Study of Ibrutinib Combined With Venetoclax in Subjects With Mantle Cell Lymphoma (MCL)

Phase 3

Completed

• Conditions: Mantle-Cell Lymphoma
• Interventions: Drug: Ibrutinib; Drug: Venetoclax; Drug: Placebo Oral tablet to match Venetoclax

• Registration Number: NCT03112174
• Lead Sponsor: Pharmacyclics LLC.

Brief Summary

This Phase 3 multinational, randomized, double-blind study is designed to compare the efficacy and safety of the combination of ibrutinib and venetoclax vs. ibrutinib and placebo in subjects with MCL.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2017-04-04
• Study First Submitted QC: 2017-04-07
• Study First Posted: 2017-04-13
• Study Start: 2017-06-19
• Primary Completion: 2024-06-26
• Study Completion: 2024-06-27
• Results First Submitted: 2025-06-10
• Status Verified: 2025-07
• Results First Submitted QC: 2025-07-02
• Last Update Submitted: 2025-07-02
• Results First Posted: 2025-07-22
• Last Update Posted: 2025-07-22

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 366

Inclusion Criteria

• Pathologically confirmed MCL (in tumor tissue), with documentation of either overexpression of cyclin D1 in association with other relevant markers (eg, CD19, CD20, PAX5, CD5) or evidence of t(11;14) as assessed by cytogenetics, fluorescent in situ hybridization (FISH), or polymerase chain reaction (PCR).
• At least 1 measurable site of disease on cross-sectional imaging (CT).
• At least 1, but no more than 5, prior treatment regimens for MCL.
• Failure to achieve at least partial response (PR) with, or documented disease progression after, the most recent treatment regimen.
• Subjects must have adequate fresh or paraffin embedded tissue.
• Adequate hematologic, hepatic and renal function.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of <= 2.

Exclusion Criteria

• History or current evidence of central nervous system lymphoma.
• Concurrent enrollment in another therapeutic investigational study or prior therapy with ibrutinib or other BTK inhibitors.
• Prior treatment with venetoclax or other BCL2 inhibitors.
• Anticancer therapy including chemotherapy, radiotherapy, small molecule and investigational agents <= 21 days prior to receiving the first dose of study drug.
• Treatment with any of the following within 7 days prior to the first dose of study drug: moderate to strong cytochrome P450 3A (CYP3A) inhibitors or strong CYP3A inducers.

Treatment Naïve Arm

Inclusion Criteria:

• Pathologically confirmed treatment-naive MCL (tumor tissue), with documentation of either overexpression of cyclin D1 in association with other relevant markers (eg, CD19, CD20, PAX5, CD5) or evidence of t(11;14), as assessed by cytogenetics, fluorescent in situ hybridization (FISH), or polymerase chain reaction (PCR).
• Men and women ≥18 years of age with a TP53 mutation.
• At least 1 measurable site of disease by CT.
• Must have adequate fresh or paraffin-embedded tissue.
• Eastern Cooperative Oncology Group (ECOG) performance status score 0 to <= 2.
• Adequate hematologic, hepatic, and renal function.

Exclusion Criteria:

