Ofatumumab + Chlorambucil vs Chlorambucil Monotherapy in Previously Untreated Patients With Chronic Lymphocytic Leukemia (COMPLEMENT 1)

A Phase III, Open Label, Randomized, Multicenter Trial of Ofatumumab Added to Chlorambucil Versus Chlorambucil Monotherapy in Previously Untreated Patients With Chronic Lymphocytic Leukemia

The purpose of this study was to evaluate the safety and efficacy of ofatumumab added to chlorambucil in patients with untreated Chronic Lymphocytic Leukemia.

Study Overview

• Status: Terminated
• Conditions: Leukaemia, Lymphocytic, Chronic
• Intervention / Treatment: Drug: chlorambucil, tablets; Drug: ofatumumab (GSK1841157) infusion

Detailed Description

Chlorambucil, is currently approved for treatment of frontline chronic lymphocytic leukemia, especially, but not limited to the ailing and elderly patient population. Several other more aggressive treatment options are available (e.g. fludarabine), however they are not suitable for all CLL patients, especially the ailing and elderly, due to greater toxicity. Ofatumumab is effective with low toxicity. The addition of ofatumumab to chlorambucil offers potentially a more effective therapy, with limited toxicity. The objective of this study was to evaluate progression-free survival (PFS), overall response and overall survival in subjects with previously untreated CLL with ofatumumab added to chlorambucil versus chlorambucil.

• Study Type: Interventional
• Enrollment (Actual): 447
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Brugge, Belgium, 8000
    • Novartis Investigative Site
  • Bruxelles, Belgium, 1200
    • Novartis Investigative Site
  • Gent, Belgium, 9000
    • Novartis Investigative Site
  • Haine-Saint-Paul, Belgium, 7100
    • Novartis Investigative Site
  • Leuven, Belgium, 3000
    • Novartis Investigative Site
• Brazil
  • Rio De Janeiro
    • Porto Alegre, Rio De Janeiro, Brazil, 91350-200
      • Novartis Investigative Site
  • São Paulo
    • Sao Paulo, São Paulo, Brazil, 05403-000
      • Novartis Investigative Site
    • Sao Paulo, São Paulo, Brazil, 05651-901
      • Novartis Investigative Site
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M4N 3M5
      • Novartis Investigative Site
  • Quebec
    • Montreal, Quebec, Canada, H3A1A1
      • Novartis Investigative Site
    • Sherbrooke, Quebec, Canada, J1H 5N4
      • Novartis Investigative Site
• Czechia
  • Brno, Czechia, 625 00
    • Novartis Investigative Site
  • Hradec Kralove, Czechia
    • Novartis Investigative Site
  • Praha 10, Czechia, 100 34
    • Novartis Investigative Site
• France
  • Creteil, France, 94010
    • Novartis Investigative Site
  • Pierre Benite, France, 69495
    • Novartis Investigative Site
• Germany
  • Baden-Wuerttemberg
    • Karlsruhe, Baden-Wuerttemberg, Germany, 76137
      • Novartis Investigative Site
    • Mannheim, Baden-Wuerttemberg, Germany, 68161
      • Novartis Investigative Site
    • Stuttgart, Baden-Wuerttemberg, Germany, 70190
      • Novartis Investigative Site
    • Ulm, Baden-Wuerttemberg, Germany, 89081
      • Novartis Investigative Site
  • Bayern
    • Erlangen, Bayern, Germany, 91052
      • Novartis Investigative Site
    • Muenchen, Bayern, Germany, 81241
      • Novartis Investigative Site
    • Regensburg, Bayern, Germany, 93049
      • Novartis Investigative Site
    • Wuerzburg, Bayern, Germany, 97070
      • 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
    • Koeln, Nordrhein-Westfalen, Germany, 50937
      • 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
• Greece
  • Athens,, Greece, 11 527
    • Novartis Investigative Site
  • Thessaloniki, Greece, 564 29
    • Novartis Investigative Site
  • Thessaloniki, Greece, 57010
    • Novartis Investigative Site
• India
  • Ahmedabad, India, 380009
    • Novartis Investigative Site
  • 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
• Ireland
  • Cork, Ireland
    • Novartis Investigative Site
  • Dublin, Ireland, 7
    • Novartis Investigative Site
  • Galway, Ireland
    • Novartis Investigative Site
  • James Street, Ireland, 8
    • Novartis Investigative Site
  • Limerick, Ireland
    • Novartis Investigative Site
  • Tullamore, Ireland
    • Novartis Investigative Site
  • Waterford, Ireland
    • Novartis Investigative Site
• Italy
  • Udine, Italy, 33100
    • Novartis Investigative Site
  • Basilicata
    • Potenza, Basilicata, Italy, 85100
      • Novartis Investigative Site
  • Campania
    • Napoli, Campania, Italy, 80131
      • Novartis Investigative Site
  • Lazio
    • Albano Laziale (Roma), Lazio, Italy, 00041
      • Novartis Investigative Site
  • Liguria
    • Genova, Liguria, Italy, 16132
      • Novartis Investigative Site
  • Lombardia
    • Brescia, Lombardia, Italy, 25123
      • Novartis Investigative Site
    • Milano, Lombardia, Italy, 20133
      • Novartis Investigative Site
    • Milano, Lombardia, Italy, 20162
      • Novartis Investigative Site
    • Milano, Lombardia, Italy, 20132
      • Novartis Investigative Site
  • Marche
    • Ascoli Piceno, Marche, Italy, 63100
      • Novartis Investigative Site
  • Piemonte
    • Novara, Piemonte, Italy, 28100
      • Novartis Investigative Site
  • Puglia
    • Bari, Puglia, Italy, 70124
      • Novartis Investigative Site
  • Sicilia
    • Palermo, Sicilia, Italy, 90146
      • Novartis Investigative Site
  • Veneto
    • Venezia - Mestre, Veneto, Italy, 30174
      • Novartis Investigative Site
    • Vicenza, Veneto, Italy, 36100
      • Novartis Investigative Site
• Netherlands
  • Amersfoort, Netherlands, 3818 ES
    • Novartis Investigative Site
  • Amsterdam, Netherlands, 1105 AZ
    • Novartis Investigative Site
  • Den Haag, Netherlands, 2545 CH
    • Novartis Investigative Site
  • Groningen, Netherlands, 9713 GZ
    • 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
  • Lodz, Poland, 93-510
    • Novartis Investigative Site
  • Slupsk, Poland, 76-200
    • Novartis Investigative Site
  • Warszawa, Poland, 02-776
    • Novartis Investigative Site
  • Wroclaw, Poland, 50-367
    • Novartis Investigative Site
• Russian Federation
  • Moscow, Russian Federation, 115478
    • Novartis Investigative Site
  • Moscow, Russian Federation, 125167
    • Novartis Investigative Site
  • Moscow, Russian Federation, 125101
    • Novartis Investigative Site
  • Novosibirsk, Russian Federation, 630051
    • 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
  • Hospitalet de Llobregat (Barcelona), Spain, 08907
    • Novartis Investigative Site
  • Madrid, Spain, 28041
    • Novartis Investigative Site
  • Madrid, Spain, 28046
    • Novartis Investigative Site
  • Madrid, Spain, 28006
