B-cell Lymphoma
Conditions
Brief summary
This study is designed to evaluate the safety and efficacy of glofitamab or mosunetuzumab in combination with gemcitabine and oxaliplatin (Glofit-GemOx or Mosun-GemOx) in participants with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) or high-grade B-cell lymphoma (HGBCL).
Interventions
DRUGGlofitamab
Participants will receive intravenous (IV) glofitamab in combination with gemcitabine and oxaliplatin for up to 8 cycles, followed by up to 4 cycles of glofitamab monotherapy.
DRUGGemcitabine
Participants will receive IV gemcitabine prior to oxaliplatin administration for up to 8 cycles.
DRUGOxaliplatin
Participants will receive IV oxaliplatin after gemcitabine administration for up to 8 cycles.
DRUGMosunetuzumab
Participants will receive IV mosunetuzumab in combination with gemcitabine and oxaliplatin for up to 8 cycles.
DRUGObinutuzumab
Participants will receive a single dose of IV obinutuzumab 7 days prior to the first administration of glofitamab.
DRUGTocilizumab
Participants will receive IV tocilizumab as needed to treat cytokine release syndrome (CRS).
Sponsors
Hoffmann-La Roche
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0,1, or 2 * Histologically confirmed B-cell lymphoma, including one of the following diagnoses per the 2016 World Health Organization (WHO) classification of lymphoid neoplasms: DLBCL, not otherwise specified (NOS); HGBCL with MYC and BCL2 and/or BCL6 rearrangements; HGBCL, NOS * R/R disease, defined as follows: Relapse: disease that has recurred following a response that lasted \>/=6 months after completion of last line of therapy; Refractory: disease that progressed during therapy or progressed within 6 months (\<6 months) of prior therapy * At least one line of prior systemic therapy * At least one bi-dimensionally measurable nodal lesion or one bi-dimensionally measurable extranodal lesion, as measured on positron emission tomography-computed tomography (PET/CT) scan * Adequate hematologic function * For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agreement to refrain from donating eggs, as follows: Women must remain abstinent or use contraceptive methods with a failure rate of \<1% per year during the treatment period and for at least 18 months after the final dose of obinutuzumab, 6 months after the final dose of gemcitabine, 9 months after the final dose of oxaliplatin, 3 months after the final dose of mosunetuzumab, 3 months after the final dose of tocilizumab, and 2 months after the final dose of glofitamab. Women must refrain from donating eggs during this same period * For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agreement to refrain from donating sperm, as follows: With a female partner of childbearing potential or pregnant female partners, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of \<1% per year during the treatment period and for at least 2 months after the final dose of glofitamab, 2 months after the final dose of mosunetuzumab, 2 months after the final dose of tocilizumab (if applicable), 3 months after the final dose of obinutuzumab, and 6 months after the final dose of oxaliplatin or gemcitabine to avoid exposing the embryo. Men must refrain from donating sperm during this same period.
Exclusion criteria
* Participant has failed only one prior line of therapy and is a candidate for stem cell transplantation * History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies (or recombinant antibody-related fusion proteins) or known sensitivity or allergy to murine products * Contraindication to obinutuzumab, gemcitabine, oxaliplatin, or tocilizumab * Prior treatment with a bispecific antibody targeting both CD20 and CD3, including glofitamab and mosunetuzumab * Grade \>1 peripheral neuropathy * Treatment with radiotherapy, chemotherapy, immunotherapy, immunosuppressive therapy, or any investigational agent for the purposes of treating cancer within 2 weeks prior to first study treatment * Treatment with monoclonal antibodies for the purposes of treating cancer within 4 weeks prior to the first study treatment * Primary or secondary central nervous system (CNS) lymphoma at the time of recruitment or history of CNS lymphoma * Current or history of CNS disease, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease * History of other malignancy that could affect compliance with the protocol or interpretation of results * Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results, including significant cardiovascular disease (such as New York Heart Association Class III or IV cardiac disease, myocardial infarction within the last 6 months, unstable arrhythmias, or unstable angina) or significant pulmonary disease (including obstructive pulmonary disease and history of bronchospasm) * Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment or any major episode of infection (as evaluated by the investigator) within 4 weeks prior to first study treatment * Suspected or latent tuberculosis * Positive test results for chronic hepatitis B virus (HBV) infection * Positive test results for hepatitis C virus (HCV) antibody * Known HIV-seropositive status * Known or suspected chronic active Epstein-Barr virus infection * Known or suspected history of hemophagocytic lymphohistiocytosis (HLH) * History of progressive multifocal leukoencephalopathy * Adverse events from prior anti-cancer therapy that have not resolved to Grade 1 or better (with the exception of alopecia and anorexia) * Administration of a live, attenuated vaccine within 4 weeks prior to the first study treatment administration or anticipation that such a live, attenuated vaccine will be required during the study * Prior solid organ transplantation * Prior allogenic stem cell transplant * Active autoimmune disease requiring treatment * Prior treatment with systemic immunosuppressive medications (including, but not limited to, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents) within 4 weeks prior to the first dose of study treatment * Corticosteroid therapy within 2 weeks prior to first dose of study treatment, with exceptions defined by the study protocol * Recent major surgery (within 4 weeks before the first study treatment) other than for diagnosis * Clinically significant history of liver disease, including cirrhosis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants With Cytokine Release Syndrome (CRS) by Grade of Severity | Baseline - 90 days after last dose of study treatment | Severity of CRS was determined according to the American Society for Transplantation and Cell Therapy (ASTCT) Consensus Grading Criteria, in which Grade 1 as fever (≥38.0°C) with or without other symptoms; Grade 2 as fever with hypotension not requiring vasopressors and/or hypoxia requiring the use of oxygen (low-flow); and Grade 3 as fever with hypotension requiring one vasopressor with or without vasopressin and/or hypoxia requiring the use of oxygen (high-flow). |
| Number of Deaths Due to Adverse Events (AEs) | Baseline - 90 days after last dose of study treatment | An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Pre-existing conditions which worsen during a study are also considered as adverse events. |
| Number of Treatment Discontinuations Due to AE | Baseline - 90 days after last dose of study treatment | An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Pre-existing conditions which worsen during a study are also considered as adverse events. |
| Proportion of Participants With Serious Adverse Events (SAEs) | Baseline - 90 days after last dose of study treatment | An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Pre-existing conditions which worsen during a study are also considered as adverse events. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tolerability of Study Treatment as Measured by Dose Interruptions, Dose Reductions, and Treatment Discontinuation Due to AEs | Up to approximately 16 months | — |
| Complete Response (CR) Based on PET/CT as Determined by the Investigator According to the 2014 Lugano Response Criteria | Up to approximately 16 months | Per the 2014 Lugano Response Criteria for malignant lymphoma a CR = complete metabolic response with a score of 1, 2, or 3 on a 5-point scale (5PS), with higher scores indicating more extensive disease. |
| Objective Response Rate (ORR), Defined as the Proportion of Participants With a Best Overall Response of Partial Response (PR) or CR, as Determined by the Investigator According to the 2014 Lugano Response Criteria | Up to approximately 16 months | Per the 2014 Lugano Response Criteria for malignant lymphoma a CR = complete metabolic response with a score of 1, 2, or 3 on a 5-point scale (5PS), while a PR = partial metabolic response with a score of 4 or 5 on 5PS with higher scores indicating more extensive disease. |
| Maximum Serum Concentration (Cmax) of Glofitamab | Cycle 1 Day 8 and Cycle 2 Day 1 | — |
Countries
Australia
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm A: Glofit-GemOx Participants received a single IV dose of obinutuzumab 7 days prior to their first dose of glofitamab. Participants then received up to 8 cycles of glofitamab + gemcitabine + oxaliplatin, followed by up to 4 additional cycles of glofitamab monotherapy (cycle length = 21 days) | 17 |
| Arm B: Mosun-GemOx Participants received up to 8 cycles of mosunetuzumab + gemcitabine + oxaliplatin (cycle length = 21 days) | 6 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 12 | 3 |
Baseline characteristics
| Characteristic | Arm B: Mosun-GemOx | Total | Arm A: Glofit-GemOx |
|---|---|---|---|
| Age, Continuous | 69.3 years STANDARD_DEVIATION 18.3 | 63.3 years STANDARD_DEVIATION 12 | 61.1 years STANDARD_DEVIATION 8.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 23 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 20 Participants | 15 Participants |
| Sex: Female, Male Female | 2 Participants | 6 Participants | 4 Participants |
| Sex: Female, Male Male | 4 Participants | 17 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 17 | 0 / 6 |
| other Total, other adverse events | 17 / 17 | 6 / 6 |
| serious Total, serious adverse events | 12 / 17 | 4 / 6 |
Outcome results
Primary
Number of Deaths Due to Adverse Events (AEs)
An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Pre-existing conditions which worsen during a study are also considered as adverse events.
