Lymphoma, Large B-Cell, Diffuse
Conditions
Brief summary
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).
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Dose Limiting Toxicities (DLTs) in the Maximum Tolerated Dose (MTD) Evaluation Period- Phase 1b | 14 days from first trial medication | 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. |
| The MTD of BI 836826 With GemOx- Phase 1b | 14 days from first trial medication | 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). |
| Overall Response, i.e. CR and PR, by Central Review Assessment- Phase II | up to 32 weeks from first trial medication administration | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Based on Investigator's Assessment- Phase 1b | up to 32 weeks from first trial medication administration. | 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 |
| Complete Response (CR) by Central Review Assessment- Phase II | up to 32 weeks from first trial medication administration. | 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. |
| 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 | up to 32 weeks from first trial medication administration. | 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. |
| Maximum Measured Plasma Concentration of BI 836826 (Cmax)- Phase 1b | up to 32 weeks from first trial medication administration. | 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. |
Countries
Belgium, Italy, Spain
Participant flow
Recruitment details
This trial was designed to consist of 2 parts. First part was an open-label, non-randomised, Phase Ib dose-escalation trial according to a standard 3+3 design to determine the maximum tolerated dose (MTD) of BI 836286 in combination with gemcitabine and oxaliplatin. Second part of the trial, an open-label randomised Phase II, was not conducted.
Pre-assignment details
All patients were screened for eligibility to participate in the trial. Patients attended specialist sites which would then ensure that they (the patients) met all inclusion/exclusion criteria. Patients were not to be randomized to trial treatment if any one of the specific entry criteria were violated.
Participants by arm
| Arm | Count |
|---|---|
| BI 836826 25 Milligram (mg) + GemOx Patients were administered (intravenous infusion) BI 836826 25 mg on Day 8 and GemOx (gemcitabine 1000 mg/metre square (m\^2) plus oxaliplatin 100 mg/m\^2) on Day 1 (up to 6 cycles of treatment); the duration of each cycle was 14 days. | 5 |
| BI 836826 50 mg + GemOx Patients were administered (intravenous infusion) BI 836826 50 mg on Day 8 and GemOx (gemcitabine 1000 mg/m\^2 plus oxaliplatin 100 mg/m\^2) on Day 1 (up to 6 cycles of treatment); the duration of each cycle was 14 days. | 8 |
| BI 836826 100 mg + GemOx Patients were administered (intravenous infusion) BI 836826 100 mg on Day 8 and GemOx (gemcitabine 1000 mg/m\^2 plus oxaliplatin 100 mg/m\^2) on Day 1 (up to 6 cycles of treatment); the duration of each cycle was 14 days. | 8 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 2 | 2 |
| Overall Study | Progressive disease | 0 | 2 | 3 |
Baseline characteristics
| Characteristic | BI 836826 25 Milligram (mg) + GemOx | BI 836826 50 mg + GemOx | BI 836826 100 mg + GemOx | Total |
|---|---|---|---|---|
| Age, Continuous | 62.4 years STANDARD_DEVIATION 26.6 | 56.5 years STANDARD_DEVIATION 14.3 | 57.9 years STANDARD_DEVIATION 14 | 58.4 years STANDARD_DEVIATION 16.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 3 Participants | 4 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 5 Participants | 4 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 8 Participants | 8 Participants | 21 Participants |
| Sex: Female, Male Female | 4 Participants | 4 Participants | 3 Participants | 11 Participants |
| Sex: Female, Male Male | 1 Participants | 4 Participants | 5 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 2 / 8 | 1 / 8 |
| other Total, other adverse events | 5 / 5 | 8 / 8 | 8 / 8 |
| serious Total, serious adverse events | 4 / 5 | 5 / 8 | 3 / 8 |
Outcome results
Primary
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.
Time frame: 14 days from first trial medication
Population: MTD evaluation set: The MTD evaluation set includes all patients who were documented to have received at least 1 dose of BI 836826 and were not replaced for the MTD evaluation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BI 836826 25 Milligram (mg) + GemOx | Number of Patients With Dose Limiting Toxicities (DLTs) in the Maximum Tolerated Dose (MTD) Evaluation Period- Phase 1b | 0 participants |
| BI 836826 50 mg + GemOx | Number of Patients With Dose Limiting Toxicities (DLTs) in the Maximum Tolerated Dose (MTD) Evaluation Period- Phase 1b | 1 participants |
| BI 836826 100 mg + GemOx | Number of Patients With Dose Limiting Toxicities (DLTs) in the Maximum Tolerated Dose (MTD) Evaluation Period- Phase 1b | 1 participants |
Primary
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.
Time frame: up to 32 weeks from first trial medication administration
Population: Primary and secondary endpoints of Phase II are not applicable (NA) since Phase II has not been conducted
Primary
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).
Time frame: 14 days from first trial medication
Population: The trial was discontinued prematurely before the MTD based on the frequency of patients with DLTs in the MTD evaluation period, i.e. the 1st treatment cycle, was reached.
Secondary
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.
Time frame: up to 32 weeks from first trial medication administration.
Population: PK parameters were not calculated because the sponsor discontinued development of BI 836826
Secondary
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.
Time frame: up to 32 weeks from first trial medication administration.
Population: Primary and secondary endpoints of Phase II are not applicable (NA) since Phase II has not been conducted
Secondary
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.
Time frame: up to 32 weeks from first trial medication administration.
Population: PK parameters were not calculated because the sponsor discontinued development of BI 836826
Secondary
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
Time frame: up to 32 weeks from first trial medication administration.
Population: Treated set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BI 836826 25 Milligram (mg) + GemOx | Overall Response Based on Investigator's Assessment- Phase 1b | CR | 1 participants |
| BI 836826 25 Milligram (mg) + GemOx | Overall Response Based on Investigator's Assessment- Phase 1b | PR | 2 participants |
| BI 836826 50 mg + GemOx | Overall Response Based on Investigator's Assessment- Phase 1b | CR | 0 participants |
| BI 836826 50 mg + GemOx | Overall Response Based on Investigator's Assessment- Phase 1b | PR | 3 participants |
| BI 836826 100 mg + GemOx | Overall Response Based on Investigator's Assessment- Phase 1b | CR | 1 participants |
| BI 836826 100 mg + GemOx | Overall Response Based on Investigator's Assessment- Phase 1b | PR | 1 participants |