Lymphoma, Large-Cell, Diffuse
Conditions
Keywords
Salvage chemotherapy, relapsed, grade 3B follicular lymphoma, efficacy, safety, DHAP, ofatumumab, refractory, Non-Hodgkin's Lymphoma, Diffuse Large B Cell Lymphoma (DLBCL), Oncology, ICE, Transformed follicular lymphoma
Brief summary
The purpose of this study is to evaluate the safety and efficacy of ofatumumab used in combination with ifosfamide, carboplatin, etoposide (ICE) or dexamethasone, cytarabine, cisplatin (DHAP) salvage chemotherapy regimens in subjects with relapsed or refractory diffuse large B cell lymphoma (DLBCL) who are eligible for autologous stem cell transplant.
Detailed description
Rituximab combined with anthracycline based chemotherapy is the most common first-line treatment for subjects with diffuse large B cell lymphoma (DLBCL). Subjects requiring second-line therapy will most often receive rituximab in combination with salvage chemotherapy as an induction therapy prior to autologous stem cell transplant. With rituximab being in first-line therapy, the response rates for subjects receiving rituximab plus salvage chemotherapy has significantly decreased. Treatment with ofatumumab may be able to overcome the resistance to rituximab in the second-line setting and offer improved response rates. The objective of this study is to evaluate the overall response rate of ofatumumab in combination with ICE or DHAP chemotherapy prior to autologous stem cell transplant. Additional objectives are to evaluate the complete response rate, ability to mobilize cluster of differentiation (CD)34+ cells, progression-free survival (PFS) and overall survival.
Interventions
DRUGofatumumab + ICE
3 cycles of treatment will be administered. Each cycle will last 21 days. ofatumumab dose: cycle 1, day 1 - 1000 milligrams (mg); cycle 1, day 8 - 1000 mg; cycle 2, day 1 and cycle 3, day 1 - 1000 mg ICE regimen: ifosfamide + mesna - 5 grams (g)/meters squared (m\^2)/24 hours (hrs) continuous on day 2 of dosing cycle; carboplatin - AUC 5 (800 mg maximum) on day 2 of dosing cycle; etoposide - 100 mg/m\^2 on days 1, 2 and 3 of dosing cycle.
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/m\^2/24 hrs continuous on day 1 of dosing cycle; cytarabine - 2 g/m\^2 q12 hrs (2 doses) on day 2 of dosing cycle.
Sponsors
GlaxoSmithKline
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subjects with CD20 positive aggressive non-Hodgkin's lymphoma (NHL) including DLBCL, transformed follicular lymphoma (FL) & grade 3b FL. Refractory to, or relapsed following, first-line treatment with rituximab combined with anthracycline- or anthracenedione-based chemotherapy as defined by the protocol. * Computed tomography (CT) with involvement of 2 or more clearly demarcated lesions with a long axis \> 1.5 centimeters (cm) and short axis ≥ 1.0 cm or 1 clearly demarcated lesion with a long axis \>2.0 cm and short axis ≥1.0 cm. * Baseline \[18F\] fluorodeoxyglucose (FDG)-positron emission tomography (PET) scans must demonstrate positive lesions compatible with CT defined anatomical tumor sites. * Age 18 yrs or older. * Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2. * Eligible for high dose chemotherapy and autologous stem cell transplant (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 required rituximab/ anthracycline- or anthracenedione-based chemotherapy, monotherapy rituximab prior to first-line therapy and / or as a maintenance therapy, or limited field radiotherapy (as defined by the protocol). * Any anti-cancer therapy, except limited field radiotherapy, within 2 weeks prior to start of study therapy. * Chronic Glucocorticoid use (limited acute use is allowed and defined by the protocol). * History of significant cerebrovascular disease. * Abnormal/ inadequate white blood cell (WBC) count, liver, and kidney function. * Clinically significant cardiac disease, active or chronic infections, serious significant diseases, other cancer within last 5 years. * Known or suspected hypersensitivity to study treatments. * Prior treatment with anti-CD20 monoclonal antibodies, at any time, or treated with other monoclonal antibodies within 3 months prior to start of study therapy, with the exception of rituximab in both instances. * Inability to comply with the protocol activities. * 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 |
|---|---|---|
| Number of Participants With Overall Response (OR), as Assessed by the Investigator | From Day 14 (Study Day 56) to Day 21 (approximately Study Day 63) of treatment Cycle 3, or earlier in the case of early withdrawal or missing response assessment for Cycle 3 | Responders with OR included participants with complete response (CR) and partial response (PR). This was based on adequate responses from the investigator assessment after the completion of treatment. CR: complete disappearance of all detectable clinical evidence of disease and disease-related symptoms. PR: at least a 50% decrease from baseline in the sum of the product of the diameters of target lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With the Ability to Mobilize at Least 2 Million Cluster of Differentiation (CD)34+ Cells Per Kilogram (kg) From Peripheral Blood | During treatment Cycle 2 (Study Days 22-42) and/or Cycle 3 (Study Days 43-63) | CD34+ cells are a mixture of stem cells and white blood cells of various degrees of maturity. 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 was defined as the collection of \>2x10\^6 CD34+ cells/kg. Only those participants, who commenced mobilization, following the administration of ofatumumab in combination with either ICE or DHAP combination chemotherapy, were assessed. |
| Progression-free Survival (PFS) | From Day 14 (Study Day 56) to Day 21 (approximately Study Day 63) of treatment Cycle 3, or earlier in the case of early withdrawal or missing response assessment for Cycle 3 | PFS is defined as the interval of time between the date of treatment start and the earlier of the date of disease progression and the date of death due to any cause. Disease progression was based on the assessments locally by investigators for the disease under study. Disease progression was based on imaging data or clinical assessment data (if radiologic assessment data were not possible or assessment was not performed). |
| Overall Survival | From Day 14 (Study Day 56) to Day 21 (approximately Study Day 63) of treatment Cycle 3, or earlier in the case of early withdrawal or missing response assessment for Cycle 3 | Overall survival is defined as the interval of time between the date of treatment start and the date of death due to any cause. For participants who did not die, time of death was censored at the date of last contact. |
| Area Under the Concentration-time Curve From Time Zero to Infinity, AUC(0-inf), of Ofatumumab at the First Infusion (Cycle 1, Day 1) and the Last Infusion (Cycle 3) | Cycle 1 Day 1 (Study Day 1; up to 1 week) and Cycle 3 (Study Day 43; up to 6 weeks) | AUC is defined as the area under the ofatumumab (Ofa) concentration-time curve as a measure of drug exposure. AUC(0-inf) is AUC from the start of infusion extrapolated to infinite time. Results are reported by first dose group and combined, as appropriate. |
| Area Under the Concentration-time Curve During the Dosing Interval (AUC(0-tau)) of Ofatumumab at the Last Infusion (Cycle 3) | Cycle 3 (Study Day 43; 3 weeks) | AUC(0-tau) is the area under the plasma concentration-time curve from time zero (0) over the dosing interval, tau, and is a measure of drug exposure. Tau is 21 days (504 hours) in this study. |
| Clearance (CL) of Ofatumumab | Study Day 1 up to Study Day 85 (up to 12 weeks) | CL is the clearance of drug from plasma, which is defined as the volume of plasma from which drug is removed per unit time. |
| Maximum Plasma Concentration (Cmax) of Ofatumumab at the First Infusion (Cycle 1 Day 1), Second Infusion (Cycle 1 Day 8), and Last Infusion (Cycle 3) | Cycle 1 Day 1 (Study Day 1; up to 48 hours), Cycle 1 Day 8 (Study Day 8; up to 24 hours), Cycle 3 (Study Day 43; up to 48 hours) | Cmax is defined as the maximum concentration of drug in plasma samples for the dosing occasion. |
| Number of Participants With CR, as Assessed by the Investigator | From Day 14 (Study Day 56) to Day 21 (approximately Study Day 63) of treatment Cycle 3, or earlier in the case of early withdrawal or missing response assessment for Cycle 3 | CR is defined as the complete disappearance of all detectable clinical evidence of disease and disease-related symptoms. |
| Terminal Phase Half-life (t1/2) of Ofatumumab | Study Day 1 up to Study Day 85 (up to 12 weeks) | t1/2 is defined as terminal phase half-life, which is the time required for the amount of the drug in the body to decrease by half. |
| Volume of Distribution at Steady State (Vss) of Ofatumumab | Study Day 1 up to Study Day 85 (up to 12 weeks) | Vss is the apparent volume of distribution when plasma concentrations are measured under steady state conditions. At steady state, the plasma concentration-time profile of the drug is similar after each dose. |
| Number of Participants Who Were Positive and Negative for Human Anti-human Antibodies (HAHA) at the Indicated Time Points | Study Day 1 up to approximately Study Day 63 | Human anti-human antibodies (HAHA) indicate immune response to the administered human monoclonal antibody in a two-step assay. A positive screening result is confirmed in a second step. Negative Conclusive is subset of Negative and is a negative HAHA test result with an ofatumumab concentration \<200 µg/mL in a pharmacokinetic sample collected at the same time as the HAHA sample. Data are presented when a HAHA sample was collected. WD, withdrawal; FU, follow up. |
| Number of Participants With the Indicated Adverse Events (AEs) Associated With Neutropenia | Study Day 1 to approximately Study Day 63 | Neutropenia is defined as an abnormal decrease in the number of neutrophils (type of white blood cell in blood) in the blood. Febrile neutropenia is the development of fever in participants with neutropenia. Pancytopenia is defined as inadequate blood-cell formation by bone marrow, resulting in a lack of all blood-cell types. |
| Number of Participants With the Indicated AEs Associated With Decreased Hemoglobin Counts | Study Day 1 to approximately Study Day 63 | Anaemia is defined as a pathological deficiency in the oxygen-carrying component of the blood, measured in unit volume concentrations of hemoglobin, red blood-cell volume, or red blood-cell number. Pancytopenia is defined as inadequate blood-cell formation by bone marrow, resulting in a lack of all blood-cell types. |
| Number of Participants With the Indicated AEs Associated With Decreased Platelet Counts | Study Day 1 to approximately Study Day 63 | Thrombocytopenia is defined as an abnormal decrease in the number of platelets in circulatory blood. Pancytopenia is defined as inadequate blood-cell formation by bone marrow, resulting in a lack of all blood-cell types. |
| Trough Plasma Concentration (Ctrough) of Ofatumumab Prior to Second Infusion (Cycle 1 Day 8), Third Infusion (Cycle 2), and Last Infusion (Cycle 3) | Cycle 1 Day 8 (Study Day 8; up to 8 hours prior to infusion start), Cycle 2 (Study Day 22; up to 7 hours prior to infusion start), Cycle 3 (Study Day 43; up to 6 hours prior to infusion start) | Ctrough is defined as the trough plasma concentration, which is the measured concentration at the end of a dosing interval (taken directly before the start of the next infusion). |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ofatumumab + DHAP Participants received 3 cycles (21 days per each cycle) of ofatumumab combined with salvage chemotherapy. Ofatumumab (1000 milligrams \[mg\]) was intravenously (IV) infused on Day 1 (or up to 3 days prior to Day 1) and Day 8 (+/-2 days) of Cycle 1 of the salvage chemotherapy, and then on Day 1 only of Cycles 2 and 3. The DHAP (dexamethasone, cytarabine, cisplatin) regimen (salvage chemotherapy) contained: dexamethasone (40 mg/day) administered orally or IV on Days 1, 2, 3, or 4 of each cycle; cisplatin (100 mg/square meter \[m\^2\]/day) as an IV continuous infusion on Day 1 of each cycle; and cytarabine 2 gram (g)/m\^2 over 3 hours (hr) every 12 hr (2 doses) for each infusion on Day 2 of each cycle. | 26 |
| Ofatumumab + ICE Participants received 3 cycles (21 days per each cycle) of ofatumumab combined with salvage chemotherapy. Ofatumumab (1000 mg) was IV infused on Day 1 (or up to 3 days prior to Day 1) and Day 8 (+/-2 days) of Cycle 1 of the salvage chemotherapy, and then on Day 1 only of Cycles 2 and 3. The ICE (ifosfamide, carboplatin, etoposide) regimen (salvage chemotherapy) contained: etoposide (100 mg/m\^2/day) administered IV on Days 1, 2, and 3 of each cycle; carboplatin (up to 800 mg) on Day 2 of each cycle; and ifosfamide plus mesna, both at 5 g/m\^2/day as an IV continuous infusion on Day 2 of each cycle. | 35 |
| Total | 61 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 |
| Overall Study | Disease Progression | 4 | 4 |
| Overall Study | Physician Decision | 1 | 4 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Ofatumumab + DHAP | Ofatumumab + ICE | Total |
|---|---|---|---|
| Age Continuous | 49.7 Years STANDARD_DEVIATION 13.79 | 53.0 Years STANDARD_DEVIATION 13.02 | 51.6 Years STANDARD_DEVIATION 13.34 |
| Number of participants in the indicated categories per best response to first line treatment Early relapsers/Refractory | 22 participants | 27 participants | 49 participants |
| Number of participants in the indicated categories per best response to first line treatment Late relapsers | 4 participants | 8 participants | 12 participants |
| Number of participants with the indicated number of risk factors 0 or 1 | 13 participants | 19 participants | 32 participants |
| Number of participants with the indicated number of risk factors 2 or 3 | 13 participants | 16 participants | 29 participants |
| Race/Ethnicity, Customized African American/African Heritage | 2 participants | 2 participants | 4 participants |
| Race/Ethnicity, Customized Asian-Central/South Asian Heritage | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Asian-Japanese/East or South East Asian Heritage | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized White | 22 participants | 33 participants | 55 participants |
| Sex: Female, Male Female | 11 Participants | 15 Participants | 26 Participants |
| Sex: Female, Male Male | 15 Participants | 20 Participants | 35 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 26 / 26 | 35 / 35 | 61 / 61 |
| serious Total, serious adverse events | 17 / 26 | 7 / 35 | 24 / 61 |
Outcome results
Primary
Number of Participants With Overall Response (OR), as Assessed by the Investigator
Responders with OR included participants with complete response (CR) and partial response (PR). This was based on adequate responses from the investigator assessment after the completion of treatment. CR: complete disappearance of all detectable clinical evidence of disease and disease-related symptoms. PR: at least a 50% decrease from baseline in the sum of the product of the diameters of target lesions.
Time frame: From Day 14 (Study Day 56) to Day 21 (approximately Study Day 63) of treatment Cycle 3, or earlier in the case of early withdrawal or missing response assessment for Cycle 3
Population: Per protocol (PP) Population: all participants who received at least one dose of ofatumumab. Participants with major protocol deviations that could have impacted the efficacy outcome, and participants not exposed to ofatumumab or without CD20+ aggressive lymphoma were excluded from assessment. CD, cluster of differentiation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ofatumumab + DHAP | Number of Participants With Overall Response (OR), as Assessed by the Investigator | 18 participants |
| Ofatumumab + ICE | Number of Participants With Overall Response (OR), as Assessed by the Investigator | 18 participants |
| Total Ofatumumab + Chemotherapy | Number of Participants With Overall Response (OR), as Assessed by the Investigator | 36 participants |
95% CI: [48.2, 85.7]
95% CI: [36.4, 71.9]
95% CI: [47.4, 73.5]
Secondary
Area Under the Concentration-time Curve During the Dosing Interval (AUC(0-tau)) of Ofatumumab at the Last Infusion (Cycle 3)
AUC(0-tau) is the area under the plasma concentration-time curve from time zero (0) over the dosing interval, tau, and is a measure of drug exposure. Tau is 21 days (504 hours) in this study.
Time frame: Cycle 3 (Study Day 43; 3 weeks)
Population: Pharmacokinetic Population. Data for participants who switched chemotherapy regimen are not included in the summaries by chemotherapy after the switch but are included in the total summaries. Data are provided for the number of participants attending each visit. Results are reported by first dose group and combined, as appropriate.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Ofatumumab + DHAP | Area Under the Concentration-time Curve During the Dosing Interval (AUC(0-tau)) of Ofatumumab at the Last Infusion (Cycle 3) | Cycle 3, 1000 mg; n=14, 13, 30 | 112676 µg*hr/mL | Geometric Coefficient of Variation 0.22 |
| Ofatumumab + DHAP | Area Under the Concentration-time Curve During the Dosing Interval (AUC(0-tau)) of Ofatumumab at the Last Infusion (Cycle 3) | Cycle 3, 300 mg; n=4, 6, 10 | 95112 µg*hr/mL | Geometric Coefficient of Variation 0.09 |
| Ofatumumab + DHAP | Area Under the Concentration-time Curve During the Dosing Interval (AUC(0-tau)) of Ofatumumab at the Last Infusion (Cycle 3) | Cycle 3 both doses; n=18, 19, 40 | 108511 µg*hr/mL | Geometric Coefficient of Variation 0.21 |
| Ofatumumab + ICE | Area Under the Concentration-time Curve During the Dosing Interval (AUC(0-tau)) of Ofatumumab at the Last Infusion (Cycle 3) | Cycle 3, 1000 mg; n=14, 13, 30 | 95341 µg*hr/mL | Geometric Coefficient of Variation 0.15 |
| Ofatumumab + ICE | Area Under the Concentration-time Curve During the Dosing Interval (AUC(0-tau)) of Ofatumumab at the Last Infusion (Cycle 3) | Cycle 3, 300 mg; n=4, 6, 10 | 83385 µg*hr/mL | Geometric Coefficient of Variation 0.33 |
| Ofatumumab + ICE | Area Under the Concentration-time Curve During the Dosing Interval (AUC(0-tau)) of Ofatumumab at the Last Infusion (Cycle 3) | Cycle 3 both doses; n=18, 19, 40 | 91391 µg*hr/mL | Geometric Coefficient of Variation 0.22 |
| Total Ofatumumab + Chemotherapy | Area Under the Concentration-time Curve During the Dosing Interval (AUC(0-tau)) of Ofatumumab at the Last Infusion (Cycle 3) | Cycle 3, 300 mg; n=4, 6, 10 | 87891 µg*hr/mL | Geometric Coefficient of Variation 0.26 |
| Total Ofatumumab + Chemotherapy | Area Under the Concentration-time Curve During the Dosing Interval (AUC(0-tau)) of Ofatumumab at the Last Infusion (Cycle 3) | Cycle 3 both doses; n=18, 19, 40 | 98236 µg*hr/mL | Geometric Coefficient of Variation 0.23 |
| Total Ofatumumab + Chemotherapy | Area Under the Concentration-time Curve During the Dosing Interval (AUC(0-tau)) of Ofatumumab at the Last Infusion (Cycle 3) | Cycle 3, 1000 mg; n=14, 13, 30 | 101948 µg*hr/mL | Geometric Coefficient of Variation 0.21 |
Secondary
Area Under the Concentration-time Curve From Time Zero to Infinity, AUC(0-inf), of Ofatumumab at the First Infusion (Cycle 1, Day 1) and the Last Infusion (Cycle 3)
AUC is defined as the area under the ofatumumab (Ofa) concentration-time curve as a measure of drug exposure. AUC(0-inf) is AUC from the start of infusion extrapolated to infinite time. Results are reported by first dose group and combined, as appropriate.
Time frame: Cycle 1 Day 1 (Study Day 1; up to 1 week) and Cycle 3 (Study Day 43; up to 6 weeks)
Population: Pharmacokinetic Population: all participants (par.) exposed to ofatumumab from whom a pharmacokinetic sample was obtained and analyzed. Data for par. who switched chemotherapy regimen are not included in the summaries by chemotherapy after the switch but are included in the total summaries. Data are provided for the par. attending each visit.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Ofatumumab + DHAP | Area Under the Concentration-time Curve From Time Zero to Infinity, AUC(0-inf), of Ofatumumab at the First Infusion (Cycle 1, Day 1) and the Last Infusion (Cycle 3) | Cycle 3, 300 mg; n=4, 6, 10 | 222713 µg*hr/mL | Geometric Coefficient of Variation 0.23 |
| Ofatumumab + DHAP | Area Under the Concentration-time Curve From Time Zero to Infinity, AUC(0-inf), of Ofatumumab at the First Infusion (Cycle 1, Day 1) and the Last Infusion (Cycle 3) | Cycle 1 Day 1, 300 mg; n=4, 17, 21 | 34056 µg*hr/mL | Geometric Coefficient of Variation 0.14 |
| Ofatumumab + DHAP | Area Under the Concentration-time Curve From Time Zero to Infinity, AUC(0-inf), of Ofatumumab at the First Infusion (Cycle 1, Day 1) and the Last Infusion (Cycle 3) | Cycle 3, both doses; n=18, 19, 40 | 250070 µg*hr/mL | Geometric Coefficient of Variation 0.22 |
| Ofatumumab + DHAP | Area Under the Concentration-time Curve From Time Zero to Infinity, AUC(0-inf), of Ofatumumab at the First Infusion (Cycle 1, Day 1) and the Last Infusion (Cycle 3) | Cycle 1 Day 1, 1000 mg; n=22, 18, 40 | 115741 µg*hr/mL | Geometric Coefficient of Variation 0.16 |
| Ofatumumab + DHAP | Area Under the Concentration-time Curve From Time Zero to Infinity, AUC(0-inf), of Ofatumumab at the First Infusion (Cycle 1, Day 1) and the Last Infusion (Cycle 3) | Cycle 3, 1000 mg; n=14, 13, 30 | 258487 µg*hr/mL | Geometric Coefficient of Variation 0.21 |
| Ofatumumab + ICE | Area Under the Concentration-time Curve From Time Zero to Infinity, AUC(0-inf), of Ofatumumab at the First Infusion (Cycle 1, Day 1) and the Last Infusion (Cycle 3) | Cycle 1 Day 1, 1000 mg; n=22, 18, 40 | 105898 µg*hr/mL | Geometric Coefficient of Variation 0.14 |
| Ofatumumab + ICE | Area Under the Concentration-time Curve From Time Zero to Infinity, AUC(0-inf), of Ofatumumab at the First Infusion (Cycle 1, Day 1) and the Last Infusion (Cycle 3) | Cycle 3, 300 mg; n=4, 6, 10 | 206389 µg*hr/mL | Geometric Coefficient of Variation 0.06 |
| Ofatumumab + ICE | Area Under the Concentration-time Curve From Time Zero to Infinity, AUC(0-inf), of Ofatumumab at the First Infusion (Cycle 1, Day 1) and the Last Infusion (Cycle 3) | Cycle 3, 1000 mg; n=14, 13, 30 | 216885 µg*hr/mL | Geometric Coefficient of Variation 0.17 |
| Ofatumumab + ICE | Area Under the Concentration-time Curve From Time Zero to Infinity, AUC(0-inf), of Ofatumumab at the First Infusion (Cycle 1, Day 1) and the Last Infusion (Cycle 3) | Cycle 3, both doses; n=18, 19, 40 | 213514 µg*hr/mL | Geometric Coefficient of Variation 0.14 |
| Ofatumumab + ICE | Area Under the Concentration-time Curve From Time Zero to Infinity, AUC(0-inf), of Ofatumumab at the First Infusion (Cycle 1, Day 1) and the Last Infusion (Cycle 3) | Cycle 1 Day 1, 300 mg; n=4, 17, 21 | 33606 µg*hr/mL | Geometric Coefficient of Variation 0.15 |
| Total Ofatumumab + Chemotherapy | Area Under the Concentration-time Curve From Time Zero to Infinity, AUC(0-inf), of Ofatumumab at the First Infusion (Cycle 1, Day 1) and the Last Infusion (Cycle 3) | Cycle 3, 1000 mg; n=14, 13, 30 | 232310 µg*hr/mL | Geometric Coefficient of Variation 0.21 |
| Total Ofatumumab + Chemotherapy | Area Under the Concentration-time Curve From Time Zero to Infinity, AUC(0-inf), of Ofatumumab at the First Infusion (Cycle 1, Day 1) and the Last Infusion (Cycle 3) | Cycle 1 Day 1, 1000 mg; n=22, 18, 40 | 111203 µg*hr/mL | Geometric Coefficient of Variation 0.16 |
| Total Ofatumumab + Chemotherapy | Area Under the Concentration-time Curve From Time Zero to Infinity, AUC(0-inf), of Ofatumumab at the First Infusion (Cycle 1, Day 1) and the Last Infusion (Cycle 3) | Cycle 1 Day 1, 300 mg; n=4, 17, 21 | 33691 µg*hr/mL | Geometric Coefficient of Variation 0.14 |
| Total Ofatumumab + Chemotherapy | Area Under the Concentration-time Curve From Time Zero to Infinity, AUC(0-inf), of Ofatumumab at the First Infusion (Cycle 1, Day 1) and the Last Infusion (Cycle 3) | Cycle 3, 300 mg; n=4, 6, 10 | 212770 µg*hr/mL | Geometric Coefficient of Variation 0.14 |
| Total Ofatumumab + Chemotherapy | Area Under the Concentration-time Curve From Time Zero to Infinity, AUC(0-inf), of Ofatumumab at the First Infusion (Cycle 1, Day 1) and the Last Infusion (Cycle 3) | Cycle 3, both doses; n=18, 19, 40 | 227263 µg*hr/mL | Geometric Coefficient of Variation 0.2 |
Secondary
Clearance (CL) of Ofatumumab
CL is the clearance of drug from plasma, which is defined as the volume of plasma from which drug is removed per unit time.
Time frame: Study Day 1 up to Study Day 85 (up to 12 weeks)
Population: Pharmacokinetic Population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Ofatumumab + DHAP | Clearance (CL) of Ofatumumab | 8.7 mL/hr | Geometric Coefficient of Variation 0.15 |
| Ofatumumab + ICE | Clearance (CL) of Ofatumumab | 9.2 mL/hr | Geometric Coefficient of Variation 0.14 |
| Total Ofatumumab + Chemotherapy | Clearance (CL) of Ofatumumab | 9.0 mL/hr | Geometric Coefficient of Variation 0.15 |
Secondary
Maximum Plasma Concentration (Cmax) of Ofatumumab at the First Infusion (Cycle 1 Day 1), Second Infusion (Cycle 1 Day 8), and Last Infusion (Cycle 3)
Cmax is defined as the maximum concentration of drug in plasma samples for the dosing occasion.
Time frame: Cycle 1 Day 1 (Study Day 1; up to 48 hours), Cycle 1 Day 8 (Study Day 8; up to 24 hours), Cycle 3 (Study Day 43; up to 48 hours)
Population: Pharmacokinetic Population. Data for participants who switched chemotherapy regimen are not included in the summaries by chemotherapy after the switch but are included in the total summaries. Data are provided for the number of participants attending each visit. Results are reported by first dose group and combined, as appropriate.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Ofatumumab + DHAP | Maximum Plasma Concentration (Cmax) of Ofatumumab at the First Infusion (Cycle 1 Day 1), Second Infusion (Cycle 1 Day 8), and Last Infusion (Cycle 3) | Cycle 1 Day 1, 1000 mg; n=22, 18, 40 | 323 µg/mL | Geometric Coefficient of Variation 0.4 |
| Ofatumumab + DHAP | Maximum Plasma Concentration (Cmax) of Ofatumumab at the First Infusion (Cycle 1 Day 1), Second Infusion (Cycle 1 Day 8), and Last Infusion (Cycle 3) | Cycle 3, 300 mg; n=4, 11, 15 | 416 µg/mL | Geometric Coefficient of Variation 0.24 |
| Ofatumumab + DHAP | Maximum Plasma Concentration (Cmax) of Ofatumumab at the First Infusion (Cycle 1 Day 1), Second Infusion (Cycle 1 Day 8), and Last Infusion (Cycle 3) | Cycle 1 Day 8, 1000 mg; n=21, 18, 39 | 431 µg/mL | Geometric Coefficient of Variation 0.23 |
| Ofatumumab + DHAP | Maximum Plasma Concentration (Cmax) of Ofatumumab at the First Infusion (Cycle 1 Day 1), Second Infusion (Cycle 1 Day 8), and Last Infusion (Cycle 3) | Cycle 1 Day 1, 300 mg; n=4, 17, 21 | 89.8 µg/mL | Geometric Coefficient of Variation 0.08 |
| Ofatumumab + DHAP | Maximum Plasma Concentration (Cmax) of Ofatumumab at the First Infusion (Cycle 1 Day 1), Second Infusion (Cycle 1 Day 8), and Last Infusion (Cycle 3) | Cycle 3, both doses; n=18, 25, 48 | 455 µg/mL | Geometric Coefficient of Variation 0.29 |
| Ofatumumab + DHAP | Maximum Plasma Concentration (Cmax) of Ofatumumab at the First Infusion (Cycle 1 Day 1), Second Infusion (Cycle 1 Day 8), and Last Infusion (Cycle 3) | Cycle 3, 1000 mg; n=14, 14, 33 | 466 µg/mL | Geometric Coefficient of Variation 0.31 |
| Ofatumumab + DHAP | Maximum Plasma Concentration (Cmax) of Ofatumumab at the First Infusion (Cycle 1 Day 1), Second Infusion (Cycle 1 Day 8), and Last Infusion (Cycle 3) | Cycle 1 Day 8, 300 mg; n=4, 13, 17 | 245 µg/mL | Geometric Coefficient of Variation 0.1 |
| Ofatumumab + ICE | Maximum Plasma Concentration (Cmax) of Ofatumumab at the First Infusion (Cycle 1 Day 1), Second Infusion (Cycle 1 Day 8), and Last Infusion (Cycle 3) | Cycle 1 Day 8, 1000 mg; n=21, 18, 39 | 368 µg/mL | Geometric Coefficient of Variation 0.21 |
| Ofatumumab + ICE | Maximum Plasma Concentration (Cmax) of Ofatumumab at the First Infusion (Cycle 1 Day 1), Second Infusion (Cycle 1 Day 8), and Last Infusion (Cycle 3) | Cycle 1 Day 1, 300 mg; n=4, 17, 21 | 80.0 µg/mL | Geometric Coefficient of Variation 0.63 |
| Ofatumumab + ICE | Maximum Plasma Concentration (Cmax) of Ofatumumab at the First Infusion (Cycle 1 Day 1), Second Infusion (Cycle 1 Day 8), and Last Infusion (Cycle 3) | Cycle 1 Day 1, 1000 mg; n=22, 18, 40 | 268 µg/mL | Geometric Coefficient of Variation 0.3 |
| Ofatumumab + ICE | Maximum Plasma Concentration (Cmax) of Ofatumumab at the First Infusion (Cycle 1 Day 1), Second Infusion (Cycle 1 Day 8), and Last Infusion (Cycle 3) | Cycle 1 Day 8, 300 mg; n=4, 13, 17 | 273 µg/mL | Geometric Coefficient of Variation 0.28 |
| Ofatumumab + ICE | Maximum Plasma Concentration (Cmax) of Ofatumumab at the First Infusion (Cycle 1 Day 1), Second Infusion (Cycle 1 Day 8), and Last Infusion (Cycle 3) | Cycle 3, 300 mg; n=4, 11, 15 | 417 µg/mL | Geometric Coefficient of Variation 0.26 |
| Ofatumumab + ICE | Maximum Plasma Concentration (Cmax) of Ofatumumab at the First Infusion (Cycle 1 Day 1), Second Infusion (Cycle 1 Day 8), and Last Infusion (Cycle 3) | Cycle 3, 1000 mg; n=14, 14, 33 | 397 µg/mL | Geometric Coefficient of Variation 0.18 |
| Ofatumumab + ICE | Maximum Plasma Concentration (Cmax) of Ofatumumab at the First Infusion (Cycle 1 Day 1), Second Infusion (Cycle 1 Day 8), and Last Infusion (Cycle 3) | Cycle 3, both doses; n=18, 25, 48 | 406 µg/mL | Geometric Coefficient of Variation 0.21 |
| Total Ofatumumab + Chemotherapy | Maximum Plasma Concentration (Cmax) of Ofatumumab at the First Infusion (Cycle 1 Day 1), Second Infusion (Cycle 1 Day 8), and Last Infusion (Cycle 3) | Cycle 3, 300 mg; n=4, 11, 15 | 417 µg/mL | Geometric Coefficient of Variation 0.24 |
| Total Ofatumumab + Chemotherapy | Maximum Plasma Concentration (Cmax) of Ofatumumab at the First Infusion (Cycle 1 Day 1), Second Infusion (Cycle 1 Day 8), and Last Infusion (Cycle 3) | Cycle 1 Day 1, 1000 mg; n=22, 18, 40 | 297 µg/mL | Geometric Coefficient of Variation 0.37 |
| Total Ofatumumab + Chemotherapy | Maximum Plasma Concentration (Cmax) of Ofatumumab at the First Infusion (Cycle 1 Day 1), Second Infusion (Cycle 1 Day 8), and Last Infusion (Cycle 3) | Cycle 3, both doses; n=18, 25, 48 | 420 µg/mL | Geometric Coefficient of Variation 0.25 |
| Total Ofatumumab + Chemotherapy | Maximum Plasma Concentration (Cmax) of Ofatumumab at the First Infusion (Cycle 1 Day 1), Second Infusion (Cycle 1 Day 8), and Last Infusion (Cycle 3) | Cycle 3, 1000 mg; n=14, 14, 33 | 421 µg/mL | Geometric Coefficient of Variation 0.25 |
| Total Ofatumumab + Chemotherapy | Maximum Plasma Concentration (Cmax) of Ofatumumab at the First Infusion (Cycle 1 Day 1), Second Infusion (Cycle 1 Day 8), and Last Infusion (Cycle 3) | Cycle 1 Day 8, 1000 mg; n=21, 18, 39 | 401 µg/mL | Geometric Coefficient of Variation 0.23 |
| Total Ofatumumab + Chemotherapy | Maximum Plasma Concentration (Cmax) of Ofatumumab at the First Infusion (Cycle 1 Day 1), Second Infusion (Cycle 1 Day 8), and Last Infusion (Cycle 3) | Cycle 1 Day 8, 300 mg; n=4, 13, 17 | 266 µg/mL | Geometric Coefficient of Variation 0.25 |
| Total Ofatumumab + Chemotherapy | Maximum Plasma Concentration (Cmax) of Ofatumumab at the First Infusion (Cycle 1 Day 1), Second Infusion (Cycle 1 Day 8), and Last Infusion (Cycle 3) | Cycle 1 Day 1, 300 mg; n=4, 17, 21 | 81.8 µg/mL | Geometric Coefficient of Variation 0.56 |
Secondary
Number of Participants Who Were Positive and Negative for Human Anti-human Antibodies (HAHA) at the Indicated Time Points
Human anti-human antibodies (HAHA) indicate immune response to the administered human monoclonal antibody in a two-step assay. A positive screening result is confirmed in a second step. Negative Conclusive is subset of Negative and is a negative HAHA test result with an ofatumumab concentration \<200 µg/mL in a pharmacokinetic sample collected at the same time as the HAHA sample. Data are presented when a HAHA sample was collected. WD, withdrawal; FU, follow up.
Time frame: Study Day 1 up to approximately Study Day 63
Population: Safety Population. Data are presented for those participants who contributed a sample.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ofatumumab + DHAP | Number of Participants Who Were Positive and Negative for Human Anti-human Antibodies (HAHA) at the Indicated Time Points | Negative at Early WD or FU; n=24, 30, 54 | 24 participants |
| Ofatumumab + DHAP | Number of Participants Who Were Positive and Negative for Human Anti-human Antibodies (HAHA) at the Indicated Time Points | Positive at Early WD or FU; n=24, 30, 54 | 0 participants |
| Ofatumumab + DHAP | Number of Participants Who Were Positive and Negative for Human Anti-human Antibodies (HAHA) at the Indicated Time Points | Negative conclusive at Early WD or FU; n=24, 30, 5 | 18 participants |
| Ofatumumab + DHAP | Number of Participants Who Were Positive and Negative for Human Anti-human Antibodies (HAHA) at the Indicated Time Points | Negative at Day 1; n=26, 35, 61 | 26 participants |
| Ofatumumab + DHAP | Number of Participants Who Were Positive and Negative for Human Anti-human Antibodies (HAHA) at the Indicated Time Points | Positive at Day 1; n=26, 35, 61 | 0 participants |
| Ofatumumab + ICE | Number of Participants Who Were Positive and Negative for Human Anti-human Antibodies (HAHA) at the Indicated Time Points | Positive at Day 1; n=26, 35, 61 | 0 participants |
| Ofatumumab + ICE | Number of Participants Who Were Positive and Negative for Human Anti-human Antibodies (HAHA) at the Indicated Time Points | Negative at Day 1; n=26, 35, 61 | 35 participants |
| Ofatumumab + ICE | Number of Participants Who Were Positive and Negative for Human Anti-human Antibodies (HAHA) at the Indicated Time Points | Positive at Early WD or FU; n=24, 30, 54 | 0 participants |
| Ofatumumab + ICE | Number of Participants Who Were Positive and Negative for Human Anti-human Antibodies (HAHA) at the Indicated Time Points | Negative at Early WD or FU; n=24, 30, 54 | 30 participants |
| Ofatumumab + ICE | Number of Participants Who Were Positive and Negative for Human Anti-human Antibodies (HAHA) at the Indicated Time Points | Negative conclusive at Early WD or FU; n=24, 30, 5 | 28 participants |
| Total Ofatumumab + Chemotherapy | Number of Participants Who Were Positive and Negative for Human Anti-human Antibodies (HAHA) at the Indicated Time Points | Negative conclusive at Early WD or FU; n=24, 30, 5 | 46 participants |
| Total Ofatumumab + Chemotherapy | Number of Participants Who Were Positive and Negative for Human Anti-human Antibodies (HAHA) at the Indicated Time Points | Negative at Early WD or FU; n=24, 30, 54 | 54 participants |
| Total Ofatumumab + Chemotherapy | Number of Participants Who Were Positive and Negative for Human Anti-human Antibodies (HAHA) at the Indicated Time Points | Positive at Day 1; n=26, 35, 61 | 0 participants |
| Total Ofatumumab + Chemotherapy | Number of Participants Who Were Positive and Negative for Human Anti-human Antibodies (HAHA) at the Indicated Time Points | Positive at Early WD or FU; n=24, 30, 54 | 0 participants |
| Total Ofatumumab + Chemotherapy | Number of Participants Who Were Positive and Negative for Human Anti-human Antibodies (HAHA) at the Indicated Time Points | Negative at Day 1; n=26, 35, 61 | 61 participants |
Secondary
Number of Participants With CR, as Assessed by the Investigator
CR is defined as the complete disappearance of all detectable clinical evidence of disease and disease-related symptoms.