Time frame: Baseline - 90 days after last dose of study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Glofit-GemOx | Number of Deaths Due to Adverse Events (AEs) | 1 Participants |
| Arm B: Mosun-GemOx | Number of Deaths Due to Adverse Events (AEs) | 0 Participants |
Primary
Number of Treatment Discontinuations Due to AE
An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Pre-existing conditions which worsen during a study are also considered as adverse events.
Time frame: Baseline - 90 days after last dose of study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Glofit-GemOx | Number of Treatment Discontinuations Due to AE | 1 Participants |
| Arm B: Mosun-GemOx | Number of Treatment Discontinuations Due to AE | 1 Participants |
Primary
Proportion of Participants With Cytokine Release Syndrome (CRS) by Grade of Severity
Severity of CRS was determined according to the American Society for Transplantation and Cell Therapy (ASTCT) Consensus Grading Criteria, in which Grade 1 as fever (≥38.0°C) with or without other symptoms; Grade 2 as fever with hypotension not requiring vasopressors and/or hypoxia requiring the use of oxygen (low-flow); and Grade 3 as fever with hypotension requiring one vasopressor with or without vasopressin and/or hypoxia requiring the use of oxygen (high-flow).
Time frame: Baseline - 90 days after last dose of study treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A: Glofit-GemOx | Proportion of Participants With Cytokine Release Syndrome (CRS) by Grade of Severity | Grade 1 | 29.4 Proportion expressed as percentage |
| Arm A: Glofit-GemOx | Proportion of Participants With Cytokine Release Syndrome (CRS) by Grade of Severity | Grade 2 | 11.8 Proportion expressed as percentage |
| Arm A: Glofit-GemOx | Proportion of Participants With Cytokine Release Syndrome (CRS) by Grade of Severity | Grade 3 | 5.9 Proportion expressed as percentage |
| Arm B: Mosun-GemOx | Proportion of Participants With Cytokine Release Syndrome (CRS) by Grade of Severity | Grade 1 | 16.7 Proportion expressed as percentage |
| Arm B: Mosun-GemOx | Proportion of Participants With Cytokine Release Syndrome (CRS) by Grade of Severity | Grade 2 | 0 Proportion expressed as percentage |
| Arm B: Mosun-GemOx | Proportion of Participants With Cytokine Release Syndrome (CRS) by Grade of Severity | Grade 3 | 0 Proportion expressed as percentage |
Primary
Proportion of Participants With Serious Adverse Events (SAEs)
An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Pre-existing conditions which worsen during a study are also considered as adverse events.
Time frame: Baseline - 90 days after last dose of study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Glofit-GemOx | Proportion of Participants With Serious Adverse Events (SAEs) | 70.6 Proportion expressed as percentage |
| Arm B: Mosun-GemOx | Proportion of Participants With Serious Adverse Events (SAEs) | 66.7 Proportion expressed as percentage |
Secondary
Complete Response (CR) Based on PET/CT as Determined by the Investigator According to the 2014 Lugano Response Criteria
Per the 2014 Lugano Response Criteria for malignant lymphoma a CR = complete metabolic response with a score of 1, 2, or 3 on a 5-point scale (5PS), with higher scores indicating more extensive disease.
