Open-label, randomised trial to evaluate the efficacy and safety of MOR00208 with bendamustine versus rituximab with bendamustine in adult patients with 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

Phase 1

Conditions: Relapsed or Refractory Diffuse Large B-Cell Lymphoma (R-R DLBCL)
MedDRA version: 21.0Level: PTClassification code 10012821Term: Diffuse large B-cell lymphoma recurrentSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 21.0Level: PTClassification code 10012822Term: Diffuse large B-cell lymphoma refractorySystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2014-004689-11-FI

Lead Sponsor: Incyte Corporation

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 450

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

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).