| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061275 |
| E.1.2 | Term | Mantle cell lymphoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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 |
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| E.2.2 | Secondary objectives of the trial |
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 were MRD positive at screening and 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.
• (one more)
TN Open-label Arm: Section 2.3.2 of the Protocol |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 ≥18 years of age with 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 ring, sponge, etc) during the period of therapy and for 90 days after the last dose of study drug |
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| E.4 | Principal 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 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
19. Subjects with chronic liver disease with hepatic impairment Child- Pugh class B or C
20. Female subject who is pregnant, breastfeeding or is considering becoming pregnant during the study or for approximately 90 days after the last dose of study drug
21. Male subject who is considering fathering a child or donating sperm during the study or for approximately 90 days after the last dose of study drug
22. Unwilling or unable to participate in all required study evaluations and procedures
23. Unable to understand the purpose and risks of the study and to provide a signed and dated informed consent form (ICF) and authorization to use protected health information (in accordance with national and local subject privacy regulations)
24. Known hypersensitivity to the active ingredient or other components of one or more study drugs |
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| E.5 End points |
| E.5.1 | 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 death- 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 until discontinuation of treatment and 30 days after the last dose
• Response (CR, PR), DOR, and PFS - 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
• OS - after progression every 12 weeks until death
Randomization Phase Primary Endpoint:
The primary efficacy endpoint of the Phase 3 portion of this study is PFS, defined as the duration from the date of randomization to the date of investigator-assessed disease progression using the Revised Response Criteria for Malignant Lymphoma (Cheson 2014), or death from any cause,
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
Treatment-naive Open-label Arm Primary Endpoint
The primary efficacy endpoint of the treatment-naive open-label arm is the complete response (CR) rate based on the best overall response 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 |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Please refer to section E.5.1 |
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| E.5.2 | 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 thereafter until PD
• MRD-negative remission rate in subjects who achieve CR. MRD negative remission is defined the same as described in Section 10.2.3 of the Protocol - 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
• PFS, 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 - 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
• OS, defined as the time from the date of the first dose of study treatment to death from any cause - after progression every 12 weeks until death
• TTNT, defined as the duration from the date of the first dose of study treatment to the start date of any anti-lymphoma treatment subsequent to study treatment - after progression every 12 weeks until death |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Please refer to section E.5.2 |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 60 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| United States |
| Belgium |
| Czechia |
| France |
| Germany |
| Hungary |
| Italy |
| Netherlands |
| Poland |
| Spain |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
Last subject last visit is on 30Sep2024 and end of study on 31Dec2024.
Rationale: Study is event driven and this is the projected time needed
to collect the OS events needed for analysis. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
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