E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with Relapsed and/or Refractory Diffuse Large B-Cell Lymphoma and Other Forms of Non-Hodgkin’s Lymphoma |
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E.1.1.1 | Medical condition in easily understood language |
Patients with DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL) or other forms of non-Hodgkin's lymphoma (NHL) who have stopped responding or have failed to respond to current cancer treatments. |
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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 | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10012821 |
E.1.2 | Term | Diffuse large B-cell lymphoma recurrent |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 23.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029601 |
E.1.2 | Term | Non-Hodgkin's lymphoma refractory |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 23.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029600 |
E.1.2 | Term | Non-Hodgkin's lymphoma recurrent |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 | 10012822 |
E.1.2 | Term | Diffuse large B-cell lymphoma refractory |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 | 10076596 |
E.1.2 | Term | Marginal zone lymphoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10067070 |
E.1.2 | Term | Follicular B-cell non-Hodgkin's lymphoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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) |
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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) |
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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 |
- Determine the safety and tolerability of the proposed Debio 1562 dose regimens in combination with rituximab - Determine the anti-tumor activity of the proposed Debio 1562 dose regimens in combination with rituximab |
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E.2.2 | Secondary objectives of the trial |
- Characterize the PK of Debio 1562 in combination with rituximab - Determine time to event outcomes [progression-free survival (PFS), time to response, duration of response (DOR), and overall survival (OS)] - Assess the immunogenicity of Debio 1562 (anti-drug antibodies, ADA) when administered in combination with rituximab |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) For Part 1 of the study, patients must have histopathologically confirmed diagnosis of relapsed and/or refractory DLBCL, FL, MZL/MALT, MCL, or other Sponsor approved NHL subtypes according to the World Health Organization (WHO) classification 2008 for which standard measures do not exist or are no longer effective. 2) For Part 2 and Part 3 of the study, patients must have histopathologically and clinically confirmed diagnosis of relapsed DLBCL. Patients will be considered to have a relapsed disease if they showed a duration of response of at least 24 weeks after their first line of therapy. The following patients with relapsed DLBCL will be enrolled: i. Patients who received only one line of previous therapy and achieved either complete response (CR) or partial response (PR) for at least 24 weeks (from the last day of the last cycle) after their first line of therapy, but whom are not eligible for high dose chemotherapy with autologous stem cell transplantation (HD-ASCT) ii. Patients who received more than one line of previous therapy (including HD-ASCT), and have achieved a duration of response (CR or PR) of at least 8 weeks (from the last day of the last cycle) after their last line of therapy 3) Patients must have received no more than six prior treatment regimens. Prior treatment with an anti- CD20 agent, either alone or in combination, is allowed. 4) Patients must be ≥ 18 years. 5) Patients must have ECOG Performance Status 0-2. 6) Patients must meet the following laboratory criteria: - Absolute neutrophil count (ANC) ≥ 1.0 x 10^9/L (1000/mm^3), - Platelet count ≥ 50 x 10^9/L (50,000/mm^3; patients must not have been transfused within 10 days previous blood drawn for laboratory assessment), -Patients receiving therapeutic anticoagulation are eligible provided their anticoagulation parameters are within range (e.g. International Normalized Ratio [INR] 2-3 on Coumadin if applicable) and they have no history of ≥ Grade 2 bleeding while on anticoagulatioin therapy. -For patients receiving therapeutic doses of anticoagulation: Platelet count ≥ 100 x 10^9/L (100,000/mm^3; must not have been transfused wihtin previous 10 days) - Hemoglobin ≥ 8.0 g/dL (may have been transfused), - Serum creatinine ≤ 2.0 x upper limit of normal (ULN) or 24-hour creatinine clearance of ≥ 60 mL/minute, - AST ≤ 2.5 x ULN; ALT ≤ 2.5 x ULN and - Total bilirubin ≤ 1.5 x ULN; patients with documented diagnosis of Gilbert syndrome are eligible if total bilirubin ≤ 3.0 x ULN. 7) Patients must have evaluable or measurable disease in accordance with the International Working Group Guidelines for Lymphoma (Cheson 2014). 8) Patients who are Hepatitis B surface antygen (HBsAg) + (must be PCR negative) who are taking antivirals are allowed to enroll. 9) Male patients and female patients of child bearing potential participating in the study must agree to use two highly effective methods of contraception throughout this study and for at least 12 weeks after the last dose of Debio 1562 and 12 months after the last dose of rituximab. Examples of acceptable birth control methods include but are not limited to the following methods: (e.g, oral, parenteral, or implantable hormonal contraceptive; tubal ligation; intra-utérine device; barrier contraceptive with spermicide; partner's latex condom or vasectomy). 10) Patients must be willing and able to sign the informed consent form and comply with the study protocol. 11) Patients must have available a pathology-informed fresh or archived tumor tissue biopsy reflecting the current DLBCL disease. If the tissue biopsy is older than 18 months from the screening visit and a fresh one cannot be available, patients should provide fine needle aspiration (FNA) samples. |
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E.4 | Principal exclusion criteria |
