Lymphoma, Large-Cell, Diffuse
Conditions
Keywords
The All Ireland Cooperative Oncology Research Group, GELTAMO, National Cancer Research Institute Lymphoma Clinical Studies Group, Genmab, ofatumumab, Japan Clinical Oncology Group, Oncology, Polish Lymphoma Research Group, Salvage chemotherapy, refractory, HOVON, DVD, relapsed, safety, efficacy, DHAP, rituximab, Autologous Stem Cell Transplant, Dutch-Belgian Cooperative Trial Group for Hematology-Oncology, Grupo Espanol de Linfomas, Nordic Lymphoma Group
Brief summary
This study is being conducted to compare the efficacy and safety of ofatumumab in addition to salvage chemotherapy versus rituximab in addition to salvage chemotherapy in CD20 positive DLBCL subjects relapsing, or with persistent disease, after first-line treatment with rituximab combined with an anthracycline-based chemotherapy regimen and be eligible for ASCT.
Detailed description
As rituximab-based regimens have become standard first-line treatment in CD20 positive DLBCL, the efficacy of rituximab combined with salvage chemotherapy in the second-line setting has decreased and there is a need for new therapies in patients progressing or relapsing after first-line rituximab-based therapy. Replacement of rituximab with ofatumumab in the second-line setting, following progression/relapse after first-line rituximab-containing regimens, offers the potential to overcome relative or complete rituximab resistance and thus improve response rates, the ability to proceed to consolidative HDT/ASCT, and overall survival.
Interventions
3 cycles of treatment will be administered. Each cycle will last 21 days. ofatumumab dose: cycle 1, day 1 - 1000 mg; cycle 1, day 8 - 1000 mg; cycle 2, day 1 and cycle 3, day 1 - 1000 mg. DHAP regimen: dexamethasone - 40 mg on days 1, 2, 3, and 4 of dosing cycle; cisplatin - 100 mg/m2/24hrs continuous on day 1 of dosing cycle; cytarabine - 2g/m2 q12 hrs (2 doses) on day 2 of dosing cycle.
DRUGRITUXIMAB + DHAP
3 cycles of treatment will be administered. Each cycle will last 21 days. rituximab dose: cycle 1, day 1 - 375 mg/m2; cycle 1, day 8 - 375 mg/m2; cycle 2, day 1 and cycle 3, day 1 - 375 mg/m2. DHAP regimen: dexamethasone - 40 mg on days 1, 2, 3, and 4 of dosing cycle; cisplatin - 100 mg/m2/24hrs continuous on day 1 of dosing cycle; cytarabine - 2g/m2 q12 hrs (2 doses) on day 2 of dosing cycle.
Sponsors
GlaxoSmithKline
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
* Subjects with CD20 positive DLBCL or grade 3b follicular lymphoma (FL) at original diagnosis. * Refractory to, or relapsed following, first-line treatment with rituximab combined with anthracycline- or anthracenedione-based chemotherapy as defined by the protocol. * CT with involvement of 2 or more clearly demarcated lesions/ nodes with a long axis \> 1.5 cm and short axis \>= 1.0cm or 1 clearly demarcated lesion/ node with a long axis \> 2.0 cm and short axis \>= 1.0 cm. * Baseline FDG-PET scans must demonstrate positive lesions compatible with CT defined anatomical tumor sites. * Age 18 yrs or older. * ECOG performance status of 0, 1 or 2. * Eligible for high dose chemotherapy and ASCT. * Resolution of toxicities from first-line therapy to a grade that in the opinion of the investigator does not contraindicate study participation. * Signed written informed consent.
Exclusion criteria
* Previous cancer therapy for lymphoma, with the exception of first-line rituximab/ anthracycline- or anthracenedione-based chemotherapy, monotherapy rituximab prior to or combined with first-line chemotherapy, as maintenance therapy, and radiotherapy in a limited field or as a part of the first-line treatment plan. * Any anti-cancer therapy, except limited field radiotherapy, within 2 weeks prior to start of study therapy. * Planned post-randomization chronic glucocorticoid use (limited acute use is allowed and defined by the protocol) unless administered as therapy for mild COPD or asthma. * Clinically significant cardiac disease, active or chronic infections, serious significant diseases, other cancer within last 5 years. History of significant cerebrovascular disease. * Prior treatment with anti-CD20 monoclonal antibodies with the exception of rituximab. * Abnormal/ inadequate WBC count, liver, and kidney function. * Pregnant or lactating women or female patients of child-bearing potential (or male patients with such partners) not willing to use adequate contraception during and up to 1 year following dosing completion.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival as Assessed by Independent Reviewers | From randomization until the date of stable disease after two cycles of salvage chemotherapy, progression, or death (assessed for up to 5 years) | Progression-free survival is defined as the interval of time from the randomization date until the date of stable disease (SD; failure to attain the criteria needed for a CR or PR and no fulfillment of the criteria for progressive disease \[PD\]) after two cycles of salvage chemotherapy, progression, or death, whichever occurs first. Disease progression was based on the assessments of independent reviewers for the disease under study. Disease progression was based on imaging data via the Revised Response Criteria for Malignant Lymphoma (RRCML). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Overall Response (OR) and Complete Response (CR) Three Months After Autologous Stem Cell Transplant | At 3 months after completion of autologous stem cell transplantation (ASCT) (assessed up to 6 months) | OR is defined as the number of participants achieving either a complete response (CR) or a partial response (PR). CR is defined as the complete disappearance of all detectable clinical evidence of disease and disease-related symptoms. PR is defined as at least a 50% decrease from Baseline in the sum of the product of the diameters of target lesions. RRCML was used to assess CR and PR. |
| Event-free Survival | From randomization to progressive disease, stable disease after completion of 2 cycles of therapy, commencement of a new treatment for DLBCL, or death due to any cause (assessed for up to 5 years) | Event-free survival is defined as the time from randomization to progressive disease (PD; disease whose course is growth, or spread of the disease), stable disease (SD; failure to attain the criteria needed for a CR or PR and no fulfillment of the criteria for PD) after completion of 2 cycles of therapy, commencement of a new treatment for diffuse large B cell lymphoma (DLBCL) (e.g., radiotherapy), or death from any cause, whichever occurs first. Disease progression was based on the assessments of independent reviewers for the disease under study. Disease progression was based on imaging data via the Revised Response Criteria for Malignant Lymphoma (RRCML). |
| Overall Survival (OS) | From randomization to death due to any cause (assessed for up to 5 years) | OS is defined as the time from randomization to death due to any cause. Participants who were still alive by the end of the study were censored. |
| Number of Participants With the Ability to Mobilize at Least 2 Million Cluster of Differentiation (CD)34+ Cells Per Kilogram From Peripheral Blood | During Cycles 2 and/or 3 (Weeks 4-9) | Stem cell mobilization is the process of stimulating the hematopoietic stem cells (CD34+) to move out of the bone marrow and into the bloodstream, where they can be collected via a process called apheresis. Successful mobilization is defined as the collection of \>2\*10\^6 CD34+ cells/kg. Only those participants, who commenced harvest, following the administration of rituximab or ofatumumab in combination with DHAP combination chemotherapy, were assessed. The number of participants with adequate harvest of CD34+ stem cells (at least 2\*10\^6 CD34+ cells/kg) after dosing of salvage therapy in Cycle 2 and Cycle 3 was analyzed. |
| Number of Participants With Overall Response (OR) and Complete Response (CR) After Salvage Chemoimmunotherapy | At completion of up to 3 cycles of salvage chemoimmunotherapy (assessed up to 9 weeks) | OR is defined as the number of participants achieving either a complete response (CR) or a partial response (PR). CR is defined as the complete disappearance of all detectable clinical evidence of disease and disease-related symptoms. PR is defined as at least a 50% decrease from Baseline in the sum of the product of the diameters of target lesions. RRCML was used to assess CR and PR. |
| Change From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) During Treatment | Baseline and the end of the treatment period (until approximately 4 to 6 weeks following Cycle 3 [assessed up to 3 months]) | The FACT-G was developed by the Functional Assessment of Chronic Illness Therapy (FACIT) group for use in adults in a wide range of oncology clinical trial populations. The 27 items of the FACT-G are scored in the following domains: Physical Well-being (7 items), Social/Family Wellbeing (7 items), Emotional Well-being (6 items), and Functional Well-being (7 items). Participants responded to the items on a five-point Likert scale ranging from 0, Not at all to 4, Very much. The total score ranges from 0 to 108; higher scores indicate a better patient-reported outcome/quality of life. Participants were asked to think back over the past week when responding to the items. |
| Change From Baseline in the Functional Assessment of Cancer Therapy Lymphoma Trial Outcome Index (FACT-Lym TOI) Total Score During Treatment | Baseline and the end of the treatment period (until approximately 4 to 6 weeks following Cycle 3 [assessed up to 3 months]) | The FACT-Lym TOI is a measure that combines the FACT-Lym subscale (15 items; responses to each item range from 0, Not at all to 4, Very much) with two domains taken from the FACT-G (responses to each item range from Not at all to Very much): Physical Well-being (7 items: lack of energy, nausea, meeting family needs, pain, side effects, feels ill, spends time in bed) and Functional Well-being (7 items: ability to work, work fulfilment, ability to enjoy life, illness acceptance, ability to sleep well, enjoying things done for fun, satisfaction with quality of life). This index is designed to be sensitive to changes in treatment regimens. The total FACT-Lym TOI score ranges from 0 to 116; higher scores indicate a better patient-reported outcome/quality of life. Participants were asked to think back over the past week when responding to the items. |
| Time to Neutrophil and Platelet Recovery After Each Cycle of Salvage Chemotherapy | From the start of each cycle for a maximum of 5 weeks per cycle (assessed during treatment period of Baseline up to approximately 3 months) | Neutrophil (absolute neutrophil count \[ANC\]) recovery is defined as ANC \>=0.5\*10\^9/Liter and increasing, and platelet (PLT) recovery is defined as PLT \>=10\*10\^9/Liter and increasing. For each cycle, time to ANC recovery is defined as the time from the first dose to the first ANC \>=0.5\*10\^9/Liter and increasing after the nadir in the cycle. For each cycle, time to PLT recovery is defined as the time from the first dose to the first PLT \>=10\*10\^9/L and increasing after the nadir in the cycle. |
| Time to Engraftment After High-dose Therapy (HDT)/ASCT | From ASCT up to 42 days post-ASCT (Baseline up to approximately 4.5 months) | Engraftment is defined as 1) three consecutive days when the ANC is ≥0.5x109/L and 2) an unsupported platelet count of ≥20x109/L, and the engraftment date is the date that this occurs. If engraftment was not achieved by Day 42 or the last observation, engraftment was deemed to be a failure, and censoring took place at Day 42 or at the last observation. |
| Number of Participants Completing Autologous Stem Cell Transplant (ASCT) | Approximately 4 to 6 weeks following Cycle 3 (assessed up to 3 months) | The number of participants who completed ASCT is reported. |
Countries
Argentina, Austria, Belgium, China, Czechia, Denmark, Estonia, Finland, Germany, Greece, Hungary, India, Ireland, Israel, Japan, Netherlands, Norway, Poland, Russia, Singapore, South Korea, Spain, Sweden, Thailand, United Kingdom, United States
Participant flow
Recruitment details
Participants who were refractory to, or had relapsed following, first-line treatment with rituximab in combination with an anthracycline- or anthracenedione-containing chemotherapy regimen, and who were eligible for autologous stem cell transplant (ASCT), were eligible for enrollment.
Pre-assignment details
Eligible participants were randomized to receive either rituximab or ofatumumab in addition to salvage chemotherapy.
