Refractory Follicular LymphomaPhase 1/2NCT02956382
Ibrutinib and Venetoclax in Relapsed and Refractory Follicular Lymphoma
A Phase 1/2 study testing Ibrutinib and Venetoclax in people with Refractory Follicular Lymphoma and Relapsed Follicular Lymphoma, run by Georgetown University at 3 sites in United States.
Trial summary
This is a phase I/II study in which patients will be enrolled in a standard 3+3 design. Once the maximum tolerated dose (MTD) is determined amongst patients with relapsed or refractory grade 1-3a follicular lymphoma, there will be a 17-patient phase II study. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Refractory Follicular Lymphoma, Relapsed Follicular Lymphoma
- What is being tested?
- Ibrutinib and Venetoclax
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 24 participants
- Where
- 3 sitesUnited States
- Study dates
- 1 Mar 2017to 7 Mar 2024
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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)Must have received at least two prior systemic therapies
- All risk by FLIPI 0-5 factors (Appendix I)
- Measurable disease 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.
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- 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)
- Adequate hematologic function independent of transfusion and growth factor support for at least 3 weeks prior to screening unless attributable to disease. Defined as:
- Absolute neutrophil count (ANC) >1000 cells/mm3 (1.0 x 109/L). ANC > 500 cells/mm3 is permissible if due to disease.
- Platelet count >50,000 cells/mm3 (50 x 109/L) unless attributable to disease. Platelet count > 20,000 cells/mm3 is permissible if due to disease.
- Hemoglobin >8.0 g/dL.
- Adequate hepatic and renal function defined as:
- 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 PTT (aPTT) <1.5 x ULN.
- Men and women ≥ 18 years of age.
- Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. (Appendix II)
- 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
Who cannot join
- Chemotherapy, monoclonal antibody, or small molecule kinase inhibitor less than or equal 21 days prior to first administration of study treatment
- Prior exposure to a Bruton's tyrosine kinase (BTK) or B-cell lymphoma 2 (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.
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- 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 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.
- Requires treatment with a strong cytochrome P450 CYP3A4/5 inhibitor. (Appendix V)
- Richter's 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 (greater than or equal moderate hepatic impairment according to the Child Pugh classification (see Appendix IX)
Trial locations and contacts
3 sites in 1 country.
United States3 sites
John Theurer Cancer Center at Hackensack University Medical Center
Hackensack, New Jersey, 07601
Seattle Cancer Care Alliance
Seattle, Washington, 98109
Georgetown Lombardi Comprehensive Cancer Center
Washington D.C., District of Columbia, 20007
About this study
This is a phase I/II study in which patients will be enrolled in a standard 3+3 design. Once the maximum tolerated dose (MTD) is determined amongst patients with relapsed or refractory grade 1-3a follicular lymphoma, there will be a 17-patient phase II study.
Read the detailed description
In vitro studies of ibrutinib and venetoclax have noted significant cytotoxicity and synergy in mantle cell lymphoma and chronic lymphocytic leukemia cell lines.Data have demonstrated synergy between the two agents in various other B-cell Non-Hodgkin Lymphoma (NHL) cell lines. The investigators theorize that the combination of ibrutinib and venetoclax will provide dual, yet unique, targeted inhibition for patients with follicular lymphoma, resulting in both significant efficacy and less nonspecific toxicity.
- Being tested
- Ibrutinib, Venetoclax
- Keywords
- Ibrutinib, Venetoclax, Follicular, Refractory, Relapsed, Lymphoma
- Medical subject headings
- Lymphoma, Follicular, Recurrence, Lymphoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
IbrutinibDrug
Also called PCI-32765
Ibrutinib is dispensed as a capsule.
VenetoclaxDrug
Also called ABT-199
Venetoclax is dispensed as a tablet.
| Study group | Role | What they receive |
|---|---|---|
| Phase I - Dose Level 0 | Experimental | Ibrutinib (capsule) - 420mg Venetoclax (tablet) - 400mg
Each medication is taken daily. Treatment cycles are 28 days long. Receives: Drug: Ibrutinib; Drug: Venetoclax |
| Phase I - Dose Level 1 | Experimental | Ibrutinib (capsule) - 560mg Venetoclax (tablet) - 400mg
Each medication is taken daily. Treatment cycles are 28 days long. Receives: Drug: Ibrutinib; Drug: Venetoclax |
| Phase I - Dose Level 2 | Experimental | Ibrutinib (capsule) - 560mg Venetoclax (tablet) - 600mg
Each medication is taken daily. Treatment cycles are 28 days long. Receives: Drug: Ibrutinib; Drug: Venetoclax |
| Phase I - Dose Level 3 | Experimental | Ibrutinib (capsule) - 560mg Venetoclax (tablet) - 800mg
Each medication is taken daily. Treatment cycles are 28 days long. Receives: Drug: Ibrutinib; Drug: Venetoclax |
| Phase II Dose | Experimental | The Phase II dose will be the maximum tolerated dose as determined in the Phase I portion. Receives: Drug: Ibrutinib; Drug: Venetoclax |
What is being measured
The primary outcome is the main question the study is designed to answer.