    • Novartis Investigative Site
  • Salamanca, Spain, 37007
    • Novartis Investigative Site
  • Valencia, Spain, 46010
    • Novartis Investigative Site
• Sweden
  • Lulea, Sweden, SE-971 80
    • Novartis Investigative Site
  • Stockholm, Sweden, SE-141 86
    • Novartis Investigative Site
  • Uppsala, Sweden, SE-751 85
    • Novartis Investigative Site
• United Kingdom
  • Bath, United Kingdom, BA1 3NG
    • Novartis Investigative Site
  • Belfast, United Kingdom, BT9 7AB
    • Novartis Investigative Site
  • Birmingham, United Kingdom, B9 5SS
    • Novartis Investigative Site
  • Bournemouth, United Kingdom, BH7 7DW
    • Novartis Investigative Site
  • Bradford, United Kingdom, BD9 6RJ
    • Novartis Investigative Site
  • Cambridge, United Kingdom, CB2 0QQ
    • Novartis Investigative Site
  • Canterbury, Kent, United Kingdom
    • Novartis Investigative Site
  • Carshalton, United Kingdom, SM5 1AA
    • Novartis Investigative Site
  • Cornwall, United Kingdom, TR1 3LJ
    • Novartis Investigative Site
  • Dudley, United Kingdom, DY1 2HQ
    • Novartis Investigative Site
  • Exeter, United Kingdom, EX2 5DW
    • Novartis Investigative Site
  • Glasgow, United Kingdom, G12 OYN
    • Novartis Investigative Site
  • Leeds, United Kingdom, LS9 7TF
    • Novartis Investigative Site
  • Liverpool, United Kingdom, L7 8XP
    • Novartis Investigative Site
  • London, United Kingdom, SE5 9RS
    • Novartis Investigative Site
  • London, United Kingdom, EC1M 6BQ
    • Novartis Investigative Site
  • Manchester, United Kingdom, M13 9WL
    • Novartis Investigative Site
  • Milton Keynes, United Kingdom, MK6 5LD
    • Novartis Investigative Site
  • Newcastle-upon-Tyne, United Kingdom, NE7 7DN
    • Novartis Investigative Site
  • Norwich, United Kingdom, NR4 7UY
    • Novartis Investigative Site
  • Oxford, United Kingdom, OX3 7LJ
    • Novartis Investigative Site
  • Peterborough, United Kingdom, PE3 9GZ
    • Novartis Investigative Site
  • Rhyl, Denbighshire, United Kingdom, LL18 5UJ
    • Novartis Investigative Site
  • Salford, United Kingdom, M6 8HD
    • Novartis Investigative Site
  • Stoke on Trent, United Kingdom, ST4 6QG
    • Novartis Investigative Site
  • Swindon, United Kingdom, SN3 6BB
    • Novartis Investigative Site
  • Uxbridge, United Kingdom, UB8 3NN
    • Novartis Investigative Site
  • Devon
    • Plymouth, Devon, United Kingdom, PL6 8DH
      • Novartis Investigative Site
  • Somerset
    • Taunton, Somerset, United Kingdom, TA1 5DA
      • Novartis Investigative Site
  • Tyne
    • Sunderland, Tyne, United Kingdom, SR4 7TP
      • Novartis Investigative Site
• United States
  • Arizona
    • Sedona, Arizona, United States, 86336
      • Novartis Investigative Site
    • Tucson, Arizona, United States, 85704
      • Novartis Investigative Site
  • California
    • Murrieta, California, United States, 92562
      • Novartis Investigative Site
  • Colorado
    • Aurora, Colorado, United States, 80012
      • Novartis Investigative Site
    • Denver, Colorado, United States, 80204
      • Novartis Investigative Site
  • Florida
    • Boca Raton, Florida, United States, 33486
      • Novartis Investigative Site
    • New Port Richey, Florida, United States, 34655
      • Novartis Investigative Site
    • Ocala, Florida, United States, 34471
      • Novartis Investigative Site
    • Ocoee, Florida, United States, 34761
      • Novartis Investigative Site
  • Georgia
    • Marietta, Georgia, United States, 30060
      • Novartis Investigative Site
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Novartis Investigative Site
  • Indiana
    • Indianapolis, Indiana, United States, 46227
      • Novartis Investigative Site
  • Missouri
    • Lee's Summit, Missouri, United States, 64064
      • Novartis Investigative Site
  • North Carolina
    • Raleigh, North Carolina, United States, 27607
      • Novartis Investigative Site
  • Texas
    • Abilene, Texas, United States, 79606-5208
      • Novartis Investigative Site
    • Arlington, Texas, United States, 76014
      • Novartis Investigative Site
    • Austin, Texas, United States, 78731
      • Novartis Investigative Site
    • Dallas, Texas, United States, 75230
      • Novartis Investigative Site
    • Dallas, Texas, United States, 75231
      • Novartis Investigative Site
    • Fort Worth, Texas, United States, 76104
      • Novartis Investigative Site
    • Midland, Texas, United States, 79701
      • Novartis Investigative Site
    • Odessa, Texas, United States, 79761
      • Novartis Investigative Site
    • San Antonio, Texas, United States, 78229
      • Novartis Investigative Site
    • San Antonio, Texas, United States, 78217
      • Novartis Investigative Site
    • Tyler, Texas, United States, 75702
      • Novartis Investigative Site
    • Waco, Texas, United States, 76712
      • Novartis Investigative Site
    • Webster, Texas, United States, 77598-4420
      • Novartis Investigative Site
  • Washington
    • Seattle, Washington, United States, 98133
      • Novartis Investigative Site
    • Vancouver, Washington, United States, 98684
      • Novartis Investigative Site
    • Yakima, Washington, United States, 98902
      • 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

Inclusion Criteria:

• confirmed CLL diagnosis and active CLL requiring treatment
• considered inappropriate for fludarabine-based therapy
• not been treated for CLL before
• 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

Exclusion Criteria:

• prior CLL therapy
• abnormal/inadequate blood values, liver, and kidney function
• certain heart problems, active or chronic infections, serious significant diseases, active autoimmune hemolytic anemia (AIHA) requiring treatment, other current cancer or within last 5 years
• 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
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ofatumumab + chlorambucil; ofatumumab dose: cycle 1 300mg day 1 and 1000mg day 8, subsequent cycles: 1000mg at day 1 every 28 days; chlorambucil dose: 10mg/m2 PO at days 1-7 every 28 days; duration: minimum of 3 cycles until best response or maximum of 12 treatment cycles	Drug: chlorambucil, tablets; 2mg tablets, chlorambucil dose: 10mg/m2 PO at days 1-7 every 28 days; duration: minimum of 3 cycles until best response or maximum of 12 cycles; Drug: ofatumumab (GSK1841157) infusion; iv infusion; dose: cycle 1 300mg day 1 and 1000mg day 8, subsequent cycles: 1000mg at day 1 every 28 days; Other Names: chlorambucil; tablets
Active Comparator: chlorambucil; chlorambucil dose: 10mg/m2 PO at days 1-7 every 28 days; duration: minimum of 3 cycles until best response or maximum of 12 cycles	Drug: chlorambucil, tablets; 2mg tablets, chlorambucil dose: 10mg/m2 PO at days 1-7 every 28 days; duration: minimum of 3 cycles until best response or maximum of 12 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 (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 enlarged 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. Par. who were alive and had not progressed at the time of analysis or if a progression event or death occurred after extensive lost-to-follow-up time or if new anti-cancer therapy was started were censored at the date of the last visit with adequate assessment.	From randomization to the date of first documented disease progression or death due to any cause, whichever occured first, reported between day of first patient randomized up to about 49 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number 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 until the 259th PFS event occurred, up to about 49 months
Number of Participants Who Were Negative for Minimal Residual Disease (MRD)	MRD 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 until the 259th PFS event occurred (Median follow-up approximately 28.9 months)
Overall Survival	Overall survival is defined as the time from randomization to death due to any cause. Each participant was followed at the time when the total IRC-assessed PFS events occurred. Participants who had not died were censored at the date of last contact.	From randomization up to about 111 months
Time to Response, as Assessed by the IRC	Time to response is defined as the time from randomization to the first response (CR, CRi, nPR, or PR). 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. Participants with unknown or missing responses were considered as non-responders. Only responders (CR, CRi, PR, nPR) were included in the analysis.	From randomization uo to about 27 months
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 enlarged 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. Par. who were alive and had not progressed at the time of analysis or if a progression event occurred after extensive lost-to-follow-up time (>= 12 weeks) were censored at the date of the last visit with adequate assessment. Par. with unknown or missing responses were considered as non-responders.	From randomization up to about 43 months
Time to Progression, as Assessed by the IRC	Time to progression is defined as the time from the date of randomization to disease progression (PD). PD requires at least one of the following: lymphadenopathy, appearance of any new lesion such as enlarged 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. Participants who were alive and had not progressed at the time of analysis or if a progression event occurred after extensive lost-to-follow-up time were censored at the date of the last visit with adequate assessment.	From randomization up to about 49 months
Time to Next Therapy	Time to next therapy is defined as the time from randomization until the start of the next-line of treatment.	From randomization up to about 49 months
Number of Participants With Improvement in ECOG Performance Status of 0 or 1	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. Grade 0, fully active, able to carry on all pre-disease performance without restriction. Grade 1, restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. Grade 2, ambulatory and capable of all selfcare, but unable to carry out any work activities; up and about more than 50% of waking hours. Grade 3, capable of only limited selfcare; confined to bed or chair more than 50% of waking hours. Grade 4, completely disabled; cannot carry on any selfcare; totally confined to bed or chair. Grade 5, dead. Participants with an ECOG performance status of 0 or 1 are shown..	Baseline, Cycle 3 Day 1, 1 month Follow-up
Number of Participants With Improvement in Constitutional Symptoms (CS)	Assessment for the presence of the following symptoms were performed at Screening, Day 1 of each treatment cycle and at every Follow-up visit: night sweats (without signs of infection); unexplained, unintentional weight loss >= 10% within the previous 6 months; recurrent, unexplained fever of greater than 38 degrees celsius or 100.5 degrees fahrenheit for 2 weeks; and extreme fatigue. The best response refers to overall best response in terms of CR, CRi, PR or nPR. Data are presented for constitutional response= yes and no.	Baseline, Cycle 3 Day 1, and 1 month Follow-up
Number of Participants With a Human Anti-human Antibody (HAHA) Positive Result	Serum samples for analysis of HAHA were collected at Baseline (Screening), Cycle 4 Day 1 (after 3 months of treatment), and at 1 month and 6 months post last dose of ofatumumab. 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 and further evaluated in the titration test to obtain a titer of HAHA.	Baseline, Cycle 4 Day 1, 1 Month Follow-up, and 6 Month Follow-up
Cmax and Ctrough of Ofatumumab	Blood samples were collected to assess the plasma concentration of ofatumumab. Maximum concentration (Cmax) and observed drug concentration prior to the next dose (Ctrough) were determined. Blood samples were collected from participants who received ofatumumab plus chlorambucil at pre-dose and 0.5 hours after the end of the ofatumumab infusion at treatment Cycle 1 and Cycle 4 (Days 1, 8, and 85). In addition, pre-dose samples were collected prior to ofatumumab administration at Cycles 2, 3, 5, 6, 9 and 12 (Days 29, 57, 113, 141, 225 and 309), depending on the duration of treatment.	Cycle 1 Day 1,Cycle 1 Day 8, Cycle 2 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1, and Cycle 9 Day 1
Total Plasma Clearance (CL) of Ofatumumab	Plasma clearance is defined as the plasma volume which is totally cleared of drug per unit of time. Blood samples were collected from participants who received ofatumumab plus chlorambucil at pre-dose and 0.5 hours after the end of the ofatumumab infusion at treatment Cycle 1 and Cycle 4 (Days 1, 8, and 85). In addition, pre-dose samples were collected prior to the ofatumumab administration at Cycles 2, 3, 5, 6, 9 and 12 (Days 29, 57, 113, 141, 225 and 309), depending on duration of treatment. Samples were also collected during clinic visits on Day 15 (during Cycle 1) and Day 43 (during Cycle 2) and at 1, 3, and 6 months post-treatment.	Cycle 4 Day 1
AUC(0-tau) of Ofatumumab	Area under the concentration time curve over the dosing interval [AUC(0-tau)] is a measure of drug exposure over time. AUC(0-tau) is defined as the area under the ofatumumab plasma concentration-time curve from dosing to time tau, where tau is the length of the dosing interval of ofatumumab. For estimation of AUC(0-tau), blood samples were collected from participants who received ofatumumab plus chlorambucil at pre-dose and 0.5 hous after the end of the ofatumumab infusion at treatment Cycle 1 and Cycle 4 (Days 1, 8, and 85). In addition, pre-dose samples were collected prior to the ofatumumab administration at Cycles 2, 3, 5, 6, 9 and 12 (Days 29, 57, 113, 141, 225 and 309), depending on duration of treatment. Samples were also collected during clinic visits on Day 15 (during Cycle 1) and Day 43 (during Cycle 2) and at 1, 3, and 6 months post-treatment.	Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 4 Day 1
Volume of Distribution at Steady State (Vss) of Ofatumumab	Volume of distribution at steady state (Vss) is defined as the distribution of a drug between plasma and the rest of the body at steady state. Blood samples were collected from participants who received ofatumumab plus chlorambucil at predose and 0.5 hour after the end of the ofatumumab infusion at treatment Cycle 1 and Cycle 4 (Days 1, 8, and 85). In addition, pre-dose samples were collected prior to ofatumumab administration at Cycles 2, 3, 5, 6, 9 and 12 (Days 29, 57, 113, 141, 225 and 309), depending on the duration of the treatment. Samples were also collected during clinic visits on Day 15 (during Cycle 1) and Day 43 (during Cycle 2) and at 1, 3, and 6 months post-treatment.	Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 4 Day 1
Plasma Half Life (t1/2) of Ofatumumab	The terminal half-life (t1/2) of ofatumumab is defined as the time required for the plasma concentration of ofatumumab to reach half of its original concentration. Blood samples were collected to assess the plasma half-life of ofatumumab. Blood samples were collected from participants who received ofatumumab plus chlorambucil pre-dose and 0.5 hours after the end of the ofatumumab infusion at treatment Cycle 1 and Cycle 4 (Days 1, 8, and 85). In addition, pre-dose samples were collected prior to ofatumumab administration at Cycles 2, 3, 5, 6, 9 and 12 (Days 29, 57, 113, 141, 225 and 309), depending on the duration of the treatment. Samples were also collected during clinic visits on Day 15 (during Cycle 1) and Day 43 (during Cycle 2) and at 1, 3, and 6 months post-treatment.	Cycle 4 Day 1
Dose-normalized Cmax of Chlorambucil and Phenylacetic Acid Mustard (PAAM)	Blood samples for the determination of serum concentrations of chlorambucil and its metabolite PAAM were collected from participants in a substudy on Cycle 3 Day 1. The maximum observed concentration (Cmax) of chlorambucil and PAAM normalized to the administered dose was determined as a measure of exposure and compared to reference data from a prior study (LEUA1001) [No NCT number available for this study; GlaxoSmithKline Document Number RM1998/00449/00].	Cycle 3 Day 1
Dose-normalized AUC(0-6) and AUC(0-inf) of Chlorambucil and Dose-normalized AUC(0-6) of Phenylacetic Acid Mustard (PAAM)	Blood samples for the determination of serum concentrations of chlorambucil and its metabolite PAAM were collected from participants in a substudy on Cycle 3 Day 1. The area under the plasma concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC[0-inf]) and over 6 hours (AUC[0-6]) of chlorambucil and AUC(0-6) of PAAM normalized to the administered dose was determined as a measure of exposure and compared to reference data from a prior study (LEUA1001) [No NCT number available for this study; GlaxoSmithKline Document Number RM1998/00449/00].	Cycle 3 Day 1
Change From Baseline in Health Related Quality of Life (HRQOL)	HRQOL was assessed using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTCQLQC30), Chronic Lymphocytic Leukemia module (EORTC QLQ-CLL16), EuorQoL-Five Dimension (EQ-5D), and HCQ. Period (P)1 (Day 85, Day 169, Day 253) and P2 (scheduled follow-up (FU) and withdrawal visits) analysis were considered. Baseline (BL) for P1 was defined as score from screening visit and BL for P2 was defined as the last on-treatment score. The 2 principal QoL outcomes were pre-specified as the Global Health scale (GHS/QOL) of the EORTC QLQ-C30 and fatigue scale of the EORTC QLQ-CLL16. For EORTC QLQ-C30,GHS/Qol, the possible scale range was 0-100 (with 100 being 'best') and a positive difference from BL is indicative of better functioning (range -100 to +100). For the EORTC QLQ-CLL16 fatigue scale, the possible scale range was 0-100 (with 0 being 'best') and a negative difference from BL represents an improvement in fatigue (range -100 to +100).	Baseline, Cycle 4 day 1, cycle 7 day 1, 1 month follow-up, 6 month follow-up, 12 month follow-up
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. Refer to the general Adverse AE/SAE module for a complete list of AEs and SAEs.	From the first dose of study medication to 60 days after the last dose of study medication and until follow-up for SAEs unless initiation of subsequent anti-CLL therapy, up to approximately 111 months.
Number of Participants With 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. Refer to the general Adverse AE/SAE module for a complete list of AEs and SAEs. 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 the first dose of study medication to 60 days after the last dose of study medication and until follow-up for SAEs unless initiation of subsequent anti-CLL therapy, up to approximately 111 months.
Number of Participants With at Least One Grade 3/Grade 4 Myelosuppression (Anemia, Neutropenia, and Thrombocytopenia)	Participants with a Grade 3 or Grade 4 myelosuppression (anemia, neutropenia, and thrombocytopenia) are presented by treatment cycle. 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 the first dose of study medication to 60 days after the last dose of study medication and until follow-up for SAEs unless initiation of subsequent anti-CLL therapy, up to approximately 111 months.
Number of Participants With Autoimmune Hemolytic Anaemia (AIHA) Disease	AIHA is a disease 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 diagnosed with AIHA are presented.	From the first dose of study medication to 60 days after the last dose of study medication and until follow-up for SAEs unless initiation of subsequent anti-CLL therapy, up to approximately 111 months.
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 are counted in this table.	From start of treatment to the last study visit/withdrawal visit (Median follow-up approximately 28.9 months)
Mean Change From Baseline in the 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. IgA, IgG, and IgM were measured in the blood samples of the participants. Baseline IgA, IgG, and IgM values are the last pre-dose assessment values performed on Cycle 1 Day 1. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.	From start of treatment up to 30 days after last treatment

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Tausch E, Beck P, Schlenk RF, Jebaraj BJ, Dolnik A, Yosifov DY, Hillmen P, Offner F, Janssens A, Babu GK, Grosicki S, Mayer J, Panagiotidis P, McKeown A, Gupta IV, Skorupa A, Pallaud C, Bullinger L, Mertens D, Dohner H, Stilgenbauer S. Prognostic and predictive role of gene mutations in chronic lymphocytic leukemia: results from the pivotal phase III study COMPLEMENT1. Haematologica. 2020 Oct 1;105(10):2440-2447. doi: 10.3324/haematol.2019.229161.
• Hillmen P, Robak T, Janssens A, Babu KG, Kloczko J, Grosicki S, Doubek M, Panagiotidis P, Kimby E, Schuh A, Pettitt AR, Boyd T, Montillo M, Gupta IV, Wright O, Dixon I, Carey JL, Chang CN, Lisby S, McKeown A, Offner F; COMPLEMENT 1 Study Investigators. Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-label phase 3 trial. Lancet. 2015 May 9;385(9980):1873-83. doi: 10.1016/S0140-6736(15)60027-7. Epub 2015 Apr 14.
• 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): December 22, 2008
• Primary Completion (Actual): March 20, 2013
• Study Completion (Actual): May 17, 2018

Study Registration Dates

• First Submitted: September 5, 2008
• First Submitted That Met QC Criteria: September 5, 2008
• First Posted (Estimate): September 8, 2008

Study Record Updates

• Last Update Posted (Actual): June 25, 2019
• Last Update Submitted That Met QC Criteria: June 5, 2019
• Last Verified: June 1, 2019

More Information

Terms related to this study

• Keywords: Safety; Ofatumumab; Efficacy; Oncology; Chronic Lymphocytic Leukemia; Untreated; Chronic Lymphocytic Leukemia (CLL), untreated
• 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; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Ofatumumab; Chlorambucil
• Other Study ID Numbers: OMB110911 (Other Identifier: Novartis)

Plan for Individual participant data (IPD)

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

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