| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed or Refractory Mantle Cell Lymphoma |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10026801 |
| E.1.2 | Term | Mantle cell lymphoma refractory |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10026800 |
| E.1.2 | Term | Mantle cell lymphoma recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective is to determine if progression-free survival (PFS), as assessed by Blinded Independent Central Review (BICR) per Lugano Classification, is superior for ibrutinib plus zilovertamab compared to ibrutinib plus placebo among subjects with relapsed or refractory (R/R) mantle cell lymphoma (MCL) that had a PR or SD after 16 weeks of ibrutinib monotherapy. |
|
| E.2.2 | Secondary objectives of the trial |
1. ORR and DOR, as assessed by BICR per Lugano Classification, among the subjects who received the combination of zilovertamab plus ibrutinib compared with the subjects who received ibrutinib plus placebo.
2. CR rate as assessed by BICR per Lugano Classification, among the subjects who received the combination of zilovertamab plus ibrutinib compared with the subjects who received ibrutinib plus placebo.
3. Proportion of subjects experiencing Grade 3 to 4 neutrophil count decrease among the subjects who received the combination of zilovertamab plus ibrutinib compared with the subjects who received ibrutinib plus placebo based on laboratory abnormalities.
4. OS among the subjects who received the combination of zilovertamab plus ibrutinib compared with the subjects who received ibrutinib plus placebo.
5. Overall safety profile among the subjects who received the combination of zilovertamab plus ibrutinib compared with the subjects who received ibrutinib plus placebo. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Men and women of age ≥18 years.
2. Subject has histologically confirmed MCL with documented overexpression of cyclin D1, or t(11;14) translocation, or relevant immunophenotype (eg, CD5, CD19, CD20, SOX11).
3. Subject has received at least one prior regimen for MCL.
4. Subject has R/R disease, defined by the following:
a. Relapse is defined as PD following an initial response to prior therapy, and
b. Refractory disease is defined as PD as a best response to prior therapy or PD within a short period of time (< 6 months).
5. Subject has at least 1 measurable site of disease that is ≥ 2.0 cm in the longest diameter and measurable in 2 perpendicular dimensions by computed tomography (CT).
6. Subject must have a combined positron emission tomography (PET)-CT performed less than 28 days prior to study entry. If the subject’s MCL is non-fluorodeoxyglucose (FDG)-avid, subject must have a bone marrow biopsy performed less than 28 days prior to study entry.
7. If a subject has toxicities due to prior therapy for the treatment of MCL, the subject must be stable and recovered to ≤ Grade 1 (except for clinically non-significant toxicities such as alopecia).
8. Subject has an Eastern Cooperative Oncology Group performance status of 0 or 1.
9. Subject must meet the following laboratory parameters:
a. Absolute neutrophil count of > 1.0 × 10^9/L independent of growth factor support within 7 days of study entry.
b. Platelet count > 75 × 10^9/L without transfusion support within 7 days of study entry.
c. Hemoglobin ≥ 8.0 g/dL maintained without transfusion support within 7 days of study entry.
d. Serum aspartate aminotransferase/serum glutamic-oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase/serum glutamic-pyruvic transaminase (ALT/SGPT) ≤ 3.0 × upper limit of normal (ULN).
e. Total bilirubin ≤ 1.5 × ULN.
f. Estimated creatinine clearance (ie, estimated glomerular filtration rate using Cockcroft-Gault) ≥ 30 mL/min.
g. International normalized ratio (INR) ≤ 1.5 and activated partial thromboplastin time ≤ 1.5 × ULN.
10. For female subjects of childbearing potential, a negative urine or serum pregnancy test within 72 hours prior to the start of ibrutinib monotherapy.
11. For female subjects of childbearing potential, willingness to use an effective method of contraception from the start of the Screening Phase until ≥ 3 months after the last dose of blinded infusion or ≥ 1 month after the last dose of ibrutinib, whichever is later. Note: A female subject is considered to be of childbearing potential unless she has had a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy; has medically documented ovarian failure (with serum estradiol and follicle-stimulating hormone levels within the institutional laboratory postmenopausal range and a negative serum or urine beta human chorionic gonadotropin [βHCG]); or is menopausal (age ≥ 50 years with amenorrhea for ≥ 6 months).
12. For male subjects who can father a child with a female partner of childbearing potential, willingness to use an effective method of contraception and refrain from sperm donation from the start of ibrutinib monotherapy until ≥ 3 months after the last dose of ibrutinib or blinded infusion, whichever is later. Note: A male subject is considered able to father a child unless he has had a bilateral vasectomy with documented aspermia or a bilateral orchiectomy. |
|
| E.4 | Principal exclusion criteria |
1. Subject has had more than one month of prior therapy with ibrutinib or any other BTK inhibitor or did not tolerate therapy with any BTK inhibitor.
