Leukaemia, Lymphocytic, Chronic
Conditions
Keywords
Safety, Untreated, Efficacy, Chronic Lymphocytic Leukemia, Chronic Lymphocytic Leukemia (CLL), untreated, Ofatumumab, Oncology
Brief 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.
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.
Interventions
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
iv infusion; dose: cycle 1 300mg day 1 and 1000mg day 8, subsequent cycles: 1000mg at day 1 every 28 days;
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS), as Assessed by the Independent Review Committee (IRC) | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Were Negative for Minimal Residual Disease (MRD) | From randomization until the 259th PFS event occurred (Median follow-up approximately 28.9 months) | 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. |
| Overall Survival | From randomization up to about 111 months | 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. |
| Time to Response, as Assessed by the IRC | From randomization uo to about 27 months | 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. |
| Duration of Response (DOR), as Assessed by the IRC | From randomization up to about 43 months | 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. |
| Time to Progression, as Assessed by the IRC | From randomization up to about 49 months | 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. |
| Time to Next Therapy | From randomization up to about 49 months | Time to next therapy is defined as the time from randomization until the start of the next-line of treatment. |
| Number of Participants With Improvement in ECOG Performance Status of 0 or 1 | Baseline, Cycle 3 Day 1, 1 month Follow-up | 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.. |
| Number of Participants With Improvement in Constitutional Symptoms (CS) | Baseline, Cycle 3 Day 1, and 1 month Follow-up | 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. |
| Number of Participants With a Human Anti-human Antibody (HAHA) Positive Result | Baseline, Cycle 4 Day 1, 1 Month Follow-up, and 6 Month Follow-up | 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. |
| Cmax and Ctrough of Ofatumumab | 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 | 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. |
| Total Plasma Clearance (CL) of Ofatumumab | Cycle 4 Day 1 | 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. |
| Number of Participants With the Best Overall Response (OR), as Assessed by the IRC | From randomization until the 259th PFS event occurred, up to about 49 months | 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. |
| Volume of Distribution at Steady State (Vss) of Ofatumumab | Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 4 Day 1 | 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. |
| Plasma Half Life (t1/2) of Ofatumumab | Cycle 4 Day 1 | 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. |
| Dose-normalized Cmax of Chlorambucil and Phenylacetic Acid Mustard (PAAM) | Cycle 3 Day 1 | 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) \[No NCT number available for this study; GlaxoSmithKline Document Number RM1998/00449/00\]. |
| Dose-normalized AUC(0-6) and AUC(0-inf) of Chlorambucil and Dose-normalized AUC(0-6) of Phenylacetic Acid Mustard (PAAM) | Cycle 3 Day 1 | 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) \[No NCT number available for this study; GlaxoSmithKline Document Number RM1998/00449/00\]. |
| Change From Baseline in Health Related Quality of Life (HRQOL) | Baseline, Cycle 4 day 1, cycle 7 day 1, 1 month follow-up, 6 month follow-up, 12 month follow-up | 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). |
| Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) | 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. | 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. |
| Number of Participants With AEs and SAEs of Maximum Severity of Grade 3 or Higher | 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. | 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). |
| Number of Participants With at Least One Grade 3/Grade 4 Myelosuppression (Anemia, Neutropenia, and Thrombocytopenia) | 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. | 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). |
| Number of Participants With Autoimmune Hemolytic Anaemia (AIHA) Disease | 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. | 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. |
| Number of Participants Who Received no Transfusion or at Least One Transfusion During the Study | From start of treatment to the last study visit/withdrawal visit (Median follow-up approximately 28.9 months) | 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. |
| Mean Change From Baseline in the Immunoglobulin (Ig) Antibodies IgA, IgG, and IgM | From start of treatment up to 30 days after last treatment | 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. |
| AUC(0-tau) of Ofatumumab | Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 4 Day 1 | 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. |
Countries
Belgium, Brazil, Canada, Czechia, France, Germany, Greece, India, Ireland, Italy, Netherlands, Poland, Russia, Spain, Sweden, United Kingdom, United States
Participant flow
Pre-assignment details
Eligible participants (par.) were stratified by age (\<65 years vs. \>=65years), stage (Binet A vs. B vs. C) and Eastern Cooperative Oncology Group (ECOG) performance status (0-1 vs. 2). Participants in each stratum were then centrally randomized in a 1:1 ratio to receive ofatumumab plus chlorambucil (O+CHL) or chlorambucil alone (CHL).
Participants by arm
| Arm | Count |
|---|---|
| Chlorambucil Participants with previously untreated chronic lymphocytic leukemia (CLL) received chlorambucil monotherapy 10 milligram (mg)/meter squared (m\^2) orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles. | 226 |
| Ofatumumab + Chlorambucil Participants with CLL received intravenous (IV) infusions of ofatumumab on Day 1 (300 mg) and Day 8 (1000 mg) in the first cycle, followed by IV infusions of 1000 mg on the first day of each subsequent 28-day cycle in combination with chlorambucil 10 mg/m\^2 orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles. | 221 |
| Total | 447 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 99 | 84 |
| Overall Study | Lost to Follow-up | 8 | 15 |
| Overall Study | Physician Decision | 16 | 5 |
| Overall Study | Study terminated by Sponsor | 70 | 79 |
| Overall Study | Withdrawal by Subject | 23 | 29 |
Baseline characteristics
| Characteristic | Ofatumumab + Chlorambucil | Total | Chlorambucil |
|---|---|---|---|
| Age, Customized Years | 69 Years | 69 Years | 70 Years |
| Race/Ethnicity, Customized African American/African Heritage | 4 Participants | 6 Participants | 2 Participants |
| Race/Ethnicity, Customized American Indian or Alaskan Native | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian - Central/South Asian Heritage | 19 Participants | 41 Participants | 22 Participants |
| Race/Ethnicity, Customized Asian - Mixed Race | 2 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 196 Participants | 397 Participants | 201 Participants |
| Sex: Female, Male Female | 79 Participants | 165 Participants | 86 Participants |
| Sex: Female, Male Male | 142 Participants | 282 Participants | 140 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 99 / 227 | 84 / 217 | 183 / 444 |
| other Total, other adverse events | 175 / 227 | 183 / 217 | 358 / 444 |
| serious Total, serious adverse events | 57 / 227 | 53 / 217 | 110 / 444 |
Outcome results
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.
Time frame: 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
Population: Intent-to-Treat (ITT) Population: all par. randomized to study treatment regardless of whether or not they received treatment. PFS was assessed by a blinded independent review committee according to the International Workshop for Chronic Lymphocytic Leukemia (IWCLL) updated National Cancer Institute-sponsored Working Group (NCI-WG) guidelines.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Chlorambucil | Progression-Free Survival (PFS), as Assessed by the Independent Review Committee (IRC) | 13.1 Months |
| Ofatumumab + Chlorambucil | Progression-Free Survival (PFS), as Assessed by the Independent Review Committee (IRC) | 22.4 Months |
p-value: <0.00195% CI: [0.45, 0.72]Log Rank
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.
Time frame: Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 4 Day 1
Population: PK Population. Only those participants available at the indicated time points were assessed. The number of participants assessed at each time point is indicated by n=X,X.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Ofatumumab + Chlorambucil | AUC(0-tau) of Ofatumumab | Cycle 1 Day 1, n=0, 193 | 2621 µg x hours/mL | Geometric Coefficient of Variation 0.76 |
| Ofatumumab + Chlorambucil | AUC(0-tau) of Ofatumumab | Cycle 1 Day 8, n=0, 208 | 25369 µg x hours/mL | Geometric Coefficient of Variation 0.87 |
| Ofatumumab + Chlorambucil | AUC(0-tau) of Ofatumumab | Cycle 4 Day 1, n=0, 183 | 65100 µg x hours/mL | Geometric Coefficient of Variation 0.73 |
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).
