| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed or Refractory Diffuse Large B-Cell Lymphoma (R-R DLBCL) |
|
| E.1.1.1 | Medical condition in easily understood language |
| A cancer of B cells, a type of white blood cell responsible for producing antibodies, which has returned after a period of improvement or that has proved resistant, or does not respond to, treatment |
|
| 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) |
|
| 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) |
|
| 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 |
To determine the efficacy of a combination of MOR00208 with BEN versus a combination of RTX with BEN in terms of progression-free survival (PFS) in:
• Adult patients with R-R DLBCL (overall population)
• A subgroup of adult patients with R-R DLBCL with low baseline peripheral blood NK-cell count (NKCC-low), defined as 100 or less NK cells per µl blood at baseline. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives will be assessed for the overall population, and NKCC-low subgroup, as appropriate.
1. To determine and compare both study arms, MOR00208 with BEN versus RTX with BEN, in terms of:
a) best objective response rate (ORR = complete response [CR] + partial response [PR]) based on the best response achieved at any time during the study
b) duration of response (DoR)
c) overall survival (OS)
d) disease control rate (DCR = CR + PR + stable disease [SD])
e) time to progression (TTP)
f) time to next treatment (TTNT)
g) safety, based on the frequency, incidence and severity of adverse events (AEs)
h) quality of life (QoL), using the EORTC QLQ-C30 and EQ-5D-5L questionnaires
2. To assess the potential immunogenicity of MOR00208 (anti-MOR00208 antibody formation)
3. To assess the pharmacokinetic (PK) profile of MOR00208.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Diagnosis/Trial Population
1. Age ≥18 years
2. Histologically confirmed diagnosis according to the World Health Organization (WHO, 2008) classification of:
a) Diffuse large B-cell lymphoma not otherwise specified (DLBCL NOS)
b) T cell/histiocyte rich large B-cell lymphoma (THRLBCL)
c) Epstein-Barr virus (EBV) positive DLBCL of the elderly (EBV-positive DLBCL)
d) Composite lymphoma with a DLBCL component with a DLBCL relapse subsequent to DLBCL treatment
e) Disease transformed from an earlier diagnosis of low grade lymphoma (i.e. an indolent pathology such as follicular lymphoma, marginal zone lymphoma) into DLBCL with a DLBCL relapse subsequent to DLBCL treatment.
3. Fresh tumour tissue for central pathology review must be provided as an adjunct to participation in this study. Should it not be possible to obtain a fresh tumour tissue sample, archival paraffin embedded tumour tissue acquired ≤3 years prior to screening for this protocol must be available for this purpose.
4. Patients must have:
a) R-R DLBCL
b) at least one bidimensionally measurable disease site. The lesion must have a greatest transverse diameter of ≥1.5 cm and greatest perpendicular diameter of ≥1.0 cm at baseline. The lesion must be positive on PET scan.
c) received at least one, but no more than three previous systemic therapy lines for the treatment of DLBCL (for further details see Sections 8.6 and 9.5). At least one previous therapy line must have included a CD20-targeted therapy (e.g. RTX).
d) Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
5. Patients after failure of ASCT or patients considered in the opinion of the investigator currently not eligible for HDC with subsequent ASCT. Documentation of the reason for ineligibility for ASCT must be present in the patient’s source data.
Laboratory Values
6. Patients must meet the following laboratory criteria at Screening:
a) absolute neutrophil count (ANC) ≥1.5 × 10E9/L (unless secondary to bone marrow involvement by DLBCL as demonstrated by bone marrow aspiration and bone marrow biopsy required for Screening)
b) platelet count ≥90 × 10E9/L (unless secondary to bone marrow involvement by DLBCL as demonstrated by bone marrow aspiration and bone marrow biopsy required for Screening) and absence of active bleeding
c) total serum bilirubin ≤2.5 × upper limit of normal (ULN) unless secondary to Gilbert’s syndrome (or pattern consistent with Gilbert’s) or documented liver involvement by lymphoma. Patients with Gilbert's syndrome or documented liver involvement by lymphoma may be included if their total bilirubin is ≤5 x ULN (see exclusion criterion 6e)
d) ALT, AST and alkaline phosphatase (AP) ≤3 × ULN or <5 × ULN in cases of documented liver involvement by lymphoma
e) serum creatinine ≤2.0 x ULN or creatinine clearance must be ≥40 mL/min, calculated using a standard Cockcroft-Gault formula
7. For a female of childbearing potential (FCBP), a negative pregnancy test must be confirmed before enrolment. An FCBP must commit to take highly effective contraceptive precautions without interruption during the study and for 3, 6 or 12 months after the last dose of MOR00208, BEN or RTX respectively, whichever is later. An FCBP must refrain from breastfeeding and donating blood or oocytes during the course of the study and for 3, 6 or 12 months after the last dose of MOR00208, BEN or RTX respectively, whichever is later. Restrictions concerning blood donations apply as well to females who are not of childbearing potential.
8. Male patients must use an effective barrier method of contraception without interruption during the study and for 3, 6 or 12 months after the last dose of MOR00208, BEN or RTX respectively, whichever is later, if the patient is sexually active with an FCBP. Males must refrain from donating blood or sperm during the study participation and for 3, 6 or 12 months after the last dose of MOR00208, BEN or RTX respectively, whichever is later.
