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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

Primary Purpose

Chronic Lymphocytic Leukemia, Non-Hodgkin Lymphoma

Status

Completed

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

ABT-199

About this trial

This is an interventional treatment trial for Chronic Lymphocytic Leukemia focused on measuring Safety, Maximum Tolerated Dose, Pharmacokinetics, ABT-199, Preliminary Efficacy, Cancer, Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia

Eligibility Criteria

18 Years - 99 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

University of Arizona Cancer Center - North Campus /ID# 52902
Ucsd /Id# 48325
Dana-Farber Cancer Institute /ID# 48324
Memorial Sloan Kettering Cancer Center /ID# 56810
University of Texas MD Anderson Cancer Center /ID# 48326
Swedish Medical Center /ID# 135853
Fred Hutchinson Cancer Research /ID# 52882
Univ of Wisconsin Hosp/Clinics /ID# 56811
Peter MacCallum Cancer Ctr /ID# 48323
Royal Melbourne Hospital /ID# 48322

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Arm A (CLL/SLL subjects)

Arm B (NHL subjects)

Arm Description

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) subjects

Non-Hodgkin lymphoma (NHL) subjects

Outcomes

Primary Outcome Measures

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.

Number of subjects with adverse events

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

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

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

Secondary Outcome Measures

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)

Preliminary efficacy assessment

Tumor response or clinical disease progression

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.

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)

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)

Full Information

NCT ID

NCT01328626

First Posted

April 1, 2011

Last Updated

February 10, 2022

Sponsor

AbbVie

Collaborators

Genentech, Inc.

1. Study Identification

Unique Protocol Identification Number

NCT01328626

Brief 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

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

2. Study Status

Record Verification Date

February 2022

Overall Recruitment Status

Completed

Study Start Date

May 23, 2011 (Actual)

Primary Completion Date

May 8, 2020 (Actual)

Study Completion Date

May 8, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

AbbVie

Collaborators

Genentech, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Chronic Lymphocytic Leukemia, Non-Hodgkin Lymphoma

Keywords

Safety, Maximum Tolerated Dose, Pharmacokinetics, ABT-199, Preliminary Efficacy, Cancer, Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

222 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm A (CLL/SLL subjects)

Arm Type

Experimental

Arm Description

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) subjects

Arm Title

Arm B (NHL subjects)

Arm Type

Experimental

Arm Description

Non-Hodgkin lymphoma (NHL) subjects

Intervention Type

Drug

Intervention Name(s)

ABT-199

Intervention Description

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.

Primary Outcome Measure Information:

Title

Determination of dose limiting toxicity (DLT), maximum tolerated dose (MTD), recommended phase two dose (RPTD), and lead-in period regimen

Description

Time Frame

Lead-in period (2-5 weeks) plus 3 weeks of study drug administration at the designated cohort dose (continuous dosing)

Title

Number of subjects with adverse events

Time Frame

First 16 weeks of study drug administration and every 4 weeks thereafter (continuous dosing for an anticipated maximum duration of 9 months)

Title

Determination of plasma peak concentration (Cmax) of ABT-199

Description

Blood and urine samples for pharmacokinetic analysis of ABT-199 will be collected at designated time points

Time Frame

Up to Week 24 for ABT-199

Title

Determination of trough concentration (Ctrough) of ABT-199

Description

Blood and urine samples for pharmacokinetic analysis of ABT-199 will be collected at designated time points

Time Frame

Up to Week 24 for ABT-199

Title

Determination of area under the concentration versus time curve (AUC) of ABT-199

Description

Blood and urine samples for pharmacokinetic analysis of ABT-199 will be collected at designated time points

Time Frame

Up to Week 24 for ABT-199

Secondary Outcome Measure Information:

Title

Food Effect - Cmax

Description

Time Frame

Approximately 3 days

Title

Preliminary efficacy assessment

Description

Tumor response or clinical disease progression

Time Frame

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)

Title

Minimal residual disease collection (MRD)

Description

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.

Time Frame

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).

Title

Food Effect - Tmax

Description

Time Frame

Approximately 3 days

Title

Food Effect - AUC

Description

Time Frame

Approximately 3 days

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

99 Years

Accepts Healthy Volunteers

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

AbbVie Inc.

Organizational Affiliation

AbbVie

Official's Role

Study Director

Facility Information:

Facility Name

University of Arizona Cancer Center - North Campus /ID# 52902

City

Tucson

State/Province

Arizona

ZIP/Postal Code

85719-1478

Country

United States

Facility Name

Ucsd /Id# 48325

City

La Jolla

State/Province

California

ZIP/Postal Code

92093

Country

United States

Facility Name

Dana-Farber Cancer Institute /ID# 48324

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02215

Country

United States

Facility Name

Memorial Sloan Kettering Cancer Center /ID# 56810

City

New York

State/Province

New York

ZIP/Postal Code

10065-6007

Country

United States

Facility Name

University of Texas MD Anderson Cancer Center /ID# 48326

City

Houston

State/Province

Texas

ZIP/Postal Code

77030

Country

United States

Facility Name

Swedish Medical Center /ID# 135853

City

Seattle

State/Province

Washington

ZIP/Postal Code

98104

Country

United States

Facility Name

Fred Hutchinson Cancer Research /ID# 52882

City

Seattle

State/Province

Washington

ZIP/Postal Code

98109

Country

United States

Facility Name

Univ of Wisconsin Hosp/Clinics /ID# 56811

City

Madison

State/Province

Wisconsin

ZIP/Postal Code

53792-0001

Country

United States

Facility Name

Peter MacCallum Cancer Ctr /ID# 48323

City

Melbourne

State/Province

Victoria

ZIP/Postal Code

3000

Country

Australia

Facility Name

Royal Melbourne Hospital /ID# 48322

City

Parkville

State/Province

Victoria

ZIP/Postal Code

3050

Country

Australia

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

28095146

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.

Results Reference

background

PubMed Identifier

34083230

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.

Results Reference

derived

PubMed Identifier

31023700

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.

Results Reference

derived

PubMed Identifier

26639348

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.

Results Reference

derived

Links:

URL

https://www.abbvieclinicaltrials.com/study/?id=M12-175&Latitude=&Longitude=&LocationName=#additional-resources-section

Description

clinical study report synopsis

Learn more about this trial

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

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