Ofatumumab Versus Rituximab Salvage Chemoimmunotherapy Followed by Autologous Stem Cell Transplant in Relapsed or Refractory Diffuse Large B Cell Lymphoma

Lymphoma, Large-Cell, Diffuse Clinical Trial

— ORCHARRD  

Official title:

Ofatumumab Versus Rituximab Salvage Chemoimmunotherapy Followed by Autologous Stem Cell Transplant (ASCT) in Relapsed or Refractory Diffuse Large B Cell Lymphoma (DLBCL)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01014208
• Other study ID #: 110928
• Status: Completed
• Phase: Phase 3
• First received: November 4, 2009
• Last updated: July 9, 2015
• Start date: March 2010
• Est. completion date: November 2014

Study information

• Verified date: February 2015
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review BoardUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

This study is being conducted to compare the efficacy and safety of ofatumumab in addition to salvage chemotherapy versus rituximab in addition to salvage chemotherapy in CD20 positive DLBCL subjects relapsing, or with persistent disease, after first-line treatment with rituximab combined with an anthracycline-based chemotherapy regimen and be eligible for ASCT.

Description:

As rituximab-based regimens have become standard first-line treatment in CD20 positive DLBCL, the efficacy of rituximab combined with salvage chemotherapy in the second-line setting has decreased and there is a need for new therapies in patients progressing or relapsing after first-line rituximab-based therapy. Replacement of rituximab with ofatumumab in the second-line setting, following progression/relapse after first-line rituximab-containing regimens, offers the potential to overcome relative or complete rituximab resistance and thus improve response rates, the ability to proceed to consolidative HDT/ASCT, and overall survival.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 447
• Est. completion date: November 2014
• Est. primary completion date: February 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Subjects with CD20 positive DLBCL or grade 3b follicular lymphoma (FL) at original diagnosis.

• Refractory to, or relapsed following, first-line treatment with rituximab combined with anthracycline- or anthracenedione-based chemotherapy as defined by the protocol.

• CT with involvement of 2 or more clearly demarcated lesions/ nodes with a long axis > 1.5 cm and short axis >= 1.0cm or 1 clearly demarcated lesion/ node with a long axis > 2.0 cm and short axis >= 1.0 cm.

• Baseline FDG-PET scans must demonstrate positive lesions compatible with CT defined anatomical tumor sites.

• Age 18 yrs or older.

• ECOG performance status of 0, 1 or 2.

• Eligible for high dose chemotherapy and ASCT.

• Resolution of toxicities from first-line therapy to a grade that in the opinion of the investigator does not contraindicate study participation.

• Signed written informed consent.

Exclusion Criteria:

• Previous cancer therapy for lymphoma, with the exception of first-line rituximab/ anthracycline- or anthracenedione-based chemotherapy, monotherapy rituximab prior to or combined with first-line chemotherapy, as maintenance therapy, and radiotherapy in a limited field or as a part of the first-line treatment plan.

• Any anti-cancer therapy, except limited field radiotherapy, within 2 weeks prior to start of study therapy.

• Planned post-randomization chronic glucocorticoid use (limited acute use is allowed and defined by the protocol) unless administered as therapy for mild COPD or asthma.

• Clinically significant cardiac disease, active or chronic infections, serious significant diseases, other cancer within last 5 years. History of significant cerebrovascular disease.

• Prior treatment with anti-CD20 monoclonal antibodies with the exception of rituximab.

• Abnormal/ inadequate WBC count, liver, and kidney function.

• Pregnant or lactating women or female patients of child-bearing potential (or male patients with such partners) not willing to use adequate contraception during and up to 1 year following dosing completion.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Large B-Cell, Diffuse
• Lymphoma, Large-Cell, Diffuse

Intervention

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/m2/24hrs continuous on day 1 of dosing cycle; cytarabine - 2g/m2 q12 hrs (2 doses) on day 2 of dosing cycle.
• RITUXIMAB + DHAP
3 cycles of treatment will be administered. Each cycle will last 21 days. rituximab dose: cycle 1, day 1 - 375 mg/m2; cycle 1, day 8 - 375 mg/m2; cycle 2, day 1 and cycle 3, day 1 - 375 mg/m2. DHAP regimen: dexamethasone - 40 mg on days 1, 2, 3, and 4 of dosing cycle; cisplatin - 100 mg/m2/24hrs continuous on day 1 of dosing cycle; cytarabine - 2g/m2 q12 hrs (2 doses) on day 2 of dosing cycle.

Locations

Country	Name	City	State
Argentina	GSK Investigational Site	Capital Federal	Buenos Aires
Argentina	GSK Investigational Site	Ciudad Autonoma de Buenos Aires	Buenos Aires
Argentina	GSK Investigational Site	La Plata	Buenos Aires
Austria	GSK Investigational Site	Graz
Austria	GSK Investigational Site	Innsbruck
Austria	GSK Investigational Site	Linz
Austria	GSK Investigational Site	Linz
Austria	GSK Investigational Site	Salzburg
Austria	GSK Investigational Site	Wien
Austria	GSK Investigational Site	Wien
Belgium	GSK Investigational Site	Brugge
Belgium	GSK Investigational Site	Bruxelles
Belgium	GSK Investigational Site	Gent
Belgium	GSK Investigational Site	Hasselt
Belgium	GSK Investigational Site	Leuven
Belgium	GSK Investigational Site	Yvoir
China	GSK Investigational Site	Beijing
China	GSK Investigational Site	Beijing
China	GSK Investigational Site	Beijing
China	GSK Investigational Site	Beijing
China	GSK Investigational Site	Beijing
China	GSK Investigational Site	Beijing
China	GSK Investigational Site	Beijing
China	GSK Investigational Site	Chengdu
China	GSK Investigational Site	Fuzhou	Fujian
China	GSK Investigational Site	Guangzhou	Guangdong
China	GSK Investigational Site	Guangzhou	Guangdong
China	GSK Investigational Site	Guangzhou	Guangdong
China	GSK Investigational Site	Hangzhou	Zhejiang
China	GSK Investigational Site	Jianan	Shandong
China	GSK Investigational Site	Jiang Su Province
China	GSK Investigational Site	Nanjing	Jiangsu
China	GSK Investigational Site	Shanghai
China	GSK Investigational Site	Shanghai
China	GSK Investigational Site	Tianjin
Czech Republic	GSK Investigational Site	Brno
Czech Republic	GSK Investigational Site	Hradec Kralove
Denmark	GSK Investigational Site	Aarhus
Denmark	GSK Investigational Site	Koebenhavn
Estonia	GSK Investigational Site	Tallinn
Estonia	GSK Investigational Site	Tartu
Finland	GSK Investigational Site	Helsinki
Finland	GSK Investigational Site	Oulu
Finland	GSK Investigational Site	Tampere
Germany	GSK Investigational Site	Aachen	Nordrhein-Westfalen
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Muenster	Nordrhein-Westfalen
Germany	GSK Investigational Site	Ulm	Baden-Wuerttemberg
Greece	GSK Investigational Site	Athens
Greece	GSK Investigational Site	Athens
Hungary	GSK Investigational Site	Budapest
Hungary	GSK Investigational Site	Budapest
Hungary	GSK Investigational Site	Debrecen
Hungary	GSK Investigational Site	Gyor
Hungary	GSK Investigational Site	Kaposvár
Hungary	GSK Investigational Site	Szeged
Hungary	GSK Investigational Site	Szombathely
India	GSK Investigational Site	Ludhiana
India	GSK Investigational Site	Pune
India	GSK Investigational Site	Vellore
Ireland	GSK Investigational Site	Dublin
Ireland	GSK Investigational Site	Galway
Ireland	GSK Investigational Site	James Street
Israel	GSK Investigational Site	Petach-Tikva
Israel	GSK Investigational Site	Ramat Gan
Japan	GSK Investigational Site	Aichi
Japan	GSK Investigational Site	Akita
Japan	GSK Investigational Site	Fukuoka
Japan	GSK Investigational Site	Hokkaido
Japan	GSK Investigational Site	Hyogo
Japan	GSK Investigational Site	Ibaraki
Japan	GSK Investigational Site	Kanagawa
Japan	GSK Investigational Site	Kanagawa
Japan	GSK Investigational Site	Kyoto
Japan	GSK Investigational Site	Miyagi
Japan	GSK Investigational Site	Nagano
Japan	GSK Investigational Site	Nagasaki
Japan	GSK Investigational Site	Okayama
Japan	GSK Investigational Site	Osaka
Japan	GSK Investigational Site	Tochigi
Japan	GSK Investigational Site	Tokushima
Japan	GSK Investigational Site	Tokyo
Japan	GSK Investigational Site	Tokyo
Japan	GSK Investigational Site	Tokyo
Japan	GSK Investigational Site	Tokyo
Korea, Republic of	GSK Investigational Site	Jellanamdo
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Seoul
Netherlands	GSK Investigational Site	Amersfoort
Netherlands	GSK Investigational Site	Amsterdam
Netherlands	GSK Investigational Site	Amsterdam
Netherlands	GSK Investigational Site	Amsterdam
Netherlands	GSK Investigational Site	Den Haag
Netherlands	GSK Investigational Site	Enschede
Netherlands	GSK Investigational Site	Groningen
Netherlands	GSK Investigational Site	Hoofddorp
Netherlands	GSK Investigational Site	Leiden
Netherlands	GSK Investigational Site	Maastricht
Netherlands	GSK Investigational Site	Nieuwegein
Netherlands	GSK Investigational Site	Nijmegen
Netherlands	GSK Investigational Site	Rotterdam
Netherlands	GSK Investigational Site	Rotterdam
Netherlands	GSK Investigational Site	Rotterdam
Netherlands	GSK Investigational Site	Sittard-geleen
Netherlands	GSK Investigational Site	Utrecht
Netherlands	GSK Investigational Site	Zwolle
Norway	GSK Investigational Site	Oslo
Poland	GSK Investigational Site	Chorzow
Poland	GSK Investigational Site	Gdansk
Poland	GSK Investigational Site	Poznan
Poland	GSK Investigational Site	Warszawa
Poland	GSK Investigational Site	Warszawa
Poland	GSK Investigational Site	Wroclaw
Russian Federation	GSK Investigational Site	Moscow
Russian Federation	GSK Investigational Site	St-Petersburg
Russian Federation	GSK Investigational Site	St. Petersburg
Singapore	GSK Investigational Site	Singapore
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Majadahonda (Madrid)
Spain	GSK Investigational Site	Murcia
Spain	GSK Investigational Site	Pamplona
Spain	GSK Investigational Site	Pozuelo de Alarcón/Madrid
Spain	GSK Investigational Site	Salamanca
Sweden	GSK Investigational Site	Göteborg
Sweden	GSK Investigational Site	Lund
Sweden	GSK Investigational Site	Stockholm
Sweden	GSK Investigational Site	Uppsala
Thailand	GSK Investigational Site	Bangkok
Thailand	GSK Investigational Site	Bangkok
Thailand	GSK Investigational Site	Bangkok
United Kingdom	GSK Investigational Site	Birmingham
United Kingdom	GSK Investigational Site	Blackpool
United Kingdom	GSK Investigational Site	Bristol
United Kingdom	GSK Investigational Site	Cambridge
United Kingdom	GSK Investigational Site	Cheltenham
United Kingdom	GSK Investigational Site	Edinburgh
United Kingdom	GSK Investigational Site	Glasgow
United Kingdom	GSK Investigational Site	Headington, Oxford
United Kingdom	GSK Investigational Site	Leeds
United Kingdom	GSK Investigational Site	Liverpool
United Kingdom	GSK Investigational Site	London
United Kingdom	GSK Investigational Site	London
United Kingdom	GSK Investigational Site	London
United Kingdom	GSK Investigational Site	London
United Kingdom	GSK Investigational Site	Manchester
United Kingdom	GSK Investigational Site	Manchester
United Kingdom	GSK Investigational Site	Newcastle upon Tyne
United Kingdom	GSK Investigational Site	Northwood
United Kingdom	GSK Investigational Site	Nottingham
United Kingdom	GSK Investigational Site	Sheffield
United Kingdom	GSK Investigational Site	Southampton
United Kingdom	GSK Investigational Site	Whitchurch, Cardiff
United Kingdom	GSK Investigational Site	Wolverhampton
United States	GSK Investigational Site	Chaple Hill	North Carolina
United States	GSK Investigational Site	Charleston	South Carolina
United States	GSK Investigational Site	Chicago	Illinois
United States	GSK Investigational Site	Chicago	Illinois
United States	GSK Investigational Site	Greenville	South Carolina
United States	GSK Investigational Site	Jackson	Mississippi
United States	GSK Investigational Site	Nashville	Tennessee
United States	GSK Investigational Site	New Haven	Connecticut
United States	GSK Investigational Site	New York	New York
United States	GSK Investigational Site	Philadelphia	Pennsylvania
United States	GSK Investigational Site	Providence	Rhode Island
United States	GSK Investigational Site	Sacramento	California
United States	GSK Investigational Site	San Antonio	Texas
United States	GSK Investigational Site	Seattle	Washington
United States	GSK Investigational Site	Syracuse	New York
United States	GSK Investigational Site	Westwood	Kansas

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

United States,  Argentina,  Austria,  Belgium,  China,  Czech Republic,  Denmark,  Estonia,  Finland,  Germany,  Greece,  Hungary,  India,  Ireland,  Israel,  Japan,  Korea, Republic of,  Netherlands,  Norway,  Poland,  Russian Federation,  Singapore,  Spain,  Sweden,  Thailand,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free Survival as Assessed by Independent Reviewers	Progression-free survival is defined as the interval of time from the randomization date until the date of stable disease (SD; failure to attain the criteria needed for a CR or PR and no fulfillment of the criteria for progressive disease [PD]) after two cycles of salvage chemotherapy, progression, or death, whichever occurs first. Disease progression was based on the assessments of independent reviewers for the disease under study. Disease progression was based on imaging data via the Revised Response Criteria for Malignant Lymphoma (RRCML).	From randomization until the date of stable disease after two cycles of salvage chemotherapy, progression, or death (assessed for up to 5 years)	No
Secondary	Number of Participants With Overall Response (OR) and Complete Response (CR) After Salvage Chemoimmunotherapy	OR is defined as the number of participants achieving either a complete response (CR) or a partial response (PR). CR is defined as the complete disappearance of all detectable clinical evidence of disease and disease-related symptoms. PR is defined as at least a 50% decrease from Baseline in the sum of the product of the diameters of target lesions. RRCML was used to assess CR and PR.	At completion of up to 3 cycles of salvage chemoimmunotherapy (assessed up to 9 weeks)	No
Secondary	Number of Participants With Overall Response (OR) and Complete Response (CR) Three Months After Autologous Stem Cell Transplant	OR is defined as the number of participants achieving either a complete response (CR) or a partial response (PR). CR is defined as the complete disappearance of all detectable clinical evidence of disease and disease-related symptoms. PR is defined as at least a 50% decrease from Baseline in the sum of the product of the diameters of target lesions. RRCML was used to assess CR and PR.	At 3 months after completion of autologous stem cell transplantation (ASCT) (assessed up to 6 months)	No
Secondary	Event-free Survival	Event-free survival is defined as the time from randomization to progressive disease (PD; disease whose course is growth, or spread of the disease), stable disease (SD; failure to attain the criteria needed for a CR or PR and no fulfillment of the criteria for PD) after completion of 2 cycles of therapy, commencement of a new treatment for diffuse large B cell lymphoma (DLBCL) (e.g., radiotherapy), or death from any cause, whichever occurs first. Disease progression was based on the assessments of independent reviewers for the disease under study. Disease progression was based on imaging data via the Revised Response Criteria for Malignant Lymphoma (RRCML).	From randomization to progressive disease, stable disease after completion of 2 cycles of therapy, commencement of a new treatment for DLBCL, or death due to any cause (assessed for up to 5 years)	No
Secondary	Overall Survival (OS)	OS is defined as the time from randomization to death due to any cause. Participants who were still alive by the end of the study were censored.	From randomization to death due to any cause (assessed for up to 5 years)	No
Secondary	Number of Participants With the Ability to Mobilize at Least 2 Million Cluster of Differentiation (CD)34+ Cells Per Kilogram From Peripheral Blood	Stem cell mobilization is the process of stimulating the hematopoietic stem cells (CD34+) to move out of the bone marrow and into the bloodstream, where they can be collected via a process called apheresis. Successful mobilization is defined as the collection of >2*10^6 CD34+ cells/kg. Only those participants, who commenced harvest, following the administration of rituximab or ofatumumab in combination with DHAP combination chemotherapy, were assessed. The number of participants with adequate harvest of CD34+ stem cells (at least 2*10^6 CD34+ cells/kg) after dosing of salvage therapy in Cycle 2 and Cycle 3 was analyzed.	During Cycles 2 and/or 3 (Weeks 4-9)	No
Secondary	Number of Participants Completing Autologous Stem Cell Transplant (ASCT)	The number of participants who completed ASCT is reported.	Approximately 4 to 6 weeks following Cycle 3 (assessed up to 3 months)	No
Secondary	Change From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) During Treatment	The FACT-G was developed by the Functional Assessment of Chronic Illness Therapy (FACIT) group for use in adults in a wide range of oncology clinical trial populations. The 27 items of the FACT-G are scored in the following domains: Physical Well-being (7 items), Social/Family Wellbeing (7 items), Emotional Well-being (6 items), and Functional Well-being (7 items). Participants responded to the items on a five-point Likert scale ranging from 0, "Not at all" to 4, "Very much." The total score ranges from 0 to 108; higher scores indicate a better patient-reported outcome/quality of life. Participants were asked to think back over the past week when responding to the items.	Baseline and the end of the treatment period (until approximately 4 to 6 weeks following Cycle 3 [assessed up to 3 months])	No
Secondary	Change From Baseline in the Functional Assessment of Cancer Therapy Lymphoma Trial Outcome Index (FACT-Lym TOI) Total Score During Treatment	The FACT-Lym TOI is a measure that combines the FACT-Lym subscale (15 items; responses to each item range from 0, "Not at all" to 4, "Very much") with two domains taken from the FACT-G (responses to each item range from "Not at all " to "Very much"): Physical Well-being (7 items: lack of energy, nausea, meeting family needs, pain, side effects, feels ill, spends time in bed) and Functional Well-being (7 items: ability to work, work fulfilment, ability to enjoy life, illness acceptance, ability to sleep well, enjoying things done for fun, satisfaction with quality of life). This index is designed to be sensitive to changes in treatment regimens. The total FACT-Lym TOI score ranges from 0 to 116; higher scores indicate a better patient-reported outcome/quality of life. Participants were asked to think back over the past week when responding to the items.	Baseline and the end of the treatment period (until approximately 4 to 6 weeks following Cycle 3 [assessed up to 3 months])	No
Secondary	Time to Neutrophil and Platelet Recovery After Each Cycle of Salvage Chemotherapy	Neutrophil (absolute neutrophil count [ANC]) recovery is defined as ANC >=0.5*10^9/Liter and increasing, and platelet (PLT) recovery is defined as PLT >=10*10^9/Liter and increasing. For each cycle, time to ANC recovery is defined as the time from the first dose to the first ANC >=0.5*10^9/Liter and increasing after the nadir in the cycle. For each cycle, time to PLT recovery is defined as the time from the first dose to the first PLT >=10*10^9/L and increasing after the nadir in the cycle.	From the start of each cycle for a maximum of 5 weeks per cycle (assessed during treatment period of Baseline up to approximately 3 months)	No
Secondary	Time to Engraftment After High-dose Therapy (HDT)/ASCT	Engraftment is defined as 1) three consecutive days when the ANC is =0.5x109/L and 2) an unsupported platelet count of =20x109/L, and the engraftment date is the date that this occurs. If engraftment was not achieved by Day 42 or the last observation, engraftment was deemed to be a failure, and censoring took place at Day 42 or at the last observation.	From ASCT up to 42 days post-ASCT (Baseline up to approximately 4.5 months)	No