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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03112174
Recruitment Status : Active, not recruiting
First Posted : April 13, 2017
Last Update Posted : September 10, 2022
Sponsor:
Collaborator:
Janssen Research & Development, LLC
Information provided by (Responsible Party):
Pharmacyclics LLC.

Tracking Information
First Submitted Date  ICMJE April 4, 2017
First Posted Date  ICMJE April 13, 2017
Last Update Posted Date September 10, 2022
Actual Study Start Date  ICMJE June 29, 2017
Estimated Primary Completion Date August 31, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 29, 2021)
  • Occurrence of Tumor Lysis Syndrome (TLS) (Safety Run-in Period) [ Time Frame: Approximately 3 months after last subject enrolled into safety run-in portion ]
    To evaluate the occurrence of tumor lysis syndrome (TLS) with the concurrent administration of ibrutinib and venetoclax.
  • Occurrence of Dose Limiting Toxicities (DLT) (Safety Run-in Period) [ Time Frame: Approximately 3 months after last subject enrolled into safety run-in portion ]
    To evaluate the occurrence of DLTs with the concurrent administration of ibrutinib and venetoclax.
  • Number of Participants With Adverse Events (AEs) (Safety Run-in Period) [ Time Frame: Up to approximately 5 years ]
    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.
  • Overall response rate (ORR) (Safety Run-in Period) [ Time Frame: approximately 1 year after last subject has stopped treatment with study drug(s) ]
    ORR is defined as CR or PR per investigator assessment according to the Revised Response Criteria for Malignant Lymphoma.
  • Duration of Response (DOR) (Safety Run-in Period) [ Time Frame: Up to approximately 5 years ]
    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.
  • Progression-free Survival (PFS) (Safety Run-in Period) [ Time Frame: approximately 1 year after last subject has stopped treatment with study drug(s) ]
    To evaluate PFS of ibrutinib and venetoclax compared to ibrutinib and placebo.
  • Overall Survival (OS) (Safety Run-in Period) [ Time Frame: Up to approximately 5 years ]
    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) (Randomization Period) [ Time Frame: approximately 1 year after last subject has stopped treatment with study drug(s) ]
    To evaluate PFS of ibrutinib and venetoclax compared to ibrutinib and placebo.
  • Complete Response (CR) (Treatment-Naive Arm) [ Time Frame: approximately 1 year after last subject has stopped treatment with study drug(s) ]
    To evaluate the complete response (CR) rate with the combination of ibrutinib and venetoclax in subjects with treatment-naive MCL
Original Primary Outcome Measures  ICMJE
 (submitted: April 7, 2017)
  • Occurrence of Tumor Lysis Syndrome (TLS) [ Time Frame: Approximately 3 months after last subject enrolled into safety run-in portion ]
    To evaluate the occurrence of tumor lysis syndrome (TLS) with the concurrent administration of ibrutinib and venetoclax.
  • Occurrence of Dose Limiting Toxicities (DLT) [ Time Frame: Approximately 3 months after last subject enrolled into safety run-in portion ]
    To evaluate the occurrence of DLTs with the concurrent administration of ibrutinib and venetoclax.
  • Progression-free Survival (PFS) [ Time Frame: approximately 1 year after last subject has stopped treatment with study drug(s) ]
    To evaluate PFS of ibrutinib and venetoclax compared to ibrutinib and placebo.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 20, 2021)
  • Complete Response (CR) (Randomization Period) [ Time Frame: approximately 1 year after last subject has stopped treatment with study drug(s) ]
    Complete response rate (CR) based on the best overall response per investigator assessment according to the Revised Response Criteria for Malignant Lymphoma.
  • Overall response rate (ORR) (Randomization Period and Treatment-Naive Arm) [ Time Frame: approximately 1 year after last subject has stopped treatment with study drug(s) ]
    ORR is defined as CR or PR per investigator assessment according to the Revised Response Criteria for Malignant Lymphoma.
  • MRD-negative remission rate in participants who achieve CR per investigator assessment (Randomization Period and Treatment-Naive Arm) [ Time Frame: approximately 1 year after last subject has stopped treatment with study drug(s) ]
    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.
  • Overall Survival (OS) (Randomization Period and Treatment-Naive Arm) [ Time Frame: Up to approximately 5 years ]
    OS is defined as the time from the date of the first dose of study treatment to death from any cause.
  • Duration of Response (DOR) (Randomization Period and Treatment-Naive Arm) [ Time Frame: Up to approximately 5 years ]
    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.
  • Time to Next Treatment (TTNT) (Randomization Period and Treatment-Naive Arm) [ Time Frame: Up to approximately 5 years ]
    TTNT is defined as the duration from the date of randomization to the start date of any anti-lymphoma treatment subsequent to study treatment.
  • Percentage of participants experiencing Adverse Events (Randomization Period) [ Time Frame: Up to approximately 5 years ]
    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.
  • Occurrence of Tumor Lysis Syndrome (TLS) (Randomization Period) [ Time Frame: Approximately 3 months after last subject enrolled into safety run-in portion ]
    To evaluate the occurrence of tumor lysis syndrome (TLS) with the concurrent administration of ibrutinib and venetoclax.
  • Cmax if Ibrutinib (Randomization Period) [ Time Frame: Week 6 ]
    Cmax if Ibrutinib.
  • Tmax if Ibrutinib (Randomization Period) [ Time Frame: Week 6 ]
    Tmax if Ibrutinib.
  • AUClast if Ibrutinib (Randomization Period) [ Time Frame: Week 6 ]
    AUClast if Ibrutinib.
  • Half-Life (T1/2) if Ibrutinib (Randomization Period) [ Time Frame: Week 6 ]
    Half-Life (T1/2) if Ibrutinib.
  • Cmax of Venetoclax (Randomization Period) [ Time Frame: Week 6 ]
    Cmax of Venetoclax.
  • Tmax of Venetoclax (Randomization Period) [ Time Frame: Week 6 ]
    Tmax of Venetoclax.
  • AUC of Venetoclax (Randomization Period) [ Time Frame: Week 6 ]
    AUC of Venetoclax.
  • Time to worsening in FACT-Lym subscale of the health-related quality of life (Randomization Period) questionnaire (FACT-Lym) [ Time Frame: Week 6 ]
    Time to worsening in FACT-Lym subscale of the health-related quality of life questionnaire (FACT-Lym) will be compared between treatment arms.
  • Duration of CR (Treatment-Naive Arm Period) [ Time Frame: Up to approximately 5 years ]
    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.
  • Progression-free Survival (PFS) (Treatment-Naive Arm Period) [ Time Frame: approximately 1 year after last subject has stopped treatment with study drug(s) ]
    To evaluate PFS of ibrutinib and venetoclax compared to ibrutinib and placebo.
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of Ibrutinib Combined With Venetoclax in Subjects With Mantle Cell Lymphoma (SYMPATICO)
Official Title  ICMJE Phase 3 Study of Ibrutinib in Combination With Venetoclax in Subjects With Mantle Cell Lymphoma
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 Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Mantle-Cell Lymphoma
Intervention  ICMJE
  • Drug: Ibrutinib
    Administered orally once daily
  • Drug: Venetoclax
    Administered orally once daily
  • Drug: Placebo Oral tablet to match Venetoclax
    Administered orally once daily
Study Arms  ICMJE
  • Experimental: Safety Run-in Period

