To Determine the Dose of BI 836826-GemOx and the Efficacy of BI 836826-GemOx Versus R-GemOx in Patients With Relapsed/Refractory DLBCL

Study Overview
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Brief Summary
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Part 1 (Phase Ib) Primary objective: To establish the maximum tolerated dose (MTD) of BI 836826 in combination with GemOx. Secondary objectives: To evaluate pharmacokinetics of BI 836826 when given in combination with GemOx and to investigate preliminary efficacy in terms of the overall response rate based on investigator's assessment. Part 2 (Phase II randomized) Primary objective: To investigate the efficacy by means of the overall response rate (PR+ CR) based on central review assessment in patients with relapsed DLBCL treated with BI 836826-GemOx compared to R-GemOx. Secondary objective: To investigate the efficacy by means of the complete remission rate based on central review assessment in patients with relapsed DLBCL treated with BI 836826-GemOx compared to Rituximab + gemcitabine + oxaliplatin (RGemOx).

Official Title
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An Open Label Multicenter Phase Ib/II Trial to Determine the Dose of BI 836826 in Combination With Gemcitabine and Oxaliplatin (GemOx) and the Efficacy of BI 836826-GemOx Versus Rituximab (R)- GemOx (R-GemOx) in Patients With Relapsed/ Refractory Diffuse Large B-cell Lymphoma (DLBCL) Who Are Not Eligible for, or Have Relapsed/Progressed After Autologous/Allogeneic Stem Cell Transplant

Conditions
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Lymphoma, Large B-Cell, Diffuse

Intervention / Treatment
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* Drug: BI 836826
* Drug: GemOx
* Drug: Rituximab
* Drug: GemOx


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Age 18 years or older Patients with histologically confirmed, relapsed/refractory, diffuse large B-cell lymphoma (including transformed follicular lymphoma) who have received an anti-CD20-supplemented, anthracycline-containing chemotherapy and are not eligible for high dose therapy followed by an autologous stem cell transplant, or have relapsed/progressed after autologous/allogenic stem cell transplant. Allogenic stem cell transplant performed at least 6 months prior to study entry is allowed if patients do not require immunosuppressive treatment and have no evidence of active graft-versus-host disease. Patient has not received anti-lymphoma treatment prior to the first dose of trial medication: within past 14 days or within time that is shorter or equal to 5 half-lives of the drug if the last anti-lymphoma treatment contained an investigational agent Screening computer tomography (CT) scan with involvement of at least 1 bi-dimensional lesion/node >1.5 cm Screening [18F] fluorodeoxyglucose (FDG)- positron emission tomography (PET) scans must demonstrate positive lesion compatible with computer tomography (CT) defined anatomical tumor sites Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, 2 Written signed informed consent consistent with International Conference on Harmonization (ICH) Good Clinical Practice (GCP) and local legislation Patients must have an acceptable organ function Women of childbearing potential must be ready and able to use highly effective methods of birth control per ICH M3(R2) that result in a low failure rate of less than 1% per year when used consistently and correctly. Non-vasectomized male patients having a female sexual partner of childbearing potential must ensure their partner is using a highly effective method of birth control as described above, during the trial and for at least 12 months after the end of the trial. Exclusion criteria: Eligible for curative salvage high dose therapy followed by stem cell transplant Primary central nervous system lymphoma or known Central nervous system (CNS) involvement Prior history of malignancy other than DLBCL except basal cell or squamous cell carcinoma of the skin, or carcinoma in situ of the uterine cervix or breast which has been treated with curative therapy. Other prior malignancies are allowed only if patient has been free of disease and without treatment other than hormones for at least past three years. Refractory to gemcitabine and/or oxaliplatin Contraindications for gemcitabine, oxaliplatin and/or rituximab as judged by the investigator. Hypersensitivity to oxaliplatin Unresolved toxicity of CTCAE grade > 1from prior anti-lymphoma therapy (except alopecia) Significant concurrent medical disease or condition which according to the investigators judgment would either compromise patient safety or interfere with the evaluation of the safety of the test drug. e.g. symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia requiring therapy with the exception of extra systoles of minor conduction abnormalities An infection requiring treatment at the start of the trial medication. Active hepatitis B or hepatitis C, or laboratory evidence for a chronic infection or HIV infection (test results done in routine diagnostics are acceptable if done within 14 days before the first study treatment dose) Women who are pregnant, nursing, or who plan to become pregnant while in the trial.This includes the female sexual partners of a male participant Known alcohol or drug abuse which could potentially interfere with trial participation according to investigators judgment Prior treatment with CD37 antibody

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BI 836826-GemOx<br> | Drug: BI 836826<br> <br> Drug: GemOx<br> <br> |
| Active Comparator: R-GemOx<br> | Drug: Rituximab<br> <br> Drug: GemOx<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Dose Limiting Toxicities (DLTs) in the Maximum Tolerated Dose (MTD) Evaluation Period- Phase 1b | DLT definition included both non-haematologic and haematologic drug-related Adverse events (AEs). Non-haematologic AEs of Common Toxicity Criteria for Adverse Events (CTCAE) Grade 3 or higher qualified for DLTs with the following exceptions: laboratory abnormalities that could be corrected with treatment within 48 h; nausea, vomiting, or diarrhoea which resolved within 48 h with adequate treatment; neuropathy considered related to oxaliplatin; or an infusion-related reactions (IRR). For haematologic AEs, the following were considered DLTs: Grade 4 neutropenia lasting >7 days (d) despite growth factors support; any febrile neutropenia which did not resolve within 48 hours with appropriate treatment; Grade 4 thrombocytopenia lasting >7 d or Grade 3/4 thrombocytopenia with clinically significant bleeding; failure to recover platelets ≥75*10^9/litres (L) by 4 weeks after start of the cycle; or failure to recover neutrophils ≥1.0*10^9/L by 4 weeks after start of the cycle. | 14 days from first trial medication | 
| The MTD of BI 836826 With GemOx- Phase 1b | MTD defined as the highest dose studied for which the number of patients with dose-limiting toxicity (DLT) was 17% or less (i.e. not more than 1 of 6 patients) during the MTD evaluation period (Cycle 1). | 14 days from first trial medication | 
| Overall Response, i.e. CR and PR, by Central Review Assessment- Phase II | Overall response based on central review assessment, i.e. CR and PR by central review assessment; CR: Disappearance of all evidence of disease PR: Regression of measurable disease and no new sites. Sponsor discontinued the trial for strategic reasons. Consequently, Phase II of the trial was not conducted and hence the endpoint is not evaluated. | up to 32 weeks from first trial medication administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Based on Investigator's Assessment- Phase 1b | Overall response based on investigator's assessment, i.e. partial remission (PR) and complete remission (CR) by investigator assessment; CR: Disappearance of all evidence of disease PR: Regression of measurable disease and no new sites | up to 32 weeks from first trial medication administration. | 
| Area Under the Plasma Concentration-time Curve Over the Time Interval From 0 to the Time of the Last Quantifiable Data Point After Drug Administration (AUC0-tz) of BI 836826- Phase 1b | Pharmacokinetic (PK) analyses were planned to be performed. However, after encountering technical difficulties and discontinuation of the BI 836826 programme, the sponsor decided not to re-analyse the samples. | up to 32 weeks from first trial medication administration. | 
| Maximum Measured Plasma Concentration of BI 836826 (Cmax)- Phase 1b | Pharmacokinetic analyses were planned to be performed. However, after encountering technical difficulties and discontinuation of the BI 836826 programme, the sponsor decided not to re-analyse the samples. | up to 32 weeks from first trial medication administration. | 
| Complete Response (CR) by Central Review Assessment- Phase II | Complete Response (CR) by central review assessment- Phase II; CR: Disappearance of all evidence of disease. Sponsor discontinued the trial for strategic reasons. Consequently, Phase II of the trial was not conducted and hence the endpoint is not evaluated. | up to 32 weeks from first trial medication administration. |