de Novo DLBCL, Diffuse Large B-cell Lymphoma, DLBCL Transformed From Indolent Lymphoma, Follicular Grade 3 Lymphoma
Conditions
Keywords
non-hodgkin lymphoma, DLBCL, relapsed, aggressive NHL, Diffuse large B-cell lymphoma, Rituximab, Rituxan, Pixantrone, NHL, non hodgkin's lymphoma, de novo DLBCL, DLBCL transformed from Indolent Lymphoma, Follicular Grade 3 Lymphoma
Brief summary
The purpose of this study is to evaluate the efficacy of Pixantrone + Rituximab compared to Gemcitabine + Rituximab in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), or follicular grade 3 lymphoma.
Detailed description
Eligible patients will be randomized to treatment with pixantrone plus rituximab or gemcitabine plus rituximab in up to six 28-day cycles. At the time patients experience progressive disease during study treatment, early follow- up, or intermediate follow-up, they enter the survival follow up period. Patients who complete study treatment or discontinue study treatment for any other reason will participate in the follow-up periods. Early Follow-Up: After treatment completion or discontinuation, patient will enter a 24-week follow-up period. Intermediate Follow-Up: After completing the 24-week early follow-up period, patient will enter an additional 72-week follow-up period. Survival Follow-Up: All patients will be monitored for survival.
Interventions
DRUGPixantrone + Rituximab
Pixantrone + Rituximab: Rituximab 375 mg/m2 IV on day 1 and pixantrone 50 mg/m2 (equivalent to 85mg/m2 pixantrone dimaleate)IV on days 1, 8, and 15. Regimen is given in 28-day cycles. Up to 6 cycles may be administered.
DRUGGemcitabine + Rituximab
Gemcitabine + Rituximab: Rituximab 375 mg/m2 IV on day 1 and gemcitabine 1000 mg/m2 IV on days 1, 8, and 15. Regimen is given in 28-day cycles. Up to 6 cycles may be administered.
Sponsors
CTI BioPharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Diagnosis of DLBCL (de novo DLBCL, or transformed from indolent lymphoma) or follicular grade 3 lymphoma on the basis of tissue biopsy. 2. Patients with de novo DLBCL must have received 1-3 treatment regimens for DLBCL. Patients with follicular grade 3 lymphoma must have received 1-3 treatment regimens for follicular lymphoma (any grade). Patients with DLBCL transformed from indolent lymphoma must have received at least 1-4 treatment regimens for NHL. 3. Received rituximab containing a multi-agent therapy for the treatment of NHL. 4. Not eligible for high-dose chemotherapy and stem cell transplant. 5. Patients with DLBCL transformed from indolent lymphoma must have had a complete or partial response to a therapy for NHL lasting at least 12 weeks.
Exclusion criteria
1. Primary refractory de novo DLBCL or primary refractory follicular grade 3 lymphoma, defined as documented progression within 12 weeks of the last cycle of the first-line multi-agent regimen. 2. Prior treatment with cumulative dose of doxorubicin or equivalent exceeding 450 mg/m2 3. Any experimental therapy ≤ 28 days prior to randomization 4. Other malignancy within last 5 years except for the following: curatively treated basal cell/squamous cell skin cancer, carcinoma in situ of the cervix, superficial transitional cell bladder carcinoma, or in situ ductal carcinoma of the breast after complete resection 5. Any contraindication or known allergy or hypersensitivity to any study drugs 6. Concomitant therapy with any anticancer agents, immunosuppressive agents, other investigational anticancer therapies. Low-dose corticosteroids for the treatment of non cancer-related illnesses are permitted.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | From the date of randomization to the date of progressive disease or death due to any cause (whichever is first reported) (Up to 100 weeks) | PFS is defined as the time of randomization to the date of disease progression or death due to any cause (whichever occurs first) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | From date of randomization to the date of the patient's death due to any cause (Up to 100 weeks) | Overall survival is from randomization to death due to any cause |
| Complete Response Rate | From date of randomization to the date of the patient's death due to any cause (Up to 100 weeks) | CRR is defined as the proportion of patients who achieve a Complete Response (CR) without additional therapy. CR is defined as the disappearance of all target lesions. |
| Overall Response Rate | From date of randomization to the date of the patient's death due to any cause (Up to 100 weeks) | ORR is defined as the proportion of patients who achieve a CR or PR without additional therapy. |
| Number of Treatment Emergent Adverse Events (TEAE) Related to Study Drug | From date of randomization to the date of the patient's death due to any cause (Up to 100 weeks) | The number of Participants with Treatment Emergent Adverse Events (TEAE) related to study drug (pixantrone or gemcitabine) |
Other
| Measure | Time frame | Description |
|---|---|---|
