:

  • Adequately treated in situ carcinoma of the cervix uteri;
  • Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin;
  • Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent.
• Subject has malabsorption syndrome or other condition that precludes enteral route of administration.

• Subject exhibits evidence of other clinically significant ongoing or recent condition(s) including, but not limited to:

  • Ongoing systemic infection (viral, bacterial, or fungal);
  • Diagnosis of fever and neutropenia within 1 week prior to study drug administration

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 99 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, United States

Administrative Information

• NCT Number: NCT01682616
• Other Study ID Numbers: M13-365
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: AbbVie
• Original Responsible Party: Abbott
• Current Study Sponsor: AbbVie
• Original Study Sponsor: Abbott
• Collaborators: Genentech, Inc.

Investigators

• Study Director: ABBVIE INC.; AbbVie

• PRS Account: AbbVie
• Verification Date: July 2022