Participants by arm
| Arm | Count |
|---|---|
| Rituximab + Chemotherapy Participants received 3 cycles (21 days per cycle) of rituximab combined with salvage chemotherapy (SC): either the DHAP regimen (3 cycles of dexamethasone, cytarabine, cisplatin \[DHAP\]) or the DVD regimen (DHAP-VIM \[etoposide, ifosfamide, mesna, methotrexate\]-DHAP). Rituximab (375 milligrams per meters squared \[mg/m\^2\]) was infused intravenously (IV) on Day (D) 1 (or up to 3 days prior to D1) and D8 (+/-2 days) of Cycle 1 of the SC, and then on D1 only of Cycles 2 and 3. The DHAP regimen (SC) contained: dexamethasone (40 mg/day) administered orally or IV on Days 1, 2, 3, or 4 of each cycle; cisplatin (100 mg/m\^2/day) as an IV continuous infusion on D1 of each cycle; and cytarabine 2 grams (g)/m\^2 over 3 hours every 12 hours (2 doses) for each infusion on D2 of each cycle. VIM: etoposide (90 mg/m\^2 IV on Days 1, 3, and 5), ifosfamide (1200 mg/m\^2 IV on Days 1, 2, 3, 4, and 5), mesna (10 or 20 mg/kilogram \[kg\] IV on Days 1, 2, 3, 4, and 5), methotrexate (30 mg/m\^2 IV on Days 1 and 5). | 223 |
| Ofatumumab + Chemotherapy Participants received 3 cycles (21 days per cycle) of ofatumumab combined with SC: either the DHAP regimen (three cycles of DHAP) or the DVD regimen (DHAP-VIM-DHAP). Ofatumumab (1000 mg/1000 milliliter \[mL\]) was infused IV on Day 1 (or up to 3 days prior to Day 1) and Day 8 (+/-2 days) of Cycle 1 of the SC, and then on Day 1 only of Cycles 2 and 3. The DHAP regimen (SC) contained: dexamethasone (40 mg/day) administered orally or IV on Days 1, 2, 3, or 4 of each cycle; cisplatin (100 mg/\[m\^2\]/day) as an IV continuous infusion on Day 1 of each cycle; and cytarabine 2 g/m\^2 over 3 hours every 12 hours (2 doses) for each infusion on Day 2 of each cycle. VIM: etoposide (90 mg/m\^2 IV on Days 1, 3, and 5), ifosfamide (1200 mg/m\^2 IV on Days 1, 2, 3, 4, and 5), mesna (10 or 20 mg/kg IV on Days 1, 2, 3, 4, and 5), methotrexate (30 mg/m\^2 IV on Days 1 and 5). | 222 |
| Total | 445 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Did Not Receive Study Drug | 2 | 0 |
| Overall Study | Lost to Follow-up | 2 | 5 |
| Overall Study | Participant Withdrew Consent | 12 | 12 |
| Overall Study | Study Closed/terminated | 78 | 83 |
Baseline characteristics
| Characteristic | Rituximab + Chemotherapy | Total | Ofatumumab + Chemotherapy |
|---|---|---|---|
| Age, Continuous | 53.4 Years STANDARD_DEVIATION 12.22 | 54.3 Years STANDARD_DEVIATION 11.55 | 55.2 Years STANDARD_DEVIATION 10.8 |
| Number of participants in the indicated categories per best response to first-line treatment Early relapsers/Refractory | 157 Participants | 316 Participants | 159 Participants |
| Number of participants in the indicated categories per best response to first-line treatment Late relapsers | 66 Participants | 129 Participants | 63 Participants |
| Number of participants with the indicated SaaIPI scores 0 or 1 | 136 Participants | 269 Participants | 133 Participants |
| Number of participants with the indicated SaaIPI scores 2 or 3 | 87 Participants | 176 Participants | 89 Participants |
| Race/Ethnicity, Customized African American/African Heritage | 4 Participants | 8 Participants | 4 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian - Central/South Asian Heritage | 3 Participants | 7 Participants | 4 Participants |
| Race/Ethnicity, Customized Asian - East Asian Heritage | 24 Participants | 55 Participants | 31 Participants |
| Race/Ethnicity, Customized Asian - Japanese Heritage | 19 Participants | 41 Participants | 22 Participants |
| Race/Ethnicity, Customized Asian - Mixed Race | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian - South East Asian Heritage | 4 Participants | 8 Participants | 4 Participants |
| Race/Ethnicity, Customized Missing | 0 Participants | 3 Participants | 3 Participants |
| Race/Ethnicity, Customized White - Arabic/North African Heritage | 1 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized White - White/Caucasian/European Heritage | 168 Participants | 319 Participants | 151 Participants |
| Sex: Female, Male Female | 88 Participants | 173 Participants | 85 Participants |
| Sex: Female, Male Male | 135 Participants | 272 Participants | 137 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 217 / 223 | 215 / 222 |
| serious Total, serious adverse events | 115 / 223 | 118 / 222 |
Outcome results
Primary
Progression-free Survival as Assessed by Independent Reviewers
Progression-free survival is defined as the interval of time from the randomization date until the date of stable disease (SD; failure to attain the criteria needed for a CR or PR and no fulfillment of the criteria for progressive disease \[PD\]) after two cycles of salvage chemotherapy, progression, or death, whichever occurs first. Disease progression was based on the assessments of independent reviewers for the disease under study. Disease progression was based on imaging data via the Revised Response Criteria for Malignant Lymphoma (RRCML).
