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

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ClinicalTrials.gov Identifier: NCT03136497
Recruitment Status : Recruiting
First Posted : May 2, 2017
Last Update Posted : August 19, 2019
Sponsor:
Collaborators:
Janssen Scientific Affairs, LLC
Genentech, Inc.
Information provided by (Responsible Party):
Hackensack Meridian Health

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Relapsed Diffuse Large B-Cell Lymphoma Refractory Diffuse Large B-Cell Lymphoma Drug: ABT-199 Drug: Ibrutinib Drug: Rituximab Phase 1

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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)
Actual Study Start Date : September 5, 2017
Estimated Primary Completion Date : May 30, 2020
Estimated Study Completion Date : May 30, 2020


Arm Intervention/treatment
Experimental: ABT-199 Plus Ibrutinib and Rituximab
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.
Drug: ABT-199
Oral dose daily until disease progression
Other Names:
  • A-1195425.0
  • Venetoclax

Drug: Ibrutinib
Oral dose daily until disease progression
Other Names:
  • PIC-32765
  • Imbruvica

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 Name: Rituxan




Primary Outcome Measures :
  1. 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).


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03136497


Contacts
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Contact: Kara Yannotti, BSN 551-996-5168 Kara.Yannotti@HackensackMeridian.org
Contact: Sabrina Kdiry, BSN 551-996-5952 Sabrina.Kdiry@HackensackMeridian.org

Locations
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United States, New Jersey
John Theurer Cancer Center at Hackensack University Medical Center Recruiting
Hackensack, New Jersey, United States, 07601
Contact: Kara Yannotti, BSN    551-996-5168    Kara.Yannotti@HackensackMeridian.org   
Contact: Sabrina Kdiry, BSN    551-996-5952    Sabrina.Kdiry@HackensackMeridian.org   
Principal Investigator: Andre Goy, MD         
Sub-Investigator: Martin Gutierrez, MD         
Sub-Investigator: Tatyana Feldman, MD         
Sub-Investigator: Alan Skarbnik, MD         
Sub-Investigator: Lori Leslie, MD         
Sub-Investigator: Ann McNeill, APN, RN         
Sponsors and Collaborators
Hackensack Meridian Health
Janssen Scientific Affairs, LLC
Genentech, Inc.
Investigators
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Principal Investigator: Andre Goy, MD Hackensack Meridian Health

Publications:
Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, Lister TA; Alliance, Australasian Leukaemia and Lymphoma Group; Eastern Cooperative Oncology Group; European Mantle Cell Lymphoma Consortium; Italian Lymphoma Foundation; European Organisation for Research; Treatment of Cancer/Dutch Hemato-Oncology Group; Grupo Español de Médula Ósea; German High-Grade Lymphoma Study Group; German Hodgkin's Study Group; Japanese Lymphorra Study Group; Lymphoma Study Association; NCIC Clinical Trials Group; Nordic Lymphoma Study Group; Southwest Oncology Group; United Kingdom National Cancer Research Institute. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014 Sep 20;32(27):3059-68.

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Responsible Party: Hackensack Meridian Health
ClinicalTrials.gov Identifier: NCT03136497     History of Changes
Other Study ID Numbers: Pro00005671
54179060LYM1004 ( Other Identifier: Janssen Scientific Affairs, LLC )
ML30063 ( Other Identifier: Genentech, Inc. )
First Posted: May 2, 2017    Key Record Dates
Last Update Posted: August 19, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Lymphoma
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Rituximab
Venetoclax
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents