Follicular Lymphoma, Grade 3b, Lymphoma, B-cell, Lymphoma, Follicular, Grade 3b, Lymphoma, Large B-Cell, Diffuse
Conditions
Keywords
Antibodies, Monoclonal, Antibody-Drug Conjugate, Antigens, CD19, Autologous Stem Cell Transplant, Drug Therapy, Follicular Lymphoma Grade 3b, Hematologic Diseases, Immune System Diseases, Immunoproliferative Disorders, Immunotherapy, Lymphatic Diseases, Lymphoma, Lymphoma, B-Cell, Lymphoma, Large B-Cell, Diffuse, Lymphoma, Non-Hodgkin, Monomethylauristatin F, Neoplasms, Neoplasms by Histologic Type, Transformed Lymphoma / DLBCL, Rituximab, Ifosfamide, Carboplatin, Etoposide
Brief summary
The purpose of this randomized, open-label study is to evaluate the safety and efficacy of denintuzumab mafodotin plus RICE (rituximab, ifosfamide, carboplatin, and etoposide) when compared to RICE alone in the treatment of patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) or Grade 3b follicular lymphoma. Eligible patients must also be candidates for autologous stem cell transplant. Patients will be randomly assigned in a 1:1 ratio to receive 3 cycles of study treatment with either denintuzumab mafodotin + RICE or RICE alone. The study will assess whether there is a difference between the 2 groups in the side effects that are reported and the number of patients who achieve complete remission at the end of their study treatment.
Interventions
Denintuzumab mafodotin 3 mg/kg by intravenous (IV) infusion, every 3 weeks for up to 3 cycles.
DRUGrituximab
375 mg/m\^2 by IV infusion, every 3 weeks for up to 3 cycles
DRUGifosfamide
5000 mg/m\^2 by IV infusion over a 24-hour period, every 3 weeks for up to 3 cycles
DRUGcarboplatin
AUC 5mg/mL x min by IV infusion, every 3 weeks for up to 3 cycles
DRUGetoposide
100 mg/m\^2 per day by IV infusion for 3 days, every 3 weeks for up to 3 cycles
Sponsors
Seagen Inc.
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
* Pathologically confirmed diagnosis of relapsed or refractory diffuse large B-cell lymphoma (DLBCL; including de novo and transformed DLBCL) or Grade 3b follicular lymphoma * Available representative tissue from the most recent biopsy after the last therapy; if such tissue is not available, a fresh biopsy must be obtained * Received only frontline CD20-directed immunotherapy with anthracycline- or anthracenedione-based multi-agent chemotherapy. Monotherapy rituximab or other CD20-directed immunotherapy as maintenance therapy prior to frontline chemotherapy, and radiotherapy in a limited field or as part of the frontline treatment plan are permitted. * Achieved a response of stable disease, partial response, or complete response following the last cycle of frontline treatment. In addition, patients must have relapsed less than or equal to 6 months from the completion of frontline therapy at the time of initial dosing in this clinical trial. * Considered eligible for high-dose chemotherapy followed by autologous stem cell transplant (ASCT) * Fluorodeoxyglucose (FDG)-avid disease by positive emission tomography (PET), and measurable disease greater than 1.5 cm in diameter * Eastern Cooperative Oncology Group (ECOG) performance less than or equal to 2 * Adequate kidney and hematologic function assessed from baseline laboratory data
Exclusion criteria
* Previous history of indolent lymphoma treated with more than 1 multi-agent chemotherapy regimen or previous cancer therapy for recurrent DLBCL or Grade 3b follicular lymphoma * History of autologous or allogeneic stem cell transplant * History of another primary invasive cancer, hematologic malignancy, or myelodysplastic syndrome that has not been in remission for at least 1 year * History of progressive multifocal leukoencephalopathy (PML) * Cerebral/meningeal disease related to the underlying malignancy that has not been definitively treated * Known urinary tract obstruction * Patients with the following ocular conditions: corneal disorders, monocular vision (i.e., best corrected visual acuity greater than or equal to 20/200 in one eye), or active ocular disorders requiring treatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complete Remission Rate Per Independent Review Facility | Up to 4 months | Number of patients with complete metabolic response by PET (positive emission tomography) and CT (computed tomography) scans, or complete radiologic response by CT only. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Laboratory Abnormalities | Up to 4 months | Number of participants who experienced a maximum post-baseline laboratory toxicity of Grade 3 or higher (per National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.03). |
| Objective Response Rate (ORR) | Up to 4 months | ORR is defined as the proportion of patients with complete remission (CR) or partial remission (PR) per independent review facility (IRF) at the end of treatment. |
| Duration of Complete Response (CR) | Up to 27.9 months | Defined as the time from the start of the first radiographic documentation of CR per investigator to the first documentation of progressive disease, death due to any cause, or receipt of subsequent anticancer therapy, whichever comes first. |
| Duration of Objective Response (OR) | Up to 27.9 months | Duration of OR is defined as the time from the start of the first radiographic documentation of OR per investigator to the first documentation of PD, death due to any cause, or receipt of subsequent anticancer therapy, whichever comes first. |
| Number of Participants With Adverse Events (AEs) | Up to 4 months | Treatment-emergent adverse events (TEAEs) are presented and defined as newly occurring (not present at baseline) or worsening after first dose of investigational product. AE severity and seriousness are assessed independently. 'Severity' characterizes the intensity of an AE and is graded using the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03. An AE is considered 'serious' if it is life-threatening, fatal, requires hospitalization, or is otherwise considered to be medically significant. |
| Overall Survival (OS) | Up to 30 months | OS is defined as the time from date of randomization to date of death due to any cause. In the absence of confirmation of death, survival time will be censored at the last date the patient is known to be alive. |
| Number of Patients Achieving Peripheral Blood Stem Cell (PBSC) Mobilization | Up to 30 months | Defined as the number of patients who are able to adequately mobilize PBSC per investigator assessment on or after completion of study treatment, prior to subsequent anticancer therapy. |
| Number of Patients Receiving Autologous Stem Cell Transplant (ASCT) | Up to 30 months | Number of patients receiving ASCT after completion of study treatment (EOT), prior to subsequent anticancer therapy. |
| Progression-free Survival (PFS) | Up to 30 months | PFS is defined as the time from randomization to first documentation of disease progression per investigator, death due to any cause, or receipt of subsequent anticancer therapy, whichever comes first. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| RICE Rituximab, ifosfamide, carboplatin, and etoposide
rituximab: 375 mg/m2 by IV infusion, every 3 weeks for up to 3 cycles
ifosfamide: 5000 mg/m2 by IV infusion over a 24-hour period, every 3 weeks for up to 3 cycles
carboplatin: AUC 5 by IV infusion, every 3 weeks for up to 3 cycles
etoposide: 100 mg/m2 per day by IV infusion for 3 days, every 3 weeks for up to 3 cycles | 41 |
| 19A+RICE Denintuzumab mafodotin plus rituximab, ifosfamide, carboplatin, and etoposide
denintuzumab mafodotin: Denintuzumab mafodotin 3 mg/kg by intravenous (IV) infusion, every 3 weeks for up to 3 cycles.
rituximab: 375 mg/m2 by IV infusion, every 3 weeks for up to 3 cycles
ifosfamide: 5000 mg/m2 by IV infusion over a 24-hour period, every 3 weeks for up to 3 cycles
carboplatin: AUC 5 by IV infusion, every 3 weeks for up to 3 cycles
etoposide: 100 mg/m2 per day by IV infusion for 3 days, every 3 weeks for up to 3 cycles | 40 |
| Total | 81 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 6 | 9 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Study Termination by Sponsor | 32 | 27 |
| Overall Study | Withdrawal by Subject | 3 | 3 |
Baseline characteristics
| Characteristic | RICE | 19A+RICE | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 13 Participants | 16 Participants | 29 Participants |
| Age, Categorical Between 18 and 65 years | 28 Participants | 24 Participants | 52 Participants |
| Age, Continuous | 60.0 years | 62.5 years | 61.0 years |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Grade 0 | 17 Participants | 19 Participants | 36 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Grade 1 | 21 Participants | 21 Participants | 42 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Grade 2 | 3 Participants | 0 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 5 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 37 Participants | 35 Participants | 72 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) White | 37 Participants | 36 Participants | 73 Participants |
| Region of Enrollment United States | 41 participants | 40 participants | 81 participants |
| Sex: Female, Male Female | 16 Participants | 13 Participants | 29 Participants |
| Sex: Female, Male Male | 25 Participants | 27 Participants | 52 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 6 / 40 | 9 / 40 |
| other Total, other adverse events | 40 / 40 | 40 / 40 |
| serious Total, serious adverse events | 13 / 40 | 19 / 40 |
Outcome results
Primary
Complete Remission Rate Per Independent Review Facility
Number of patients with complete metabolic response by PET (positive emission tomography) and CT (computed tomography) scans, or complete radiologic response by CT only.
Time frame: Up to 4 months
Population: The modified Intent-to-Treat (mITT) analysis set includes all patients who were randomized to the recommended dose level of 19A+RICE or RICE and received at least 1 cycle of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RICE | Complete Remission Rate Per Independent Review Facility | 18 Participants |
| 19A+RICE | Complete Remission Rate Per Independent Review Facility | 25 Participants |
Secondary
Duration of Complete Response (CR)
Defined as the time from the start of the first radiographic documentation of CR per investigator to the first documentation of progressive disease, death due to any cause, or receipt of subsequent anticancer therapy, whichever comes first.
Time frame: Up to 27.9 months
Population: The modified Intent-to-Treat (mITT) analysis set includes all patients who were randomized to the recommended dose level of 19A+RICE or RICE and received at least 1 cycle of study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| RICE | Duration of Complete Response (CR) | NA months |
| 19A+RICE | Duration of Complete Response (CR) | NA months |
Secondary
Duration of Objective Response (OR)
Duration of OR is defined as the time from the start of the first radiographic documentation of OR per investigator to the first documentation of PD, death due to any cause, or receipt of subsequent anticancer therapy, whichever comes first.
Time frame: Up to 27.9 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| RICE | Duration of Objective Response (OR) | NA months |
| 19A+RICE | Duration of Objective Response (OR) | NA months |
Secondary
Number of Participants With Adverse Events (AEs)
Treatment-emergent adverse events (TEAEs) are presented and defined as newly occurring (not present at baseline) or worsening after first dose of investigational product. AE severity and seriousness are assessed independently. 'Severity' characterizes the intensity of an AE and is graded using the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03. An AE is considered 'serious' if it is life-threatening, fatal, requires hospitalization, or is otherwise considered to be medically significant.
Time frame: Up to 4 months
Population: The safety analysis set includes all patients who received any amount of denintuzumab mafodotin or any component of RICE. Treatment group is determined using the actual treatment arm received, regardless of the randomization treatment assignment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| RICE | Number of Participants With Adverse Events (AEs) | Treatment-emergent AE (TEAE) | 39 Participants |
| RICE | Number of Participants With Adverse Events (AEs) | Treatment-related AEs | 38 Participants |
| RICE | Number of Participants With Adverse Events (AEs) | Grade 3 or Higher TEAEs | 31 Participants |
| RICE | Number of Participants With Adverse Events (AEs) | Serious AEs (SAEs) | 13 Participants |
| RICE | Number of Participants With Adverse Events (AEs) | Treatment-related SAEs | 9 Participants |
| RICE | Number of Participants With Adverse Events (AEs) | AEs Leading to Dose Delay | 3 Participants |
| RICE | Number of Participants With Adverse Events (AEs) | AEs Leading to Dose Reduction | 3 Participants |
| RICE | Number of Participants With Adverse Events (AEs) | AEs Leading to Treatment Discontinuation | 2 Participants |
| 19A+RICE | Number of Participants With Adverse Events (AEs) | AEs Leading to Treatment Discontinuation | 3 Participants |
| 19A+RICE | Number of Participants With Adverse Events (AEs) | Treatment-emergent AE (TEAE) | 40 Participants |
| 19A+RICE | Number of Participants With Adverse Events (AEs) | Treatment-related SAEs | 13 Participants |
| 19A+RICE | Number of Participants With Adverse Events (AEs) | Treatment-related AEs | 40 Participants |
| 19A+RICE | Number of Participants With Adverse Events (AEs) | AEs Leading to Dose Reduction | 5 Participants |
| 19A+RICE | Number of Participants With Adverse Events (AEs) | Grade 3 or Higher TEAEs | 38 Participants |
| 19A+RICE | Number of Participants With Adverse Events (AEs) | AEs Leading to Dose Delay | 8 Participants |
| 19A+RICE | Number of Participants With Adverse Events (AEs) | Serious AEs (SAEs) | 19 Participants |
Secondary
Number of Participants With Laboratory Abnormalities
Number of participants who experienced a maximum post-baseline laboratory toxicity of Grade 3 or higher (per National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.03).
Time frame: Up to 4 months
Population: The safety analysis set includes all patients who received any amount of denintuzumab mafodotin or any component of RICE. Treatment group is determined using the actual treatment arm received, regardless of the randomization treatment assignment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| RICE | Number of Participants With Laboratory Abnormalities | Any Hematology Test | 37 Participants |
| RICE | Number of Participants With Laboratory Abnormalities | Hemoglobin Low | 19 Participants |
| RICE | Number of Participants With Laboratory Abnormalities | Leukocytes High | 1 Participants |
| RICE | Number of Participants With Laboratory Abnormalities | Leukocytes Low | 23 Participants |
| RICE | Number of Participants With Laboratory Abnormalities | Lymphocytes High | 2 Participants |
| RICE | Number of Participants With Laboratory Abnormalities | Lymphocytes Low | 34 Participants |
| RICE | Number of Participants With Laboratory Abnormalities | Neutrophils Low | 22 Participants |
| RICE | Number of Participants With Laboratory Abnormalities | Platelets Low | 26 Participants |
| RICE | Number of Participants With Laboratory Abnormalities | Any Chemistry Test | 18 Participants |
| RICE | Number of Participants With Laboratory Abnormalities | Aspartate Aminotransferase High | 1 Participants |
| RICE | Number of Participants With Laboratory Abnormalities | Alanine Aminotransferase High | 3 Participants |
| RICE | Number of Participants With Laboratory Abnormalities | Calcium High | 4 Participants |
| RICE | Number of Participants With Laboratory Abnormalities | Calcium Low | 0 Participants |
| RICE | Number of Participants With Laboratory Abnormalities | Creatinine High | 0 Participants |
| RICE | Number of Participants With Laboratory Abnormalities | Glucose High | 4 Participants |
| RICE | Number of Participants With Laboratory Abnormalities | Phosphate Low | 9 Participants |
| RICE | Number of Participants With Laboratory Abnormalities | Potassium Low | 3 Participants |
| RICE | Number of Participants With Laboratory Abnormalities | Sodium Low | 4 Participants |
| RICE | Number of Participants With Laboratory Abnormalities | Urate High | 2 Participants |
| 19A+RICE | Number of Participants With Laboratory Abnormalities | Glucose High | 3 Participants |
| 19A+RICE | Number of Participants With Laboratory Abnormalities | Any Hematology Test | 37 Participants |
| 19A+RICE | Number of Participants With Laboratory Abnormalities | Alanine Aminotransferase High | 3 Participants |
| 19A+RICE | Number of Participants With Laboratory Abnormalities | Hemoglobin Low | 18 Participants |
| 19A+RICE | Number of Participants With Laboratory Abnormalities | Aspartate Aminotransferase High | 2 Participants |
| 19A+RICE | Number of Participants With Laboratory Abnormalities | Leukocytes High | 0 Participants |
| 19A+RICE | Number of Participants With Laboratory Abnormalities | Urate High | 0 Participants |
| 19A+RICE | Number of Participants With Laboratory Abnormalities | Leukocytes Low | 24 Participants |
| 19A+RICE | Number of Participants With Laboratory Abnormalities | Calcium High | 0 Participants |
| 19A+RICE | Number of Participants With Laboratory Abnormalities | Lymphocytes High | 0 Participants |
| 19A+RICE | Number of Participants With Laboratory Abnormalities | Phosphate Low | 8 Participants |
| 19A+RICE | Number of Participants With Laboratory Abnormalities | Lymphocytes Low | 31 Participants |
| 19A+RICE | Number of Participants With Laboratory Abnormalities | Calcium Low | 2 Participants |
| 19A+RICE | Number of Participants With Laboratory Abnormalities | Neutrophils Low | 22 Participants |
| 19A+RICE | Number of Participants With Laboratory Abnormalities | Sodium Low | 3 Participants |
| 19A+RICE | Number of Participants With Laboratory Abnormalities | Platelets Low | 35 Participants |
| 19A+RICE | Number of Participants With Laboratory Abnormalities | Creatinine High | 1 Participants |
| 19A+RICE | Number of Participants With Laboratory Abnormalities | Any Chemistry Test | 16 Participants |
| 19A+RICE | Number of Participants With Laboratory Abnormalities | Potassium Low | 5 Participants |
Secondary
Number of Patients Achieving Peripheral Blood Stem Cell (PBSC) Mobilization
Defined as the number of patients who are able to adequately mobilize PBSC per investigator assessment on or after completion of study treatment, prior to subsequent anticancer therapy.