Time frame: Baseline, Cycle 4 day 1, cycle 7 day 1, 1 month follow-up, 6 month follow-up, 12 month follow-up
Population: ITT population. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the ITT Population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Chlorambucil | Change From Baseline in Health Related Quality of Life (HRQOL) | P1, Cycle 4 Day 1, QLQC30 GHS/QoL score, n=139,159 | 1.92 Scores on a scale | Standard Deviation 21.22 |
| Chlorambucil | Change From Baseline in Health Related Quality of Life (HRQOL) | P1, Cycle 7 Day 1, QLQC30 GHS/QoL score, n=52, 55 | 8.01 Scores on a scale | Standard Deviation 22.2 |
| Chlorambucil | Change From Baseline in Health Related Quality of Life (HRQOL) | P1,Cycle 4 Day 1,QLQCLL16 fatigue score, n=145,163 | -4.71 Scores on a scale | Standard Deviation 27.48 |
| Chlorambucil | Change From Baseline in Health Related Quality of Life (HRQOL) | P1, Cycle 7 Day 1,QLQCLL16 fatigue score, n=55,57 | -1.21 Scores on a scale | Standard Deviation 25.43 |
| Chlorambucil | Change From Baseline in Health Related Quality of Life (HRQOL) | P2,1 month FU, QLQC30 GHS/QoL score, n=118, 150 | 4.79 Scores on a scale | Standard Deviation 23.13 |
| Chlorambucil | Change From Baseline in Health Related Quality of Life (HRQOL) | P2, 6 month FU, QLQC30 GHS/QoL score, n=83, 129 | 3.01 Scores on a scale | Standard Deviation 22.07 |
| Chlorambucil | Change From Baseline in Health Related Quality of Life (HRQOL) | P2, 12 month FU, QLQC30 GHS/QoL score, n=48, 96 | 3.82 Scores on a scale | Standard Deviation 18.27 |
| Chlorambucil | Change From Baseline in Health Related Quality of Life (HRQOL) | P2, 1 month FU, QLQCLL16 fatigue score, n=121, 152 | -1.24 Scores on a scale | Standard Deviation 21.75 |
| Chlorambucil | Change From Baseline in Health Related Quality of Life (HRQOL) | P2, 6 month FU, QLQCLL16 fatigue score, n=85, 131 | -7.06 Scores on a scale | Standard Deviation 18.96 |
| Chlorambucil | Change From Baseline in Health Related Quality of Life (HRQOL) | P2, 12 month FU, QLQCLL16 fatigue score, n=51, 95 | -2.94 Scores on a scale | Standard Deviation 17.86 |
| Ofatumumab + Chlorambucil | Change From Baseline in Health Related Quality of Life (HRQOL) | P2, 1 month FU, QLQCLL16 fatigue score, n=121, 152 | -0.33 Scores on a scale | Standard Deviation 19.13 |
| Ofatumumab + Chlorambucil | Change From Baseline in Health Related Quality of Life (HRQOL) | P1, Cycle 4 Day 1, QLQC30 GHS/QoL score, n=139,159 | 6.08 Scores on a scale | Standard Deviation 21.08 |
| Ofatumumab + Chlorambucil | Change From Baseline in Health Related Quality of Life (HRQOL) | P2, 6 month FU, QLQC30 GHS/QoL score, n=83, 129 | 3.75 Scores on a scale | Standard Deviation 20.83 |
| Ofatumumab + Chlorambucil | Change From Baseline in Health Related Quality of Life (HRQOL) | P1, Cycle 7 Day 1, QLQC30 GHS/QoL score, n=52, 55 | 6.97 Scores on a scale | Standard Deviation 17.55 |
| Ofatumumab + Chlorambucil | Change From Baseline in Health Related Quality of Life (HRQOL) | P2, 12 month FU, QLQCLL16 fatigue score, n=51, 95 | 0.88 Scores on a scale | Standard Deviation 16.91 |
| Ofatumumab + Chlorambucil | Change From Baseline in Health Related Quality of Life (HRQOL) | P1,Cycle 4 Day 1,QLQCLL16 fatigue score, n=145,163 | -4.60 Scores on a scale | Standard Deviation 24.23 |
| Ofatumumab + Chlorambucil | Change From Baseline in Health Related Quality of Life (HRQOL) | P2, 12 month FU, QLQC30 GHS/QoL score, n=48, 96 | 1.22 Scores on a scale | Standard Deviation 17.69 |
| Ofatumumab + Chlorambucil | Change From Baseline in Health Related Quality of Life (HRQOL) | P1, Cycle 7 Day 1,QLQCLL16 fatigue score, n=55,57 | -9.36 Scores on a scale | Standard Deviation 22.93 |
| Ofatumumab + Chlorambucil | Change From Baseline in Health Related Quality of Life (HRQOL) | P2, 6 month FU, QLQCLL16 fatigue score, n=85, 131 | -2.93 Scores on a scale | Standard Deviation 19.34 |
| Ofatumumab + Chlorambucil | Change From Baseline in Health Related Quality of Life (HRQOL) | P2,1 month FU, QLQC30 GHS/QoL score, n=118, 150 | 0.56 Scores on a scale | Standard Deviation 18.31 |
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.