1) Patients with a diagnosis of CLL or Small Lymphocytic Lymphoma 2) For Part 2 and Part 3 of the study, patients with primary refractory DLBCL (defined as progression of disease within 24 weeks after first line of treatment). 3) For Part 2 and Part 3 of the study, patients that are eligible to undergo first time HD-ASCT. 4) For Part 2 and Part 3 of the study, patients with R/R FL, MZL/MALT, MCL, or any other NHL subtypes according to the WHO classification. 5) The following exclusions, with regard to prior therapy apply: - Not recovered from prior chemotherapy or radiation as per Investigator’s judgment. - Anti-CD20 monoclonal antibody therapy within 14 days of starting study treatment. - Prior therapy with other anti-CD37-targeting therapy. - Radioimmunotherapy within two months prior to starting study treatment. - Small molecule anti-cancer therapeutic agent, and all investigational agents within 5 x t½ or 14 days whichever is shorter. - Allogeneic stem cell transplantation in the safety run-in period. In Part 2 and Part 3 of the study, patients who have had an allogeneic stem cell transplant may be eligible if their GVHD is controlled, after investigator/Sponsor discussion. - Chronic, systemic treatment with corticosteroids unless the dose has been stable for >7 days and is equivalent to ≤ 10 mg of prednisone per day. - Patients who have not recovered from prior surgery. Patients must have recovered or stabilized from the side effects of any major or minor surgical procedures prior to study treatment. 6) Patients who have had a prior anaphylactic or other severe infusion reaction such that the patient is unable to tolerate antibody administration. 7) Patients who have known central nervous system, meningeal, or epidural disease including brain metastases. 8) Patients who have received or are to receive vaccination with live viruses within 30 days of Cycle 1 Day1. 9) Impaired cardiac function or clinically significant cardiac disease such as: - New York Heart Association Class III or IV cardiac disease, including preexisting clinically significant ventricular arrhythmia, congestive heart failure, or cardiomyopathy; - Unstable angina pectoris ≤ 6 months prior to starting study drug; - Acute myocardial infarction ≤ 6 months prior to starting study drug; or - Other clinically significant heart disease e.g., ≥ grade 3 hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen. 10) Patients with ≥ Grade 2 peripheral neuropathy. 11) Patients with active hepatitis A, B or C infection. 12) Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, psychiatric illness that would limit compliance with study requirements, active autoimmune disease requiring immunosuppressive therapy, severe immune deficiency. 13) Known diagnosis of human immunodeficiency virus (HIV) infection. 14) Patients with a concurrent primary malignancy that requires treatment or that would confound the disease response interpretation for the disease under study. 15) WCBP who are pregnant or breast feeding. 16) Patients currently presenting interstitial lung disease, diffuse parenchymal lung disease, or with a past history of severe/Grade 3 parenchymal lung disorders.
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E.5 End points |
E.5.1 | Primary end point(s) |
- Treatment-emergent adverse events (TEAES), clinically-significant changes in clinical laboratory test results, ECG and vital sign measurements - Number of patients with clinical responses as assessed by the Lugano Classification of response assessments. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
-AEs will be monitored continuously throughout the study from the time of the first dose of study treatment until 30 days after the patient's last study treatment or until the event has resolved or stabilized or an outcome has been reached, whichever comes first. Clinical laboratory tests will be performed at each study visit. ECG assessments will be performed at each IMP dosing visit, at D2 visits in each study part; at screening visit, at EOT visit and possibly at 30-day FU visit. Vital signs will be assessed at each study visit, except for the D2 and D3 visits in each study part (i.e. C1D2/C1D3 and C3D2/C3D3 in study part 1 (Q3W) and C1D2/C1D3 and C2D2/C2D3 in study part 2 (Q3W and QW)). - Performed approximately every 6 weeks, beginning at C1D1.
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E.5.2 | Secondary end point(s) |
- PK parameters (evaluated as deemed appropriate but not limited to): Cmax, AUC0-t,AUCinf terminal half-life (t½), clearance (CL), volume of distribution at steady state (Vss), Tmax, for both Debio 1562 and rituximab - Calculation of time to event parameters - Progression-free survival (PFS) and Overall survival (OS) - Time to response and duration of response (DOR) - Immunogenicity of Debio 1562: presence of human anti-drug antibody (ADA) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- PK parameters will be assessed at each study visit - Calculation of time to event parameters will be assessed as follows: - PFS: Every 12 weeks (± 4 weeks) from time of last on-study tumor assessment until PD, or starting a subsequent anti-cancer therapy. - OS: Every 12 weeks (± 4 weeks) from time of 30-day FU visit, for up to 1 year from last patient’s first dose (C1D1) - Time to response and DOR will be estimated for all evaluable patients who achieve an objective response (PR or CR) - ADA assessment performed at D1 of each cycle, EOT visit and 30-day FU visit |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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 | No |
E.8.2.3 | Other | No |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 34 |
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 |
Belgium |
Bulgaria |
Czechia |
Hungary |
Italy |
Poland |
Ukraine |
United States |
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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
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The End of Study will be defined as the latter of the completion of the Safety follow-up visit for the last patient remaining on treatment or one year from the last accrued patient’s first visit |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |