Neoplasms

Blood and Lymph Conditions

Immune System Diseases

All Conditions

Rare Diseases

Lymphoma

Lymphoma, B-Cell

Lymphoma, Non-Hodgkin

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphosarcoma

B-cell Lymphoma

Antineoplastic Agents

All Drugs and Chemicals

Ofatumumab

The first dose administered of ofatumumab should be 300 mg to minimize infusion reactions. The initial rate of the first infusion of 1000 mg ofatumumab (0.3mg/ml) should be 12ml/h. If no infusion reactions occur the infusion rate should be increased every 30 minutes, to a maximum of 400 ml/h. If this schedule is followed, the infusion duration will be approximately 4.5 hours.

Chadi Nabhan, MD

This is a phase II open label study that looks at the efficacy and toxicity of Ofatumumab monotherapy in patients with relapsed and/or refractory diffuse large B-cell lymphoma (DLBCL). Patients will receive weekly infusions of Ofatumumab of 1000 mg each for 8 weeks (induction phase) followed by continuing the study drugs every other week in subsequent cycles (maintenance phase). Each 4 weeks of therapy will be calculated as one cycle. Treatment will continue until disease progression, toxicity, patient's withdrawal, or investigator's discretion.

Ofatumumab is a fully human monoclonal IgG1κ-antibody targeting a novel cluster of differentiation antigen 20(CD20)-epitope. Preclinical data show that ofatumumab is active against B-cell lymphoma/chronic lymphocytic leukemia cell-lines with low CD20-antigen density and an increased expression of complement inhibitory molecules. Ofatumumab was superior to rituximab in its ability to induce lysis in B-cell lines and also killed fresh B-chronic lymphocytic leukemia cells that were resistant to rituximab. Ofatumumab has a slower off-rate and more stable CD20 binding in comparison with rituximab and targets a different epitope of the CD20 antigen than rituximab \[Teeling, 2004, Teeling, 2006\]. In cynomolgus monkeys, the duration of B-cell depletion from peripheral blood and lymph nodes induced by ofatumumab was longer than that of rituximab \[Dechant, 2003\].

Ofatumumab's ability to induce complement-dependent cytotoxicity (CDC) has been specifically studied in isolated lymphoma cells from chemotherapy refractory DLBCL patients \[Cillessen, 2007\]. Ofatumumab and rituximab induced CDC of all DLBCL samples tested, including the DLBCL cell lines SUDHL-4, SUDHL-5 and HT and lymphoma cells derived from ten chemotherapy-refractory DLBCL patients.

Ofatumumab was significantly more effective in inducing CDC in nine of the ten DLBCL tumor samples when compared with rituximab (p=0.001). The lethal doses (LD50) for ofatumumab (0.1 ± 2.8 μg/mL) were significantly lower when compared with the LD50 for rituximab (6.4 ± 4.9μg/mL, p=0.04). Sensitivity of DLBCL patient cells to ofatumumab- and rituximab-induced CDC negatively correlated with expression of complement defense molecule CD59, but not with expression of CD46 or CD55. Functional inhibition of CD55 and CD59 using blocking mAb demonstrated that ofatumumab-induced CDC of DLBCL tumor cells was less sensitive to expression of these complement defense molecules than rituximab-induced CDC.

Thus, chemotherapy-refractory DLBCL cases are sensitive to CD20 mAb-induced CDC with ofatumumab being the most effective mAb, especially in patients expressing high levels of CD59.

Safety and efficacy of ofatumumab, has been analyzed in multicenter dose-escalating phase I/II studies in chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL). Three cohorts of patients including 33 patients with relapsed or refractory CLL received weekly infusions of ofatumumab for four weeks as follows: cohort A, the first infusion was 100 mg and three subsequent infusions of 500 mg; cohort B, the first infusion was 300 mg and three subsequent infusions of 1000 mg; cohort C, the first infusion was 500 mg and three subsequent infusions of 2000 mg. The maximum tolerated dose was not reached. The majority of related adverse events occurred at first infusion, and the number of adverse events decreased at each subsequent infusion. Seventeen (51%) of 33 patients experienced infections, 88% of them of grade 1-2. One event of interstitial pneumonia was fatal; all other cases resolved within one month. The response rate in cohort C was 50% (13/26 patients) \[Coiffier, 2008\].

Interim data from a single arm study in refractory CLL was presented at ASH 2008 \[Osterborg, 2008\]. The activity of ofatumumab was evaluated in 138 patients with refractory CLL: 59 were refractory to both fludarabine and alemtuzumab (double-refractory: DR) and 79 were refractory to fludarabine and considered inappropriate candidates for alemtuzumab due to bulky tumor in their lymph nodes (bulky fludarabine-refractory: BFR group). Patients received 8 weekly infusions of ofatumumab followed by 4 monthly infusions. The first dose was 300mg, doses 2-12 were 2000 mg. Median time to next CLL therapy was 9 months for the DR group and 8 months for the BFR group. The median overall survival was about 14 months for the DR group and 15 months for the BFR group. Response at week 12 was significantly correlated with longer survival for both groups. Ofatumumab was associated with infusion-related adverse events on the first infusion day in 46% of patients in the DR group and 38% in the BFR group, which were grade 3 in 7% and 3% of events, respectively. There were no grade 4 infusion-related events. These events generally subsided with subsequent infusions.

The most common grade 3 or 4 toxicities were infections (25% in DR; 27% in BFR group) and hematologic events including neutropenia (12% in DR; 10% in BFR group) and anemia (8% in DR; 4% in BFR group). Death within 8 weeks from start of treatment occurred in 2 patients (3%) in the DR group (sepsis, n=1; fungal pneumonia, n=1) and 3 patients (4%) in the BFR group (PD, n=1; sepsis, n=1; myocardial infarction, n=1).

In a phase I/II study evaluating safety and efficacy of ofatumumab in relapsed or refractory FL grade 1-2, 4 dose-groups of 10 patients received 4 weekly infusions of 300, 500, 700, or 1000 mg \[Hagenbeek, 2008\]. Patients had a median of two prior FL therapies and 13% had elevated lactate dehydrogenase (LDH). No safety concerns or maximum tolerated dose were identified. Most adverse events occurred on the first infusion day and were common toxicity criteria (CTC) grade 1-2. Eight related events were grade 3. Treatment caused immediate and profound B-cell depletion. The response rate was not dose dependent (dose expressed as mg/patient, mg/kg body weight or body surface area (mg/m2)) with responses obtained in all 4 dose groups (300 mg: 5 of 8 subjects (63%); 500 mg: 3 of 10 subjects (30%); 700 mg: 2 of 10 subjects (20%); and 1000 mg: 5 of 10 subjects (50%). Median time to progression (TTP) for all patients was 8.8 months. Median TTP for responders, duration of response, and time to next anti-FL therapy has not been reached at a median follow-up of 9.2 months. Ofatumumab was able to induce responses in 8 of 14 patients relapsing following rituximab, including 3 of 4 rituximab refractory patients.

Ofatumumab is currently being evaluated in patients with rituximab-refractory FL (Hx-CD20-405), relapsed DLBCL (GEN-415), rituximab-relapsed/refractory DLBCL in combination with salvage chemotherapy (OMB110927) and in a phase III trial in relapsed/refractory DLBCL (OMB110928) at a dose of 1000mg, and in combination with chemotherapy in FL (Hx-CD20-409) at doses of 500mg and 1000mg.

Patients With Relapsed or Refractory Diffuse Large B Cell Non Hodgkin Lymphomas

A Phase II Open-label Study of Single Agent Ofatumumab in Patients With Relapsed and/or Refractory Diffuse Large B Cell Non Hodgkin Lymphomas

OR = # of patients with a Complete Response (CR) plus # of patients with a Partial Response (PR) divided by the total # of evaluable patients.

A CR is defined as:

1. Disappearance of all disease.
2. If nodal masses that Positron Emission Tomography (PET)- positive prior to therapy; they must be PET negative
3. If the nodal masses were Variably or PET negative; they must regress to normal.
4. No palpable liver or spleen
5. Palpable nodal masses are no longer palpable
6. Negative bone marrow biopsy

A PR is defined as:

1. Regression of measurable disease and no new sites of disease.
2. \> 50% decrease in Sum of Product of Diameters (SPD) of up to 6 largest masses with no increase in the size of other nodes. If the nodal masses were PET positive prior to therapy then PET positive at previously involved sites is allowed. If they were Variably or PET negative then regression on CT is required.
3. No increase in the size of the liver or spleen

OCB = # patients with a CR + # of patients with a PR + # patients with Stable Disease (SD) divided by the number of evaluable patients CR and PR is defined in Outcome Measure #1

SD is defined as:

1. Failure to attain CR/PR or Progressive Disease (PD)
2. PET remains positive.

PD is defined as:

1. Any new lesion \> 1.5 cm in longest axis
2. An increase 50% or more of previously involved sites from nadir
3. 50% increase in SPD of more than one node or 50% increase in the longest diameter of a previously identified node that is \> 1 cm in shortest axis
4. PET remains positive if it was positive before therapy.

University of Illinois at Chicago

Oncology Specialists, S.C.

Principal Investigator

The first dose administered of ofatumumab should be 300 mg to minimize infusion reactions. The initial rate of the first infusion of 1000 mg ofatumumab (0.3mg/ml) should be 12ml/h. If no infusion reactions occur the infusion rate should be increased every 30 minutes, to a maximum of 400 ml/h. If this schedule is followed, the infusion duration will be approximately 4.5 hours.

Ofatumumab: The first dose administered of ofatumumab should be 300 mg to minimize infusion reactions. The initial rate of the first infusion of 1000 mg ofatumumab (0.3mg/ml) should be 12ml/h. If no infusion reactions occur the infusion rate should be increased every 30 minutes, to a maximum of 400 ml/h. If this schedule is followed, the infusion duration will be approximately 4.5 hours.

Age, Categorical

Sex: Female, Male

United States

Region of Enrollment

Research Manager

Ofatumumab: The first dose administered of ofatumumab should be 300 mg to minimize infusion reactions. The initial rate of the first infusion of 1000 mg ofatumumab (0.3mg/ml) should be 12ml/h. If no infusion reactions occur the infusion rate should be increased every 30 minutes, to a maximum of 400 ml/h. If this schedule is followed, the infusion duration will be approximately 4.5 hours.

Analysis was per protocol. Patients were evaluated every 2 cycles for Overall Response, up to 80 weeks.

Overall Response (OR)

Overall Clinical Benefit (OCB)

Overall Study

Lymphoma, Large B-Cell, Diffuse

Diffuse Large B-Cell Lymphoma

Antirheumatic Agents

Antibodies

Rituximab

Immunoglobulins

10 MBq/kg b.w., in escalated doses with lilotomab pre-dosing

Dose finding study, starting on 10 MBq/kg b.w. Betalutin® (lutetium (177Lu)-lilotomab satetraxetan), single injection with lilotomab pre-dosing.

Betalutin

Timothy Illidge, PhD MB BS

This study is a phase 1, dose finding, open-label study in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). This is a dose escalating study to define the maximum tolerated dose (MTD) of lutetium (177Lu)-lilotomab satetraxetan (Betalutin®) in DLBCL patients who are not eligible for autologous stem cell transplant. The study will also assess safety and tolerability, pharmacokinetics, biodistribution and efficacy.

Study of Betalutin for Treatment of Relapsed or Refractory Non-Hodgkin Lymphoma (LYMRIT-37-05)

A Phase 1 Dose Finding Study of Lutetium (177Lu)-Lilotomab Satetraxetan (Betalutin®) in Patients With Relapsed/Refractory, Diffuse Large B-cell Lymphoma, Not Eligible for Autologous Stem Cell Transplant

To determine the MTD of Betalutin that can be administered to DBLCL patients with lilotomab. The MTD was the highest dose at which less than two out of six participants experienced a dose limiting toxicity (DLT) defined as:

* Haematologic toxicity:

  * Grade 4 neutropenia observed for greater than 7 days' duration
  * Grade 4 thrombocytopenia observed for greater than 7 days' duration
  * Grade 3 or 4 neutropenia associated with fever (≥38.5°C) of any duration
  * Grade 3 or 4 thrombocytopenia with bleeding
  * Thrombocytopenia with any requirement for more than one platelet transfusion before recovering to Grade 1 or less
  * Grade 4 anaemia, unexplained by underlying disease
* Non-haematologic toxicity:

  * Grade 3 nausea/vomiting/diarrhoea lasting longer than 72 hours despite maximal care or Grade 4
  * Any other Grade 3 or 4 non-haematologic toxicities
  * Any Grade 3 or 4 electrolyte abnormalities that do not resolve to Grade 1 or baseline within 24 hours

Efficacy evaluations are measured by tumour response rates using CT and PET/CT imaging with responses classified as described in "Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification" (Cheson, 2014). The Cheson criteria, 2014 are a combined score taking into consideration, positive or negative scored PET scan, the contrast enhanced CT images and bone marrow biopsies when available.

Dosimetry will be evaluated by the estimated absorbed radiation dose to target organs.

Nordic Nanovector

Treatment emergent adverse events were summarized separately after rituximab and after Betalutin/lilotomab

Betalutin® (lutetium (177Lu)-lilotomab satetraxetan) 10 MBq/kg, single injection with lilotomab 60 mg/m2 .

60/10

Betalutin® (lutetium (177Lu)-lilotomab satetraxetan) 10 MBq/kg, single injection with lilotomab 100 mg/m2.

100/10

Betalutin® (lutetium (177Lu)-lilotomab satetraxetan) 15 MBq/kg, single injection with lilotomab 100 mg/m2 .

100/15

Betalutin® (lutetium (177Lu)-lilotomab satetraxetan) 20 MBq/kg, single injection with lilotomab 100 mg/m2 pre-dosing on Day 0.

100/20

Betalutin® (lutetium (177Lu)-lilotomab satetraxetan) 10 MBq/kg, single injection with lilotomab 60 mg/m2 pre-dosing on Day 0 following rituximab pre-treatment on Day -14.

Betalutin® (lutetium (177Lu)-lilotomab satetraxetan) 10 MBq/kg, single injection with lilotomab 100 mg/m2 pre-dosing on Day 0 following rituximab pre-treatment on Day -14.

Betalutin® (lutetium (177Lu)-lilotomab satetraxetan) 15 MBq/kg, single injection with lilotomab 100 mg/m2 pre-dosing on Day 0 following rituximab pre-treatment on Day -14.

Betalutin® (lutetium (177Lu)-lilotomab satetraxetan) 20 MBq/kg, single injection with lilotomab 100 mg/m2 pre-dosing on Day 0 following rituximab pre-treatment on Day -14.

Received rituximab pre-treatment on Day -14. Did not receive Betalutin or lilotomab

Rituximab Only

Total

Age, Continuous

Ethnicity (NIH/OMB)

Race (NIH/OMB)

0-5 scale (5 the worst outcome) 0 Fully active, able to carry on all pre-disease performance without restriction

1. Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g. light house work, office work
2. Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours
3. Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4. Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5. Dead

ECOG score

Eligible participants who received rituximab

Head of Clinical Operations

Betalutin® (lutetium (177Lu)-lilotomab satetraxetan) 10 MBq/kg, single injection with lilotomab 60 mg/m2 pre-dosing.

Betalutin® (lutetium (177Lu)-lilotomab satetraxetan) 10 MBq/kg, single injection with lilotomab 100 mg/m2 pre-dosing.

Betalutin® (lutetium (177Lu)-lilotomab satetraxetan) 15 MBq/kg, single injection with lilotomab 100 mg/m2 pre-dosing.

Betalutin® (lutetium (177Lu)-lilotomab satetraxetan) 20 MBq/kg, single injection with lilotomab 100 mg/m2 pre-dosing.

Number of Participants With DLTs to Determine the MTD

Participants who had a baseline and at least one post-baseline computed tomography scan

The Best Overall Tumour Response

Liver

Spleen

Kidneys

Image-based Red Marrow

Total Body

Participants having dosimetry evaluation and having the schedule of whole body imaging or SPECT/CT scans

Dosimetry

Received Rituximab

Received Lilotomab and Betalutin

Antibodies, Bispecific

Blinatumomab

By study design, two dose regimens were assessed in this study. In Stage 1, Cohort 1, participants received blinatumomab in a dose-escalating manner: 9 µg/day for the first week, followed by 28 µg/day for the second week, then 112 µg/day for the remaining 6 weeks of treatment during cycle 1. In Cohort 2, the next participants enrolled and received a constant dose of 112 µg/day blinatumomab. The dosing regimen with the more favorable benefit-risk profile was then selected for Stage 2, Cohort 3.

Administered by continuous intravenous infusion over 8 weeks in the first cycle and 4 weeks in the second cycle.

- MD

The purpose of this study is to confirm whether the bispecific T-cell engager blinatumomab is effective and safe in the treatment of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL).

DLBCL is an aggressive malignant disease which evolves from B-cells and affects mainly the lymphatic tissue. Due to its aggressive nature the disease is characterized by a fast course which is lethal without therapy. Potentially curative therapy options are available even at advanced stages. Standard-first line leads to a high initial response rate (85-90%) and an approximate cure rate of 50% of patients. Patients refractory to or with early relapse after this treatment (10-15%) have a very poor prognosis.

Blinatumomab is a bispecific single-chain antibody derivative against CD19 and CD3, designed to link B-cells and T-cells resulting in T-cell activation and a cytotoxic T-cell response against CD19 expressing cells.

This study consisted of a screening period, treatment period, and a follow-up efficacy and survival period. The core study comprises the treatment period to the 30 days after the last infusion. The first cycle consisted of a continuous intravenous (CIV) infusion over 8 weeks. Participants who achieved a Complete Response (CR) or Partial Response (PR) or had stable disease after the first treatment cycle were eligible to receive a second (consolidation) cycle of treatment over 4 weeks, following a 4-week treatment-free interval. After the last treatment cycle, efficacy and survival follow-up visits occurred for up to 24 months from treatment start. Participants who relapsed during the follow-up period may have received an additional 8 weeks of treatment.

Two dose regimens were assessed in this study. Stage 1 comprised 2 dose cohorts. In Cohort 1, the first 6 participants were to receive blinatumomab in a dose-escalating manner: 9 µg/day for the first week, followed by 28 µg/day for the second week, then 112 µg/day for the remaining 6 weeks of treatment during Cycle 1. In Cohort 2, the next 6 participants enrolled were to receive a constant dose of 112 µg/day blinatumomab. Before the initiation of stage 2, a pre-planned data monitoring committee (DMC) meeting was held to assess the safety profile of Cohort 1 and Cohort 2. The dosing regimen with the more favorable benefit-risk profile was to be selected for Cohort 3.

Clinical Study With Blinatumomab in Patients With Relapsed/Refractory Diffuse Large B-cell Lymphoma (DLBCL)

An Open Label, Multicenter, Exploratory Phase 2 Study to Evaluate the Efficacy and Safety of the Bispecific T-Cell Engager (BiTE®) Blinatumomab in Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)

Overall response within the first treatment cycle was assessed according to Cheson criteria by a central reader. Response was evaluated using computerized tomography (CT) scans and positron emission tomography (PET) (to assess nodal disease/organ enlargement due to nodal/diffuse infiltration), and bone marrow biopsy (to assess bone marrow infiltration). Overall objective response rate (ORR) is the percentage of participants with a best overall response of complete response (CR) or partial response (PR).

Complete response is defined as the disappearance of all evidence of disease and partial response is defined as regression of measureable disease and no new sites.

Response within the first treatment cycle was assessed according to Cheson criteria by a central reader. Response was evaluated using computerized tomography (CT) scans and positron emission tomography (PET) (to assess nodal disease/organ enlargement due to nodal/diffuse infiltration), and bone marrow biopsy (to assess bone marrow infiltration). Complete response is defined as the disappearance of all evidence of disease.

Response within the first treatment cycle was assessed according to Cheson criteria by a central reader. Response was evaluated using computerized tomography (CT) scans and positron emission tomography (PET) (to assess nodal disease/organ enlargement due to nodal/diffuse infiltration), and bone marrow biopsy (to assess bone marrow infiltration). Partial response is defined as regression (\<50% decrease in size of masses) of measureable disease and no new sites.

The time from documentation of the first assessment of either partial or complete response until the start of new anti-tumor treatment (excluding any stem cell transplantation), progression of disease, or death, whichever is the earliest event. A patient who did not have new anti-tumor treatment (excluding any stem cell transplantation), progression of disease, or death was censored at last tumor assessment date. Disease progression is defined as any new lesion or increase by ≥ 50% of previously involved sites from nadir.

The time from documentation of the first assessment of complete response until the start of new anti-tumor treatment (excluding any stem cell transplantation), progression of disease, or death, whichever is the earliest event. A patient who did not have new anti-tumor treatment (excluding any stem cell transplantation), progression of disease, or death was censored at last tumor assessment date. Disease progression is defined as any new lesion or increase by ≥ 50% of previously involved sites from nadir.

The time from documentation of the first assessment of partial response until the start of new anti-tumor treatment (excluding any stem cell transplantation), progression of disease, or death, whichever is the earliest event. A patient who did not have new anti-tumor treatment (excluding any stem cell transplantation), progression of disease, or death was censored at last tumor assessment date. Disease progression is defined as any new lesion or increase by ≥ 50% of previously involved sites from nadir.

The time from the date of first blinatumomab infusion until the date of diagnosis of progression of lymphoma, the start date of new anti-tumor treatment (excluding any stem cell transplantation) or date of death, whichever is the earliest. Patients alive who did not have progression or new anti-tumor treatment (excluding any stem cell transplantation) were censored at last date of tumor assessment.

The time from the date of first blinatumomab infusion until death as a result of any cause. Patients still alive were censored on the last documented visit date or the date of the last phone contact when the patient was last known to have been alive. For patients who withdrew their informed consent, only information until the date of withdrawal was analyzed.

Adverse events were evaluated for severity according to the grading scale provided in the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.

An adverse event or suspected adverse drug reaction was considered "serious" if it resulted in one of the following outcomes:

* Resulted in death;
* Was life-threatening;
* Required inpatient hospitalization or prolongation of existing hospitalization;
* Resulted in persistent or significant incapacity or substantial disruption to conduct normal life functions;
* Was a congenital anomaly or birth defect;
* Was a medically important condition.

The Investigator used medical judgment to determine whether there was a causal relationship (ie, related \[reasonably possible\] or unrelated \[not reasonably possible\]) between an adverse event and blinatumomab.

Blinatumomab serum levels were analyzed using a validated cluster of differentiation (CD)69 activation bioassay with a lower limit of quantification (LLOQ) of 50 pg/mL. Steady-state concentration (Css) was based on actual dose received, rather than based on cohort or time or day.

Leukocyte (white blood cells) counts were analyzed by differential blood count analysis.

Lymphocyte counts were analyzed by differential blood count analysis.

CD19+ B-cell counts were analyzed by flow cytometry.

CD3+ T-cell counts were analyzed by flow cytometry.

CD4+ T-cell counts were analyzed by flow cytometry.

CD8+ T-cell counts were analyzed by flow cytometry.

CD19+ B-cells and CD3+ T-cell counts were analyzed by flow cytometry.

CD4+ T-cells and CD8+ T-cell counts were analyzed by flow cytometry.

CD4+ naive T-cell counts are native T-cells characterized by the cell-surface expression of CD197 and CD45RA and were analyzed by flow cytometry.

