Mantle Cell Lymphoma MedDRA version: 20.0 Level: PT Classification code 10061275 Term: Mantle cell lymphoma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Sponsors
Pharmacyclics LLC
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: For SRI and Randomization Phase Disease-Related • 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 that is =2.0 cm in the longest diameter and measurable in 2 perpendicular dimensions per CT • At least 1, but no more than 5, prior treatment regimens for MCL including at least 1 prior rituximab/anti-CD20 containing regimen • 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. Laboratory • Adequate hematologic function • Adequate hepatic and renal function Demographic • Men and women = 18 years of age • Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 For Treatment-naive Open-label Arm: 1. 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) • A report from the local laboratory is acceptable if available; however, it must be reviewed and approved by the central pathology laboratory to verify the above criteria prior to enrollment • If the report from the local laboratory is not available, a tumor block or slides must be sent to the central pathology laboratory for confirmation of the MCL diagnosis prior to enrollment. 2. Men and women =65 years of age, or if less than 65 years of age must have a TP53 mutation 3. At least 1 measurable site of disease that is =2.0 cm in the longest diameter and measurable in 2 perpendicular dimensions per CT 4. Subjects must have adequate fresh or paraffin-embedded tissue 5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of = 2 6. Adequate hematologic function independent of transfusion and growth factor support for at least 7 days prior to first dose, with the exception of pegylated G CSF (pegfilgrastim) and darbepoeitin which require at least 14 days prior to the first dose defined as: • Absolute neutrophil count (ANC) >1000 cells/mm3 (1.0 x 109/L) • Platelet count >50,000 cells/mm3 (50 x 109/L) • Hemoglobin >8.0 g/dL 7. Adequate hepatic and renal function defined as: • Serum aspartate transaminase (AST) or alanine transaminase (ALT) = 3.0 x upper limit of normal (ULN) • Estimated Creatinine Clearance (CrCl) =30 mL/min (Cockcroft-Gault) • Bilirubin =1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non hepatic origin) 8. Prothrombin time (PT) or International normal ratio (INR) <1.5 x upper limit of normal (ULN) and PTT (activated partial thromboplastin time [aPTT]) <1.5 x ULN (unless abnormalities are unrelated to coagulopathy or bleeding disorder). When treated with warfarin or other vitamin K antagonists, then INR =3.0 9. Male and female subjects of reproductive potential who agree to use both a highly effective method of birth control (eg, implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], complete abstinence , or sterilized partner) and a barrier method (eg, condoms, cervical
Exclusion criteria
Exclusion criteria: For SRI and Randomization Phase Disease-Related • History or current evidence of central nervous system lymphoma Concurrent Conditions • 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: o moderate or strong cytochrome P450 3A (CYP3A) inhibitors o moderate or strong CYP3A inducers For Treatment-naive Open-label Arm: 1. Blastoid variant of MCL 2. History or current evidence of central nervous system lymphoma 3. Concurrent enrollment in another therapeutic investigational study or prior therapy, including ibrutinib or other BTK inhibitors 4. Prior treatment with venetoclax or other BCL2 inhibitors 5. 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 • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease. • Adequately treated carcinoma in situ without evidence of disease. 6. Vaccinated with live, attenuated vaccines within 4 weeks of the first dose of study drug 7. Clinically significant infection requiring IV systemic treatment that was completed =14 days before the first dose of study drug 8. Any uncontrolled active systemic infection 9. Known bleeding disorders (eg, von Willebrand's disease or hemophilia) 10. History of stroke or intracranial hemorrhage within 6 months prior to enrollment 11. Known history of human immunodeficiency virus (HIV) or active with hepatitis C virus (HCV) or hepatitis B virus (HBV). Subjects who are positive for hepatitis B core antibody, or hepatitis C antibody must have a negative polymerase chain reaction (PCR) result before enrollment. Those who are hepatitis B surface antigen (HBsAg) or PCR positive will be excluded. 12. Major surgery within 4 weeks of the first dose of study drug. 13. 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 14. 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 15. 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 16. 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 • Moderate or strong CYP3A inducers 17. Administration or consumption of any of the following within 3 days prior to the first dose of study drug: • grapefruit or grapefruit products • Seville oranges (including marmalade containing Seville oranges) • star fruit 18. Known allergy to xanthi
