| 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 |
| Medical condition: Diffuse lymph nodes cancer attacking large antibody producing cells that has progressed after previous 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 | 10012818 |
| E.1.2 | Term | Diffuse large B-cell lymphoma |
| 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 activity of a combination of LEN with MOR00208 in terms of objective response rate (ORR = complete response [CR] + partial response [PR]) in adult patients with R-R DLBCL. |
|
| E.2.2 | Secondary objectives of the trial |
1.To determine the disease control rate (DCR = CR + PR + stable disease [SD])
2.To determine the duration of response (DoR)
3.To determine the activity of a combination of LEN with MOR00208 in terms of progression-free survival (PFS)
4.To determine the overall survival (OS)
5.To determine time to progression (TTP)
6.To determine the time to next treatment (TTNT)
7.To determine the safety of LEN combined with MOR00208 assessed according to the frequency and severity of adverse events (AEs)
8.To assess the potential immunogenicity of MOR00208
9.To assess the pharmacokinetics (PK) of MOR00208
10.To make a preliminary evaluation of ORR, DCR, DoR, PFS, OS, TTP and TTNT in patients treated with a combination of LEN plus MOR00208 in cohorts with a “low risk”, “low-intermediate”, “high-intermediate” and “high” International Prognostic Index (IPI)
For full list please refer to the protocol. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age >18 years
2. Histologically confirmed diagnosis of DLBCL not otherwise specified (NOS); T cell/histiocyte rich large B-cell lymphoma (THRLBCL); Epstein-Barr virus (EBV) positive DLBCL of the elderly (EBV-positive DLBCL), Grade 3b Follicular Lymphoma, Composite lymphoma with a DLBCL component with a subsequent DLBCL relapse, according to the Revised European American Lymphoma/World Health Organization (REAL/WHO) classification. Additionally, patients with the evidence of histological transformation to DLBCL from an earlier diagnosis of low grade lymphoma (i.e. an indolent pathology such as follicular lymphoma,
marginal zone lymphoma, chronic lymphocytic leukemia) into DLBCL with a subsequent DLBCL relapse are also eligible.
3. Fresh tumour tissue for central pathology review and correlative studies must be provided as an adjunct to participation in this study.
Should it not be possible to obtain a fresh tumour tissue sample from the patient, 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) relapsed and/or refractory disease as defined in the protocol
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 lesions must be positive on PET scan.
c) received at least one, but no more than three previous systemic regimens for the treatment of DLBCL and one therapy line must have included a CD20-targeted therapy (e.g. RTX)
d) an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
5. Patients not considered in the opinion of the investigator eligible, or patients unwilling to undergo intensive salvage therapy including ASCT because of, but not limited to, advanced age, comorbidities, impossibility or, refusal to perform ASCT. Documentation of the reason for a patient’s ineligibility must be provided 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 × 109/L (unless secondary to bone marrow involvement by DLBCL as demonstrated by recent bone marrow aspiration and bone marrow biopsy)
b) platelet count ≥90 × 109/L (unless secondary to bone marrow involvement by DLBCL as demonstrated by recent bone marrow aspiration and bone marrow biopsy)
c) total serum bilirubin ≤2.5 × upper limit of normal (ULN) unless secondary to Gilbert's syndrome or documented liver involvement by lymphoma. Patients with Gilbert's syndrome or with documented liver involvement by lymphoma may be included if their total bilirubin is ≤5 × ULN (see exclusion criterion 5g)
d) alanine transaminase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (AP) ≤3 × ULN or <5 × ULN in cases of documented liver involvement
e) serum creatinine clearance must be ≥60 mL/minute either measured or calculated using a standard Cockcroft and Gault formula (Cockroft and Gault, 1976)
General Provisions
7. Females of childbearing potential (FCBP) must:
a) not be pregnant as confirmed by a negative serum pregnancy test at screening and a medically supervised urine pregnancy test prior to starting study therapy
b) refrain from breastfeeding and donating blood or oocytes during the course of the study and for 3 months after the last dose of study medication. Restrictions concerning blood donation apply as well to females who are not of childbearing potential
c) agree to ongoing pregnancy testing during the course of the study, and after study therapy has ended. This applies even if the patient practices complete and continued sexual abstinence
d) commit to continued abstinence from heterosexual intercourse if it is in accordance with her lifestyle (which must be reviewed on a monthly basis) or agree to use and be able to comply with the use of effective contraception without interruption during the study and for 3 months after the last dose of study medication
8. Males must use an effective barrier method of contraception without interruption, refrain from donating blood or sperm during the study participation and for 3 months after the last dose of study medication if the patient is sexually active with a FCBP
9. In the opinion of the investigator the patients must:
a) be able and willing to receive adequate prophylaxis and/or therapy for thromboembolic events
b) be able to understand, give written informed consent, and comply with all study-related procedures, medication use, and evaluations
c) not have a history of noncompliance in relation to medical regimens or be considered potentially unreliable and/or uncooperative
d) be able to understand the reason for complying with the special conditions of the pregnancy prevention risk management plan and give written acknowledgement of this.