Central memory T cells are characterized by the cell-surface expression of CD197 but not CD45RA and were analyzed by flow cytometry.

Effector memory T cells are characterized by the lack of expression of CD197 and CD45RA and were analyzed by flow cytometry.

CD8+ naive T-cell counts are native T-cells characterized by the cell-surface expression of CD197 and CD45RA and were analyzed by flow cytometry.

Terminally differentiated effector memory T cells are characterized by the cell-surface expression of CD45RA but not CD197 and were analyzed by flow cytometry.

Amgen Research (Munich) GmbH

Adverse Events were not pre-specified to be monitored/assessed after 10 July 2014.

Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.

Participants received blinatumomab administered CIV 9 µg/day for the first week, followed by 28 µg/day for the second week, then 112 µg/day for the remaining 6 weeks of treatment during Cycle 1. Participants who achieved a CR or PR, or had stable disease after the first treatment cycle were eligible to receive a second (consolidation) cycle of treatment over 4 weeks, following a 4-week treatment-free interval.

Cohort 1: Blinatumomab 9/28/112 µg/d

Participants received blinatumomab administered CIV at a constant dose of 112 µg/day for 8 weeks of treatment during Cycle 1. Participants who achieved CR or PR, or had stable disease after the first treatment cycle were eligible to receive a second (consolidation) cycle of treatment over 4 weeks, following a 4-week treatment-free interval.

Cohort 2: Blinatumomab 112 µg/d

Participants received blinatumomab administered CIV 9 µg/day for the first week, followed by 28 µg/day for the second week, then 112 µg/day for the remaining 6 weeks of treatment during Cycle 1. Participants who achieved CR or PR, or had stable disease after the first treatment cycle were eligible to receive a second (consolidation) cycle of treatment over 4 weeks, following a 4-week treatment-free interval.

Cohort 3: Blinatumomab 9/28/112 µg/d

Cohort 1+3: Blinatumomab 9/28/112µg/d

All participants who received blinatumomab by continuous intravenous infusion during the core study.

Blinatumomab Overall

Participants received blinatumomab administered via a continuous intravenous infusion (CIV) 9 µg/day for the first week, followed by 28 µg/day for the second week, then 112 µg/day for the remaining 6 weeks of treatment during Cycle 1. Participants who achieved a complete response (CR) or partial response (PR), or had stable disease after the first treatment cycle were eligible to receive a second (consolidation) cycle of treatment over 4 weeks, following a 4-week treatment-free interval.

Participants received blinatumomab administered CIV at a constant dose of 112 µg/day for 8 weeks of treatment during Cycle 1. Participants who achieved a CR or PR, or had stable disease after the first treatment cycle were eligible to receive a second (consolidation) cycle of treatment over 4 weeks, following a 4-week treatment-free interval.

Gender

White

Race/Ethnicity, Customized

Relapsed

Refractory

Relapsed/refractory Status to Last Prior Treatment

None

≥ 1

Number of Previous Autologous Hematopoietic Stem Cell Transplants (HSCT)

Study Director

Cohort 1: Blinatumomab 9/28/112 μg/d

Participants received blinatumomab CIV at a constant dose of 112 µg/day for 8 weeks of treatment during Cycle 1. Participants who achieved a CR or PR, or had stable disease after the first treatment cycle were eligible to receive a second (consolidation) cycle of treatment over 4 weeks, following a 4-week treatment-free interval.

Cohort 2: Blinatumomab 112 μg/d

Cohort 3: Blinatumomab 9/28/112 μg/d

Efficacy Set includes all participants who completed at least 7 days of infusion on the highest intended dose level.