• Blastoid variant of MCL
• History or current evidence of CNS lymphoma.
• Concurrent enrollment in another therapeutic investigational study or prior therapy including ibrutinib or other BTK inhibitors.
• Prior treatment with venetoclax or other BCL2 inhibitors.
• Vaccinated with live, attenuated vaccines within 4 weeks of the first dose of study drug.
• Clinically significant infection requiring IV systemic treatment that was completed <=14 days before the first dose of study drug.
• Any uncontrolled active systemic infection.
• Known bleeding disorders (eg, von Willebrand's disease or hemophilia).
• History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
• History of HIV or active HCV or HBV.
• Major surgery within 4 weeks of the first dose of study drug.
• Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator's opinion, could compromise the participant's safety or put the study outcomes at undue risk.
• Currently active, clinically significant cardiovascular disease; 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.
• Treatment with any of the following within 7 days prior to the first dose of study drug: Moderate or strong cytochrome P450 3A (CYP3A) inhibitors or moderate or strong CYP3A inducers.
• Known allergy to xanthine oxidase inhibitors and/or rasburicase for subjects with known risk factors (as defined by high tumor burden and/or diminished renal function, as detailed in "Study Design" section above) for TLS.
• Chronic liver disease with hepatic impairment Child-Pugh class B or C.
• Unwilling or unable to participate in all required study evaluations and procedures.
• Known hypersensitivity to the active ingredient or other components of one or more study drugs.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Safety Run-in	Ibrutinib	Participants with a low or high risk of TLS enroll into the open-label Safety Run-in Period to receive concurrent ibrutinib at 560 mg once daily and venetoclax starting at 20 mg, and gradually ramp up to a target dose of 400 mg once daily over a 5-week period.
Safety Run-in	Venetoclax	Participants with a low or high risk of TLS enroll into the open-label Safety Run-in Period to receive concurrent ibrutinib at 560 mg once daily and venetoclax starting at 20 mg, and gradually ramp up to a target dose of 400 mg once daily over a 5-week period.
Randomization Phase: Ibrutinb + Venetoclax	Ibrutinib	Participants randomized to ibrutinib and venetoclax for approximately 104 weeks, followed by ibrutinib monotherapy until disease progression (PD), unacceptable toxicity or withdrawal of consent. Venetoclax is discontinued after 104 weeks of treatment, regardless of response assessment.
Treatment-naive Open-label Arm	Ibrutinib	Participants are treated with ibrutinib 560 mg and venetoclax 400 mg, administered using the 5-week ramp-up schedule.
Randomization Phase: Ibrutinb + Venetoclax	Venetoclax	Participants randomized to ibrutinib and venetoclax for approximately 104 weeks, followed by ibrutinib monotherapy until disease progression (PD), unacceptable toxicity or withdrawal of consent. Venetoclax is discontinued after 104 weeks of treatment, regardless of response assessment.
Randomization Phase: Ibrutinib + Placebo	Placebo Oral tablet to match Venetoclax	Participants randomized to ibrutinib and placebo for approximately 104 weeks, followed by ibrutinib monotherapy until PD, unacceptable toxicity or withdrawal of consent. Placebo is discontinued after 104 weeks of treatment, regardless of response assessment.
Treatment-naive Open-label Arm	Venetoclax	Participants are treated with ibrutinib 560 mg and venetoclax 400 mg, administered using the 5-week ramp-up schedule.
Randomization Phase: Ibrutinib + Placebo	Ibrutinib	Participants randomized to ibrutinib and placebo for approximately 104 weeks, followed by ibrutinib monotherapy until PD, unacceptable toxicity or withdrawal of consent. Placebo is discontinued after 104 weeks of treatment, regardless of response assessment.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Tumor Lysis Syndrome (TLS) Events (Safety Run-in)	After at least 3 months of treatment, with an overall median treatment duration of 20.0 months	TLS events are defined as follows: * Clinical TLS: any event that meets Howard criteria (N Engl J Med 2011;364:1844-1854) with the following exceptions: * For the purpose of TLS assessment during the Safety Run-in Period, only those increases in serum creatinine \> 1.0 mg/dL from pre-treatment baseline will be considered clinical TLS.; * In participants with renal dysfunction at baseline (CrCl \< 60 mL/min), clinical TLS is defined as the presence of laboratory TLS plus either seizures, cardiac dysrhythmia, or death.; * Laboratory TLS: any event that meets Howard criteria (N Engl J Med 2011;364:1844-1854) for laboratory TLS, that does not resolve within 72 hours despite protocol required management.
Number of Participants With Dose Limiting Toxicities (DLT) (Safety Run-in)	After at least 3 months of treatment, with an overall median treatment duration of 20.0 months	DLT: any Grade (Gr) 3 or higher non-TLS adverse event (AE) at least possibly related to study drug occurring during the DLT assessment period with the following clarifications: Non-Hematologic DLTs: Gr ≥3 nausea, vomiting or diarrhea uncontrolled despite maximum medical supportive care and persisting \>5 days; Gr 3 fatigue persisting \>7 days; Gr 3 infection is not a DLT, however an infection with lifethreatening consequences or requiring urgent intervention (Gr 4) was considered a DLT; Treatment delay of any study drug \>7 days for toxicity.; Hematologic DLTs: Gr 3 neutropenia is not a DLT, however, Gr 4 neutropenia (ANC \<500/mm\^3) lasting for \> 7 days is a DLT; Gr 3 or 4 neutropenia complicated by fever ≥38.5°C or infection; Gr 4 thrombocytopenia (\<25,000/mm\^3) that persists for \> 7 days; Gr 3 or 4 thrombocytopenia associated with Gr 2 or greater bleeding; Gr 3 anemia is not a DLT, however, Gr 4 anemia is a DLT; Treatment delay of any study drug \>7 days for hematologic toxicity.
Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	From first dose of study drug until the end of treatment + 30 days, with an overall median treatment duration of 20.0 months	AE: any untoward medical occurrence in a participant that does not necessarily have a causal relationship with treatment. The investigator assesses the relationship of each event to the use of study. Serious adverse event (SAE): an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent any of the outcomes listed above. Treatment-emergent adverse events/treatment-emergent serious adverse events (TEAEs/TESAEs): any event that began or worsened in severity on or after the first dose of study drug. Event severity is graded as mild (1), moderate (2), severe (3), life threatening (4), death (5).
Progression-free Survival (PFS) (Randomization Phase)	For an overall median time on study of 61.34 months	PFS is defined as the time from the date of randomization to the date of disease progression using the Revised Response Criteria for Malignant Lymphoma (Cheson 2014), or death from any cause, whichever occurs first.
Complete Response (CR) Rate (Treatment-Naive Arm)	For an overall median time on study of 40.51 months	CR rate is defined as the percentage of participants with a CR according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2014).

Secondary Outcome Measures

Name	Time	Method
Overall Survival (OS) (Safety Run-in)	For an overall median time on study of 74.78 months	OS is defined as the time from the date of the first dose of study treatment to death from any cause.
Progression-free Survival (PFS) (Safety Run-in)	For an overall median time on study of 74.78 months	PFS is defined as the time from the date of the first dose of study treatment to the date of disease progression using the Revised Response Criteria for Malignant Lymphoma (Cheson 2014), or death from any cause, whichever occurs first.
Duration of Response (DOR) (Safety Run-in)	For an overall median time on study of 74.78 months	DOR is defined for participants who achieve an overall response as the time from the first occurrence of response (CR or PR according to the Revised Response Criteria for Malignant Lymphoma \[Cheson 2014\]) to disease progression or death, whichever occurs first.
Overall Response Rate (ORR) (Safety Run-in)	For an overall median time on study of 74.78 months	ORR is defined as the percentage of participants with CR or PR per investigator assessment according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2014).
Percentage of Participants With a Complete Response (CR) (Randomization Phase)	For an overall median time on study of 61.34 months	Complete response rate (CR) based on the best overall response per investigator assessment according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2014).
Overall Response Rate (ORR) (Randomization Phase and Treatment-Naive Arm)	For an overall median time on study of 61.34 months (Randomization Phase) and 40.51 months (Treatment-Naïve arm)	ORR is defined as the percentage of participants with CR or PR per investigator assessment according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2014).
MRD-negative Remission Rate in Participants Who Achieve CR Per Investigator Assessment (Randomization Phase and Treatment-Naive Arm)	For an overall median time on study of 61.34 months (Randomization Phase) and 40.51 months (Treatment-Naïve arm)	MRD-negative remission rate is defined as the percentage of participants with undetectable MRD at documented CR in participants who were MRD positive at screening as assessed by flow cytometry in bone marrow and/or peripheral blood, with requirement of confirmation of MRD negativity in the subsequent peripheral blood 12 weeks later.
Overall Survival (OS) (Randomization Phase and Treatment-Naive Arm)	For an overall median time on study of 61.34 months (Randomization Phase) and 40.51 months (Treatment-Naïve arm)	OS is defined as the time from the date of randomization (Randomization Phase) or the first dose of study treatment (Treatment-Naïve arm) to death from any cause.
Duration of Response (DOR) (Randomization Phase and Treatment-Naive Arm)	For an overall median time on study of 61.34 months (Randomization Phase) and 40.51 months (Treatment-Naïve arm)	DOR is defined as the time frame for participants who achieve an overall response as the time from the first occurrence of response (CR or PR according to the Revised Response Criteria for Malignant Lymphoma \[Cheson 2014\]) to disease progression or death, whichever occurs first.
Time to Next Treatment (TTNT) (Randomization Phase and Treatment-Naive Arm)	For an overall median time on study of 61.34 months (Randomization Phase) and 40.51 months (Treatment-Naïve arm)	TTNT is defined as the duration from the date of randomization (Randomization Phase) or date of first dose of study treatment (Treatment-Naive Arm) to the start date of any anti-lymphoma treatment subsequent to study treatment. Post-treatment stem cell transplantation, chimeric antigen receptor (CAR) T-cell therapy, or other cellular therapies were not considered subsequent anti-cancer treatments for participants responding to the study treatment (CR or PR).
Number of Participants With TEAEs (Randomization Phase)	From first dose of study drug until the end of treatment + 30 days, with an overall median treatment duration of 19.5 months	AE: any untoward medical occurrence in a participant that does not necessarily have a causal relationship with treatment. The investigator assesses the relationship of each event to the use of study. Serious adverse event (SAE): an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent any of the outcomes listed above. Treatment-emergent adverse events/treatment-emergent serious adverse events (TEAEs/TESAEs): any event that began or worsened in severity on or after the first dose of study drug. Event severity is graded as mild (1), moderate (2), severe (3), life threatening (4), death (5).
Number of Participants With TLS TEAEs (Randomization Phase)	From first dose of study drug until the end of treatment + 7 days, with an overall median treatment duration 19.5 months	Treatment-emergent adverse events/treatment-emergent serious adverse events (TEAEs/TESAEs): any event that began or worsened in severity on or after the first dose of study drug (SD). Event severity is graded as mild (1), moderate (2), severe (3), life threatening (4), death (5).