Time frame: From Day 14 (Study Day 56) to Day 21 (approximately Study Day 63) of treatment Cycle 3, or earlier in the case of early withdrawal or missing response assessment for Cycle 3
Population: PP Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ofatumumab + DHAP | Number of Participants With CR, as Assessed by the Investigator | 11 participants |
| Ofatumumab + ICE | Number of Participants With CR, as Assessed by the Investigator | 11 participants |
| Total Ofatumumab + Chemotherapy | Number of Participants With CR, as Assessed by the Investigator | 22 participants |
Secondary
Number of Participants With the Ability to Mobilize at Least 2 Million Cluster of Differentiation (CD)34+ Cells Per Kilogram (kg) From Peripheral Blood
CD34+ cells are a mixture of stem cells and white blood cells of various degrees of maturity. 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 was defined as the collection of \>2x10\^6 CD34+ cells/kg. Only those participants, who commenced mobilization, following the administration of ofatumumab in combination with either ICE or DHAP combination chemotherapy, were assessed.
Time frame: During treatment Cycle 2 (Study Days 22-42) and/or Cycle 3 (Study Days 43-63)
Population: Stem Cell Mobilization Population. All participants in the PP Population in whom stem cell mobilization was attempted and CD34+ cell data are available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ofatumumab + DHAP | Number of Participants With the Ability to Mobilize at Least 2 Million Cluster of Differentiation (CD)34+ Cells Per Kilogram (kg) From Peripheral Blood | 23 participants |
| Ofatumumab + ICE | Number of Participants With the Ability to Mobilize at Least 2 Million Cluster of Differentiation (CD)34+ Cells Per Kilogram (kg) From Peripheral Blood | 20 participants |
| Total Ofatumumab + Chemotherapy | Number of Participants With the Ability to Mobilize at Least 2 Million Cluster of Differentiation (CD)34+ Cells Per Kilogram (kg) From Peripheral Blood | 43 participants |
Secondary
Number of Participants With the Indicated Adverse Events (AEs) Associated With Neutropenia
Neutropenia is defined as an abnormal decrease in the number of neutrophils (type of white blood cell in blood) in the blood. Febrile neutropenia is the development of fever in participants with neutropenia. Pancytopenia is defined as inadequate blood-cell formation by bone marrow, resulting in a lack of all blood-cell types.
Time frame: Study Day 1 to approximately Study Day 63
Population: Safety Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ofatumumab + DHAP | Number of Participants With the Indicated Adverse Events (AEs) Associated With Neutropenia | Any Event of Decreased Neutrophils; n=26, 35, 61 | 12 participants |
| Ofatumumab + DHAP | Number of Participants With the Indicated Adverse Events (AEs) Associated With Neutropenia | Neutropenia; n=12, 11, 23 | 7 participants |
| Ofatumumab + DHAP | Number of Participants With the Indicated Adverse Events (AEs) Associated With Neutropenia | Febrile Neutropenia; n=12, 11, 23 | 8 participants |
| Ofatumumab + DHAP | Number of Participants With the Indicated Adverse Events (AEs) Associated With Neutropenia | Pancytopenia; n=12, 11, 23 | 1 participants |
| Ofatumumab + ICE | Number of Participants With the Indicated Adverse Events (AEs) Associated With Neutropenia | Pancytopenia; n=12, 11, 23 | 0 participants |
| Ofatumumab + ICE | Number of Participants With the Indicated Adverse Events (AEs) Associated With Neutropenia | Any Event of Decreased Neutrophils; n=26, 35, 61 | 11 participants |
| Ofatumumab + ICE | Number of Participants With the Indicated Adverse Events (AEs) Associated With Neutropenia | Febrile Neutropenia; n=12, 11, 23 | 1 participants |
| Ofatumumab + ICE | Number of Participants With the Indicated Adverse Events (AEs) Associated With Neutropenia | Neutropenia; n=12, 11, 23 | 11 participants |
| Total Ofatumumab + Chemotherapy | Number of Participants With the Indicated Adverse Events (AEs) Associated With Neutropenia | Pancytopenia; n=12, 11, 23 | 1 participants |
| Total Ofatumumab + Chemotherapy | Number of Participants With the Indicated Adverse Events (AEs) Associated With Neutropenia | Neutropenia; n=12, 11, 23 | 18 participants |
| Total Ofatumumab + Chemotherapy | Number of Participants With the Indicated Adverse Events (AEs) Associated With Neutropenia | Febrile Neutropenia; n=12, 11, 23 | 9 participants |
| Total Ofatumumab + Chemotherapy | Number of Participants With the Indicated Adverse Events (AEs) Associated With Neutropenia | Any Event of Decreased Neutrophils; n=26, 35, 61 | 23 participants |
Secondary
Number of Participants With the Indicated AEs Associated With Decreased Hemoglobin Counts
Anaemia is defined as a pathological deficiency in the oxygen-carrying component of the blood, measured in unit volume concentrations of hemoglobin, red blood-cell volume, or red blood-cell number. Pancytopenia is defined as inadequate blood-cell formation by bone marrow, resulting in a lack of all blood-cell types.