Time frame: Up to approximately 16 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Glofit-GemOx | Complete Response (CR) Based on PET/CT as Determined by the Investigator According to the 2014 Lugano Response Criteria | 23.5 percentage |
| Arm B: Mosun-GemOx | Complete Response (CR) Based on PET/CT as Determined by the Investigator According to the 2014 Lugano Response Criteria | 50.0 percentage |
Secondary
Maximum Serum Concentration (Cmax) of Glofitamab
Time frame: Cycle 1 Day 8 and Cycle 2 Day 1
Population: The pharmacokinetic population consisted of all participants that received at least one dose of glofitamab or mosunetuzumab and who had data from at least one post-dose sample.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm A: Glofit-GemOx | Maximum Serum Concentration (Cmax) of Glofitamab | Pre-infusion Cycle 1 Day 8 | 0 ug/mL |
| Arm A: Glofit-GemOx | Maximum Serum Concentration (Cmax) of Glofitamab | Within 30 mins post infusion Cycle 1 Day 8 | 0.6 ug/mL |
| Arm A: Glofit-GemOx | Maximum Serum Concentration (Cmax) of Glofitamab | 12 hours post infusion Cycle 1 Day 8 | 0.6 ug/mL |
| Arm A: Glofit-GemOx | Maximum Serum Concentration (Cmax) of Glofitamab | 24 hours post infusion Cycle 1 Day 8 | 0.5 ug/mL |
| Arm A: Glofit-GemOx | Maximum Serum Concentration (Cmax) of Glofitamab | 48 hours post infusion Cycle 1 Day 8 | 0.3 ug/mL |
| Arm A: Glofit-GemOx | Maximum Serum Concentration (Cmax) of Glofitamab | Pre-infusion Cycle 2 Day 1 | 0.8 ug/mL |
| Arm A: Glofit-GemOx | Maximum Serum Concentration (Cmax) of Glofitamab | Within 30 minutes post infusion Cycle 2 Day 1 | 9 ug/mL |
| Arm A: Glofit-GemOx | Maximum Serum Concentration (Cmax) of Glofitamab | 6 hours post infusion Cycle 2 Day 1 | 7.8 ug/mL |
| Arm A: Glofit-GemOx | Maximum Serum Concentration (Cmax) of Glofitamab | 20 hours post infusion Cycle 2 Day 1 | 6.5 ug/mL |
| Arm A: Glofit-GemOx | Maximum Serum Concentration (Cmax) of Glofitamab | 44 hours post infusion Cycle 2 Day 1 | 3.8 ug/mL |
Secondary
Objective Response Rate (ORR), Defined as the Proportion of Participants With a Best Overall Response of Partial Response (PR) or CR, as Determined by the Investigator According to the 2014 Lugano Response Criteria
Per the 2014 Lugano Response Criteria for malignant lymphoma a CR = complete metabolic response with a score of 1, 2, or 3 on a 5-point scale (5PS), while a PR = partial metabolic response with a score of 4 or 5 on 5PS with higher scores indicating more extensive disease.
Time frame: Up to approximately 16 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Glofit-GemOx | Objective Response Rate (ORR), Defined as the Proportion of Participants With a Best Overall Response of Partial Response (PR) or CR, as Determined by the Investigator According to the 2014 Lugano Response Criteria | 35.3 Proportion expressed as percentage |
| Arm B: Mosun-GemOx | Objective Response Rate (ORR), Defined as the Proportion of Participants With a Best Overall Response of Partial Response (PR) or CR, as Determined by the Investigator According to the 2014 Lugano Response Criteria | 50.0 Proportion expressed as percentage |
Secondary
Tolerability of Study Treatment as Measured by Dose Interruptions, Dose Reductions, and Treatment Discontinuation Due to AEs
Time frame: Up to approximately 16 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A: Glofit-GemOx | Tolerability of Study Treatment as Measured by Dose Interruptions, Dose Reductions, and Treatment Discontinuation Due to AEs | AEs leading to treatment discontinuation | 5.9 percentage of participants |
| Arm A: Glofit-GemOx | Tolerability of Study Treatment as Measured by Dose Interruptions, Dose Reductions, and Treatment Discontinuation Due to AEs | AEs leading to dose modification or interruption | 29.4 percentage of participants |
| Arm B: Mosun-GemOx | Tolerability of Study Treatment as Measured by Dose Interruptions, Dose Reductions, and Treatment Discontinuation Due to AEs | AEs leading to treatment discontinuation | 16.7 percentage of participants |
| Arm B: Mosun-GemOx | Tolerability of Study Treatment as Measured by Dose Interruptions, Dose Reductions, and Treatment Discontinuation Due to AEs | AEs leading to dose modification or interruption | 50.0 percentage of participants |