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Ibrutinib and Venetoclax in Treating Patients with Relapsed or Refractory Follicular Lymphoma

Trial Status: Active

This phase I / II trial studies the side effects and best dose of ibrutinib and venetoclax and to see how well they work in treating patients with follicular lymphoma that has returned after a period of improvement or does not respond to treatment. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Venetoclax may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Giving ibrutinib and venetoclax may work better in treating patients with follicular lymphoma.

Inclusion Criteria

  • Relapsed or refractory, histologically confirmed follicular lymphoma, grade I, II, or IIIa which requires therapy defined by at least one of the following: * Constitutional symptoms * Cytopenias * High tumor burden (single mass > 7 cm, three masses > 3 cm, symptomatic splenomegaly, organ compression or compromise, ascites, pleural effusion) * Any other clinical indication for treatment per investigator discretion; for example, patients with masses that do not fulfill the above stated dimensions but require therapy as determined by treating physician are eligible
  • Must have received at least one prior systemic therapy
  • All risk by Follicular Lymphoma International Prognostic Index (FLIPI) 0-5 factors
  • Measurable disease must be present either on physical examination or imaging studies; non-measurable disease alone is not acceptable; any tumor mass > 1.5 cm is acceptable; lesions that are considered non-measurable include the following: * Bone lesions (lesions if present should be noted) * Ascites * Pleural/pericardial effusion * Lymphangitis cutis/pulmonis * Bone marrow (involvement by lymphoma should be noted)
  • Absolute neutrophil count (ANC) >= 1000 cells/mm^3 (1.0 x 10^9/L) at least 3 weeks prior to screening unless attributable to disease; ANC > 500 cells/mm^3 is permissible if due to disease
  • Platelet count >= 50,000 cells/mm^3 (50 x 10^9/L) at least 3 weeks prior to screening unless attributable to disease; platelet count >= 20,000 cells/mm^3 is permissible if due to disease
  • Hemoglobin >= 8.0 g/dL at least 3 weeks prior to screening unless attributable to disease
  • Serum aspartate transaminase (AST) or alanine transaminase (ALT) =< 2.5 x upper limit of normal (ULN); serum aspartate transaminase (AST) or alanine transaminase (ALT) =< 5 is permissible if due to disease
  • Bilirubin =< 1.5 x ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin); bilirubin =< 3 x ULN is permissible if due to disease
  • Estimated creatinine clearance >= 50 ml/min (Cockcroft-Gault based on actual weight)
  • Prothrombin time (PT)/international normalized ratio (INR) < 1.5 x ULN and partial thromboplastin time (PTT) (activated [a]PTT) < 1.5 x ULN
  • Eastern Cooperative Oncology Group (ECOG) performance status of =< 2
  • Female subjects who are of non-reproductive potential (i.e., post-menopausal by history - no menses for >= 1 year; OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral oophorectomy); female subjects of childbearing potential must have a negative serum pregnancy test upon study entry
  • Male and female subjects who agree to use highly effective methods of birth control (e.g., condoms, implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], sexual abstinence, or sterilized partner) during the period of therapy and for 30 days after the last dose of study drug

