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

Study Overview
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Brief Summary
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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.

Official Title
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Phase 3 Study of Ibrutinib in Combination With Venetoclax in Subjects With Mantle Cell Lymphoma

Conditions
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Mantle-Cell Lymphoma

Intervention / Treatment
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* Drug: Ibrutinib
* Drug: Venetoclax
* Drug: Placebo Oral tablet to match Venetoclax


Participation Criteria
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Eligibility Criteria
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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/PET). 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 or 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. Must have adequate fresh or paraffin-embedded tissue. Eastern Cooperative Oncology Group (ECOG) performance status score 0-2. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Safety Run-in Period<br>Subjects are enrolled into the open-label Safety Run-in Period to evaluate the occurrence of tumor lysis syndrome (TLS) and DLTs with the concurrent administration of ibrutinib and venetoclax. Safety run-in phase for the study is closed to further enrollment as of 07-Nov-2018. | Drug: Ibrutinib<br>* Administered orally once daily<br>Drug: Venetoclax<br>* Administered orally once daily<br>|
| Experimental: Phase 3: Ibrutinb + Venetoclax<br>Subjects will be randomized to receive ibrutinib and venetoclax/placebo until clinical disease progression or unacceptable toxicity | Drug: Ibrutinib<br>* Administered orally once daily<br>Drug: Venetoclax<br>* Administered orally once daily<br>|
| Placebo Comparator: Phase 3: Ibrutinib + Placebo<br>Subjects will be randomized to receive ibrutinib and venetoclax/placebo until clinical disease progression or unacceptable toxicity | Drug: Ibrutinib<br>* Administered orally once daily<br>Drug: Placebo Oral tablet to match Venetoclax<br>* Administered orally once daily<br>|
| Experimental: Treatment-naive<br>This open-label arm is designed to explore the efficacy and safety of the combination of ibrutinib and venetoclax in subjects with treatment-naive MCL. Approximately 75 subjects (of which  25 subjects with TP53 mutation) will be enrolled and treated with ibrutinib and venetoclax. | Drug: Ibrutinib<br>* Administered orally once daily<br>Drug: Venetoclax<br>* Administered orally once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of Tumor Lysis Syndrome (TLS) (Safety Run-in Period) | To evaluate the occurrence of tumor lysis syndrome (TLS) with the concurrent administration of ibrutinib and venetoclax. | Approximately 3 months after last subject enrolled into safety run-in portion | 
| Occurrence of Dose Limiting Toxicities (DLT) (Safety Run-in Period) | To evaluate the occurrence of DLTs with the concurrent administration of ibrutinib and venetoclax. | Approximately 3 months after last subject enrolled into safety run-in portion | 
| Number of Participants With Adverse Events (AEs) (Safety Run-in Period) | An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. The investigator assesses the relationship of each event to the use of study. A serious adverse event (SAE) is 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) are defined as any event that began or worsened in severity on or after the first dose of study drug. | Up to approximately 5 years | 
| Overall response rate (ORR) (Safety Run-in Period) | ORR is defined as CR or PR per investigator assessment according to the Revised Response Criteria for Malignant Lymphoma. | approximately 1 year after last subject has stopped treatment with study drug(s) | 
| Duration of Response (DOR) (Safety Run-in Period) | DOR is defined as participants who achieve an overall response as the time from the first occurrence of response (CR or PR) to disease progression or death, whichever occurs first. | Up to approximately 5 years | 
| Progression-free Survival (PFS) (Safety Run-in Period) | To evaluate PFS of ibrutinib and venetoclax compared to ibrutinib and placebo. | approximately 1 year after last subject has stopped treatment with study drug(s) | 