Time frame: From randomization until the date of stable disease after two cycles of salvage chemotherapy, progression, or death (assessed for up to 5 years)
Population: Intent-to-Treat (ITT) Population: all participants who were randomized and commenced study therapy (at least one dose of a study drug)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rituximab + Chemotherapy | Progression-free Survival as Assessed by Independent Reviewers | 2.14 Months |
| Ofatumumab + Chemotherapy | Progression-free Survival as Assessed by Independent Reviewers | 1.81 Months |
p-value: 0.33395% CI: [0.89, 1.42]Stratified Log-rank test
Secondary
Change From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) During Treatment
The FACT-G was developed by the Functional Assessment of Chronic Illness Therapy (FACIT) group for use in adults in a wide range of oncology clinical trial populations. The 27 items of the FACT-G are scored in the following domains: Physical Well-being (7 items), Social/Family Wellbeing (7 items), Emotional Well-being (6 items), and Functional Well-being (7 items). Participants responded to the items on a five-point Likert scale ranging from 0, Not at all to 4, Very much. The total score ranges from 0 to 108; higher scores indicate a better patient-reported outcome/quality of life. Participants were asked to think back over the past week when responding to the items.
Time frame: Baseline and the end of the treatment period (until approximately 4 to 6 weeks following Cycle 3 [assessed up to 3 months])
Population: ITT Population. Only those participants who provided data were assessed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rituximab + Chemotherapy | Change From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) During Treatment | -2.561 scores on a scale | Standard Error 0.7671 |
| Ofatumumab + Chemotherapy | Change From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) During Treatment | -2.591 scores on a scale | Standard Error 0.7696 |
p-value: 0.97895% CI: [-2.11, 2.17]ANCOVA
Secondary
Change From Baseline in the Functional Assessment of Cancer Therapy Lymphoma Trial Outcome Index (FACT-Lym TOI) Total Score During Treatment
The FACT-Lym TOI is a measure that combines the FACT-Lym subscale (15 items; responses to each item range from 0, Not at all to 4, Very much) with two domains taken from the FACT-G (responses to each item range from Not at all to Very much): Physical Well-being (7 items: lack of energy, nausea, meeting family needs, pain, side effects, feels ill, spends time in bed) and Functional Well-being (7 items: ability to work, work fulfilment, ability to enjoy life, illness acceptance, ability to sleep well, enjoying things done for fun, satisfaction with quality of life). This index is designed to be sensitive to changes in treatment regimens. The total FACT-Lym TOI score ranges from 0 to 116; higher scores indicate a better patient-reported outcome/quality of life. Participants were asked to think back over the past week when responding to the items.
Time frame: Baseline and the end of the treatment period (until approximately 4 to 6 weeks following Cycle 3 [assessed up to 3 months])
Population: ITT Population. Only those participants who provided data were assessed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rituximab + Chemotherapy | Change From Baseline in the Functional Assessment of Cancer Therapy Lymphoma Trial Outcome Index (FACT-Lym TOI) Total Score During Treatment | -2.028 scores on a scale | Standard Error 0.9196 |
| Ofatumumab + Chemotherapy | Change From Baseline in the Functional Assessment of Cancer Therapy Lymphoma Trial Outcome Index (FACT-Lym TOI) Total Score During Treatment | -3.156 scores on a scale | Standard Error 0.9204 |
p-value: 0.38795% CI: [-1.434, 3.691]ANCOVA
Secondary
Event-free Survival
Event-free survival is defined as the time from randomization to progressive disease (PD; disease whose course is growth, or spread of the disease), stable disease (SD; failure to attain the criteria needed for a CR or PR and no fulfillment of the criteria for PD) after completion of 2 cycles of therapy, commencement of a new treatment for diffuse large B cell lymphoma (DLBCL) (e.g., radiotherapy), or death from any cause, whichever occurs first. Disease progression was based on the assessments of independent reviewers for the disease under study. Disease progression was based on imaging data via the Revised Response Criteria for Malignant Lymphoma (RRCML).