Steady-State Pharmacokinetics (PK) of Ibrutinib: Maximum Observed Plasma Concentration (Cmax) (Randomization Phase)	Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose	Pre-dose concentrations were applied as 24-hour concentrations in order to calculate steady-state PK parameters.
Steady-State PK of Ibrutinib: Time to Cmax (Tmax) (Randomization Phase)	Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose	Pre-dose concentrations were applied as 24-hour concentrations in order to calculate steady-state PK parameters.
Steady-State PK of Ibrutinib: Area Under the Concentration-Time Curve From Time Zero to the Time of the Last Measurable Concentration (AUClast) (Randomization Phase)	Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose	Pre-dose concentrations were applied as 24-hour concentrations in order to calculate steady-state PK parameters.
Steady-State PK of Ibrutinib: Terminal Elimination Half-Life (t1/2,Term) (Randomization Phase)	Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose	Pre-dose concentrations were applied as 24-hour concentrations in order to calculate steady-state PK parameters.
Steady-State PK of Ibrutinib: Time of Last Measurable Concentration (Tlast) (Randomization Phase)	Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose	Pre-dose concentrations were applied as 24-hour concentrations in order to calculate steady-state PK parameters.
Steady-State PK of Ibrutinib: Area Under the Concentration-Time Curve From 0-24 Hours (AUC0-24) (Randomization Phase)	Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose	Pre-dose concentrations were applied as 24-hour concentrations in order to calculate steady-state PK parameters.
Steady-State PK of Ibrutinib: Terminal Elimination Rate Constant (λz) (Randomization Phase)	Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose	Pre-dose concentrations were applied as 24-hour concentrations in order to calculate steady-state PK parameters.
Steady-State PK of Ibrutinib: Apparent Total Clearance at Steady State (CLss/F) (Randomization Phase)	Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose	Pre-dose concentrations were applied as 24-hour concentrations in order to calculate steady-state PK parameters.
Steady-State PK of Venetoclax: Cmax (Randomization Phase)	Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose	Pre-dose concentrations were applied as 24-hour concentrations in order to calculate steady-state PK parameters.
Steady-State PK of Venetoclax: AUC0-24 (Randomization Phase)	Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose	Pre-dose concentrations were applied as 24-hour concentrations in order to calculate steady-state PK parameters.
Steady-State PK of Venetoclax: Time to Cmax (Tmax) (Randomization Phase)	Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose	Pre-dose concentrations were applied as 24-hour concentrations in order to calculate steady-state PK parameters.
Steady-State PK of Venetoclax: CLss/F (Randomization Phase)	Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose	Pre-dose concentrations were applied as 24-hour concentrations in order to calculate steady-state PK parameters.
Time to Worsening in Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) Subscale of the Health-related Quality of Life (Randomization Phase)	For an overall median time on study of 61.34 months (Randomization Phase)	The FACT-Lym lymphoma-specific additional concerns subscale responses to all items are rated on a 5-point scale ranging from 0 "not at all" to 4 "very much". The lymphoma subscale includes 15 items and scores range from 0 to 60, with higher scores representing better functional status and well-being. A 5-point change in the Lym subscale was selected as a conservative estimate of clinically meaningful deterioration in lymphoma symptoms.
Duration of CR (Treatment-Naive Arm)	For an overall median time on study of 40.51 months	Duration of CR, defined for subjects who achieve CR according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2014) as the time from the first occurrence of CR to disease progression or death, whichever occurs first.
Progression-free Survival (PFS) (Treatment-Naive Arm)	For an overall median time on study of 40.51 months	PFS is defined as the time from the date of the first dose of study treatment to the date of disease progression using the Revised Response Criteria for Malignant Lymphoma (Cheson 2014), or death from any cause, whichever occurs first.

Trial Locations

Locations (120)

The University of Arizona Cancer Centre-North Campus; 🇺🇸 Tucson, Arizona, United States

City of Hope; 🇺🇸 Duarte, California, United States

UCLA Department of Medicine-Hematology/Oncology; 🇺🇸 Los Angeles, California, United States

Orlando Health Inc.; 🇺🇸 Orlando, Florida, United States

The University of Kansas Cancer Center and Medical Pavilion; 🇺🇸 Westwood, Kansas, United States

Norton Cancer Institute; 🇺🇸 Louisville, Kentucky, United States

Barbara Ann Karmanos Cancer institute; 🇺🇸 Detroit, Michigan, United States

Memorial Sloan Kettering Cancer Center; 🇺🇸 New York, New York, United States

Stony Brook University; 🇺🇸 New York, New York, United States

Levine Cancer Institute; 🇺🇸 Charlotte, North Carolina, United States

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