Time frame: 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
Population: Pharmacokinetic (PK) Population: all participants for whom a pharmacokinetic sample was obtained and analyzed.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Ofatumumab + Chlorambucil | Cmax and Ctrough of Ofatumumab | Cmax, Cycle 1 Day 1, n=0, 176 | 51.8 Micrograms/Milliliter (µg/mL) | Geometric Coefficient of Variation 1.03 |
| Ofatumumab + Chlorambucil | Cmax and Ctrough of Ofatumumab | Cmax, Cycle 1 Day 8, n=0, 193 | 241 Micrograms/Milliliter (µg/mL) | Geometric Coefficient of Variation 0.46 |
| Ofatumumab + Chlorambucil | Cmax and Ctrough of Ofatumumab | Cmax, Cycle 4 Day 1, n=0, 169 | 285 Micrograms/Milliliter (µg/mL) | Geometric Coefficient of Variation 0.44 |
| Ofatumumab + Chlorambucil | Cmax and Ctrough of Ofatumumab | Ctrough, Cycle 1 Day 8, n=0, 99 | 2.5 Micrograms/Milliliter (µg/mL) | Geometric Coefficient of Variation 5.85 |
| Ofatumumab + Chlorambucil | Cmax and Ctrough of Ofatumumab | Ctrough, Cycle 2 Day 1, n=0, 138 | 5.2 Micrograms/Milliliter (µg/mL) | Geometric Coefficient of Variation 15.37 |
| Ofatumumab + Chlorambucil | Cmax and Ctrough of Ofatumumab | Ctrough, Cycle 3 Day 1, n=0, 142 | 6.2 Micrograms/Milliliter (µg/mL) | Geometric Coefficient of Variation 17.06 |
| Ofatumumab + Chlorambucil | Cmax and Ctrough of Ofatumumab | Ctrough, Cycle 4 Day 1, n=0, 147 | 15.5 Micrograms/Milliliter (µg/mL) | Geometric Coefficient of Variation 7.99 |
| Ofatumumab + Chlorambucil | Cmax and Ctrough of Ofatumumab | Ctrough, Cycle 5 Day 1, n=0, 149 | 33.5 Micrograms/Milliliter (µg/mL) | Geometric Coefficient of Variation 3.61 |
| Ofatumumab + Chlorambucil | Cmax and Ctrough of Ofatumumab | Ctrough, Cycle 6 Day 1, n=0, 155 | 45.9 Micrograms/Milliliter (µg/mL) | Geometric Coefficient of Variation 2.77 |
| Ofatumumab + Chlorambucil | Cmax and Ctrough of Ofatumumab | Ctrough, Cycle 9 Day 1, n=0, 56 | 55.6 Micrograms/Milliliter (µg/mL) | Geometric Coefficient of Variation 3.5 |
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) \[No NCT number available for this study; GlaxoSmithKline Document Number RM1998/00449/00\].
Time frame: Cycle 3 Day 1
Population: Chlorambucil/PAAM pharmacokinetic (PK) Population (substudy): all participants for whom a chlorambucil/PAAM sample is obtained and analyzed.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Chlorambucil | Dose-normalized AUC(0-6) and AUC(0-inf) of Chlorambucil and Dose-normalized AUC(0-6) of Phenylacetic Acid Mustard (PAAM) | Chlorambucil AUC(0-6)/Dose | 67.84 Hours*nanogram/milliliter/milligram | Standard Deviation 0.24 |
| Chlorambucil | Dose-normalized AUC(0-6) and AUC(0-inf) of Chlorambucil and Dose-normalized AUC(0-6) of Phenylacetic Acid Mustard (PAAM) | Chlorambucil AUC(0-inf)/Dose | 74.42 Hours*nanogram/milliliter/milligram | Standard Deviation 0.23 |
| Chlorambucil | Dose-normalized AUC(0-6) and AUC(0-inf) of Chlorambucil and Dose-normalized AUC(0-6) of Phenylacetic Acid Mustard (PAAM) | PAAM AUC(0-6)/Dose | 71.52 Hours*nanogram/milliliter/milligram | Standard Deviation 0.26 |
| Ofatumumab + Chlorambucil | Dose-normalized AUC(0-6) and AUC(0-inf) of Chlorambucil and Dose-normalized AUC(0-6) of Phenylacetic Acid Mustard (PAAM) | Chlorambucil AUC(0-6)/Dose | 65.43 Hours*nanogram/milliliter/milligram | Standard Deviation 0.44 |
| Ofatumumab + Chlorambucil | Dose-normalized AUC(0-6) and AUC(0-inf) of Chlorambucil and Dose-normalized AUC(0-6) of Phenylacetic Acid Mustard (PAAM) | Chlorambucil AUC(0-inf)/Dose | 67.10 Hours*nanogram/milliliter/milligram | Standard Deviation 0.45 |
| Ofatumumab + Chlorambucil | Dose-normalized AUC(0-6) and AUC(0-inf) of Chlorambucil and Dose-normalized AUC(0-6) of Phenylacetic Acid Mustard (PAAM) | PAAM AUC(0-6)/Dose | 80.32 Hours*nanogram/milliliter/milligram | Standard Deviation 0.26 |
90% CI: [0.77, 1.4]
90% CI: [0.82, 1.5]
90% CI: [0.72, 1.1]
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) \[No NCT number available for this study; GlaxoSmithKline Document Number RM1998/00449/00\].
Time frame: Cycle 3 Day 1
Population: Chlorambucil/PAAM pharmacokinetic (PK) Population (substudy): all participants for whom a chlorambucil/PAAM sample is obtained and analyzed.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Chlorambucil | Dose-normalized Cmax of Chlorambucil and Phenylacetic Acid Mustard (PAAM) | Chlorambucil Cmax/Dose | 27.1 nanograms per milliliter per milligram | Standard Deviation 0.32 |
| Chlorambucil | Dose-normalized Cmax of Chlorambucil and Phenylacetic Acid Mustard (PAAM) | PAAM Cmax/Dose | 19.3 nanograms per milliliter per milligram | Standard Deviation 0.23 |
| Ofatumumab + Chlorambucil | Dose-normalized Cmax of Chlorambucil and Phenylacetic Acid Mustard (PAAM) | Chlorambucil Cmax/Dose | 38.4 nanograms per milliliter per milligram | Standard Deviation 0.36 |
| Ofatumumab + Chlorambucil | Dose-normalized Cmax of Chlorambucil and Phenylacetic Acid Mustard (PAAM) | PAAM Cmax/Dose | 24.3 nanograms per milliliter per milligram | Standard Deviation 0.3 |
90% CI: [0.53, 0.94]
90% CI: [0.63, 0.99]
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.
Time frame: From randomization up to about 43 months
Population: ITT population. Only those participants with data available at the indicated time points were analyzed. Only responders (CR, CRi, PR, nPR) were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Chlorambucil | Duration of Response (DOR), as Assessed by the IRC | 13.2 Months |
| Ofatumumab + Chlorambucil | Duration of Response (DOR), as Assessed by the IRC | 22.1 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.
Time frame: From start of treatment up to 30 days after last treatment
Population: Safety Population. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the Safety Population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Chlorambucil | Mean Change From Baseline in the Immunoglobulin (Ig) Antibodies IgA, IgG, and IgM | IgA, n=175, 186 | 0.047 Gram per liter | Standard Deviation 0.5706 |
| Chlorambucil | Mean Change From Baseline in the Immunoglobulin (Ig) Antibodies IgA, IgG, and IgM | IgG, n=175, 186 | -0.458 Gram per liter | Standard Deviation 3.6177 |
| Chlorambucil | Mean Change From Baseline in the Immunoglobulin (Ig) Antibodies IgA, IgG, and IgM | IgM n=175, 186 | -0.398 Gram per liter | Standard Deviation 4.7864 |
| Ofatumumab + Chlorambucil | Mean Change From Baseline in the Immunoglobulin (Ig) Antibodies IgA, IgG, and IgM | IgA, n=175, 186 | 0.048 Gram per liter | Standard Deviation 0.4257 |
| Ofatumumab + Chlorambucil | Mean Change From Baseline in the Immunoglobulin (Ig) Antibodies IgA, IgG, and IgM | IgG, n=175, 186 | -0.268 Gram per liter | Standard Deviation 2.543 |
| Ofatumumab + Chlorambucil | Mean Change From Baseline in the Immunoglobulin (Ig) Antibodies IgA, IgG, and IgM | IgM n=175, 186 | -0.031 Gram per liter | Standard Deviation 0.2507 |
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.
