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

NCT01682616 | Completed Phase 1 FDA Drug

• 1 other identifier: M13-365
• Study Type: interventional
• Target: 49
• Locations: 2 countries
• Sites: 6

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.

Conditions

Small Lymphocytic Lymphoma; Chronic Lymphocytic Leukemia

Keywords

Safety; Small Lymphocytic Lymphoma; Chronic Lymphocytic Leukemia; Rituximab; Tolerability; Pharmacokinetics; ABT-199; Cancer; Preliminary; Efficacy; Maximum Tolerated Dose; Venetoclax

Outcome Measures

Primary Outcomes (1)

• 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.

  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.

  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.

Secondary Outcomes (8)

• Determination of peak concentration (Cmax) of ABT-199 and/or Rituximab.

  PK samples collected up to Month 6 for ABT-199 and Rituximab

• Assess the exploratory efficacy of the combination ABT-199 and rituximab.

  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.

• Determination of trough concentration (Ctrough) of ABT-199 and/or Rituximab

  PK samples collected up to Month 6 for ABT-199 and Rituximab

• Determination of area under the concentration versus time curve (AUC) of ABT-199 and/or Rituximab

  PK samples collected up to Month 6 for ABT-199 and Rituximab

• Assess the exploratory efficacy of the combination ABT-199 and rituximab

  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.

Other Outcomes (1)

• Assess the exploratory pharmacodynamics and pharmacogenetics of the combination of ABT-199 and rituximab.

  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.

Study Arms (1)

Arm 1

EXPERIMENTAL

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

Drug: ABT-199; Drug: Rituximab

Interventions

ABT-199 DRUG

ABT-199 is taken continuously once daily. This is a dose escalation study, therefore the dose of ABT-199 will change throughout the study.

Also known as: venetoclax

Arm 1

Rituximab DRUG

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.

Arm 1

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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;

Sponsors & Collaborators

• AbbVie: lead
• Genentech, Inc.: collaborator

Study Sites (6)

Moores Cancer Center at UC San Diego /ID# 70398

La Jolla, California, 92093, United States

Location

Northwestern University Feinberg School of Medicine /ID# 71593

Chicago, Illinois, 60611-2927, United States

Location

North Shore University Hospital /ID# 71813

New Hyde Park, New York, 11040, United States

Location

Duke Cancer Center /ID# 71393

Durham, North Carolina, 27710-3000, United States

Location

Peter MacCallum Cancer Ctr /ID# 70394

Melbourne, Victoria, 3000, Australia

Location

The Royal Melbourne Hospital /ID# 70393

Parkville, Victoria, 3050, Australia

Location

Related Publications (3)

• 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.

  PMID: 35829925 DERIVED

• 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.

  PMID: 31023700 DERIVED

• 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.

  PMID: 28089635 DERIVED

Related Links

• clinical study report synopsis

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasms

Interventions

venetoclax; Rituximab

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• ABBVIE INC.

  AbbVie

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: June 26, 2012
• First Posted: September 11, 2012
• Study Start: July 25, 2012
• Primary Completion: June 23, 2022
• Study Completion: June 23, 2022
• Last Updated: June 6, 2023

Record last verified: 2023-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (4); AU (2)