Time frame: From randomization to progressive disease, stable disease after completion of 2 cycles of therapy, commencement of a new treatment for DLBCL, or death due to any cause (assessed for up to 5 years)
Population: ITT Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rituximab + Chemotherapy | Event-free Survival | 1.84 Months |
| Ofatumumab + Chemotherapy | Event-free Survival | 1.74 Months |
p-value: 0.34695% CI: [0.9, 1.36]Stratified log-rank test
Secondary
Number of Participants Completing Autologous Stem Cell Transplant (ASCT)
The number of participants who completed ASCT is reported.
Time frame: Approximately 4 to 6 weeks following Cycle 3 (assessed up to 3 months)
Population: ITT Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rituximab + Chemotherapy | Number of Participants Completing Autologous Stem Cell Transplant (ASCT) | 83 Participants |
| Ofatumumab + Chemotherapy | Number of Participants Completing Autologous Stem Cell Transplant (ASCT) | 74 Participants |
p-value: 0.448195% CI: [0.56, 1.27]Cochran-Mantel-Haenszel
Secondary
Number of Participants With Overall Response (OR) and Complete Response (CR) After Salvage Chemoimmunotherapy
OR is defined as the number of participants achieving either a complete response (CR) or a partial response (PR). CR is defined as the complete disappearance of all detectable clinical evidence of disease and disease-related symptoms. PR is defined as at least a 50% decrease from Baseline in the sum of the product of the diameters of target lesions. RRCML was used to assess CR and PR.
Time frame: At completion of up to 3 cycles of salvage chemoimmunotherapy (assessed up to 9 weeks)
Population: ITT Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rituximab + Chemotherapy | Number of Participants With Overall Response (OR) and Complete Response (CR) After Salvage Chemoimmunotherapy | Independent reviewer-assessed OR | 94 Participants |
| Rituximab + Chemotherapy | Number of Participants With Overall Response (OR) and Complete Response (CR) After Salvage Chemoimmunotherapy | Independent reviewer-assessed CR | 48 Participants |
| Ofatumumab + Chemotherapy | Number of Participants With Overall Response (OR) and Complete Response (CR) After Salvage Chemoimmunotherapy | Independent reviewer-assessed OR | 84 Participants |
| Ofatumumab + Chemotherapy | Number of Participants With Overall Response (OR) and Complete Response (CR) After Salvage Chemoimmunotherapy | Independent reviewer-assessed CR | 34 Participants |
p-value: 0.405395% CI: [0.56, 1.24]Cochran-Mantel-Haenszel
p-value: 0.116795% CI: [0.39, 1.1]Cochran-Mantel-Haenszel
Secondary
Number of Participants With Overall Response (OR) and Complete Response (CR) Three Months After Autologous Stem Cell Transplant
OR is defined as the number of participants achieving either a complete response (CR) or a partial response (PR). CR is defined as the complete disappearance of all detectable clinical evidence of disease and disease-related symptoms. PR is defined as at least a 50% decrease from Baseline in the sum of the product of the diameters of target lesions. RRCML was used to assess CR and PR.
Time frame: At 3 months after completion of autologous stem cell transplantation (ASCT) (assessed up to 6 months)
Population: ITT Population. Only participants completing HDT/ASCT are included.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rituximab + Chemotherapy | Number of Participants With Overall Response (OR) and Complete Response (CR) Three Months After Autologous Stem Cell Transplant | Independent reviewer-assessed CR | 44 Participants |
| Rituximab + Chemotherapy | Number of Participants With Overall Response (OR) and Complete Response (CR) Three Months After Autologous Stem Cell Transplant | Independent reviewer-assessed OR | 57 Participants |
| Ofatumumab + Chemotherapy | Number of Participants With Overall Response (OR) and Complete Response (CR) Three Months After Autologous Stem Cell Transplant | Independent reviewer-assessed OR | 53 Participants |
| Ofatumumab + Chemotherapy | Number of Participants With Overall Response (OR) and Complete Response (CR) Three Months After Autologous Stem Cell Transplant | Independent reviewer-assessed CR | 43 Participants |
p-value: 0.820995% CI: [0.55, 2.43]Cochran-Mantel-Haenszel
p-value: 0.631395% CI: [0.62, 2.43]Cochran-Mantel-Haenszel
Secondary
Number of Participants With the Ability to Mobilize at Least 2 Million Cluster of Differentiation (CD)34+ Cells Per Kilogram From Peripheral Blood
Stem cell mobilization is the process of stimulating the hematopoietic stem cells (CD34+) to move out of the bone marrow and into the bloodstream, where they can be collected via a process called apheresis. Successful mobilization is defined as the collection of \>2\*10\^6 CD34+ cells/kg. Only those participants, who commenced harvest, following the administration of rituximab or ofatumumab in combination with DHAP combination chemotherapy, were assessed. The number of participants with adequate harvest of CD34+ stem cells (at least 2\*10\^6 CD34+ cells/kg) after dosing of salvage therapy in Cycle 2 and Cycle 3 was analyzed.
