Back to resultsPhase II Study of Ofatumumab Plus Ifosfamide, Carboplatin, Etoposide (ICE) or Dexamethasone, Cytarabine, Cisplatin (DHAP) Chemotherapy Regimen in Relapsed/ Refractory Diffuse Large B Cell Lymphoma (DLBCL)
Primary Purpose
Lymphoma, Large-Cell, Diffuse
Status
Completed
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
ofatumumab + ICE
ofatumumab + DHAP
Sponsored by
About this trial
This is an interventional treatment trial for Lymphoma, Large-Cell, Diffuse focused on measuring 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
Eligibility Criteria
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.
Sites / Locations
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
ofatumumab + DHAP or ICE chemotherapy regimen
Arm Description
This study is a single arm study, but the Investigators are required to prospectively choose to treat all of their subjects with either ICE or DHAP chemotherapy regimens in combination with ofatumumab. Regardless of whether the subject receives ICE or DHAP chemotherapy, all subjects will receive the same ofatumumab regimen and dose.
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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.
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.
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).
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.
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.
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.
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.
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.
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).
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.
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.
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.
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.
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.
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT00823719
Brief Title
Phase II Study of Ofatumumab Plus Ifosfamide, Carboplatin, Etoposide (ICE) or Dexamethasone, Cytarabine, Cisplatin (DHAP) Chemotherapy Regimen in Relapsed/ Refractory Diffuse Large B Cell Lymphoma (DLBCL)
Official Title
A Single Arm, Safety and Efficacy Study of Ofatumumab in Combination With ICE or DHAP Chemotherapy in Relapsed or Refractory Aggressive Lymphoma Prior to Autologous Stem Cell Transplantation
Study Type
Interventional
2. Study Status
Record Verification Date
February 2013
Overall Recruitment Status
Completed
Study Start Date
May 2009 (undefined)
Primary Completion Date
July 2011 (Actual)
Study Completion Date
September 2011 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
GlaxoSmithKline
4. Oversight
Data Monitoring Committee
No
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Lymphoma, Large-Cell, Diffuse
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
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
61 (Actual)
8. Arms, Groups, and Interventions
Arm Title
ofatumumab + DHAP or ICE chemotherapy regimen
Arm Type
Experimental
Arm Description
This study is a single arm study, but the Investigators are required to prospectively choose to treat all of their subjects with either ICE or DHAP chemotherapy regimens in combination with ofatumumab. Regardless of whether the subject receives ICE or DHAP chemotherapy, all subjects will receive the same ofatumumab regimen and dose.
Intervention Type
Drug
Intervention Name(s)
ofatumumab + ICE
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
ofatumumab + DHAP
Intervention Description
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.
Primary Outcome Measure Information:
Title
Number of Participants With Overall Response (OR), as Assessed by the Investigator
Description
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
Secondary Outcome Measure Information:
Title
Number of Participants With CR, as Assessed by the Investigator
Description
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
Title
Number of Participants With the Ability to Mobilize at Least 2 Million Cluster of Differentiation (CD)34+ Cells Per Kilogram (kg) From Peripheral Blood
Description
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)
Title
Progression-free Survival (PFS)
Description
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
Title
Overall Survival
Description
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
Title
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)
Description
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)
Title
Area Under the Concentration-time Curve During the Dosing Interval (AUC(0-tau)) of Ofatumumab at the Last Infusion (Cycle 3)
Description
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)
Title
Clearance (CL) of Ofatumumab
Description
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)
Title
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)
Description
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)
Title
Trough Plasma Concentration (Ctrough) of Ofatumumab Prior to Second Infusion (Cycle 1 Day 8), Third Infusion (Cycle 2), and Last Infusion (Cycle 3)
Description
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)
Title
Terminal Phase Half-life (t1/2) of Ofatumumab
Description
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)
Title
Volume of Distribution at Steady State (Vss) of Ofatumumab
Description
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)
Title
Number of Participants Who Were Positive and Negative for Human Anti-human Antibodies (HAHA) at the Indicated Time Points
Description
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
Title
Number of Participants With the Indicated Adverse Events (AEs) Associated With Neutropenia
Description
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
Title
Number of Participants With the Indicated AEs Associated With Decreased Hemoglobin Counts
Description
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
Title
Number of Participants With the Indicated AEs Associated With Decreased Platelet Counts
Description
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
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
GSK Clinical Trials
Organizational Affiliation
GlaxoSmithKline
Official's Role
Study Director
12. IPD Sharing Statement
Citations:
PubMed Identifier
23692856
Citation
Matasar MJ, Czuczman MS, Rodriguez MA, Fennessy M, Shea TC, Spitzer G, Lossos IS, Kharfan-Dabaja MA, Joyce R, Fayad L, Henkel K, Liao Q, Edvardsen K, Jewell RC, Fecteau D, Singh RP, Lisby S, Moskowitz CH. Ofatumumab in combination with ICE or DHAP chemotherapy in relapsed or refractory intermediate grade B-cell lymphoma. Blood. 2013 Jul 25;122(4):499-506. doi: 10.1182/blood-2012-12-472027. Epub 2013 May 21.
Results Reference
derived
Learn more about this trial
Phase II Study of Ofatumumab Plus Ifosfamide, Carboplatin, Etoposide (ICE) or Dexamethasone, Cytarabine, Cisplatin (DHAP) Chemotherapy Regimen in Relapsed/ Refractory Diffuse Large B Cell Lymphoma (DLBCL)
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