Ofatumumab Added to Fludarabine-Cyclophosphamide vs Fludarabine-Cyclophosphamide Combination in Relapsed Subjects With Chronic Lymphocytic Leukemia

A Phase III, Open Label, Randomized Trial of Ofatumumab Added to Fludarabine-Cyclophosphamide vs. Fludarabine-Cyclophosphamide Combination in Subjects With Relapsed Chronic Lymphocytic Leukemia

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).

Study Overview

• Status: Completed
• Conditions: Leukaemia, Lymphocytic, Chronic
• Intervention / Treatment: Drug: OFC Infusion; Drug: FC infusion

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.

• Study Type: Interventional
• Enrollment (Actual): 365
• Phase: Phase 3

Contacts and Locations

Study Locations

• Brazil
  • Porto Alegre, Brazil, 91350
    • Novartis Investigational site
  • Rio de Janeiro, Brazil, 20211-030
    • Novartis Investigative Site
  • Rio de Janeiro, Brazil, 20230-130
    • Novartis Investigation Site
  • Rio de Janeiro, Brazil, 21941-913
    • Novartis Investigative Site
  • Sao Paulo, Brazil, 03102-002
    • Novartis Investigational site
  • Goiás
    • Brasilia, Goiás, Brazil, 70390-150
      • Novartis Investigative Site
  • Rio Grande Do Sul
    • Porto Alegre, Rio Grande Do Sul, Brazil, 90610000
      • Novartis Investigative Site
  • São Paulo
    • Sao Paulo, São Paulo, Brazil, 05403-000
      • Novartis Investigative Site
• Bulgaria
  • Pleven, Bulgaria, 5800
    • Novartis Investigative Site
  • Plovdiv, Bulgaria, 4000
    • Novartis Investigative Site
  • Sofia, Bulgaria, 1233
    • Novartis Investigative Site
  • Sofia, Bulgaria
    • Novartis Investigative Site
  • Sofia, Bulgaria, 1407
    • Novartis Investigational site
  • Sofia, Bulgaria, 1606
    • Novartis Investigational site
  • Varna, Bulgaria, 9010
    • Novartis Investigative Site
• Canada
  • British Columbia
    • New Westminster, British Columbia, Canada, V3L 3W4
      • Novartis Investigative Site
  • Ontario
    • Kitchener, Ontario, Canada, N2G 1G3
      • Novartis Investigative Site
    • Newmarket, Ontario, Canada, L3Y 2P9
      • Novartis Investigative Site
    • Ottawa, Ontario, Canada, K1H 8L6
      • Novartis Investigative Site
  • Quebec
    • Greenfield Park, Quebec, Canada, J4V 2H1
      • Novartis Investigative Site
    • Montreal, Quebec, Canada, H1T 2M4
      • Novartis Investigative Site
    • Sherbrooke, Quebec, Canada, J1H 5N4
      • Novartis Investigative Site
  • Saskatchewan
    • Saskatoon, Saskatchewan, Canada, S7N 4H4
      • Novartis Investigative Site
• Germany
  • Hamburg, Germany, 22767
    • Novartis Investigational site
  • Lubeck, Germany, 23562
    • Novartis Investigational site
  • Baden-Wuerttemberg
    • Karlsruhe, Baden-Wuerttemberg, Germany, 76137
      • Novartis Investigative Site
    • Stuttgart, Baden-Wuerttemberg, Germany, 70376
      • Novartis Investigative Site
    • Stuttgart, Baden-Wuerttemberg, Germany, 70190
      • Novartis Investigative Site
    • Villingen-Schwenningen, Baden-Wuerttemberg, Germany, 78052
      • Novartis Investigative Site
  • Bayern
    • Muenchen, Bayern, Germany, 81241
      • Novartis Investigative Site
  • Hessen
    • Frankfurt, Hessen, Germany, 65929
      • Novartis Investigative Site
    • Kassel, Hessen, Germany, 34119
      • Novartis Investigative Site
  • Niedersachsen
    • Hannover, Niedersachsen, Germany, 30625
      • Novartis Investigative Site
    • Lehrte, Niedersachsen, Germany, 31275
      • Novartis Investigative Site
  • Nordrhein-Westfalen
    • Essen, Nordrhein-Westfalen, Germany, 45122
      • Novartis Investigative Site
    • Moenchengladbach-Rheydt, Nordrhein-Westfalen, Germany, 41239
      • Novartis Investigative Site
    • Muenster, Nordrhein-Westfalen, Germany, 48149
      • Novartis Investigative Site
  • Saarland
    • Saarbruecken, Saarland, Germany, 66113
      • Novartis Investigative Site
  • Sachsen
    • Dresden, Sachsen, Germany, 01307
      • Novartis Investigative Site
• Greece
  • Athens, Greece, 11527
    • Novartis Investigative Site
  • Athens,, Greece, 11 527
    • Novartis Investigative Site
  • Thessaloniki, Greece, 564 29
    • Novartis Investigative Site
  • Thessaloniki, Greece, 57010
    • Novartis Investigative Site
• India
  • Bangalore, India, 560029
    • Novartis Investigative Site
  • Mumbai, India, 400012
    • Novartis Investigative Site
  • Mumbai, India, 400014
    • Novartis Investigative Site
  • New Delhi, India, 110029
    • Novartis Investigative Site
  • Pune, India, 411001
    • Novartis Investigative Site
  • Vadodara, India, 390007
    • Novartis Investigative Site
• Italy
  • Basilicata
    • Potenza, Basilicata, Italy, 85100
      • Novartis Investigative Site
  • Lazio
    • Roma, Lazio, Italy, 00041
      • Novartis Investigative Site
    • Roma, Lazio, Italy, 00161
      • Novartis Investigative Site
  • Liguria
    • Genova, Liguria, Italy, 16132
      • Novartis Investigative Site
  • Lombardia
    • Pavia, Lombardia, Italy, 27100
      • Novartis Investigative Site
  • Marche
    • Ascoli Piceno, Marche, Italy, 63100
      • Novartis Investigative Site
  • Piemonte
    • Alessandria, Piemonte, Italy, 15100
      • Novartis Investigative Site
    • Novara, Piemonte, Italy, 28100
      • Novartis Investigative Site
  • Sicilia
    • Catania, Sicilia, Italy, 95124
      • Novartis Investigative Site
    • Palermo, Sicilia, Italy, 90146
      • Novartis Investigative Site
• Mexico
  • Mexico City, Mexico, CP 14080
    • Novartis Investigative Site
  • Jalisco
    • Guadalajara, Jalisco, Mexico, 44280
      • Novartis Investigative Site
  • Nuevo León
    • Monterrey, Nuevo León, Mexico, 64710
      • Novartis Investigative Site
    • Monterrey, Nuevo León, Mexico, 64460
      • Novartis Investigative Site
• Netherlands
  • Amersfoort, Netherlands, 3818 ES
    • Novartis Investigative Site
  • Den Haag, Netherlands, 2545 CH
    • Novartis Investigative Site
  • Nijmegen, Netherlands, 6525 GA
    • Novartis Investigative Site
  • Rotterdam, Netherlands, 3075 EA
    • Novartis Investigative Site
  • Rotterdam, Netherlands, 3015 CE
    • Novartis Investigative Site
• Poland
  • Bialystok, Poland, 15-276
    • Novartis Investigative Site
  • Chorzow, Poland, 41-500
    • Novartis Investigative Site
  • Krakow, Poland, 31-501
    • Novartis Investigative Site
  • Lodz, Poland, 93-510
    • Novartis Investigative Site
  • Opole, Poland, 45-372
    • Novartis Investigative Site
  • Slupsk, Poland, 76-200
    • Novartis Investigative Site
  • Szczecin, Poland, 71-242
    • Novartis Investigative Site
  • Warszawa, Poland, 02-781
    • Novartis Investigative Site
  • Warszawa, Poland, 02-507
    • Novartis Investigative Site
  • Warszawa, Poland, 02-776
    • Novartis Investigative Site
  • Wroclaw, Poland, 50-367
    • Novartis Investigative Site
• Romania
  • Bucharest, Romania, 022328
    • Novartis Investigative Site
  • Bucharest, Romania, 050098
    • Novartis Investigative Site
  • Iasi, Romania, 700483
    • Novartis Investigative Site
  • Iasi, Romania, 300328
• Russian Federation
  • Kazan, Russian Federation, 420029
    • Novartis Investigative Site
  • Moscow, Russian Federation, 115478
    • Novartis Investigative Site
  • Moscow, Russian Federation, 125167
    • Novartis Investigative Site
  • Moscow, Russian Federation, 125101
    • Novartis Investigative Site
  • Novosibirsk, Russian Federation, 630087
    • Novartis Investigative Site
  • St'Petersburg, Russian Federation, 191024
    • Novartis Investigative Site
  • St. Petersburg, Russian Federation, 197 089
    • Novartis Investigative Site
• Spain
  • Barcelona, Spain, 08025
    • Novartis Investigative Site
  • Barcelona, Spain, 08003
    • Novartis Investigative Site
  • Barcelona, Spain, 08916
    • Novartis Investigative Site
  • Madrid, Spain, 28046
    • Novartis Investigative Site
  • Madrid, Spain, 28006
    • Novartis Investigative Site
  • Madrid, Spain, 28040
    • Novartis Investigative Site
  • Salamanca, Spain, 37007
    • Novartis Investigative Site
  • Sevilla, Spain, 41014
    • Novartis Investigative Site
• Taiwan
  • Taichung, Taiwan, 404
    • Novartis Investigative Site
  • Taipei, Taiwan, 112
    • Novartis Investigative Site
  • Taipei, Taiwan, 404
    • Novartis Investigational site
  • Taipei city, Taiwan, 100
    • Novartis Investigative Site
• Thailand
  • Bangkok, Thailand, 10330
    • Novartis Investigative Site
  • Bangkok, Thailand, 10700
    • Novartis Investigative Site
  • Bangkok, Thailand, 10400
    • Novartis Investigative Site
• Ukraine
  • Cherkasy, Ukraine, 18009
    • Novartis Investigative Site
  • Dnipropetrovsk, Ukraine, 49102
    • Novartis Investigative Site
  • Kharkiv, Ukraine, 61070
    • Novartis Investigative Site
  • Khmelnytskyi, Ukraine, 29000
    • Novartis Investigative Site
  • Kyiv, Ukraine, 03022
    • Novartis Investigative Site
  • Kyiv, Ukraine, 04112
    • Novartis Investigative Site
  • Lviv, Ukraine, 79044
    • Novartis Investigative Site
  • Makiivka, Ukraine, 86132
    • Novartis Investigative Site
  • Simferopil, Ukraine, 95023
    • Novartis Investigational site
  • Vinnitsa, Ukraine, 21018
    • Novartis Investigative Site
  • Zhytomyr, Ukraine, 10002
    • Novartis Investigational site
• United Kingdom
  • Birmingham, United Kingdom, B9 5SS
    • Novartis Investigative Site
  • Bradford, United Kingdom, BD96RJ
    • Novartis Investigative Site
  • Burton on Trent, United Kingdom, DE13 0RB
    • Novartis Investigative Site
  • Cottingham, United Kingdom, HU16 5JQ
    • Novartis Investigative Site
  • Dudley, United Kingdom, DY1 2HQ
    • Novartis Investigative Site
  • Glasgow, United Kingdom, G12 OYN
    • Novartis Investigative Site
  • Leicester, United Kingdom, LE1 5WW
    • Novartis Investigative Site
  • London, United Kingdom, SE5 9RS
    • Novartis Investigative Site
  • Manchester, United Kingdom, M13 9WL
    • Novartis Investigative Site
  • Sutton, United Kingdom, SM5 1AA
    • Novartis Investigative Site
  • Swindon, United Kingdom, SN3 6BB
    • Novartis Investigative Site
  • Truro, United Kingdom, TR1 3LJ
    • Novartis Investigative Site
  • Uxbridge, United Kingdom, UB8 3NN
    • Novartis Investigative Site
• United States
  • Florida
    • Boca Raton, Florida, United States, 33486
      • Novartis Investigative Site
  • Illinois
    • Chicago, Illinois, United States, 60612-3833
      • Novartis Investigative Site
  • Maryland
    • Clinton, Maryland, United States, 20735
      • Novartis Investigative Site
  • Missouri
    • Kansas City, Missouri, United States, 64128
      • Novartis Investigative Site
    • Saint Louis, Missouri, United States, 63110
      • Novartis Investigative Site
  • Tennessee
    • Memphis, Tennessee, United States, 38120
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Ofatumumab, Fludarabine, Cyclophosphamide; Ofatumumab Cycle 1-Day 1 300mg, Cycle 1-Day 8 1000mg, then Cycles 2-6 Day 1 1000mg every 28 days, Fludarabine 25mg/m2 Days 1-3 every 28 days for 6 cycles, Cyclophosphamide 250 mg/m2 Days 1-3 every 28 days for 6 cycles	Drug: OFC Infusion; Ofatumumab Cycle 1-Day 1 300mg, Cycle 1-Day 8 1000mg, then Cycles 2-6 Day 1 1000mg every 28 days, Fludarabine 25mg/m2 Days 1-3 every 28 days for 6 cycles, Cyclophosphamide 250 mg/m2 Days 1-3 every 28 days for 6 cycles
ACTIVE_COMPARATOR: Fludarabine, Cyclophosphamide; Fludarabine 25mg/m2 Days 1-3 every 28 days for 6 cycles, Cyclophosphamide 250 mg/m2 Days 1-3 every 28 days for 6 cycles	Drug: FC infusion; Fludarabine 25mg/m2 Days 1-3 every 28 days for 6 cycles, Cyclophosphamide 250mg/m2 Days 1-3 every 28 days for 6 cycles

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival (PFS), as Assessed by the Independent Review Committee (IRC)	PFS is defined as the interval of time between the date of randomization and the earlier of the date of disease progression (progressive disease,PD) and the date of death due to any cause. PD requires at least one of the following: lymphadenopathy, appearance of any new lesion such as enlargerd lymph nodes (>1.5 cm) spleen or liver or other infiltrates or an increase by 50% or more in the greatest diameter of any previous site; an increase by 50% or more in the previously noted enlargement of the liver or spleen, an increase by 50% or more in the numbers of blood lymphocytes with at least 5000 lymphocytes per microliter, transformation to a more aggressive histology, or occurrence of cytopenia attributable to chronic lymphocytic leukaemia (CLL).	From randomization up to 5 years after last dose of study drug

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	Overall survival is defined as the time from randomization to death due to any cause. Each participant was followed at the time when the last IRC-assessed PFS events occurred. Participants who had not died were censored at the date of last contact.	From randomization up to 5 years after last dose of study drug
Time to Response, as Assessed by the IRC	Time to response is defined as the time from randomization to the first response. Complete Response/remission(CR) all the criteria at least 2 months after last treatment: no lymphadenopathy(Ly) > 1.5 cm/ hepatomegaly/spleenomegaly/constitutional symptoms; neutrophils >1500 per microliter(µL), platelets(PL) >100,000/µL, hemoglobin(Hb) >11 grams/deciliter(g/dL), lymphocytes(LC) <4000/µL, bone marrow(BM) sample must be normocellular for age, <30% LC, no lymphoid nodule. Incomplete bone marrow recovery(CRi): CR criteria, persistent anemia/thrombocytopenia/neutropenia unrelated to CLL but related to drug toxicity. Partial Remission/response(PR): >=50% decrease in LC, Ly, size of liver and spleen and at least one of the following results: PL >100,000/µL or 50% improvement over Baseline(BL), Hb >11 g/dL or 50% improvement over BL. Nodular PR(nPR): persistent nodules BM.	From randomization up to 5 years after last dose of study drug
Duration of Response (DOR), as Assessed by the IRC	DOR is defined as the time from the initial response (CR, CRi, nPR, or PR) to the first documented sign of PD or death due to any cause. PD requires at least one of the following: lymphadenopathy, appearance of any new lesion such as enlargerd lymph nodes (>1.5 cm) spleen or liver or other infiltrates or an increase by 50% or more in the greatest diameter of any previous site; an increase by 50% or more in the previously noted enlargement of the liver or spleen, an increase by 50% or more in the numbers of blood lymphocytes with at least 5000 lymphocytes per microliter, transformation to a more aggressive histology, or occurrence of cytopenia attributable to chronic lymphocytic leukaemia.	From time of initial response to disease progression or death, whichever came first (up to 5 years after the last dose of study drug)
Time to Progression, as Assessed by the IRC	Time to progression is defined as the time from the date of randomization to PD. PD requires at least one of the following: lymphadenopathy, appearance of any new lesion such as enlargerd lymph nodes (>1.5 cm) spleen or liver or other infiltrates or an increase by 50% or more in the greatest diameter of any previous site; an increase by 50% or more in the previously noted enlargement of the liver or spleen, an increase by 50% or more in the numbers of blood lymphocytes with at least 5000 lymphocytes per microliter, transformation to a more aggressive histology, or occurrence of cytopenia attributable to chronic lymphocytic leukaemia.	From randomization up to 5 years after the last dose of study drug
Time to Next Therapy	Time to next therapy is defined as the time from randomization until the start of the next-line of treatment. Data are presented for participants who took anti-cancer therapies and participants in the ITT population.	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)
Number of Participants With Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status	The ECOG performance status scales and criteria are used by doctors and researchers to assess how a participant's disease is progressing, how the disease affects the daily living, and determines appropriate treatment and prognosis. ECOG performance status are measured at Cycle 2 Day1, Cycle 3 Day1, Cycle 4 Day1, Cycle 5 Day1 and Cycle 6 Day1. During follow period, 1 M after study drug therapy, then every 3 month up to 5 year (up to 60 months). Improvement is defined as a decrease from baseline by at least one step on the ECOG performance status scale (yes/no).	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)
Number of Participants With no B-Symptoms or at Least One B-symptoms Over the Time	Participants with no B-symptoms (B-Sy) (no night sweat, no weight loss, no fever and no extreme fatigue) and at least one indicated B-sy(night sweats, weight loss, fever or extreme fatigue) were presented at Screening, Cycle 1 Day 1, Cycle 2 Day1, Cycle 3 Day1, Cycle 4 Day1, Cycle 5 Day1, Cycle 6 Day 1 and during follow up period at 1 M after study drug therapy, then every 3 M up to 5 year (up to 60 months).	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)
Percentage of Participants With the Best Overall Response (OR), as Assessed by the IRC	OR is defined as the number of participants achieving an objective response (complete response [CR], CR with incomplete bone marrow recovery [CRi], partial response [PR], and nodular PR [nPR]). CR (all the criteria at least 2 months after last treatment): no lymphadenopathy (Ly) > 1.5 cm/ hepatomegaly/ splenomegaly/ constitutional symptoms; neutrophils >1500 per microliter (µL), platelets (PL) >100,000/µL, hemoglobin (Hb) >11 grams/deciliter (g/dL), lymphocytes (LC) <4000/µL, bone marrow (BM) sample must be normocellular for age, <30% LC, no lymphoid nodule. CRi: CR criteria, persistent anemia/thrombocytopenia/neutropenia unrelated to CLL but related to drug toxicity. PR: >=50% decrease in LC, Ly, size of liver and spleen and at least one of the following results: PL >100,000/µL or 50% improvement over Baseline (BL), Hb >11 g/dL or 50% improvement over BL. nPR: persistent nodules BM.	From randomization up to 5 years after last dose of study drug
Percentage of Participants With the Best OR, as Assessed by the Investigator	OR is defined as the number of participants achieving an objective response (complete response [CR], CR with incomplete bone marrow recovery [CRi], partial response [PR], and nodular PR [nPR]). CR (all the criteria at least 2 months after last treatment): no lymphadenopathy (Ly) > 1.5 cm/ hepatomegaly/ splenomegaly/ constitutional symptoms; neutrophils >1500 per microliter (µL), platelets (PL) >100,000/µL, hemoglobin (Hb) >11 grams/deciliter (g/dL), lymphocytes (LC) <4000/µL, bone marrow (BM) sample must be normocellular for age, <30% LC, no lymphoid nodule. CRi: CR criteria, persistent anemia/thrombocytopenia/neutropenia unrelated to CLL but related to drug toxicity. PR: >=50% decrease in LC, Ly, size of liver and spleen and at least one of the following results: PL >100,000/µL or 50% improvement over Baseline (BL), Hb >11 g/dL or 50% improvement over BL. nPR: persistent nodules BM. Responder = CR + CRi + NPR + PR	From randomization up to 5 years after last dose of study drug
Number of Participants Who Were Negative for Minimal Residual Disease (MRD) Assessed by IRC	MRD refers to small number of leukemic cells that remain in the participant during treatment or after treatment at the time the participant achieved a confirmed CR. MRD analysis was performed for the participants who were suspected of achieving a primary endpoint CR. MDR was performed by flow cytometry on a bone marrow or peripheral blood sample taken at least 2 months after final treatment. MRD negative was defined as less than one CLL cell per 10000 leukocytes.	From randomization up to 5 years after last dose of study drug
Number of Participants Who Were Negative for MRD Assessed by Investigator	MRD refers to small number of leukemic cells that remain in the participant during treatment or after treatment at the time the participant achieved a confirmed CR. MRD analysis was performed for the participants who were suspected of achieving a primary endpoint CR. MDR was performed by flow cytometry on a bone marrow or peripheral blood sample taken at least 2 months after final treatment. MRD negative was defined as less than one CLL cell per 10000 leukocytes.	From randomization up to 5 years after last dose of study drug
Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)	An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury.	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)
Number of Participants With a Human Anti-human Antibody (HAHA) Positive Result at Indicated Time Points	Serum samples for analysis of HAHA were collected at Baseline (Screening), after 3 cycles were compelted, after 1 M and 6 M post last dose. All samples were first tested in a screening step; positive samples from the screening were further evaluated in a confirmation test. The confirmed positive samples were reported as HAHA-positive.	From start of study drug until 60 days after the last dose of study medication
Number of Participants With Autoimmune Hemolytic Anaemia (AIHA)	AIHA is a condition where the body's immune system fails to recognize red blood cells as "self" and begins destroying these red blood cells. The number of participants experienced AIHA are presented.	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)
Number of Participants With Drug Related Infections Reported as AEs and SAEs of Maximum Severity of Grade 3 or Higher	An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury. Maximum severity grades were evaluated according to the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) version 3.0 (1, mild; 2, moderate; 3, severe; 4, life-threatening/disabling; 5, death).	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)
Number of Participants With at Least One Grade 3/Grade 4 Myelosuppression Adverse Events	Participants with at least one Grade 3 or Grade 4 myelosuppression (anemia, neutropenia, and thrombocytopenia) are presented. Myelosuppression is defined as the decrease in the ability of the bone marrow to produce blood cells. AEs were graded according to NCI common terminology criteria for adverse events (CTCAE) grade, version 3.0 (1, mild; 2, moderate; 3, severe; 4, life-threatening/disabling; 5, death).	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)
Number of Participants Who Received no Transfusion or at Least One Transfusion During the Study	Participants who received no transfusion and at least one transfusion during the study are presented. Participants who took any blood products or blood supportive care product are included.	From randomization up to 5 years after last dose of study drug
Mean Level of Immunoglobulin (Ig) Antibodies IgA, IgG, and IgM	Immunoglobulins, or antibodies, are large proteins used by the immune system to identify and neutralize foreign particles such as bacteria and viruses. Their normal blood levels indicate proper immune status. Low levels indicate immuno-suppression. Blood samples were collected from each participant and IgA, IgG, and IgM were measured at Baseline, and 1M and 6M after last dose during follow up period.	Baseline, 1M and 6M follow up
Change From Baseline in Cluster of Differentiation (CD) Cell Counts, CD5+ and CD19+	CD5+ and CD19+ cells were counted by flow cytometry at Screening (Baseline) on Cycle 1 Day 1, 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 during the treatment period and after last dose of study drug at 1 M and then every three month follow up up to 45 M. Flow cytometry is a technique for counting and examining microscopic particles with an electronic detection apparatus. Baseline is defined as the assessment closest to but prior to first dose (e.g. day 1 if available, otherwise, screening). Change from Baseline was calculated as the post-Baseline value minus the Baseline value.	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
Change From Baseline in Cell Counts, CD5- CD19+	CD5- CD19+ cells were counted by flow cytometry at Screening (baseline) at 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 during treatment period and after last dose of study drug at 1 M and then every three month up to 45 M during follow up period. Flow cytometry is a technique for counting and examining microscopic particles with an electronic detection apparatus. Baseline is defined as the assessment closest to but prior to first dose (e.g. Day 1 if available otherwise screening). Change from Baseline was calculated as the post-Baseline value minus the Baseline value.	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
Prognostic and Biological Markers Correlating With Clinical Response	Blood samples were collected for the assessment of the following prognostic markers at BL: immunoglobulin heavy chain variable region(IgVH) homology; Zeta-Chain-Associated Protein Kinase 70(ZAP70), VH3-21 usage; Cytogenetics (by fluorescent in situ hybridization [FISH]); beta 2 microglobulin. Cox-regression model was used to explore the relationship between progression-free survival and the following explanatory variables: treatment group, cytogenetics (analyzed by FISH included 6q-,11q-, +12q, 17p-, 13q-) , ZAP-70 (positive, negative or intermediate), VH3-21 usage (Yes and No), IgVH homology (>98%, 97%-98% and <97%), beta 2 microglobulin (>3500 microgram per liter [µg/L] and <=3500 µg/L). For each covariate, a hazard ratio <1 indicates a lower risk on the first effect tested compared with the other effects tested. Cytogenetics Group (based on >=20%)=cytogenetics (CY G).	From randomization up to 5 years after last dose of study drug
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)	The EORTC QLQ-CLL16 is comprised of 16 questions that address 5 domains of health-related quality of life (HRQoL) important in CLL. There are 4 multi-item scales - fatigue (2 items), treatment side effects ([TSE], 4 items), disease symptoms (disease effects scale [DES], 4 items), and infection scale [IS] (4 items) - and single item scales (social activities [Social Problems (SP) Scale] and future health worries[Future Health (FH) Scale].). These are measured on a four point scale where 1 = not at all and 4 = very much. These scores are transformed to give a rating from 0 - 100, where 0 =no symptoms or problems and 100 = a severe symptoms or problems. EORTC QLQ-CLL16 was assessed at Screening; Cycle 4 Day 1 and during follow-up 1 M and every 3 M up to 24 months. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. The Baseline value was obtained at randomization.	Screening, Cycle 3 Day 1, and 1 M and every 3 month post last dose up to 24 month.
Change From Baseline in Patient Reported Outcome (PRO) as Assessed by EuroQoL Five-Dimension (EQ-5D) Score at Indicated Visit	EQ-5D is comprised of a 5-item health status measure and a visual analogue scale (VAS) and is used to generate two scores: the utility score and the thermometer score. The utility score measures mobility, self-care, usual activities, pain, discomfort, and anxiety/depression. Responses to each of the 5 health states are measured on a 3-point scale (level 1 = no problem; level 2 = some or moderate problem(s) and level 3 = unable, or extreme problems). Responses are typically converted into health utilities or valuations on a scale ranging from 0 (death) to 1 (perfect health). The thermometer score ranges from 0 (worst imaginable health state) to 100 (best imaginable health state). Change from Baseline was calculated as the post-Baseline value minus the Baseline value. A Negative health status describes health state worse than death.Baseline is the most recent, non-missing value prior to or on the first study drug dose date.	Screening, Cycle 3 Day 1, and 1 M and every 3 month post last dose up to 24 month.
Change From Baseline in the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Score	EORTC QLQ-C30, a self-reported, cancer-specific instrument assessing 15 domains: physical, role, emotional, cognitive and social functioning, pain,fatigue, nausea and vomiting, insomnia, loss of appetite, constipation, diarrhea, and dyspnea, financial difficulties and a global health status/quality of life (QOF). Functional and symptoms scales were measured on four point Likert scale where 1 = not at all and 4 = very much. Pat. assessed at Screening; Cycle 4 Day 1 and during follow-up 1 M and every 3 M up to 24 months. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Baseline is the most recent, non-missing value prior to or on the first study treatment dose date. Clinically meaningful changes or minimally important differences (MIDs)have been previously established for the EORTC QLQ C30, and categorized as 'small' if the mean change in scores is 5-10 points, 'moderate' if 10-20 points, and 'large' if >20points.	Screening, Cycle 3 Day 1, and 1 M and every 3 month post last dose up to 24 month.
Mean of Health Change Questionnaire (HCQ)	The HCQ consists of a single question in which the participant is asked if he/she has experienced any change in his/her health overall since beginning the study. For HCQ, values from 1 to 9 were assigned to the 9 responses in the HCQ questionnaire, ranging from 1 for 'my health is a great deal better' to 9 for 'my health is a great deal worse' since the beginning of the study. Lower scores represent better conditions.	Screening, Cycle 3 Day 1, and 1 M and every 3 month post last dose up to 24 month.
Mean Area Under the Time-concentration Curve (AUC) Curve Over the Dosing Interval (AUC[0-tau]) of Ofatumumab	Area under the time-concentration curve (AUC) over the dosing interval (AUC[0-tau]) was evaluated. Blood samples were collected from participants who received ofatumumab plus fludarabine and cyclophosphamide predose and 0.5 h after the end of the ofatumumab infusion at treatment Cycle 1 and Cycle 4 (Days 1, 8, and 85). In addition, predose samples were collected prior to ofatumumab administration at Cycles 2, 3, 5, and 6 (Days 29, 57, 113, and 141).	Cycle 1 Week 1, Cycle 1 Week 2, Cycles 2,3,4,5,6
Maximum Concentration (Cmax) and Observed Drug Concentration Prior to the Next Dose (Ctrough) of Ofatumumab	Blood samples were collected to assess the plasma concentration of ofatumumab.Cmax and Ctrough were determined. Blood samples were collected from participants who received ofatumumab plus fludarabine and cyclophosphamide predose and 0.5 h after the end of the ofatumumab infusion at treatment Cycle 1 and Cycle 4 (Days 1, 8, and 85). In addition, predose samples were collected prior to ofatumumab administration at Cycles 2, 3, 5, and 6 (Days 29, 57, 113, and 141).	Cycle 1 Week 1, Cycle 1 Week 2, Cycles 2,3,4,5
Time of Occurrence of Cmax (Tmax) of Ofatumumab	Blood samples were collected from participants who received ofatumumab plus fludarabine and cyclophosphamide predose and 0.5 h after the end of the ofatumumab infusion at treatment Cycle 1 and Cycle 4.	Cycle 1 Week 1, Cycle 1 Week 2, Cycle 4

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 12, 2009
• Primary Completion (ACTUAL): December 17, 2014
• Study Completion (ACTUAL): October 25, 2017

Study Registration Dates

• First Submitted: January 15, 2009
• First Submitted That Met QC Criteria: January 15, 2009
• First Posted (ESTIMATE): January 16, 2009

Study Record Updates

• Last Update Posted (ACTUAL): June 18, 2020
• Last Update Submitted That Met QC Criteria: June 5, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Keywords: Safety; Ofatumumab; Efficacy; Relapsed; Oncology; Chronic Lymphocytic Leukemia
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia, B-Cell; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid
• Other Study ID Numbers: 110913

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No