    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.

    Interventions:
    • Drug: Ibrutinib
    • Drug: Venetoclax
  • Experimental: Phase 3: Ibrutinb + Venetoclax
    Subjects will be randomized to receive ibrutinib and venetoclax/placebo until clinical disease progression or unacceptable toxicity
    Interventions:
    • Drug: Ibrutinib
    • Drug: Venetoclax
  • Placebo Comparator: Phase 3: Ibrutinib + Placebo
    Subjects will be randomized to receive ibrutinib and venetoclax/placebo until clinical disease progression or unacceptable toxicity
    Interventions:
    • Drug: Ibrutinib
    • Drug: Placebo Oral tablet to match Venetoclax
  • Experimental: Treatment-naive

    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.

    Interventions:
    • Drug: Ibrutinib
    • Drug: Venetoclax
Publications * Wang M, Ramchandren R, Chen R, Karlin L, Chong G, Jurczak W, Wu KL, Bishton M, Collins GP, Eliadis P, Peyrade F, Lee Y, Eckert K, Neuenburg JK, Tam CS. Concurrent ibrutinib plus venetoclax in relapsed/refractory mantle cell lymphoma: the safety run-in of the phase 3 SYMPATICO study. J Hematol Oncol. 2021 Oct 30;14(1):179. doi: 10.1186/s13045-021-01188-x.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: November 12, 2021)
352
Original Estimated Enrollment  ICMJE
 (submitted: April 7, 2017)
287
Estimated Study Completion Date  ICMJE August 31, 2023
Estimated Primary Completion Date August 31, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Belgium,   Canada,   Czechia,   France,   Germany,   Greece,   Hungary,   Italy,   Korea, Republic of,   Netherlands,   Poland,   Spain,   Turkey,   Ukraine,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03112174
Other Study ID Numbers  ICMJE PCYC-1143-CA
2017-000129-12 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Pharmacyclics LLC.
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Pharmacyclics LLC.
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Janssen Research & Development, LLC
Investigators  ICMJE Not Provided
PRS Account Pharmacyclics LLC.
Verification Date September 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP