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)

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Lymphoma, Large-Cell, Diffuse

Intervention / Treatment
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* Drug: ofatumumab + ICE
* Drug: ofatumumab + DHAP


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ofatumumab + DHAP or ICE chemotherapy regimen<br>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. | Drug: ofatumumab + ICE<br>* 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.<br>Drug: ofatumumab + DHAP<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 | 
| 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. | During treatment Cycle 2 (Study Days 22-42) and/or Cycle 3 (Study Days 43-63) | 
| 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). | 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 | 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. | 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 | 
| 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. | Cycle 1 Day 1 (Study Day 1; up to 1 week) and Cycle 3 (Study Day 43; up to 6 weeks) | 
| 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. | Cycle 3 (Study Day 43; 3 weeks) | 
| 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. | Study Day 1 up to Study Day 85 (up to 12 weeks) | 
| 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. | 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) | 
| 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). | 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) | 
| 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. | Study Day 1 up to Study Day 85 (up to 12 weeks) | 
| 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. | Study Day 1 up to Study Day 85 (up to 12 weeks) | 
| 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. | Study Day 1 up to approximately Study Day 63 | 
| 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. | Study Day 1 to approximately Study Day 63 | 
| 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. | Study Day 1 to approximately Study Day 63 | 
| 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. | Study Day 1 to approximately Study Day 63 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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