Time frame: Up to 30 months
Population: The modified Intent-to-Treat (mITT) analysis set includes all patients who were randomized to the recommended dose level of 19A+RICE or RICE and received at least 1 cycle of study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| RICE | Number of Patients Achieving Peripheral Blood Stem Cell (PBSC) Mobilization | Patients with attempted stem cell collection(s) | 28 Participants |
| RICE | Number of Patients Achieving Peripheral Blood Stem Cell (PBSC) Mobilization | Patients with sufficient stem cell collection | 26 Participants |
| 19A+RICE | Number of Patients Achieving Peripheral Blood Stem Cell (PBSC) Mobilization | Patients with attempted stem cell collection(s) | 24 Participants |
| 19A+RICE | Number of Patients Achieving Peripheral Blood Stem Cell (PBSC) Mobilization | Patients with sufficient stem cell collection | 21 Participants |
Secondary
Number of Patients Receiving Autologous Stem Cell Transplant (ASCT)
Number of patients receiving ASCT after completion of study treatment (EOT), prior to subsequent anticancer therapy.
Time frame: Up to 30 months
Population: The modified Intent-to-Treat (mITT) analysis set includes all patients who were randomized to the recommended dose level of 19A+RICE or RICE and received at least 1 cycle of study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| RICE | Number of Patients Receiving Autologous Stem Cell Transplant (ASCT) | Patients planned to receive ASCT at EOT | 28 Participants |
| RICE | Number of Patients Receiving Autologous Stem Cell Transplant (ASCT) | Patients who received ASCT at EOT | 25 Participants |
| 19A+RICE | Number of Patients Receiving Autologous Stem Cell Transplant (ASCT) | Patients planned to receive ASCT at EOT | 25 Participants |
| 19A+RICE | Number of Patients Receiving Autologous Stem Cell Transplant (ASCT) | Patients who received ASCT at EOT | 22 Participants |
Secondary
Objective Response Rate (ORR)
ORR is defined as the proportion of patients with complete remission (CR) or partial remission (PR) per independent review facility (IRF) at the end of treatment.
Time frame: Up to 4 months
Population: The modified Intent-to-Treat (mITT) analysis set includes all patients who were randomized to the recommended dose level of 19A+RICE or RICE and received at least 1 cycle of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RICE | Objective Response Rate (ORR) | 30 Participants |
| 19A+RICE | Objective Response Rate (ORR) | 32 Participants |
Secondary
Overall Survival (OS)
OS is defined as the time from date of randomization to date of death due to any cause. In the absence of confirmation of death, survival time will be censored at the last date the patient is known to be alive.
Time frame: Up to 30 months
Population: The modified Intent-to-Treat (mITT) analysis set includes all patients who were randomized to the recommended dose level of 19A+RICE or RICE and received at least 1 cycle of study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| RICE | Overall Survival (OS) | NA months |
| 19A+RICE | Overall Survival (OS) | NA months |
Secondary
Progression-free Survival (PFS)
PFS is defined as the time from randomization to first documentation of disease progression per investigator, death due to any cause, or receipt of subsequent anticancer therapy, whichever comes first.
Time frame: Up to 30 months
Population: The modified Intent-to-Treat (mITT) analysis set includes all patients who were randomized to the recommended dose level of 19A+RICE or RICE and received at least 1 cycle of study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| RICE | Progression-free Survival (PFS) | NA months |
| 19A+RICE | Progression-free Survival (PFS) | NA months |