| Overall Survival (OS) (Safety Run-in Period) | OS is defined as the time from the date of the first dose of study treatment to death from any cause. | Up to approximately 5 years | 
| Progression-free Survival (PFS) (Randomization Period) | To evaluate PFS of ibrutinib and venetoclax compared to ibrutinib and placebo. | approximately 1 year after last subject has stopped treatment with study drug(s) | 
| Complete Response (CR) (Treatment-Naive Arm) | To evaluate the complete response (CR) rate with the combination of ibrutinib and venetoclax in subjects with treatment-naive MCL | approximately 1 year after last subject has stopped treatment with study drug(s) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response (CR) (Randomization Period) | Complete response rate (CR) based on the best overall response per investigator assessment according to the Revised Response Criteria for Malignant Lymphoma. | approximately 1 year after last subject has stopped treatment with study drug(s) | 
| Overall response rate (ORR) (Randomization Period and Treatment-Naive Arm) | ORR is defined as CR or PR per investigator assessment according to the Revised Response Criteria for Malignant Lymphoma. | approximately 1 year after last subject has stopped treatment with study drug(s) | 
| MRD-negative remission rate in participants who achieve CR per investigator assessment (Randomization Period and Treatment-Naive Arm) | MRD-negative remission is defined as undetectable MRD at documented CR in subjects 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. | approximately 1 year after last subject has stopped treatment with study drug(s) | 
| Overall Survival (OS) (Randomization Period and Treatment-Naive Arm) | OS is defined as the time from the date of the first dose of study treatment to death from any cause. | Up to approximately 5 years | 
| Duration of Response (DOR) (Randomization Period and Treatment-Naive Arm) | DOR is defined as participants who achieve an overall response as the time from the first occurrence of response (CR or PR) to disease progression or death, whichever occurs first. | Up to approximately 5 years | 
| Time to Next Treatment (TTNT) (Randomization Period and Treatment-Naive Arm) | TTNT is defined as the duration from the date of randomization to the start date of any anti-lymphoma treatment subsequent to study treatment. | Up to approximately 5 years | 
| Percentage of participants experiencing Adverse Events (Randomization Period) | An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. | Up to approximately 5 years | 
| Occurrence of Tumor Lysis Syndrome (TLS) (Randomization Period) | To evaluate the occurrence of tumor lysis syndrome (TLS) with the concurrent administration of ibrutinib and venetoclax. | Approximately 3 months after last subject enrolled into safety run-in portion | 
| Cmax if Ibrutinib (Randomization Period) | Cmax if Ibrutinib. | Week 6 | 
| Tmax if Ibrutinib (Randomization Period) | Tmax if Ibrutinib. | Week 6 | 
| AUClast if Ibrutinib (Randomization Period) | AUClast if Ibrutinib. | Week 6 | 
| Half-Life (T1/2) if Ibrutinib (Randomization Period) | Half-Life (T1/2) if Ibrutinib. | Week 6 | 
| Cmax of Venetoclax (Randomization Period) | Cmax of Venetoclax. | Week 6 | 
| Tmax of Venetoclax (Randomization Period) | Tmax of Venetoclax. | Week 6 | 
| AUC of Venetoclax (Randomization Period) | AUC of Venetoclax. | Week 6 | 
| Time to worsening in FACT-Lym subscale of the health-related quality of life (Randomization Period) questionnaire (FACT-Lym) | Time to worsening in FACT-Lym subscale of the health-related quality of life questionnaire (FACT-Lym) will be compared between treatment arms. | Week 6 | 
| Duration of CR (Treatment-Naive Arm Period) | Duration of CR, defined for subjects who achieve CR as the time from the first occurrence of CR to disease progression or death, whichever occurs first. | Up to approximately 5 years | 
| Progression-free Survival (PFS) (Treatment-Naive Arm Period) | To evaluate PFS of ibrutinib and venetoclax compared to ibrutinib and placebo. | approximately 1 year after last subject has stopped treatment with study drug(s) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PCYC, MCL, Non-Hodgkin's Lymphoma, NHL, ibrutinib, venetoclax, Pharmacyclics