| Individual Concentration-time Profiles of Patients Will be Compared to Existing Data Using Simulations (Visual Predictive Checks) | within 1 hour of initiation of infusion to 24-48 hours after start of pixantrone infusion | To characterize the PK profile of pixantrone when co-administered with rituximab. Plasma samples for PK analysis will be collected relative to the D-1 dose of pixantrone in one of the 6 treatment cycles for each participating patient. The goal is to enroll approx. 20 patients, active at 20 sites- Beatson West of Scotland Cancer Center, Uni. Hospital Kralovske Vinohrady, Uni. Hospital Hradec Kralove Hematooncology, Hospital Nuernberg, St. Marien Hospital Hamm, Puerta del Mar Hospital, Tokuda Hospital Sofia, National Center of Hematology & Transfusiology, UMHAT SV. IVAN RILSKI, Moritz Kaposi General Hospital, Uni. of Debrecen, Polish Red Cross Marine Hospital, Kharkiv Regional Clinical Oncology Center, National Inst. of Cancer Ukraine, Cherkasy Regional Oncology Center, Inst. of Blood Pathology & Transfusion Medicine, Uni. Hospital Martin, National Onclogy Inst., Uni. Hospital with Outpatient Clinic F.D. Roosevelt Banska Bystrica, Uni. Hospital J.A. Reiman Presov |
| To Generate Individual Secondary PK Parameters (eg, Exposure, Half-life Etc.) Using Descriptive Statistics | within 1 hour of initiation of infusion to 24-48 hours after start of pixantrone infusion | To characterize the PK profile of pixantrone when co-administered with rituximab. Plasma samples for PK analysis will be collected relative to the D-1 dose of pixantrone in one of the 6 treatment cycles for each participating patient. The goal is to enroll approx. 20 patients, active at 20 sites- Beatson West of Scotland Cancer Center, Uni. Hospital Kralovske Vinohrady, Uni. Hospital Hradec Kralove Hematooncology, Hospital Nuernberg, St. Marien Hospital Hamm, Puerta del Mar Hospital, Tokuda Hospital Sofia, National Center of Hematology & Transfusiology, UMHAT SV. IVAN RILSKI, Moritz Kaposi General Hospital, Uni. of Debrecen, Polish Red Cross Marine Hospital, Kharkiv Regional Clinical Oncology Center, National Inst. of Cancer Ukraine, Cherkasy Regional Oncology Center, Inst. of Blood Pathology & Transfusion Medicine, Uni. Hospital Martin, National Onclogy Inst., Uni. Hospital with Outpatient Clinic F.D. Roosevelt Banska Bystrica, Uni. Hospital J.A. Reiman Presov |
Countries
Austria, Belgium, Bulgaria, Czechia, Denmark, France, Germany, Hungary, Italy, Poland, Romania, Russia, Slovakia, Spain, Ukraine, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pixantrone + Rituximab Pixantrone and Rituximab
Pixantrone + Rituximab: Pixantrone + Rituximab: Rituximab 375 mg/m2 IV on day 1 and pixantrone 50 mg/m2 (equivalent to 85mg/m2 pixantrone dimaleate)IV on days 1, 8, and 15. Regimen is given in 28-day cycles. Up to 6 cycles may be administered. | 155 |
| Gemcitabine + Rituximab Gemcitabine and Rituximab
Gemcitabine + Rituximab: Gemcitabine + Rituximab: Rituximab 375 mg/m2 IV on day 1 and gemcitabine 1000 mg/m2 IV on days 1, 8, and 15. Regimen is given in 28-day cycles. Up to 6 cycles may be administered. | 157 |
| Total | 312 |
Baseline characteristics
| Characteristic | Pixantrone + Rituximab | Gemcitabine + Rituximab | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 119 Participants | 127 Participants | 246 Participants |
| Age, Categorical Between 18 and 65 years | 36 Participants | 30 Participants | 66 Participants |
| Ann Arbor Stage I-III | 81 Participants | 76 Participants | 157 Participants |
| Ann Arbor Stage IV | 74 Participants | 81 Participants | 155 Participants |
| IPI Score IPI Score 0-2 | 73 Participants | 73 Participants | 146 Participants |
| IPI Score IPI Score 3 or more | 82 Participants | 84 Participants | 166 Participants |
| Number ofprior lines of therapy 0-2 | 137 Participants | 139 Participants | 276 Participants |
| Number ofprior lines of therapy 3 or more | 18 Participants | 18 Participants | 36 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 | 4 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 147 Participants | 155 Participants | 302 Participants |
| Sex: Female, Male Female | 86 Participants | 90 Participants | 176 Participants |
| Sex: Female, Male Male | 69 Participants | 67 Participants | 136 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 12 / 153 | 16 / 149 |
| other Total, other adverse events | 153 / 153 | 148 / 149 |
| serious Total, serious adverse events | 59 / 153 | 57 / 149 |
Outcome results
Primary
Progression Free Survival (PFS)
PFS is defined as the time of randomization to the date of disease progression or death due to any cause (whichever occurs first)
Time frame: From the date of randomization to the date of progressive disease or death due to any cause (whichever is first reported) (Up to 100 weeks)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pixantrone + Rituximab | Progression Free Survival (PFS) | 7.3 Months |
| Gemcitabine + Rituximab | Progression Free Survival (PFS) | 6.3 Months |
Secondary
Complete Response Rate
CRR is defined as the proportion of patients who achieve a Complete Response (CR) without additional therapy. CR is defined as the disappearance of all target lesions.