Time frame: Study Day 1 to approximately Study Day 63
Population: Safety Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ofatumumab + DHAP | Number of Participants With the Indicated AEs Associated With Decreased Hemoglobin Counts | Any Event of Decreased Hemoglobin; n=26, 35, 61 | 16 participants |
| Ofatumumab + DHAP | Number of Participants With the Indicated AEs Associated With Decreased Hemoglobin Counts | Pancytopenia; n=16, 18, 34 | 1 participants |
| Ofatumumab + DHAP | Number of Participants With the Indicated AEs Associated With Decreased Hemoglobin Counts | Haemoglobin Decreased; n=16, 18, 34 | 3 participants |
| Ofatumumab + DHAP | Number of Participants With the Indicated AEs Associated With Decreased Hemoglobin Counts | Anaemia; n=16, 18, 34 | 14 participants |
| Ofatumumab + ICE | Number of Participants With the Indicated AEs Associated With Decreased Hemoglobin Counts | Haemoglobin Decreased; n=16, 18, 34 | 2 participants |
| Ofatumumab + ICE | Number of Participants With the Indicated AEs Associated With Decreased Hemoglobin Counts | Anaemia; n=16, 18, 34 | 16 participants |
| Ofatumumab + ICE | Number of Participants With the Indicated AEs Associated With Decreased Hemoglobin Counts | Pancytopenia; n=16, 18, 34 | 0 participants |
| Ofatumumab + ICE | Number of Participants With the Indicated AEs Associated With Decreased Hemoglobin Counts | Any Event of Decreased Hemoglobin; n=26, 35, 61 | 18 participants |
| Total Ofatumumab + Chemotherapy | Number of Participants With the Indicated AEs Associated With Decreased Hemoglobin Counts | Pancytopenia; n=16, 18, 34 | 1 participants |
| Total Ofatumumab + Chemotherapy | Number of Participants With the Indicated AEs Associated With Decreased Hemoglobin Counts | Any Event of Decreased Hemoglobin; n=26, 35, 61 | 34 participants |
| Total Ofatumumab + Chemotherapy | Number of Participants With the Indicated AEs Associated With Decreased Hemoglobin Counts | Anaemia; n=16, 18, 34 | 30 participants |
| Total Ofatumumab + Chemotherapy | Number of Participants With the Indicated AEs Associated With Decreased Hemoglobin Counts | Haemoglobin Decreased; n=16, 18, 34 | 5 participants |
Secondary
Number of Participants With the Indicated AEs Associated With Decreased Platelet Counts
Thrombocytopenia is defined as an abnormal decrease in the number of platelets in circulatory blood. Pancytopenia is defined as inadequate blood-cell formation by bone marrow, resulting in a lack of all blood-cell types.
Time frame: Study Day 1 to approximately Study Day 63
Population: Safety Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ofatumumab + DHAP | Number of Participants With the Indicated AEs Associated With Decreased Platelet Counts | Thrombocytopenia; n=21, 19, 40 | 20 participants |
| Ofatumumab + DHAP | Number of Participants With the Indicated AEs Associated With Decreased Platelet Counts | Any Event of Decreased Platelets; n=26, 35, 61 | 21 participants |
| Ofatumumab + DHAP | Number of Participants With the Indicated AEs Associated With Decreased Platelet Counts | Pancytopenia; n=21, 19, 40 | 1 participants |
| Ofatumumab + ICE | Number of Participants With the Indicated AEs Associated With Decreased Platelet Counts | Thrombocytopenia; n=21, 19, 40 | 19 participants |
| Ofatumumab + ICE | Number of Participants With the Indicated AEs Associated With Decreased Platelet Counts | Any Event of Decreased Platelets; n=26, 35, 61 | 19 participants |
| Ofatumumab + ICE | Number of Participants With the Indicated AEs Associated With Decreased Platelet Counts | Pancytopenia; n=21, 19, 40 | 0 participants |
| Total Ofatumumab + Chemotherapy | Number of Participants With the Indicated AEs Associated With Decreased Platelet Counts | Any Event of Decreased Platelets; n=26, 35, 61 | 40 participants |
| Total Ofatumumab + Chemotherapy | Number of Participants With the Indicated AEs Associated With Decreased Platelet Counts | Pancytopenia; n=21, 19, 40 | 1 participants |
| Total Ofatumumab + Chemotherapy | Number of Participants With the Indicated AEs Associated With Decreased Platelet Counts | Thrombocytopenia; n=21, 19, 40 | 39 participants |
Secondary
Overall Survival
Overall survival is defined as the interval of time between the date of treatment start and the date of death due to any cause. For participants who did not die, time of death was censored at the date of last contact.
Time frame: From Day 14 (Study Day 56) to Day 21 (approximately Study Day 63) of treatment Cycle 3, or earlier in the case of early withdrawal or missing response assessment for Cycle 3
Population: PP Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ofatumumab + DHAP | Overall Survival | 433.0 days |
| Ofatumumab + ICE | Overall Survival | NA days |
| Total Ofatumumab + Chemotherapy | Overall Survival | 508.0 days |
Secondary
Progression-free Survival (PFS)
PFS is defined as the interval of time between the date of treatment start and the earlier of the date of disease progression and the date of death due to any cause. Disease progression was based on the assessments locally by investigators for the disease under study. Disease progression was based on imaging data or clinical assessment data (if radiologic assessment data were not possible or assessment was not performed).
Time frame: From Day 14 (Study Day 56) to Day 21 (approximately Study Day 63) of treatment Cycle 3, or earlier in the case of early withdrawal or missing response assessment for Cycle 3
Population: PP Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ofatumumab + DHAP | Progression-free Survival (PFS) | 301.0 days |
| Ofatumumab + ICE | Progression-free Survival (PFS) | 288.0 days |
| Total Ofatumumab + Chemotherapy | Progression-free Survival (PFS) | 288.0 days |
Secondary
Terminal Phase Half-life (t1/2) of Ofatumumab
t1/2 is defined as terminal phase half-life, which is the time required for the amount of the drug in the body to decrease by half.
Time frame: Study Day 1 up to Study Day 85 (up to 12 weeks)
Population: Pharmacokinetic Population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Ofatumumab + DHAP | Terminal Phase Half-life (t1/2) of Ofatumumab | 595 hr | Geometric Coefficient of Variation 0.35 |
| Ofatumumab + ICE | Terminal Phase Half-life (t1/2) of Ofatumumab | 646 hr | Geometric Coefficient of Variation 0.47 |
| Total Ofatumumab + Chemotherapy | Terminal Phase Half-life (t1/2) of Ofatumumab | 624 hr | Geometric Coefficient of Variation 0.42 |
Secondary
Trough Plasma Concentration (Ctrough) of Ofatumumab Prior to Second Infusion (Cycle 1 Day 8), Third Infusion (Cycle 2), and Last Infusion (Cycle 3)
Ctrough is defined as the trough plasma concentration, which is the measured concentration at the end of a dosing interval (taken directly before the start of the next infusion).
