A Study of ABT-199 Plus Ibrutinib and Rituximab in Patients With Relapsed/Refractory Diffuse Large B-cell Lymphoma

June 3, 2024 updated by: Hackensack Meridian Health

Phase Ib Dose Finding Study of ABT-199 (A-1195425.0) Plus Ibrutinib (PCI-32765) and Rituximab in Patients With Relapsed/Refractory Diffuse Large B-cell NHL (DLBCL)

A Study of Venetoclax Plus Ibrutinib and Rituximab in Patients with Relapsed/Refractory Diffuse Large B-cell Lymphoma (DLBCL).

Our hypothesis is that the combination therapy of BTK (Bruton's tyrosine kinase) Inhibitor Ibrutinib plus Venetoclax and Rituximab in relapsed or refractory DLBCL will have an increased activity with acceptable toxicity. Furthermore, this new novel therapeutic combination will be safe and well tolerated among this patient population.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

This is a Phase 1b, single-arm, open-label, single-center study of venetoclax (ABT-199) in combination with ibrutinib and rituximab in Subjects with Relapsed/Refractory DLBCL. The trial consists of a dose-escalation of venetoclax in combination with standard doses of ibrutinib and rituximab. For the dose escalation part of the study, a standard 3+3 design will be utilized. Once the MTD has been established, the dose escalation part will be followed by a dose expansion part in a cohort with a maximum of 24 subjects with DLBCL. The purpose of the dose expansion part is to investigate the efficacy of the combination. Between the dose-escalation and dose-expansion, the maximum number of subjects will be 30.

Cycle length will be 28 days. Venetoclax will be administered orally QD (Once Daily), continuously for 24 cycles. Ibrutinib will be administered orally QD, continuously for 24 cycles. Rituximab will be administered IV per institutional standards. weekly X 4 (Cycle 1); once on Day 1 of cycles 2-6 only, then every other cycle until Cycle 24 (total 18 doses of Rituxan from C1D1), Commercially available rituximab IV will be used.

Study Type

Interventional

Enrollment (Actual)

10

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • New Jersey
      • Hackensack, New Jersey, United States, 07601
        • John Theurer Cancer Center at Hackensack University Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • ECOG (Eastern Cooperative Oncology Group) Performance Status </= 2.
  • Histologically or cytologically confirmed diagnosis of advanced DLBCL.
  • Ability and willingness to comply with the requirements of the study protocol
  • Prior therapy: relapsed or refractory patients who have received one prior therapy are eligible. If treated with small molecule, washout therapy with a period of greater than 5 times the half-life of the molecule. Patients who have previously received high-dose chemotherapy with peripheral stem cell support are eligible. Washout period of 21 days.
  • Presence of at least one lymph node evaluable or mass measurable for response.
  • Age greater than or equal to 18 years.
  • Recovery from any previous treatment therapy.
  • Laboratory parameters:
  • Absolute neutrophil count (ANC) 1000/mm3 independent of growth factor support (unless the treating physician deems the neutropenia is related to bone marrow involvement, then an ANC of > 750/mm3 is allowed)
  • Platelets 100,000/mm3 or 50,000/mm3 if bone marrow involvement independent of transfusion support in either situation
  • Total bilirubin ≤ 1.5 x ULN unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin
  • Aspartate Aminotransferase (AST, SGOT) and Alanine Aminotransferase (ALT, SGPT) ≤ 3 x upper limit of normal (ULN)
  • Creatinine: Creatinine Clearance (CrCl) 50 ml/min (calculated using Cockcroft-Gault Formula-Appendix 2) -Prothrombin time (PT)or international normalized ratio and partial thromboplastin time (PTT) not to exceed 1.2 times the institution's normal range
  • Women of childbearing potential and men who are sexually active must be practicing a highly effective method of birth control during and after the study consistent with local regulations regarding the use of birth control methods for subjects participating in clinical trials. Men must agree to not donate sperm during and after the study. For females, these restrictions apply for 3 months after Venetoclax and 12 months after Rituximab For males, these restrictions apply for 3 months after the last dose of study drug.
  • Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin [-hCG]) or urine pregnancy test at Screening. Women who are pregnant or breastfeeding are ineligible for this study.
  • Sign (or their legally-acceptable representatives must sign) an informed consent document indicating that they understand the purpose of and procedures required for the study, including biomarkers, and are willing to participate in the study

Exclusion Criteria:

  • Known central nervous system lymphoma.
  • History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
  • Requires anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon).
  • Received the following agents within 7 days prior to the first dose of venetoclax or requires chronic treatment with strong Cytochrome P450 3A4 (CYP3A) inhibitors (e.g., ketoconazole, ritonavir, clarithromycin, itraconazole, voriconazole), moderate CYP3A inhibitors (e.g., erythromycin, ciprofloxacin, diltiazem, fluconazole, verapamil), strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, St. John's wort) or moderate CYP3A inducers (e.g., bosentan, efavirenz, etravirine). (See Appendix 4)
  • Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification.
  • Vaccinated with live, attenuated vaccines within 4 weeks of randomization.
  • Use of any other standard chemotherapy, radiation therapy, or experimental drug therapy for the treatment of DLBCL within 21 days of starting treatment
  • Known history of human immunodeficiency virus (HIV) or active Hepatitis C Virus or active Hepatitis B Virus infection or any uncontrolled active systemic infection or human T-cell leukemia virus 1 (HTLV-1) seropositive status
  • Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of ibrutinib capsules, venetoclax or rituximab or put the study outcomes at undue risk.
  • History of uncontrolled or symptomatic angina
  • Ejection fraction below the institutional normal limit
  • History of other malignancy that could affect compliance with the protocol or interpretation of results
  • Patients with a history of curatively treated basal or squamous cell carcinoma of the skin or in situ carcinoma of the cervix are generally eligible. Patients with a malignancy that has been treated, but not with curative intent, will also be excluded, unless the malignancy has been in remission without treatment for 2 years prior to enrollment.
  • Evidence of other clinically significant uncontrolled condition(s) including, but not limited to, uncontrolled systemic infection (viral, bacterial, or fungal)
  • Major surgery (within 4 weeks prior to the start of the first dose of study treatment), other than for diagnosis
  • Women who are pregnant or lactating
  • Female patients who are not surgically sterile or postmenopausal (for at least 1 year) must practice at least one of the following methods of birth control throughout the duration of study participation and for at least 12 months after study treatment:
  • Total abstinence from sexual intercourse
  • A vasectomized partner
  • Hormonal contraceptives (oral, parenteral, vaginal ring, or transdermal) that started at least 3 months prior to study drug administration
  • Double-barrier method (condom diaphragm or cervical cup with spermicidal contraceptive sponge, jellies, or cream)
  • Non-vasectomized male patients must comply with at least one of the following methods of birth control throughout the duration of study participation and for at least 12 months after study treatment:
  • A partner who is surgically sterile or postmenopausal (for at least 1 year) or who is taking hormonal contraceptives (oral, parenteral, vaginal ring, or transdermal) for at least 3 months prior to study drug administration
  • Total abstinence from sexual intercourse
  • Double-barrier method (condom diaphragm or cervical cup with spermicidal, contraceptive sponge, jellies, or cream)
  • Malabsorption syndrome or other condition that precludes enteral route of administration
  • Known allergy to both xanthine oxidase inhibitors and rasburicase

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Sequential Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: 400mg ABT-199
Cycle length will be 28 days. 400mg ABT-199 will be administered orally QD (Once Daily), continuously for 24 cycles. Ibrutinib will be administered orally QD, continuously for 24 cycles. Rituximab will be administered IV per institutional standards. weekly X 4 (Cycle 1); once on Day 1 of cycles 2-6 only, then every other cycle until Cycle 24 (total 18 doses of Rituxan from C1D1), Commercially available rituximab IV will be used.
Drug: Ibrutinib
Oral dose daily until disease progression
Other Names:
  • Imbruvica
  • PIC-32765
Drug: Rituximab
Rituximab will be administered IV per institutional standards. weekly X 4 (Cycle 1); once on Day 1 of cycles 2-6 only, then every other cycle until Cycle 24 (total 18 doses of Rituxan from C1D1
Other Names:
  • Rituxan
Drug: 400mg ABT-199
Oral dose daily until disease progression
Other Names:
  • Venetoclax
  • A-1195425.0
Experimental: 800mg ABT-199
Cycle length will be 28 days. 800mg ABT-199 will be administered orally QD (Once Daily), continuously for 24 cycles. Ibrutinib will be administered orally QD, continuously for 24 cycles. Rituximab will be administered IV per institutional standards. weekly X 4 (Cycle 1); once on Day 1 of cycles 2-6 only, then every other cycle until Cycle 24 (total 18 doses of Rituxan from C1D1), Commercially available rituximab IV will be used.
Drug: Ibrutinib
Oral dose daily until disease progression
Other Names:
  • Imbruvica
  • PIC-32765
Drug: Rituximab
Rituximab will be administered IV per institutional standards. weekly X 4 (Cycle 1); once on Day 1 of cycles 2-6 only, then every other cycle until Cycle 24 (total 18 doses of Rituxan from C1D1
Other Names:
  • Rituxan
Drug: 800mg ABT-199
Oral dose daily until disease progression
Other Names:
  • Venetoclax
  • A-1195425.0

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Maximum Tolerated Dose (MTD)
Time Frame: 29 days
Define maximum tolerated dose and /or recommended phase II dose for the combinations of venetoclax (ABT-199, GDC-0199) plus Ibrutinib (PCI-32765) and rituximab in Relapsed or Refractory DLBCL by assessing the incidence of dose limiting toxicities (DLTs).
29 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of Treatment-emergent Adverse Events.
Time Frame: 36 Months
Adverse events will be assessed using the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE), version 4.03.
36 Months
Efficacy as Assessed by Progression Free Survival (PFS)
Time Frame: 36 Months
The duration of PFS is defined as the time from the beginning of the first cycle of treatment to the date of progressive disease or death from any cause. PFS will be estimated using Kaplan-Meier method.
36 Months
Efficacy as Assessed by Overall Survival (OS)
Time Frame: 36 Months
The duration of OS is defined as the time from the beginning of the first cycle of treatment to the date of death from any cause. OS will be estimated using Kaplan-Meier method.
36 Months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Hackensack Meridian Health

Collaborators

Janssen Scientific Affairs, LLC
Genentech, Inc.

Investigators

  • Principal Investigator: Andre Goy, MD, Hackensack Meridian Health

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 5, 2017

Primary Completion (Actual)

November 9, 2020

Study Completion (Actual)

November 9, 2020

Study Registration Dates

First Submitted

April 20, 2017

First Submitted That Met QC Criteria

April 27, 2017

First Posted (Actual)

May 2, 2017

Study Record Updates

Last Update Posted (Actual)

September 23, 2024

Last Update Submitted That Met QC Criteria

June 3, 2024

Last Verified

June 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Pro00005671
  • 54179060LYM1004 (Other Identifier: Janssen Scientific Affairs, LLC)
  • ML30063 (Other Identifier: Genentech, Inc.)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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