Time frame: During Cycles 2 and/or 3 (Weeks 4-9)
Population: ITT Population. Only participants commencing leukapheresis are included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rituximab + Chemotherapy | Number of Participants With the Ability to Mobilize at Least 2 Million Cluster of Differentiation (CD)34+ Cells Per Kilogram From Peripheral Blood | 121 Participants |
| Ofatumumab + Chemotherapy | Number of Participants With the Ability to Mobilize at Least 2 Million Cluster of Differentiation (CD)34+ Cells Per Kilogram From Peripheral Blood | 120 Participants |
p-value: 0.116195% CI: [0.83, 9.5]Cochran-Mantel-Haenszel
Secondary
Overall Survival (OS)
OS is defined as the time from randomization to death due to any cause. Participants who were still alive by the end of the study were censored.
Time frame: From randomization to death due to any cause (assessed for up to 5 years)
Population: ITT Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rituximab + Chemotherapy | Overall Survival (OS) | 13.17 Months |
| Ofatumumab + Chemotherapy | Overall Survival (OS) | 13.86 Months |
p-value: 0.37795% CI: [0.7, 1.15]Stratified log-rank test
Secondary
Time to Engraftment After High-dose Therapy (HDT)/ASCT
Engraftment is defined as 1) three consecutive days when the ANC is ≥0.5x109/L and 2) an unsupported platelet count of ≥20x109/L, and the engraftment date is the date that this occurs. If engraftment was not achieved by Day 42 or the last observation, engraftment was deemed to be a failure, and censoring took place at Day 42 or at the last observation.
Time frame: From ASCT up to 42 days post-ASCT (Baseline up to approximately 4.5 months)
Population: Safety population. Only participants completing HDT/ASCT are included.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rituximab + Chemotherapy | Time to Engraftment After High-dose Therapy (HDT)/ASCT | 24.0 Days |
| Ofatumumab + Chemotherapy | Time to Engraftment After High-dose Therapy (HDT)/ASCT | NA Days |
p-value: 0.03595% CI: [0.36, 1]Stratified Log-Rank
Secondary
Time to Neutrophil and Platelet Recovery After Each Cycle of Salvage Chemotherapy
Neutrophil (absolute neutrophil count \[ANC\]) recovery is defined as ANC \>=0.5\*10\^9/Liter and increasing, and platelet (PLT) recovery is defined as PLT \>=10\*10\^9/Liter and increasing. For each cycle, time to ANC recovery is defined as the time from the first dose to the first ANC \>=0.5\*10\^9/Liter and increasing after the nadir in the cycle. For each cycle, time to PLT recovery is defined as the time from the first dose to the first PLT \>=10\*10\^9/L and increasing after the nadir in the cycle.
