Clinical trial NCT00824265: Ofatumumab Added to Fludarabine-Cyclophosphamide vs Fludarabine-Cyclophosphamide Combination in Relapsed Subjects With Chronic Lymphocytic Leukemia
Official title: A Phase III, Open Label, Randomized Trial of Ofatumumab Added to Fludarabine-Cyclophosphamide vs. Fludarabine-Cyclophosphamide Combination in Subjects With Relapsed Chronic Lymphocytic Leukemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Leukaemia, Lymphocytic, Chronic
Keywords: Relapsed
Oncology
Safety
Chronic Lymphocytic Leukemia
Ofatumumab
Efficacy
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2009-01-16
Enrollment: 365
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study was to evaluate the safety and efficacy of ofatumumab added to fludarabine-cyclophosphamide in patients with relapsed Chronic Lymphocytic Leukemia (CLL).

Detailed description: Fludarabine is currently approved for treatment of relapsed Chronic Lymphocytic Leukemia. Studies have shown that drugs in combination with fludarabine have shown more effectiveness than fludarabine alone. The addition of ofatumumab to fludarabine-cyclophosphamide combination offers potentially a more effective therapy, without additional toxicity.

The objective of this study was to determine the effect of ofatumumab added to fludarabine and cyclophosphamide in patients with Chronic Lymphocytic Leukemia who have responded previously to therapy but later develop progressive disease and require additional therapy.

Eligibility criteria: Key Inclusion Criteria:

* confirmed and active CLL requiring treatment
* at least one previous treatment for CLL and having achieved a complete or partial remission/response but after a period of 6 or more months, shows evidence of disease progression
* fully active at a minimum or fully capable of selfcare and up and about more than 50% of waking hours
* age 18yrs or older
* signed written informed consent

Key Exclusion Criteria:

* diagnosis of refractory CLL (failure to achieve a complete or partial remission/response or disease progression within 6 months of last anti-CLL treatment
* abnormal/inadequate blood values, liver and kidney function
* certain heart problems, serious significant diseases, AIHA, other current cancers or within the last 5 years
* active or chronic infections
* use of drugs to suppress allergic or inflammatory responses (glucocorticoids)
* CLL transformation
* CLL central nervous system involvement
* current participation in other clinical study
* inability to comply with the protocol activities
* lactating or pregnant women or female patients of child-bearing potential (or male patients with such partners) not willing to use adequate contraception

Primary outcomes:
measure: Progression-free Survival (PFS), as Assessed by the Independent Review Committee (IRC)
timeFrame: From randomization up to 5 years after last dose of study drug
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: From randomization up to 5 years after last dose of study drug
measure: Time to Response, as Assessed by the IRC
timeFrame: From randomization up to 5 years after last dose of study drug
measure: Duration of Response (DOR), as Assessed by the IRC
timeFrame: From time of initial response to disease progression or death, whichever came first (up to 5 years after the last dose of study drug)
measure: Time to Progression, as Assessed by the IRC
timeFrame: From randomization up to 5 years after the last dose of study drug
measure: Time to Next Therapy
timeFrame: From the start of study drug until the start of the next anti-CLL therapy (up to 5 years after the last dose of study drug)
measure: Number of Participants With Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status
timeFrame: Cycle 2 Day1, Cycle 3 Day1, Cycle 4 Day1, Cycle 5 Day1, Cycle 6 Day1, follow up (FU) at 1Month (M) after study drug therapy, 3M, then every 3 month up to 5 year (up to 60 months)
measure: Number of Participants With no B-Symptoms or at Least One B-symptoms Over the Time
timeFrame: Screening, Cycle1 Day 1, Cycle 2 Day1, Cycle 3 Day1, Cycle 4 Day1, Cycle 5 Day1, Cycle 6 Day 1 and During at 1M after study drug therapy, 3M, then every 3 M up to 5 year (up to 60 months)
measure: Percentage of Participants With the Best Overall Response (OR), as Assessed by the IRC
timeFrame: From randomization up to 5 years after last dose of study drug
measure: Percentage of Participants With the Best OR, as Assessed by the Investigator
timeFrame: From randomization up to 5 years after last dose of study drug
measure: Number of Participants Who Were Negative for Minimal Residual Disease (MRD) Assessed by IRC
timeFrame: From randomization up to 5 years after last dose of study drug
measure: Number of Participants Who Were Negative for MRD Assessed by Investigator
timeFrame: From randomization up to 5 years after last dose of study drug
measure: Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)
timeFrame: From first dose of study medication to 60 Days after the last dose of study medication (for an AE), or up to 5 years after the last dose of study drug or until the time of the next anti-CLL therapy (for SAE)
measure: Number of Participants With a Human Anti-human Antibody (HAHA) Positive Result at Indicated Time Points
timeFrame: From start of study drug until 60 days after the last dose of study medication
measure: Number of Participants With Autoimmune Hemolytic Anaemia (AIHA)
timeFrame: From first dose of study medication to 60 days after the last dose of study medication (for an AE), or up to 5 years after the last dose of study drug or until the time of the next anti-CLL therapy (for SAE)
measure: Number of Participants With Drug Related Infections Reported as AEs and SAEs of Maximum Severity of Grade 3 or Higher
timeFrame: From first dose of study medication to 60 days after the last dose of study medication (for an AE), or up to 5 years after the last dose of study drug or until the time of the next anti-CLL therapy (for SAE)
measure: Number of Participants With at Least One Grade 3/Grade 4 Myelosuppression Adverse Events
timeFrame: From first dose of study medication to 60 days after the last dose of study medication (for an AE), or up to 5 years after the last dose of study drug or until the time of the next anti-CLL therapy (for SAE)
measure: Number of Participants Who Received no Transfusion or at Least One Transfusion During the Study
timeFrame: From randomization up to 5 years after last dose of study drug
measure: Mean Level of Immunoglobulin (Ig) Antibodies IgA, IgG, and IgM
timeFrame: Baseline, 1M and 6M follow up
measure: Change From Baseline in Cluster of Differentiation (CD) Cell Counts, CD5+ and CD19+
timeFrame: Screening, Cycle 1 Day1, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 2 Day 15, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 and after last dose at 1 M and then every three months up to 45 M during Follow-up Period
measure: Change From Baseline in Cell Counts, CD5- CD19+
timeFrame: Screening, Cycle 1 Day1, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 2 Day 15, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 and after last dose at 1 M and then every three month up to 45 M during Follow-up Period
measure: Prognostic and Biological Markers Correlating With Clinical Response
timeFrame: From randomization up to 5 years after last dose of study drug
measure: Changes in Patient Reported Outcome (PRO) Measures and Scores for European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, Chronic Lymphocytic Leukaemia 16 Item Module (EORTC QLQ-CLL 16)
timeFrame: Screening, Cycle 3 Day 1, and 1 M and every 3 month post last dose up to 24 month.
measure: Change From Baseline in Patient Reported Outcome (PRO) as Assessed by EuroQoL Five-Dimension (EQ-5D) Score at Indicated Visit
timeFrame: Screening, Cycle 3 Day 1, and 1 M and every 3 month post last dose up to 24 month.
measure: Change From Baseline in the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Score
timeFrame: Screening, Cycle 3 Day 1, and 1 M and every 3 month post last dose up to 24 month.
measure: Mean of Health Change Questionnaire (HCQ)
timeFrame: Screening, Cycle 3 Day 1, and 1 M and every 3 month post last dose up to 24 month.
measure: Mean Area Under the Time-concentration Curve (AUC) Curve Over the Dosing Interval (AUC[0-tau]) of Ofatumumab
timeFrame: Cycle 1 Week 1, Cycle 1 Week 2, Cycles 2,3,4,5,6
measure: Maximum Concentration (Cmax) and Observed Drug Concentration Prior to the Next Dose (Ctrough) of Ofatumumab
timeFrame: Cycle 1 Week 1, Cycle 1 Week 2, Cycles 2,3,4,5
measure: Time of Occurrence of Cmax (Tmax) of Ofatumumab
timeFrame: Cycle 1 Week 1, Cycle 1 Week 2, Cycle 4
Other outcomes:
Locations:
city: Boca Raton
country: United States
facility: Novartis Investigative Site
state: Florida
city: Chicago
country: United States
facility: Novartis Investigative Site
state: Illinois
city: Clinton
country: United States
facility: Novartis Investigative Site
state: Maryland
city: Kansas City
country: United States
facility: Novartis Investigative Site
state: Missouri
city: Saint Louis
country: United States
facility: Novartis Investigative Site
state: Missouri
city: Memphis
country: United States
facility: Novartis Investigative Site
state: Tennessee
city: Brasilia
country: Brazil
facility: Novartis Investigative Site
state: Goiás
city: Porto Alegre
country: Brazil
facility: Novartis Investigative Site
state: Rio Grande Do Sul
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: São Paulo
city: Porto Alegre
country: Brazil
facility: Novartis Investigational Site
city: Rio de Janeiro
country: Brazil
facility: Novartis Investigative Site
city: Rio de Janeiro
country: Brazil
facility: Novartis Investigation Site
city: Rio de Janeiro
country: Brazil
facility: Novartis Investigative Site
city: Sao Paulo
country: Brazil
facility: Novartis Investigational Site
city: Pleven
country: Bulgaria
facility: Novartis Investigative Site
city: Plovdiv
country: Bulgaria
facility: Novartis Investigative Site
city: Sofia
country: Bulgaria
facility: Novartis Investigative Site
city: Sofia
country: Bulgaria
facility: Novartis Investigational Site
city: Sofia
country: Bulgaria
facility: Novartis Investigational Site
city: Sofia
country: Bulgaria
facility: Novartis Investigative Site
city: Varna
country: Bulgaria
facility: Novartis Investigative Site
city: New Westminster
country: Canada
facility: Novartis Investigative Site
state: British Columbia
city: Kitchener
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Newmarket
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Ottawa
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Greenfield Park
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Sherbrooke
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Saskatoon
country: Canada
facility: Novartis Investigative Site
state: Saskatchewan
city: Karlsruhe
country: Germany
facility: Novartis Investigative Site
state: Baden-Wuerttemberg
city: Stuttgart
country: Germany
facility: Novartis Investigative Site
state: Baden-Wuerttemberg
city: Stuttgart
country: Germany
facility: Novartis Investigative Site
state: Baden-Wuerttemberg
city: Villingen-Schwenningen
country: Germany
facility: Novartis Investigative Site
state: Baden-Wuerttemberg
city: Muenchen
country: Germany
facility: Novartis Investigative Site
state: Bayern
city: Frankfurt
country: Germany
facility: Novartis Investigative Site
state: Hessen
city: Kassel
country: Germany
facility: Novartis Investigative Site
state: Hessen
city: Hannover
country: Germany
facility: Novartis Investigative Site
state: Niedersachsen
city: Lehrte
country: Germany
facility: Novartis Investigative Site
state: Niedersachsen
city: Essen
country: Germany
facility: Novartis Investigative Site
state: Nordrhein-Westfalen
city: Moenchengladbach-Rheydt
country: Germany
facility: Novartis Investigative Site
state: Nordrhein-Westfalen
city: Muenster
country: Germany
facility: Novartis Investigative Site
state: Nordrhein-Westfalen
city: Saarbruecken
country: Germany
facility: Novartis Investigative Site
state: Saarland
city: Dresden
country: Germany
facility: Novartis Investigative Site
state: Sachsen
city: Hamburg
country: Germany
facility: Novartis Investigational Site
city: Lubeck
country: Germany
facility: Novartis Investigational Site
city: Athens,
country: Greece
facility: Novartis Investigative Site
city: Athens
country: Greece
facility: Novartis Investigative Site
city: Thessaloniki
country: Greece
facility: Novartis Investigative Site
city: Thessaloniki
country: Greece
facility: Novartis Investigative Site
city: Bangalore
country: India
facility: Novartis Investigative Site
city: Mumbai
country: India
facility: Novartis Investigative Site
city: Mumbai
country: India
facility: Novartis Investigative Site
city: New Delhi
country: India
facility: Novartis Investigative Site
city: Pune
country: India
facility: Novartis Investigative Site
city: Vadodara
country: India
facility: Novartis Investigative Site
city: Potenza
country: Italy
facility: Novartis Investigative Site
state: Basilicata
city: Roma
country: Italy
facility: Novartis Investigative Site
state: Lazio
city: Roma
country: Italy
facility: Novartis Investigative Site
state: Lazio
city: Genova
country: Italy
facility: Novartis Investigative Site
state: Liguria
city: Pavia
country: Italy
facility: Novartis Investigative Site
state: Lombardia
city: Ascoli Piceno
country: Italy
facility: Novartis Investigative Site
state: Marche
city: Alessandria
country: Italy
facility: Novartis Investigative Site
state: Piemonte
city: Novara
country: Italy
facility: Novartis Investigative Site
state: Piemonte
city: Catania
country: Italy
facility: Novartis Investigative Site
state: Sicilia
city: Palermo
country: Italy
facility: Novartis Investigative Site
state: Sicilia
city: Guadalajara
country: Mexico
facility: Novartis Investigative Site
state: Jalisco
city: Monterrey
country: Mexico
facility: Novartis Investigative Site
state: Nuevo León
city: Monterrey
country: Mexico
facility: Novartis Investigative Site
state: Nuevo León
city: Mexico City
country: Mexico
facility: Novartis Investigative Site
city: Amersfoort
country: Netherlands
facility: Novartis Investigative Site
city: Den Haag
country: Netherlands
facility: Novartis Investigative Site
city: Nijmegen
country: Netherlands
facility: Novartis Investigative Site
city: Rotterdam
country: Netherlands
facility: Novartis Investigative Site
city: Rotterdam
country: Netherlands
facility: Novartis Investigative Site
city: Bialystok
country: Poland
facility: Novartis Investigative Site
city: Chorzow
country: Poland
facility: Novartis Investigative Site
city: Krakow
country: Poland
facility: Novartis Investigative Site
city: Lodz
country: Poland
facility: Novartis Investigative Site
city: Opole
country: Poland
facility: Novartis Investigative Site
city: Slupsk
country: Poland
facility: Novartis Investigative Site
city: Szczecin
country: Poland
facility: Novartis Investigative Site
city: Warszawa
country: Poland
facility: Novartis Investigative Site
city: Warszawa
country: Poland
facility: Novartis Investigative Site
city: Warszawa
country: Poland
facility: Novartis Investigative Site
city: Wroclaw
country: Poland
facility: Novartis Investigative Site
city: Bucharest
country: Romania
facility: Novartis Investigative Site
city: Bucharest
country: Romania
facility: Novartis Investigative Site
city: Iasi
country: Romania
city: Iasi
country: Romania
facility: Novartis Investigative Site
city: Kazan
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Novosibirsk
country: Russian Federation
facility: Novartis Investigative Site
city: St'Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: St. Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Salamanca
country: Spain
facility: Novartis Investigative Site
city: Sevilla
country: Spain
facility: Novartis Investigative Site
city: Taichung
country: Taiwan
facility: Novartis Investigative Site
city: Taipei city
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigational Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Cherkasy
country: Ukraine
facility: Novartis Investigative Site
city: Dnipropetrovsk
country: Ukraine
facility: Novartis Investigative Site
city: Kharkiv
country: Ukraine
facility: Novartis Investigative Site
city: Khmelnytskyi
country: Ukraine
facility: Novartis Investigative Site
city: Kyiv
country: Ukraine
facility: Novartis Investigative Site
city: Kyiv
country: Ukraine
facility: Novartis Investigative Site
city: Lviv
country: Ukraine
facility: Novartis Investigative Site
city: Makiivka
country: Ukraine
facility: Novartis Investigative Site
city: Simferopil
country: Ukraine
facility: Novartis Investigational Site
city: Vinnitsa
country: Ukraine
facility: Novartis Investigative Site
city: Zhytomyr
country: Ukraine
facility: Novartis Investigational Site
city: Birmingham
country: United Kingdom
facility: Novartis Investigative Site
city: Bradford
country: United Kingdom
facility: Novartis Investigative Site
city: Burton on Trent
country: United Kingdom
facility: Novartis Investigative Site
city: Cottingham
country: United Kingdom
facility: Novartis Investigative Site
city: Dudley
country: United Kingdom
facility: Novartis Investigative Site
city: Glasgow
country: United Kingdom
facility: Novartis Investigative Site
city: Leicester
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: Manchester
country: United Kingdom
facility: Novartis Investigative Site
city: Sutton
country: United Kingdom
facility: Novartis Investigative Site
city: Swindon
country: United Kingdom
facility: Novartis Investigative Site
city: Truro
country: United Kingdom
facility: Novartis Investigative Site
city: Uxbridge
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Robak T, Warzocha K, Govind Babu K, Kulyaba Y, Kuliczkowski K, Abdulkadyrov K, Loscertales J, Kryachok I, Kloczko J, Rekhtman G, Homenda W, Blonski JZ, McKeown A, Chang CN, Bal V, Lisby S, Gupta IV, Grosicki S. Health-related quality of life and patient-reported outcomes of ofatumumab plus fludarabine and cyclophosphamide versus fludarabine and cyclophosphamide in the COMPLEMENT 2 trial of patients with relapsed CLL. Leuk Lymphoma. 2017 Jul;58(7):1598-1606. doi: 10.1080/10428194.2016.1253837. Epub 2016 Nov 10.
citation: Robak T, Warzocha K, Govind Babu K, Kulyaba Y, Kuliczkowski K, Abdulkadyrov K, Loscertales J, Kryachok I, Kloczko J, Rekhtman G, Homenda W, Blonski JZ, McKeown A, Gorczyca MM, Carey JL, Chang CN, Lisby S, Gupta IV, Grosicki S. Ofatumumab plus fludarabine and cyclophosphamide in relapsed chronic lymphocytic leukemia: results from the COMPLEMENT 2 trial. Leuk Lymphoma. 2017 May;58(5):1084-1093. doi: 10.1080/10428194.2016.1233536. Epub 2016 Oct 12.
citation: Jewell RC, Laubscher K, Lewis E, Fang L, Gafoor Z, Carey J, McKeown A, West S, Wright O, Sedoti D, Dixon I, Hottenstein CS, Chan G. Assessment of the effect of ofatumumab on cardiac repolarization. J Clin Pharmacol. 2015 Jan;55(1):114-21. doi: 10.1002/jcph.376. Epub 2014 Aug 21.