Overall Objective Response Rate During Treatment Cycle 1

Percentage of Participants With a Best Overall Response of Complete Response

Percentage of Participants With a Best Overall Response of Partial Response

Efficacy set with an overall objective response of CR or PR during the first treatment cycle

Duration of Objective Response

Efficacy set with a best overall response of CR during the first treatment cycle

Duration of Complete Response

Efficacy set with a best overall response of PR during the first treatment cycle

Duration of Partial Response

Progression-free Survival (PFS)

Overall Survival (OS)

Any adverse event (AE)

AE of Grade ≥ 3

AE of Grade ≥ 4

Serious adverse event (SAE)

Fatal adverse events

Led to discontinuation of study drug

Led to interruption of study drug

Related adverse events

Related AE Grade ≥ 3

Related AE Grade ≥ 4

Serious related adverse events

Related AE led to discontinuation of study drug

Related AE led to interruption of study drug

Number of Participants With Adverse Events

Participants received blinatumomab administered via a continuous intravenous infusion (CIV) 9 µg/day.

Blinatumomab 9 μg/d

Participants received blinatumomab CIV 28 µg/day.

Blinatumomab 28 μg/d

Participants received blinatumomab administered CIV 112 µg/day.

Blinatumomab 112 μg/d

Pharmacokinetic (PK) data set (all participants who received any infusion of blinatumomab and had at least one PK sample collected).

Blinatumomab Steady State Serum Concentration

Screening (N = 25)

Day 1 Prior (N = 24)

Day 8 (N = 21)

Day 15 (N = 16)

Day 29 (N = 11)

Day 43 (N = 8)

End of Infusion (N = 9)

End of Core Study (N = 6)

3-Month Follow-up (N = 5)

6-Month Follow-up (N = 6)

9-Month Follow-up (N = 4)

12-Month Follow-up (N = 4)

15-Month Follow-up (N = 3)

Enrolled participants with available data at each time point. All participants are included in pre-infusion and follow-up data points, only those participants in Cohorts 1 and 3 who had the same treatment schedule of 9/28/112 µg/day step dosing are included in the infusion time points (day 8 through end of infusion).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Patients With Relapsed or Refractory Diffuse Large B Cell Non Hodgkin Lymphomas	NCT01078922	Non-Hodgkin Lym...	Ofatumumab	18 Years -	Oncology Specialists, S.C.
Study of Betalutin for Treatment of Relapsed or Refractory Non-Hodgkin Lymphoma (LYMRIT-37-05)	NCT02658968	Relapsed, Diffu... Refractory Diff...	Betalutin	18 Years -	Nordic Nanovector
Study of Betalutin for Treatment of Relapsed or Refractory Non-Hodgkin Lymphoma (LYMRIT-37-05)	NCT02658968	Relapsed, Diffu... Refractory Diff...	Betalutin	18 Years -	Nordic Nanovector
Clinical Study With Blinatumomab in Patients With Relapsed/Refractory Diffuse Large B-cell Lymphoma (DLBCL)	NCT01741792	Diffuse Large B...	Blinatumomab	18 Years -	Amgen Research (Munich) GmbH
Patients With Relapsed or Refractory Diffuse Large B Cell Non Hodgkin Lymphomas	NCT01078922	Non-Hodgkin Lym...	Ofatumumab	18 Years -	Oncology Specialists, S.C.
Patients With Relapsed or Refractory Diffuse Large B Cell Non Hodgkin Lymphomas	NCT01078922	Non-Hodgkin Lym...	Ofatumumab	18 Years -	Oncology Specialists, S.C.
Combination of Obinutuzumab and Venetoclax in Relapsed or Refractory DLBCL	NCT02987400	Lymphoma, Large...	Venetoclax Obinutuzumab	18 Years -	Arbeitsgemeinschaft medikamentoese Tumortherapie
Study of Betalutin for Treatment of Relapsed or Refractory Non-Hodgkin Lymphoma (LYMRIT-37-05)	NCT02658968	Relapsed, Diffu... Refractory Diff...	Betalutin	18 Years -	Nordic Nanovector
Clinical Study With Blinatumomab in Patients With Relapsed/Refractory Diffuse Large B-cell Lymphoma (DLBCL)	NCT01741792	Diffuse Large B...	Blinatumomab	18 Years -	Amgen Research (Munich) GmbH

Spots Global Cancer Trial Database for refractory dlbcl