Ofatumumab + Chlorambucil vs Chlorambucil Monotherapy in Previously Untreated Patients With Chronic Lymphocytic Leukemia

Leukaemia, Lymphocytic, Chronic Clinical Trial

— COMPLEMENT 1  

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00748189
• Other study ID #: OMB110911
• Secondary ID: OMB110911
• Status: Terminated
• Phase: Phase 3
• Start date: December 22, 2008
• Est. completion date: May 17, 2018

Study information

• Verified date: June 2019
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 447
• Est. completion date: May 17, 2018
• Est. primary completion date: March 20, 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Leukaemia, Lymphocytic, Chronic
• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid

Intervention

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
• ofatumumab (GSK1841157) infusion
iv infusion; dose: cycle 1 300mg day 1 and 1000mg day 8, subsequent cycles: 1000mg at day 1 every 28 days;

Locations

Country	Name	City	State
Belgium	Novartis Investigative Site	Brugge
Belgium	Novartis Investigative Site	Bruxelles
Belgium	Novartis Investigative Site	Gent
Belgium	Novartis Investigative Site	Haine-Saint-Paul
Belgium	Novartis Investigative Site	Leuven
Brazil	Novartis Investigative Site	Porto Alegre	Rio De Janeiro
Brazil	Novartis Investigative Site	Sao Paulo	São Paulo
Brazil	Novartis Investigative Site	Sao Paulo	São Paulo
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	Sherbrooke	Quebec
Canada	Novartis Investigative Site	Toronto	Ontario
Czechia	Novartis Investigative Site	Brno
Czechia	Novartis Investigative Site	Hradec Kralove
Czechia	Novartis Investigative Site	Praha 10
France	Novartis Investigative Site	Creteil
France	Novartis Investigative Site	Pierre Benite
Germany	Novartis Investigative Site	Erlangen	Bayern
Germany	Novartis Investigative Site	Essen	Nordrhein-Westfalen
Germany	Novartis Investigative Site	Frankfurt	Hessen
Germany	Novartis Investigative Site	Hannover	Niedersachsen
Germany	Novartis Investigative Site	Karlsruhe	Baden-Wuerttemberg
Germany	Novartis Investigative Site	Kassel	Hessen
Germany	Novartis Investigative Site	Koeln	Nordrhein-Westfalen
Germany	Novartis Investigative Site	Lehrte	Niedersachsen
Germany	Novartis Investigative Site	Mannheim	Baden-Wuerttemberg
Germany	Novartis Investigative Site	Moenchengladbach-Rheydt	Nordrhein-Westfalen
Germany	Novartis Investigative Site	Muenchen	Bayern
Germany	Novartis Investigative Site	Muenster	Nordrhein-Westfalen
Germany	Novartis Investigative Site	Regensburg	Bayern
Germany	Novartis Investigative Site	Saarbruecken	Saarland
Germany	Novartis Investigative Site	Stuttgart	Baden-Wuerttemberg
Germany	Novartis Investigative Site	Ulm	Baden-Wuerttemberg
Germany	Novartis Investigative Site	Wuerzburg	Bayern
Greece	Novartis Investigative Site	Athens,
Greece	Novartis Investigative Site	Thessaloniki
Greece	Novartis Investigative Site	Thessaloniki
India	Novartis Investigative Site	Ahmedabad
India	Novartis Investigative Site	Bangalore
India	Novartis Investigative Site	Mumbai
India	Novartis Investigative Site	Mumbai
India	Novartis Investigative Site	New Delhi
India	Novartis Investigative Site	Pune
Ireland	Novartis Investigative Site	Cork
Ireland	Novartis Investigative Site	Dublin
Ireland	Novartis Investigative Site	Galway
Ireland	Novartis Investigative Site	James Street
Ireland	Novartis Investigative Site	Limerick
Ireland	Novartis Investigative Site	Tullamore
Ireland	Novartis Investigative Site	Waterford
Italy	Novartis Investigative Site	Albano Laziale (Roma)	Lazio
Italy	Novartis Investigative Site	Ascoli Piceno	Marche
Italy	Novartis Investigative Site	Bari	Puglia
Italy	Novartis Investigative Site	Brescia	Lombardia
Italy	Novartis Investigative Site	Genova	Liguria
Italy	Novartis Investigative Site	Milano	Lombardia
Italy	Novartis Investigative Site	Milano	Lombardia
Italy	Novartis Investigative Site	Milano	Lombardia
Italy	Novartis Investigative Site	Napoli	Campania
Italy	Novartis Investigative Site	Novara	Piemonte
Italy	Novartis Investigative Site	Palermo	Sicilia
Italy	Novartis Investigative Site	Potenza	Basilicata
Italy	Novartis Investigative Site	Udine
Italy	Novartis Investigative Site	Venezia - Mestre	Veneto
Italy	Novartis Investigative Site	Vicenza	Veneto
Netherlands	Novartis Investigative Site	Amersfoort
Netherlands	Novartis Investigative Site	Amsterdam
Netherlands	Novartis Investigative Site	Den Haag
Netherlands	Novartis Investigative Site	Groningen
Netherlands	Novartis Investigative Site	Nijmegen
Netherlands	Novartis Investigative Site	Rotterdam
Netherlands	Novartis Investigative Site	Rotterdam
Poland	Novartis Investigative Site	Bialystok
Poland	Novartis Investigative Site	Chorzow
Poland	Novartis Investigative Site	Lodz
Poland	Novartis Investigative Site	Slupsk
Poland	Novartis Investigative Site	Warszawa
Poland	Novartis Investigative Site	Wroclaw
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Novosibirsk
Russian Federation	Novartis Investigative Site	St'Petersburg
Russian Federation	Novartis Investigative Site	St. Petersburg
Spain	Novartis Investigative Site	Barcelona
Spain	Novartis Investigative Site	Barcelona
Spain	Novartis Investigative Site	Hospitalet de Llobregat (Barcelona)
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Salamanca
Spain	Novartis Investigative Site	Valencia
Sweden	Novartis Investigative Site	Lulea
Sweden	Novartis Investigative Site	Stockholm
Sweden	Novartis Investigative Site	Uppsala
United Kingdom	Novartis Investigative Site	Bath
United Kingdom	Novartis Investigative Site	Belfast
United Kingdom	Novartis Investigative Site	Birmingham
United Kingdom	Novartis Investigative Site	Bournemouth
United Kingdom	Novartis Investigative Site	Bradford
United Kingdom	Novartis Investigative Site	Cambridge
United Kingdom	Novartis Investigative Site	Canterbury, Kent
United Kingdom	Novartis Investigative Site	Carshalton
United Kingdom	Novartis Investigative Site	Cornwall
United Kingdom	Novartis Investigative Site	Dudley
United Kingdom	Novartis Investigative Site	Exeter
United Kingdom	Novartis Investigative Site	Glasgow
United Kingdom	Novartis Investigative Site	Leeds
United Kingdom	Novartis Investigative Site	Liverpool
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	Manchester
United Kingdom	Novartis Investigative Site	Milton Keynes
United Kingdom	Novartis Investigative Site	Newcastle-upon-Tyne
United Kingdom	Novartis Investigative Site	Norwich
United Kingdom	Novartis Investigative Site	Oxford
United Kingdom	Novartis Investigative Site	Peterborough
United Kingdom	Novartis Investigative Site	Plymouth	Devon
United Kingdom	Novartis Investigative Site	Rhyl, Denbighshire
United Kingdom	Novartis Investigative Site	Salford
United Kingdom	Novartis Investigative Site	Stoke on Trent
United Kingdom	Novartis Investigative Site	Sunderland	Tyne
United Kingdom	Novartis Investigative Site	Swindon
United Kingdom	Novartis Investigative Site	Taunton	Somerset
United Kingdom	Novartis Investigative Site	Uxbridge
United States	Novartis Investigative Site	Abilene	Texas
United States	Novartis Investigative Site	Arlington	Texas
United States	Novartis Investigative Site	Aurora	Colorado
United States	Novartis Investigative Site	Austin	Texas
United States	Novartis Investigative Site	Boca Raton	Florida
United States	Novartis Investigative Site	Chicago	Illinois
United States	Novartis Investigative Site	Dallas	Texas
United States	Novartis Investigative Site	Dallas	Texas
United States	Novartis Investigative Site	Denver	Colorado
United States	Novartis Investigative Site	Fort Worth	Texas
United States	Novartis Investigative Site	Indianapolis	Indiana
United States	Novartis Investigative Site	Lee's Summit	Missouri
United States	Novartis Investigative Site	Marietta	Georgia
United States	Novartis Investigative Site	Midland	Texas
United States	Novartis Investigative Site	Murrieta	California
United States	Novartis Investigative Site	New Port Richey	Florida
United States	Novartis Investigative Site	Ocala	Florida
United States	Novartis Investigative Site	Ocoee	Florida
United States	Novartis Investigative Site	Odessa	Texas
United States	Novartis Investigative Site	Raleigh	North Carolina
United States	Novartis Investigative Site	San Antonio	Texas
United States	Novartis Investigative Site	San Antonio	Texas
United States	Novartis Investigative Site	Seattle	Washington
United States	Novartis Investigative Site	Sedona	Arizona
United States	Novartis Investigative Site	Tucson	Arizona
United States	Novartis Investigative Site	Tyler	Texas
United States	Novartis Investigative Site	Vancouver	Washington
United States	Novartis Investigative Site	Waco	Texas
United States	Novartis Investigative Site	Webster	Texas
United States	Novartis Investigative Site	Yakima	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Belgium,  Brazil,  Canada,  Czechia,  France,  Germany,  Greece,  India,  Ireland,  Italy,  Netherlands,  Poland,  Russian Federation,  Spain,  Sweden,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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)
Secondary	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