Recommended Phase 2 Dose (RP2D)
The maximum tolerated dose of Ibrutinib and Venetoclax as determined by number of DLTs observed. • If 0/3 DLT is observed, dose escalation will continue to the next upper dose level. • If ≥ 2/3 DLTs are observed, then the dose finding procedure will be terminated.
- If 1/3 DLT is observed, then 3 additional patients will be enrolled in the same dose level. If no DLT is observed from the additional 3 patients, then dose escalation will continue to the next upper dose level. If any DLT is observed from the 3 additional patients, then the previously lower dose will be chosen as the MTD and the dose finding procedure will be terminated.
Measured: Cycle 1 (28 days)
Dose Level 2 Overall Response Rate
Number of participants on the recommended phase II dose level 2, with a partial or complete response, as determined by the revised Lugano Response Criteria for Non-Hodgkin Lymphoma,
Measured: 36 months
Secondary outcomes (4)
Pharmacokinetics of Ibrutinib (Cmax) Phase 1
Cmax- Maximiumum concentration of Ibrutinib of subjects in Phase 1.
Measured: Cycle 1 (28 days)
Pharmacokinetics of Ibrutinib (Tmax) Phase 1
Tmax (time to maximum) plasma concentrations of ibrutinib for subjects in phase 1
Measured: Cycle 1 (28 days)
Pharmacokinetics of Ibrutinib (AUC) Phase 1
Area Under the Curve (AUC) 0 to 24 hours for subjects in phase 1
Measured: Cycle 1 (28 days)
Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.03
Toxicity (attribute and grade) will be summarized for each dose level (0, 1, 2, 3) for all patients who receive at least one dose of study treatment.
Measured: 36 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Nov 2016 (estimated)
- Study start1 Mar 2017
- Primary completion23 May 2023
- Study completion7 Mar 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Refractory Follicular LymphomaStudies of the same condition, open and under way.
- More trials run by Georgetown UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 24 participants (actual)
Sponsor and investigators
- Lead sponsor
- Georgetown University
- Sponsor type
- University, hospital or other
- Collaborators
- AbbVie, Pharmacyclics LLC., Hackensack Meridian Health
- Responsible party
- Sponsor
- Investigators
- Chaitra Ujjani, MD, Study chair, Seattle Cancer Care Alliance
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02956382
- Sponsor's protocol ID
- 2016-0014
- Status last verified
- Jun 2025
- First submitted
- 2 Nov 2016
- Last updated
- 18 Jul 2025
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 18 Jul 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Ibrutinib and Venetoclax in Relapsed and Refractory Follicular Lymphoma
- ClinicalTrials.gov ID
- NCT02956382
- Acronym / sponsor ID
- 2016-0014
- Keywords
- Ibrutinib, Venetoclax, Follicular, Refractory, Relapsed, Lymphoma
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 24 participants (actual)
- Lead sponsor
- Georgetown UniversityUniversity, hospital or other
- Collaborators
- AbbVie, Pharmacyclics LLC., Hackensack Meridian Health
- Study start
- 1 Mar 2017 (actual)
- Primary completion
- 23 May 2023 (actual)
- Study completion
- 7 Mar 2024 (actual)
- First posted
- 7 Nov 2016 (estimated)
- Results
- Posted 21 May 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This is a phase I/II study in which patients will be enrolled in a standard 3+3 design. Once the maximum tolerated dose (MTD) is determined amongst patients with relapsed or refractory grade 1-3a follicular lymphoma, there will be a 17-patient phase II study.
