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

Pharmacyclics LLC.366 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

366

Conditions

Mantle-Cell Lymphoma

Interventions

IbrutinibDRUG

Administered orally once daily

VenetoclaxDRUG

Administered orally once daily

Placebo Oral tablet to match VenetoclaxDRUG

Administered orally once daily

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Relapsed/Refractory Arm 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.

Locations (120)

Outcomes

Primary Outcomes

Number of Participants With Tumor Lysis Syndrome (TLS) Events (Safety Run-in)

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.

Time frame: After at least 3 months of treatment, with an overall median treatment duration of 20.0 months

Number of Participants With Dose Limiting Toxicities (DLT) (Safety Run-in)

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.

Time frame: After at least 3 months of treatment, with an overall median treatment duration of 20.0 months

Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)

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).

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

Secondary Outcomes

Overall Survival (OS) (Safety Run-in)

OS is defined as the time from the date of the first dose of study treatment to death from any cause.

Time frame: For an overall median time on study of 74.78 months

Progression-free Survival (PFS) (Safety Run-in)

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.

Time frame: For an overall median time on study of 74.78 months

Duration of Response (DOR) (Safety Run-in)

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.

Time frame: For an overall median time on study of 74.78 months

Overall Response Rate (ORR) (Safety Run-in)

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).

Time frame: For an overall median time on study of 74.78 months

Percentage of Participants With a Complete Response (CR) (Randomization Phase)

Complete response rate (CR) based on the best overall response per investigator assessment according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2014).

Time frame: For an overall median time on study of 61.34 months

Overall Response Rate (ORR) (Randomization Phase and Treatment-Naive 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).

Time frame: For an overall median time on study of 61.34 months (Randomization Phase) and 40.51 months (Treatment-Naïve arm)

MRD-negative Remission Rate in Participants Who Achieve CR Per Investigator Assessment (Randomization Phase and Treatment-Naive 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.

Time frame: For an overall median time on study of 61.34 months (Randomization Phase) and 40.51 months (Treatment-Naïve arm)

Overall Survival (OS) (Randomization Phase and Treatment-Naive 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.

Time frame: For an overall median time on study of 61.34 months (Randomization Phase) and 40.51 months (Treatment-Naïve arm)

Duration of Response (DOR) (Randomization Phase and Treatment-Naive 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 frame: For an overall median time on study of 61.34 months (Randomization Phase) and 40.51 months (Treatment-Naïve arm)

Time to Next Treatment (TTNT) (Randomization Phase and Treatment-Naive 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).

Time frame: For an overall median time on study of 61.34 months (Randomization Phase) and 40.51 months (Treatment-Naïve arm)

Number of Participants With TEAEs (Randomization Phase)

Time frame: From first dose of study drug until the end of treatment + 30 days, with an overall median treatment duration of 19.5 months

Number of Participants With TLS TEAEs (Randomization Phase)

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).

Time frame: From first dose of study drug until the end of treatment + 7 days, with an overall median treatment duration 19.5 months

Steady-State Pharmacokinetics (PK) of Ibrutinib: Maximum Observed Plasma Concentration (Cmax) (Randomization Phase)

Pre-dose concentrations were applied as 24-hour concentrations in order to calculate steady-state PK parameters.