Time frame: From date of randomization to the date of the patient's death due to any cause (Up to 100 weeks)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pixantrone + Rituximab | Complete Response Rate | 55 Participants |
| Gemcitabine + Rituximab | Complete Response Rate | 34 Participants |
Secondary
Number of Treatment Emergent Adverse Events (TEAE) Related to Study Drug
The number of Participants with Treatment Emergent Adverse Events (TEAE) related to study drug (pixantrone or gemcitabine)
Time frame: From date of randomization to the date of the patient's death due to any cause (Up to 100 weeks)
Population: Safety Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pixantrone + Rituximab | Number of Treatment Emergent Adverse Events (TEAE) Related to Study Drug | 140 Participants |
| Gemcitabine + Rituximab | Number of Treatment Emergent Adverse Events (TEAE) Related to Study Drug | 140 Participants |
Secondary
Overall Response Rate
ORR is defined as the proportion of patients who achieve a CR or PR without additional therapy.
Time frame: From date of randomization to the date of the patient's death due to any cause (Up to 100 weeks)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pixantrone + Rituximab | Overall Response Rate | 61.9 percentage of patients |
| Gemcitabine + Rituximab | Overall Response Rate | 43.9 percentage of patients |
Secondary
Overall Survival
Overall survival is from randomization to death due to any cause
Time frame: From date of randomization to the date of the patient's death due to any cause (Up to 100 weeks)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pixantrone + Rituximab | Overall Survival | 13.3 Months |
| Gemcitabine + Rituximab | Overall Survival | 19.6 Months |
Other Pre-specified
Individual Concentration-time Profiles of Patients Will be Compared to Existing Data Using Simulations (Visual Predictive Checks)
To characterize the PK profile of pixantrone when co-administered with rituximab. Plasma samples for PK analysis will be collected relative to the D-1 dose of pixantrone in one of the 6 treatment cycles for each participating patient. The goal is to enroll approx. 20 patients, active at 20 sites- Beatson West of Scotland Cancer Center, Uni. Hospital Kralovske Vinohrady, Uni. Hospital Hradec Kralove Hematooncology, Hospital Nuernberg, St. Marien Hospital Hamm, Puerta del Mar Hospital, Tokuda Hospital Sofia, National Center of Hematology & Transfusiology, UMHAT SV. IVAN RILSKI, Moritz Kaposi General Hospital, Uni. of Debrecen, Polish Red Cross Marine Hospital, Kharkiv Regional Clinical Oncology Center, National Inst. of Cancer Ukraine, Cherkasy Regional Oncology Center, Inst. of Blood Pathology & Transfusion Medicine, Uni. Hospital Martin, National Onclogy Inst., Uni. Hospital with Outpatient Clinic F.D. Roosevelt Banska Bystrica, Uni. Hospital J.A. Reiman Presov
Time frame: within 1 hour of initiation of infusion to 24-48 hours after start of pixantrone infusion
Other Pre-specified
To Generate Individual Secondary PK Parameters (eg, Exposure, Half-life Etc.) Using Descriptive Statistics
To characterize the PK profile of pixantrone when co-administered with rituximab. Plasma samples for PK analysis will be collected relative to the D-1 dose of pixantrone in one of the 6 treatment cycles for each participating patient. The goal is to enroll approx. 20 patients, active at 20 sites- Beatson West of Scotland Cancer Center, Uni. Hospital Kralovske Vinohrady, Uni. Hospital Hradec Kralove Hematooncology, Hospital Nuernberg, St. Marien Hospital Hamm, Puerta del Mar Hospital, Tokuda Hospital Sofia, National Center of Hematology & Transfusiology, UMHAT SV. IVAN RILSKI, Moritz Kaposi General Hospital, Uni. of Debrecen, Polish Red Cross Marine Hospital, Kharkiv Regional Clinical Oncology Center, National Inst. of Cancer Ukraine, Cherkasy Regional Oncology Center, Inst. of Blood Pathology & Transfusion Medicine, Uni. Hospital Martin, National Onclogy Inst., Uni. Hospital with Outpatient Clinic F.D. Roosevelt Banska Bystrica, Uni. Hospital J.A. Reiman Presov
Time frame: within 1 hour of initiation of infusion to 24-48 hours after start of pixantrone infusion