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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)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT00823719
First received: January 8, 2009
Last updated: March 7, 2013
Last verified: February 2013
  Purpose

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.


Condition Intervention Phase
Lymphoma, Large-Cell, Diffuse
Drug: ofatumumab + ICE
Drug: ofatumumab + DHAP
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Number of Participants With Overall Response (OR), as Assessed by the Investigator [ 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 ] [ Designated as safety issue: No ]
    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 [ 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 ] [ Designated as safety issue: No ]
    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 [ Time Frame: During treatment Cycle 2 (Study Days 22-42) and/or Cycle 3 (Study Days 43-63) ] [ Designated as safety issue: No ]
    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) [ 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 ] [ Designated as safety issue: No ]
    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 [ 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 ] [ Designated as safety issue: No ]
    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) [ Time Frame: Cycle 1 Day 1 (Study Day 1; up to 1 week) and Cycle 3 (Study Day 43; up to 6 weeks) ] [ Designated as safety issue: No ]
    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) [ Time Frame: Cycle 3 (Study Day 43; 3 weeks) ] [ Designated as safety issue: No ]
    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 [ Time Frame: Study Day 1 up to Study Day 85 (up to 12 weeks) ] [ Designated as safety issue: No ]
    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) [ 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) ] [ Designated as safety issue: No ]
    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) [ 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) ] [ Designated as safety issue: No ]
    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 [ Time Frame: Study Day 1 up to Study Day 85 (up to 12 weeks) ] [ Designated as safety issue: No ]
    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 [ Time Frame: Study Day 1 up to Study Day 85 (up to 12 weeks) ] [ Designated as safety issue: No ]
    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 [ Time Frame: Study Day 1 up to approximately Study Day 63 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Study Day 1 to approximately Study Day 63 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Study Day 1 to approximately Study Day 63 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Study Day 1 to approximately Study Day 63 ] [ Designated as safety issue: No ]
    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.


Enrollment: 61
Study Start Date: May 2009
Study Completion Date: September 2011
Primary Completion Date: July 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: ofatumumab + DHAP or ICE chemotherapy regimen
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

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.

Drug: ofatumumab + DHAP

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.


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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00823719

Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided by GlaxoSmithKline

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT00823719     History of Changes
Other Study ID Numbers: 110927
Study First Received: January 8, 2009
Results First Received: June 21, 2012
Last Updated: March 7, 2013
Health Authority: United States: Institutional Review Board
United States: Food and Drug Administration

Keywords provided by GlaxoSmithKline:
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

Additional relevant MeSH terms:
Lymphoma
Lymphoma, Large B-Cell, Diffuse
Immune System Diseases
Immunoproliferative Disorders
Lymphatic Diseases
Lymphoma, B-Cell
Lymphoma, Non-Hodgkin
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Antibodies, Monoclonal
Immunologic Factors
Pharmacologic Actions
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on November 25, 2014