2. Subject has concurrent enrollment in another therapeutic investigational study.
3. Subject has transfusion-dependent thrombocytopenia.
4. Subject has received anticancer therapy, including chemotherapy, monoclonal antibody, or targeted agents within 21 days (or at least 5 drug half-lives, whichever is shorter) prior to the start of ibrutinib monotherapy.
5. Subject has a history of other malignancy, with the exception of non-melanomatous skin cancer or carcinoma in situ (eg, cervix, bladder, breast), or indolent prostate cancer, unless disease free for at least 3 years prior to study entry.
6. Subject has known active or prior central nervous system (CNS) involvement with lymphoma (eg, detectable cerebrospinal fluid malignant cells or brain metastases). Subjects with prior CNS involvement are eligible if they have had no evidence of active CNS disease for ≥ 12 months prior to study entry.
7. Subject has a history or presence of CNS disorder (eg, as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, cerebral edema, posterior reversible encephalopathy syndrome, or any autoimmune disease with CNS involvement) within 6 months of study entry.
8. Subject has a history of clinically significant cardiac disease within 6 months of study entry.
9. Subject has active or prior cardiac (atrial or ventricular) lymphoma involvement.
10. Subject has a history of atrial fibrillation or left or right bundle branch block.
11. Subject has a history of symptomatic deep vein thrombosis or pulmonary embolism ≤ 6 months of study entry.
12. Subject has chronic liver disease with hepatic impairment, Child-Pugh class B or C.
13. Subject has a known bleeding disorder.
14. Subject has had a prior stem cell transplant that requires ongoing immunosuppressive therapy or active clinical graft versus host disease.
15. Subject has primary severe immunodeficiency.
16. Subject has a history of human immunodeficiency virus infection or has active hepatitis B or C infection.
17. Subjects may not have any active infection requiring IV antimicrobial (anti-viral, antibiotic, anti-fungal) therapy at the time of study entry. Subjects with an infection requiring IV antimicrobial therapy must have completed all antimicrobial therapy ≤ 14 days of study entry. Subjects with a recent self-limited infection that has clinically resolved may complete a prescribed course of antimicrobial therapy after study entry as long as they are asymptomatic with no clinical evidence of infection for ≥ 7 days prior to study entry.
18. Subject has been vaccinated with a live, attenuated vaccine ≤ 4 weeks of the first dose of ibrutinib.
19. Subject has a history of hypersensitivity reaction to any of the agents used in this study.
20. Subject requires treatment with a strong CYP3A inhibitor/inducer.
21. Subject is unable to swallow capsules or tablets, or has 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.
22. Subject has had major surgery ≤ 4 weeks of the first dose of ibrutinib.
23. Subject has any medical condition likely to interfere with assessment of safety or efficacy of the study drug.
24. Subject is unlikely to complete all protocol-required study visits or procedures, including follow-up visits, or comply with the study requirements for participation in the Investigator’s opinion.
25. Subject is not willing to practice contraception.
26. Subject is pregnant.
27. Subject is breastfeeding (unless the subject agrees to discontinue breastfeeding during protocol therapy and for ≥ 3 months after the last infusion and for ≥ 1 month after the last dose of ibrutinib, whichever is later).
Exclusion Criteria for Randomized Double-Blind Treatment Phase
• Best response of CR.
• Progressive disease at any time during the 16-week Open-Label Ibrutinib Monotherapy Treatment Phase.
• More than 2 ibrutinib dose reductions and/or 2 interruptions with a duration of >7 days each.
• Atrial fibrillation of grade 1 or 2 unresolved at the time of randomization. Occurrence of atrial fibrillation of grade 3 or 4 any time prior to randomization.
• An unacceptable safety profile deemed by the Investigator as related to ibrutinib therapy.
• Any non-hematological ≥ Grade 3 toxicity unresolved at the time of randomization.
• Any hematological Grade 4 toxicity unresolved at the time of randomization.
• Other Investigator concerns (eg, inadequate compliance with therapy or study assessments). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is Progression Free Survival (PFS), assessed by BICR per Lugano Classification |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Key secondary endpoints include:
• ORR and DOR assessed by BICR per Lugano Classification.
• CR rate, DOCR, and time to CR assessed by BICR per Lugano Classification.
• Proportion of Grade 3 to 4 neutrophil count decrease.
• OS. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| Immunogenicity and biomarker assessments |
|
| 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 | No |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Initial Open-Label Ibrutinib Monotherapy Treatment Phase |
|
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 70 |
| 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 |
| Israel |
| Korea, Republic of |
| United States |
| France |
| Poland |
| Spain |
| Germany |
| Italy |
| Belgium |
| Hungary |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
LVLS
The study will be considered complete when the last subject has completed their final follow-up visit or procedure (per Table 1) or has experienced a PFS event or death. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