Time frame: Cycle 1 Day 8 (Study Day 8; up to 8 hours prior to infusion start), Cycle 2 (Study Day 22; up to 7 hours prior to infusion start), Cycle 3 (Study Day 43; up to 6 hours prior to infusion start)
Population: Pharmacokinetic Population. Data for participants who switched chemotherapy regimen are not included in the summaries by chemotherapy after the switch but are included in the total summaries. Data are provided for the number of participants attending each visit. Results are reported by first dose group and combined, as appropriate.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Ofatumumab + DHAP | Trough Plasma Concentration (Ctrough) of Ofatumumab Prior to Second Infusion (Cycle 1 Day 8), Third Infusion (Cycle 2), and Last Infusion (Cycle 3) | Cycle 1 Day 8, 1000 mg; n=19, 18, 37 | 95.8 µg/mL | Geometric Coefficient of Variation 1.63 |
| Ofatumumab + DHAP | Trough Plasma Concentration (Ctrough) of Ofatumumab Prior to Second Infusion (Cycle 1 Day 8), Third Infusion (Cycle 2), and Last Infusion (Cycle 3) | Cycle 3, 300 mg; n=4, 13, 17 | 120 µg/mL | Geometric Coefficient of Variation 0.26 |
| Ofatumumab + DHAP | Trough Plasma Concentration (Ctrough) of Ofatumumab Prior to Second Infusion (Cycle 1 Day 8), Third Infusion (Cycle 2), and Last Infusion (Cycle 3) | Cycle 2, 1000 mg; n=21, 18, 39 | 138 µg/mL | Geometric Coefficient of Variation 0.49 |
| Ofatumumab + DHAP | Trough Plasma Concentration (Ctrough) of Ofatumumab Prior to Second Infusion (Cycle 1 Day 8), Third Infusion (Cycle 2), and Last Infusion (Cycle 3) | Cycle 1 Day 8, 300 mg; n=4, 15, 19 | 31.8 µg/mL | Geometric Coefficient of Variation 0.19 |
| Ofatumumab + DHAP | Trough Plasma Concentration (Ctrough) of Ofatumumab Prior to Second Infusion (Cycle 1 Day 8), Third Infusion (Cycle 2), and Last Infusion (Cycle 3) | Cycle 3, both doses; n=22, 31, 57 | 146 µg/mL | Geometric Coefficient of Variation 0.41 |
| Ofatumumab + DHAP | Trough Plasma Concentration (Ctrough) of Ofatumumab Prior to Second Infusion (Cycle 1 Day 8), Third Infusion (Cycle 2), and Last Infusion (Cycle 3) | Cycle 3, 1000 mg; n=18, 18, 40 | 153 µg/mL | Geometric Coefficient of Variation 0.43 |
| Ofatumumab + DHAP | Trough Plasma Concentration (Ctrough) of Ofatumumab Prior to Second Infusion (Cycle 1 Day 8), Third Infusion (Cycle 2), and Last Infusion (Cycle 3) | Cycle 2, 300 mg; n=4, 16, 20 | 112 µg/mL | Geometric Coefficient of Variation 0.28 |
| Ofatumumab + ICE | Trough Plasma Concentration (Ctrough) of Ofatumumab Prior to Second Infusion (Cycle 1 Day 8), Third Infusion (Cycle 2), and Last Infusion (Cycle 3) | Cycle 2, 1000 mg; n=21, 18, 39 | 147 µg/mL | Geometric Coefficient of Variation 0.21 |
| Ofatumumab + ICE | Trough Plasma Concentration (Ctrough) of Ofatumumab Prior to Second Infusion (Cycle 1 Day 8), Third Infusion (Cycle 2), and Last Infusion (Cycle 3) | Cycle 1 Day 8, 300 mg; n=4, 15, 19 | 28.3 µg/mL | Geometric Coefficient of Variation 0.93 |
| Ofatumumab + ICE | Trough Plasma Concentration (Ctrough) of Ofatumumab Prior to Second Infusion (Cycle 1 Day 8), Third Infusion (Cycle 2), and Last Infusion (Cycle 3) | Cycle 1 Day 8, 1000 mg; n=19, 18, 37 | 106 µg/mL | Geometric Coefficient of Variation 0.23 |
| Ofatumumab + ICE | Trough Plasma Concentration (Ctrough) of Ofatumumab Prior to Second Infusion (Cycle 1 Day 8), Third Infusion (Cycle 2), and Last Infusion (Cycle 3) | Cycle 2, 300 mg; n=4, 16, 20 | 71.5 µg/mL | Geometric Coefficient of Variation 0.81 |
| Ofatumumab + ICE | Trough Plasma Concentration (Ctrough) of Ofatumumab Prior to Second Infusion (Cycle 1 Day 8), Third Infusion (Cycle 2), and Last Infusion (Cycle 3) | Cycle 3, 300 mg; n=4, 13, 17 | 76.7 µg/mL | Geometric Coefficient of Variation 0.65 |
| Ofatumumab + ICE | Trough Plasma Concentration (Ctrough) of Ofatumumab Prior to Second Infusion (Cycle 1 Day 8), Third Infusion (Cycle 2), and Last Infusion (Cycle 3) | Cycle 3, 1000 mg; n=18, 18, 40 | 122 µg/mL | Geometric Coefficient of Variation 0.45 |
| Ofatumumab + ICE | Trough Plasma Concentration (Ctrough) of Ofatumumab Prior to Second Infusion (Cycle 1 Day 8), Third Infusion (Cycle 2), and Last Infusion (Cycle 3) | Cycle 3, both doses; n=22, 31, 57 | 100 µg/mL | Geometric Coefficient of Variation 0.59 |
| Total Ofatumumab + Chemotherapy | Trough Plasma Concentration (Ctrough) of Ofatumumab Prior to Second Infusion (Cycle 1 Day 8), Third Infusion (Cycle 2), and Last Infusion (Cycle 3) | Cycle 3, 300 mg; n=4, 13, 17 | 85.2 µg/mL | Geometric Coefficient of Variation 0.6 |
| Total Ofatumumab + Chemotherapy | Trough Plasma Concentration (Ctrough) of Ofatumumab Prior to Second Infusion (Cycle 1 Day 8), Third Infusion (Cycle 2), and Last Infusion (Cycle 3) | Cycle 1 Day 8, 1000 mg; n=19, 18, 37 | 101 µg/mL | Geometric Coefficient of Variation 0.98 |
| Total Ofatumumab + Chemotherapy | Trough Plasma Concentration (Ctrough) of Ofatumumab Prior to Second Infusion (Cycle 1 Day 8), Third Infusion (Cycle 2), and Last Infusion (Cycle 3) | Cycle 3, both doses; n=22, 31, 57 | 117 µg/mL | Geometric Coefficient of Variation 0.54 |
| Total Ofatumumab + Chemotherapy | Trough Plasma Concentration (Ctrough) of Ofatumumab Prior to Second Infusion (Cycle 1 Day 8), Third Infusion (Cycle 2), and Last Infusion (Cycle 3) | Cycle 3, 1000 mg; n=18, 18, 40 | 134 µg/mL | Geometric Coefficient of Variation 0.44 |
| Total Ofatumumab + Chemotherapy | Trough Plasma Concentration (Ctrough) of Ofatumumab Prior to Second Infusion (Cycle 1 Day 8), Third Infusion (Cycle 2), and Last Infusion (Cycle 3) | Cycle 2, 1000 mg; n=21, 18, 39 | 142 µg/mL | Geometric Coefficient of Variation 0.38 |
| Total Ofatumumab + Chemotherapy | Trough Plasma Concentration (Ctrough) of Ofatumumab Prior to Second Infusion (Cycle 1 Day 8), Third Infusion (Cycle 2), and Last Infusion (Cycle 3) | Cycle 2, 300 mg; n=4, 16, 20 | 78.2 µg/mL | Geometric Coefficient of Variation 0.75 |
| Total Ofatumumab + Chemotherapy | Trough Plasma Concentration (Ctrough) of Ofatumumab Prior to Second Infusion (Cycle 1 Day 8), Third Infusion (Cycle 2), and Last Infusion (Cycle 3) | Cycle 1 Day 8, 300 mg; n=4, 15, 19 | 29.1 µg/mL | Geometric Coefficient of Variation 0.79 |
Secondary
Volume of Distribution at Steady State (Vss) of Ofatumumab
Vss is the apparent volume of distribution when plasma concentrations are measured under steady state conditions. At steady state, the plasma concentration-time profile of the drug is similar after each dose.
Time frame: Study Day 1 up to Study Day 85 (up to 12 weeks)
Population: Pharmacokinetic Population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Ofatumumab + DHAP | Volume of Distribution at Steady State (Vss) of Ofatumumab | 7.12 Liters | Geometric Coefficient of Variation 0.38 |
| Ofatumumab + ICE | Volume of Distribution at Steady State (Vss) of Ofatumumab | 8.13 Liters | Geometric Coefficient of Variation 0.5 |
| Total Ofatumumab + Chemotherapy | Volume of Distribution at Steady State (Vss) of Ofatumumab | 7.68 Liters | Geometric Coefficient of Variation 0.46 |