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Safety Run-in Period: To evaluate the occurrence of tumor lysis syndrome (TLS) and dose-limiting toxicities (DLTs) with the concurrent administration of ibrutinib and venetoclax. Randomization Phase: To evaluate whether the combination of ibrutinib and venetoclax will result in prolongation of PFS compared to ibrutinib and placebo in subjects with relapsed or refractory MCL. Treatment-naive Open-label Arm: To evaluate the complete response (CR) rate with the combination of ibrutinib and venetoclax in subjects with treatment-naive MCL;Secondary Objective: Safety Run-in Period: To evaluate response (partial and complete response), progression-free survival (PFS), duration of response (DOR), and overall survival (OS). Randomization Phase: • To evaluate whether the combination of ibrutinib and venetoclax will increase the complete response rate, the overall response rate (ORR), the minimal residual disease (MRD) negative remission rate in subjects who achieve CR, OS, DOR, and time-to-next treatment (TTNT) compared to ibrutinib and placebo. • To evaluate the frequency, severity, and relatedness of AEs; frequency, severity and management of TLS; AEs requiring dose reductions and/or discontinuation of study drug, or leading to death. • To determine the pharmacokinetics of ibrutinib and venetoclax. • To evaluate whether the combination of ibrutinib and venetoclax will improve quality of life using a Health-related quality of life questionnaire compared to ibrutinib and placebo. TN Open-label Arm: Refer to section 2.3.2 of the Protocol;Primary end point(s): Safety Run-in Period (including timepoints) • Frequency of TLS and DLTs- weekly for the 1st 5 weeks • Frequency, severity, and relatedness of AEs- weekly for the 1st 6 weeks, then bi-weekly until week 13, then every 4 weeks for the 1st year, every 2 months for year 2 and 3, then every 3 months thereafter until PD • Frequency of AEs causing study drug discontinuation, or dose reductions or leading to dea | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Randomization Phase Secondary Endpoints (including timepoints): Efficacy: • Complete response rate (CR) based on the best overall response according to the revised criteria- every 3 months for the first year starting with week 13; every 4 months during the second and third years, and every 6 months thereafter until PD • Objective response rate (ORR), defined as CR or PR according to the revised criteria- every 3 months for the first year starting with week 13; every 4 months during the second and third years, and every 6 months thereafter until PD • MRD-negative remission rate in subjects who achieve CR. A MRD-negative remission is defined as undetectable MRD as assessed by flow cytometry in both bone marrow and peripheral blood collected at the time of CR, with requirement of confirmation of MRD negativity in the subsequent peripheral blood 12 weeks later-every 3 months for the first year starting with week 13; every 4 months during the second and third years, and every 6 months thereafter until PD Treatment-Naive Open-Label Arm Secondary Endpoints • Overall response rate (ORR), defined as CR or PR according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2014) - every 3 months for the first year starting with week 13; every 4 months during the second and third years, and every 6 months thereafter until PD • Duration of Response (DOR), defined for subjects 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 - every 3 months for the first year starting with week 13; every 4 months during the second and third years, and every 6 months thereafter until PD • 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 - every 3 months for the first year starting with week 13; every 4 months during the second and third years, and every 6 months | — |
Countries
Australia, Belgium, Canada, Czech Republic, France, Germany, Greece, Hungary, Italy, Netherlands, Poland, Spain, United Kingdom, United States
Contacts
Public ContactClinical Trial Information
Pharmacyclics LLC
Outcome results
None listed