Detailed description
In vitro studies of ibrutinib and venetoclax have noted significant cytotoxicity and synergy in mantle cell lymphoma and chronic lymphocytic leukemia cell lines.Data have demonstrated synergy between the two agents in various other B-cell Non-Hodgkin Lymphoma (NHL) cell lines. The investigators theorize that the combination of ibrutinib and venetoclax will provide dual, yet unique, targeted inhibition for patients with follicular lymphoma, resulting in both significant efficacy and less nonspecific toxicity.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 5
| Arm | Type | Receives |
|---|---|---|
| Phase I - Dose Level 0 | Experimental | Drug: Ibrutinib, Drug: VenetoclaxIbrutinib (capsule) - 420mg Venetoclax (tablet) - 400mg Each medication is taken daily. Treatment cycles are 28 days long. |
| Phase I - Dose Level 1 | Experimental | Drug: Ibrutinib, Drug: VenetoclaxIbrutinib (capsule) - 560mg Venetoclax (tablet) - 400mg Each medication is taken daily. Treatment cycles are 28 days long. |
| Phase I - Dose Level 2 | Experimental | Drug: Ibrutinib, Drug: VenetoclaxIbrutinib (capsule) - 560mg Venetoclax (tablet) - 600mg Each medication is taken daily. Treatment cycles are 28 days long. |
| Phase I - Dose Level 3 | Experimental | Drug: Ibrutinib, Drug: VenetoclaxIbrutinib (capsule) - 560mg Venetoclax (tablet) - 800mg Each medication is taken daily. Treatment cycles are 28 days long. |
| Phase II Dose | Experimental | Drug: Ibrutinib, Drug: VenetoclaxThe Phase II dose will be the maximum tolerated dose as determined in the Phase I portion. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (25 listed)
- Relapsed or refractory, histologically confirmed follicular lymphoma, grade I, II, or IIIa which requires therapy defined by at least one of the following:
- High tumor burden (single mass > 7 cm, three masses > 3 cm, symptomatic splenomegaly, organ compression or compromise, ascites, pleural effusion)Must have received at least two prior systemic therapies
- All risk by FLIPI 0-5 factors (Appendix I)
- Measurable disease 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.
- Adequate hematologic function independent of transfusion and growth factor support for at least 3 weeks prior to screening unless attributable to disease. Defined as:
Key exclusion criteria (34 listed)
- Chemotherapy, monoclonal antibody, or small molecule kinase inhibitor less than or equal 21 days prior to first administration of study treatment
- Prior exposure to a Bruton's tyrosine kinase (BTK) or B-cell lymphoma 2 (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:
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| IbrutinibAlso: PCI-32765Ibrutinib is dispensed as a capsule. | Drug | Phase I - Dose Level 0, Phase I - Dose Level 1, Phase I - Dose Level 2, Phase I - Dose Level 3, Phase II Dose |
| VenetoclaxAlso: ABT-199Venetoclax is dispensed as a tablet. | Drug | Phase I - Dose Level 0, Phase I - Dose Level 1, Phase I - Dose Level 2, Phase I - Dose Level 3, Phase II Dose |
Primary outcome
Recommended Phase 2 Dose (RP2D)
Time frame: Cycle 1 (28 days)
The maximum tolerated dose of Ibrutinib and Venetoclax as determined by number of DLTs observed. • If 0/3 DLT is observed, dose escalation will continue to the next upper dose level. • If ≥ 2/3 DLTs are observed, then the dose finding procedure will be terminated. • If 1/3 DLT is observed, then 3 additional patients will be enrolled in the same dose level. If no DLT is observed from the additional 3 patients, then dose escalation will continue to the next upper dose level. If any DLT is observed from the 3 additional patients, then the previously lower dose will be chosen as the MTD and the dose finding procedure will be terminated.
Dose Level 2 Overall Response Rate
Time frame: 36 months
Number of participants on the recommended phase II dose level 2, with a partial or complete response, as determined by the revised Lugano Response Criteria for Non-Hodgkin Lymphoma,
4 secondary outcomes
Pharmacokinetics of Ibrutinib (Cmax) Phase 1
Time frame: Cycle 1 (28 days)
Pharmacokinetics of Ibrutinib (Tmax) Phase 1
Time frame: Cycle 1 (28 days)
Pharmacokinetics of Ibrutinib (AUC) Phase 1
Time frame: Cycle 1 (28 days)
Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.03
Time frame: 36 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Jul 2025.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Chaitra Ujjani, MD study chair
Seattle Cancer Care Alliance
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Ibrutinib and Venetoclax in people with Refractory Follicular Lymphoma and Relapsed Follicular Lymphoma, run by Georgetown University at 3 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 25 inclusion and 34 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 18 Jul 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 21 May 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Recommended Phase 2 Dose (RP2D) (time frame: Cycle 1 (28 days)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Jul 2025.