9. In the opinion of the investigator, the patients must:
a) be able to comply with all study-related procedures, medication use, and evaluations
b) be able to understand and give informed consent
c) not be considered to be potentially unreliable and/or not cooperative. |
|
| E.4 | Principal exclusion criteria |
Exclusionary Diagnosis Criteria
1. Patients who have:
a) any other histological type of lymphoma including, e.g., primary mediastinal (thymic) large B-cell (PMBL) or Burkitt’s lymphoma
b) primary refractory DLBCL
c) patients with known "double/triple hit" DLBCL genetics characterised by simultaneous detection of MYC with BCL2 and/or BCL6 translocation, as defined by fluorescence in situ hybridisation (FISH). MYC, BCL2, BCL6 testing prior to study enrolment is not required.
d) central nervous system (CNS) lymphoma involvement in present or past medical history
Exclusionary Previous and Current Treatment Criteria
2. Patients who had a major surgery (for definition, see Section 8.1) less than 30 days prior to Day 1 dosing
3. Patients who have, within 14 days prior to Day 1 dosing:
a) not discontinued CD20-targeted therapy, chemotherapy, radiotherapy, investigational anticancer therapy or other lymphoma-specific therapy (for exceptions see Section 9.5.3)
b) received live vaccines
c) required parenteral antimicrobial therapy for active, intercurrent systemic infections
4. Patients who:
a) in the opinion of the investigator, have not recovered sufficiently from the adverse toxic effects of prior therapies, major surgeries (for definition, see Section 8.1) or significant traumatic injuries
b) were previously treated with CD19-targeted therapy or BEN
c) have a history of previous severe allergic reactions to compounds of similar biological or chemical composition to MOR00208, RTX, murine proteins or BEN, or the excipients contained in the study drug formulations
d) have undergone ASCT within a period of ≤3 months prior to signing the ICF. Patients who have a more distant history of ASCT must exhibit full haematological recovery before enrolment into the study.
e) have undergone previous allogeneic stem cell transplantation
f) concurrently use other anticancer or experimental treatments (for exceptions see Section 9.5.3)
Exclusionary Medical History Criteria
5. Prior history of malignancies other than DLBCL, unless the patient has been free of the disease for ≥3 years prior to Screening. Exceptions to the ≥3-year time limit include history of the following:
a) basal cell carcinoma of the skin
b) squamous cell carcinoma of the skin
c) carcinoma in situ of the cervix
d) carcinoma in situ of the breast
e) carcinoma in situ of the bladder
f) incidental histological finding of prostate cancer (Tumour/Node/Metastasis [TNM] stage of T1a or T1b)
6. Patients with:
a) positive hepatitis B and/or C serology
b) known seropositivity for or history of active viral infection with human immunodeficiency virus (HIV)
c) evidence of active, severe uncontrolled systemic infections (e.g., tuberculosis [TB], opportunistic infections) or sepsis
d) a history or evidence of severely immunocompromised state
e) a history or evidence of severe hepatic impairment (total serum bilirubin > 3 mg/dL), jaundice unless secondary to Gilbert's syndrome or documented liver involvement by lymphoma (see inclusion criterion 6c)
f) a history or evidence of clinically significant cardiovascular, cerebrovascular, CNS and/or other disease that, in the investigator’s opinion, would preclude participation in the study or compromise the patient’s ability to give informed consent (for additional explanations, see Section 8.6). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Co-Primary Endpoints:
1. PFS in the overall study population (FAS)
2. PFS in the NKCC-low subgroup |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Screening; C3:D1±3 days; C6:D28±4 days; C7-24:D1±3 days; end of treatment; FU for PFS (every 3 months ± 2 weeks) |
|
| E.5.2 | Secondary end point(s) |
- Best ORR, DoR, OS, DCR, TTP and TTNT
- Frequency, incidence and severity of AEs
- QoL
- Anti-MOR00208 antibody formation
- PK of MOR00208
- Exploratory biomarkers (e.g., CD19, CD20, BCL2, BCL6 expression, changes in B-, T- and NKCC over time, CD16 expression on NK cells, ADCC capacity, and gene expression analysis for cell-of-origin subtyping).
The secondary endpoints will be analysed in the overall population (FAS) and NKCC-low subgroup. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Best ORR, DoR, OS, DCR, TTP and TTNT - screening; C3:D1±3 days, C6:D28±4 days, C7-24:D1±3 days, end of treatment, FU for PFS (every 3 months ± 2 weeks)
- AEs - all visits
- QoL - Screening; C1:D1; C2-24:D1±3 days; end of treatment
- Anti-MOR00208 Ab formation - C1:D1; C3,5,7,9,11,13,15,17,19,21,23:D1±3 days; end of treatment
- PK of MOR00208 - C1:D1,2,3,4,15; C2:D1±3 days; C3:D1±3 days, D15±1 day; C4-24:D1±3 days; end of treatment
- Biomarkers:
- CD19, CD20, BCL2, BCL6 expression - screening; C1:D1; C2-24:D1±3 days
- B-, T- and NK cell counting - C1:D1, D4, D15±1 day; C2:D1±3 days; C4:D1±3 days, D15±1 day; C5:D1±3 days; C8:D1±3 days
- CD16 expression on NK cells, ADCC capacity - C1:D1
- gene expression analysis for cell-of-origin subtyping - C1:D1
|
|
| 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 | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Immunogenicity, Biomarkers |
|
| 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) | 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 | No |
| E.8.1.5 | Parallel group | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 89 |
| 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 |
| Singapore |
| Australia |
| Canada |
| Israel |
| Korea, Republic of |
| Serbia |
| United Kingdom |
| United States |
| Austria |
| Bulgaria |
| Croatia |
| Czechia |
| Finland |
| France |
| Germany |
| Hungary |
| Italy |
| Poland |
| Portugal |
| Romania |
| Slovakia |
| Spain |
| Türkiye |
|
| 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
|
| Last patient’s last visit on site for the 30-Day Safety Follow-Up visit or Follow-Up visit for PFS, whichever comes last |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 30 |
| 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 | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 30 |
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