Exclusion Criteria

  • Chemotherapy, monoclonal antibody, or small molecule kinase inhibitor =< 21 days prior to first administration of study treatment
  • Prior exposure to a BTK or BCL-2 inhibitor
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to ibrutinib or venetoclax
  • Known allergy to xanthine oxidase inhibitors and/or rasburicase for subjects at risk for tumor lysis syndrome
  • History of other malignancies, except: * Malignancy treated with curative intent and with no known active disease present for >= 3 years before the first dose of study drug and felt to be at low risk for recurrence by treating physician * Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease * Adequately treated carcinoma in situ without evidence of disease
  • Concurrent systemic immunosuppressant therapy (e.g., cyclosporine A, tacrolimus, etc., or chronic administration [> 14 days] of > 20 mg/day of prednisone) within 28 days of the first dose of study drug
  • Undergone an allogeneic stem cell transplant within the past 1 year
  • Current or history of graft versus host disease
  • Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug
  • Recent infection requiring systemic treatment that was completed =< 14 days before the first dose of study drug
  • Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved to Common Terminology Criteria for Adverse Event (CTCAE, version 4.03), grade =< 1, or to the levels dictated in the inclusion/exclusion criteria with the exception of alopecia
  • Known bleeding disorders (e.g., von Willebrand’s disease) or hemophilia
  • History of stroke or intracranial hemorrhage within 6 months prior to enrollment
  • Known human immunodeficiency virus (HIV) infection
  • Active infection with hepatitis C virus (HCV) or hepatitis B virus (HBV) * Subjects who are positive for hepatitis B core antibody, hepatitis B surface antigen, hepatitis C antibody, must have a negative polymerase chain reaction (PCR) result for the respective disease before enrollment; those who are PCR positive will be excluded
  • Any uncontrolled active systemic infection
  • Major surgery within 4 weeks of first dose of study drug
  • Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator’s opinion, could compromise the subject’s safety or put the study outcomes at undue risk
  • Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization
  • Unable to swallow capsules or tablets or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction
  • Concomitant use of warfarin or other vitamin K antagonists
  • Subjects who received a strong cytochrome P450 (CYP) 3A inhibitor within 7 days prior to the first dose of ibrutinib or subjects who require continuous treatment with a strong CYP3A inhibitor
  • High-grade transformation confirmed by biopsy
  • Malabsorption syndrome or other condition precluding enteral route of administration
  • Known central nervous system (CNS) involvement by lymphoma
  • Erythema multiforme, toxic epidermal necrolysis, or Stevens-Johnson syndrome
  • Lactating or pregnant
  • Unwilling or unable to participate in all required study evaluations and procedures
  • Unable to understand the purpose and risks of the study and to provide a signed and dated informed consent form (ICF) and authorization to use protected health information (in accordance with national and local subject privacy regulations)
  • Currently active, clinically significant hepatic impairment (>= moderate hepatic impairment according to the Child Pugh classification [class B or C])

District of Columbia

MedStar Georgetown University Hospital
Status: ACTIVE
Contact: Catherine Elizabeth Lai
Phone: 202-444-2223

New Jersey

Hackensack University Medical Center
Status: ACTIVE
Contact: Lori Leslie
Phone: 551-996-3033


University of Washington Medical Center - Montlake
Status: ACTIVE
Contact: Chaitra S. Ujjani
Phone: 205-612-7405


I. To determine the recommended phase II doses of ibrutinib and venetoclax for combination in relapsed and refractory follicular lymphoma. (Phase I)

II. To determine the efficacy of ibrutinib and venetoclax when combined in relapsed and refractory follicular lymphoma. (Phase II)


I. To determine the pharmacokinetics of ibrutinib and venetoclax when dosed in combination in relapsed and refractory follicular lymphoma. (Phase I)

II. To determine the safety and tolerability of ibrutinib and venetoclax when combined in relapsed and refractory follicular lymphoma. (Phase II)


I. To evaluate mutations of resistance via next-generation sequencing to the regimen when administered in combination in relapsed and refractory follicular lymphoma.

II. To evaluate for an association between BCL-2 and other family member protein levels of expression and efficacy of the regimen.

III. To evaluate the feasibility of developing tumor cell cultures from bone marrow aspirates with lymphomatous involvement in order to better characterize activity of the combination.

OUTLINE: This is a phase I, dose-escalation study followed by a phase II study.

Patients receive ibrutinib orally (PO) once daily (QD) and venetoclax PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 or 12 months for up to 10 years.

Trial Phase Phase I/II

Trial Type Treatment

Lead Organization
MedStar Georgetown University Hospital

Principal Investigator
Catherine Elizabeth Lai

  • Primary ID 2016-0014
  • Secondary IDs NCI-2017-02169
  • ID NCT02956382