Time frame: From the start of each cycle for a maximum of 5 weeks per cycle (assessed during treatment period of Baseline up to approximately 3 months)
Population: Safety Population. Only those participants available for analysis in the given cycle were assessed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Rituximab + Chemotherapy | Time to Neutrophil and Platelet Recovery After Each Cycle of Salvage Chemotherapy | Neutrophils, Cycle 1, n=223, 222 | 8.0 days |
| Rituximab + Chemotherapy | Time to Neutrophil and Platelet Recovery After Each Cycle of Salvage Chemotherapy | Neutrophils, Cycle 2, n=196, 199 | 8.0 days |
| Rituximab + Chemotherapy | Time to Neutrophil and Platelet Recovery After Each Cycle of Salvage Chemotherapy | Neutrophils, Cycle 3, n=137, 129 | 10.0 days |
| Rituximab + Chemotherapy | Time to Neutrophil and Platelet Recovery After Each Cycle of Salvage Chemotherapy | Platelets, Cycle 1, n=223, 222 | 13.0 days |
| Rituximab + Chemotherapy | Time to Neutrophil and Platelet Recovery After Each Cycle of Salvage Chemotherapy | Platelets, Cycle 2, n=196, 199 | 13.0 days |
| Rituximab + Chemotherapy | Time to Neutrophil and Platelet Recovery After Each Cycle of Salvage Chemotherapy | Platelets, Cycle 3, n=137, 129 | 13.0 days |
| Ofatumumab + Chemotherapy | Time to Neutrophil and Platelet Recovery After Each Cycle of Salvage Chemotherapy | Platelets, Cycle 2, n=196, 199 | 13.0 days |
| Ofatumumab + Chemotherapy | Time to Neutrophil and Platelet Recovery After Each Cycle of Salvage Chemotherapy | Neutrophils, Cycle 1, n=223, 222 | 11.0 days |
| Ofatumumab + Chemotherapy | Time to Neutrophil and Platelet Recovery After Each Cycle of Salvage Chemotherapy | Platelets, Cycle 1, n=223, 222 | 12.0 days |
| Ofatumumab + Chemotherapy | Time to Neutrophil and Platelet Recovery After Each Cycle of Salvage Chemotherapy | Neutrophils, Cycle 2, n=196, 199 | 11.0 days |
| Ofatumumab + Chemotherapy | Time to Neutrophil and Platelet Recovery After Each Cycle of Salvage Chemotherapy | Platelets, Cycle 3, n=137, 129 | 13.0 days |
| Ofatumumab + Chemotherapy | Time to Neutrophil and Platelet Recovery After Each Cycle of Salvage Chemotherapy | Neutrophils, Cycle 3, n=137, 129 | 7.0 days |
Comparison: Statistics are presented for Category-Neutrophils, Cycle 1. Confidence Interval (CI) estimated using the Brookmeyer-Crowley method. HR are estimated using the Pike estimator. A hazard ratio \<1 indicates a lower probability of recovery with Ofatumumab compared to Rituximab. HR was adjusted for stratification factors.p-value: 0.47995% CI: [0.74, 1.16]Stratified Log-Rank
Comparison: Statistics are presented for Category-Neutrophils, Cycle 2. Confidence Interval (CI) estimated using the Brookmeyer-Crowley method. HR are estimated using the Pike estimator. A hazard ratio \<1 indicates a lower probability of recovery with Ofatumumab compared to Rituximab. HR was adjusted for stratification factors.p-value: 0.05995% CI: [0.64, 1.02]Stratified Log-Rank
Comparison: Statistics are presented for Category-Neutrophils, Cycle 3. Confidence Interval (CI) estimated using the Brookmeyer-Crowley method. HR are estimated using the Pike estimator. A hazard ratio \<1 indicates a lower probability of recovery with Ofatumumab compared to Rituximab. HR was adjusted for stratification factors.p-value: 0.45195% CI: [0.83, 1.48]Stratified Log-Rank
Comparison: Statistics are presented for Category-Platelets, Cycle 1. Confidence Interval (CI) estimated using the Brookmeyer-Crowley method. HR are estimated using the Pike estimator. A hazard ratio \<1 indicates a lower probability of recovery with Ofatumumab compared to Rituximab. HR was adjusted for stratification factors.p-value: 0.59795% CI: [0.86, 1.29]Stratified Log-Rank
Comparison: Statistics are presented for Category-Platelets, Cycle 2. Confidence Interval (CI) estimated using the Brookmeyer-Crowley method. HR are estimated using the Pike estimator. A hazard ratio \<1 indicates a lower probability of recovery with Ofatumumab compared to Rituximab. HR was adjusted for stratification factors.p-value: 0.19995% CI: [0.7, 1.1]Stratified Log-Rank
Comparison: Statistics are presented for Category-Platelets, Cycle 3. Confidence Interval (CI) estimated using the Brookmeyer-Crowley method. HR are estimated using the Pike estimator. A hazard ratio \<1 indicates a lower probability of recovery with Ofatumumab compared to Rituximab. HR was adjusted for stratification factors.p-value: 0.10295% CI: [0.93, 1.59]Stratified Log-Rank