Clinical Trials /

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

NCT03136497

Description:

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.

Related Conditions:
  • Diffuse Large B-Cell Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: Pro00005671
  • SECONDARY ID: 54179060LYM1004
  • SECONDARY ID: ML30063
  • NCT ID: NCT03136497

Conditions

  • Relapsed Diffuse Large B-Cell Lymphoma
  • Refractory Diffuse Large B-Cell Lymphoma

Interventions

DrugSynonymsArms
ABT-199A-1195425.0, VenetoclaxABT-199 Plus Ibrutinib and Rituximab
IbrutinibPIC-32765, ImbruvicaABT-199 Plus Ibrutinib and Rituximab
RituximabRituxanABT-199 Plus Ibrutinib and Rituximab

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
ABT-199 Plus Ibrutinib and RituximabExperimentalCycle 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.
  • ABT-199
  • Ibrutinib
  • Rituximab

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD)
Time Frame:29 days
Safety Issue:
Description: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

Measure:Incidence of treatment-emergent adverse events.
Time Frame:36 Months
Safety Issue:
Description:Adverse events will be assessed using the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE), version 4.03.
Measure:Efficacy as assessed by progression free survival (PFS)
Time Frame:36 Months
Safety Issue:
Description: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.
Measure:Efficacy as assessed by overall survival (OS)
Time Frame:36 Months
Safety Issue:
Description: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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Hackensack Meridian Health

Last Updated

August 15, 2019