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.
- 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
- 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
- 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
- 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,
- 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
- 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
- Known allergy to both xanthine oxidase inhibitors and rasburicase