|
|
| E.4 | Principal exclusion criteria |
Exclusionary Diagnosis
1. Patients who have:
a) any other histological type of lymphoma including primary mediastinal (thymic) large B-cell (PMBL) or Burkitt lymphoma
b) primary refractory DLBCL
c) a history of "double/triple hit" genetics DLBCL characterised by simultaneous detection of MYC with BCL2 and/or BCL6 translocation(s) defined by fluorescence in situ hybridisation. MYC, BCL2, BCL6 testing prior to study enrolment is not required
Exclusionary Previous and Current Treatment
2. 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
b) undergone major surgery or suffered from significant traumatic injury
c) received live vaccines.
d) required parenteral antimicrobial therapy for active, intercurrent infections
3. Patients who:
a) have, in the opinion of the investigator, not recovered sufficiently from the adverse toxic effects of prior therapies
b) were previously treated with CD19-targeted therapy or IMiDs® (e.g. thalidomide, LEN)
c) have a history of hypersensitivity to compounds of similar biological or chemical composition to MOR00208, IMiDs® and/or the excipients contained in the study drug formulations
d) have undergone ASCT within the period ≤ 3 months prior to signing the informed consent form. Patients who have a more distant history of ASCT must exhibit full haematological recovery before enrolment into the study
e) have undergone previous allogenic stem cell transplantation
f) have a history of deep venous thrombosis/embolism, threatening thromboembolism or known thrombophilia or are at high risk for a thromboembolic event in the opinion of the investigator and who are not willing/able to take venous thromboembolic event prophylaxis during the entire treatment period
g) concurrently use other anticancer or experimental treatments
Exclusionary Patient’s Medical History
4. Prior history of malignancies other than DLBCL, unless the patient has been free of the disease for ≥5 years prior to screening. Exceptions to the ≥5 year time limit include a 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)
5. 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) CNS lymphoma involvement –present or past medical history
d) history or evidence of clinically significant cardiovascular, CNS and/or other systemic disease that would in the investigator’s opinion preclude participation in the study or compromise the patient’s ability to give informed consent.
e) history or evidence of rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption
f) gastrointestinal abnormalities including the inability to take oral medication, requiring intravenous alimentation, or prior surgical procedure affecting absorption
g) history or evidence of severe hepatic impairment (total serum bilirubin > 3mg/dL), jaundice unless secondary to Gilbert's syndrome or documented liver involvement by lymphoma (see inclusion criterion 6c) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| ORR, defined as the proportion of complete and partial responders (ORR = CR + PR) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. DCR, DoR, PFS, OS, TTP and TTNT
2. Incidence and severity of AEs
3. Determination and characterisation of a potential anti-MOR00208 antibody formation
4. PK analysis of MOR00208
5. Absolute and percentage change from baseline in measurements of B-, T- and NK cell populations
6. Analysis of exploratory and diagnostic biomarkers (e.g. CD19, CD20, BCL2, and BCL6 expression, CD16 expression on NK cells, ADCC capacity), gene expression profiling for cell of origin subtyping and evaluation of AEs and ORR stratified by FcγRIIIa and FcγRIIa polymorphism) are planned to be investigated during the course of the study. |
|
| 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 | Yes |
| 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 | No |
| 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.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 49 |
| 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 |
| United States |
| France |
| Poland |
| Spain |
| Czechia |
| Germany |
| Italy |
| Belgium |
| Hungary |
| 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
|
The end of the study is defined as the date of the last visit of the last
patient completing 5 years study duration. |
|
| 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 | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
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