Time frame: From start of treatment to the last study visit/withdrawal visit (Median follow-up approximately 28.9 months)
Population: Safety Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Chlorambucil | Number of Participants Who Received no Transfusion or at Least One Transfusion During the Study | No transfusions | 159 Participants |
| Chlorambucil | Number of Participants Who Received no Transfusion or at Least One Transfusion During the Study | At least one transfusion | 68 Participants |
| Ofatumumab + Chlorambucil | Number of Participants Who Received no Transfusion or at Least One Transfusion During the Study | No transfusions | 168 Participants |
| Ofatumumab + Chlorambucil | Number of Participants Who Received no Transfusion or at Least One Transfusion During the Study | At least one transfusion | 49 Participants |
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.
Time frame: From randomization until the 259th PFS event occurred (Median follow-up approximately 28.9 months)
Population: ITT population. Only those participants with data available at the indicated time points were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Chlorambucil | Number of Participants Who Were Negative for Minimal Residual Disease (MRD) | MRD negative, irrespective of response | 8 Participants |
| Chlorambucil | Number of Participants Who Were Negative for Minimal Residual Disease (MRD) | MRD negative, with an IRC-assessed CR | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants Who Were Negative for Minimal Residual Disease (MRD) | MRD negative, irrespective of response | 26 Participants |
| Ofatumumab + Chlorambucil | Number of Participants Who Were Negative for Minimal Residual Disease (MRD) | MRD negative, with an IRC-assessed CR | 10 Participants |
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).
Time frame: 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.
Population: Safety Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Chlorambucil | Number of Participants With AEs and SAEs of Maximum Severity of Grade 3 or Higher | Any AE, Grade 4 | 31 Participants |
| Chlorambucil | Number of Participants With AEs and SAEs of Maximum Severity of Grade 3 or Higher | Any SAE, Grade 3 | 36 Participants |
| Chlorambucil | Number of Participants With AEs and SAEs of Maximum Severity of Grade 3 or Higher | Any SAE, Grade 4 | 13 Participants |
| Chlorambucil | Number of Participants With AEs and SAEs of Maximum Severity of Grade 3 or Higher | Any AE, Grade 3 | 54 Participants |
| Chlorambucil | Number of Participants With AEs and SAEs of Maximum Severity of Grade 3 or Higher | Any SAE, Grade 5 | 25 Participants |
| Chlorambucil | Number of Participants With AEs and SAEs of Maximum Severity of Grade 3 or Higher | Any AE, Grade 5 | 25 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With AEs and SAEs of Maximum Severity of Grade 3 or Higher | Any SAE, Grade 5 | 36 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With AEs and SAEs of Maximum Severity of Grade 3 or Higher | Any AE, Grade 3 | 67 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With AEs and SAEs of Maximum Severity of Grade 3 or Higher | Any AE, Grade 4 | 36 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With AEs and SAEs of Maximum Severity of Grade 3 or Higher | Any AE, Grade 5 | 36 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With AEs and SAEs of Maximum Severity of Grade 3 or Higher | Any SAE, Grade 4 | 19 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With AEs and SAEs of Maximum Severity of Grade 3 or Higher | Any SAE, Grade 3 | 34 Participants |
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.
Time frame: Baseline, Cycle 4 Day 1, 1 Month Follow-up, and 6 Month Follow-up
Population: Safety population: all participants who received at least 1 dose of a study drug. Only participants with post-ofatumumab HAHA Results are included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ofatumumab + Chlorambucil | Number of Participants With a Human Anti-human Antibody (HAHA) Positive Result | 0 Participants |
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.
Time frame: 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.
Population: Safety Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Chlorambucil | Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) | Any AE | 205 Participants |
| Chlorambucil | Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) | Any SAE | 84 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) | Any AE | 208 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) | Any SAE | 97 Participants |
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).
Time frame: 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.
Population: Safety Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chlorambucil | Number of Participants With at Least One Grade 3/Grade 4 Myelosuppression (Anemia, Neutropenia, and Thrombocytopenia) | 92 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With at Least One Grade 3/Grade 4 Myelosuppression (Anemia, Neutropenia, and Thrombocytopenia) | 83 Participants |
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.
Time frame: 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.
Population: Safety Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chlorambucil | Number of Participants With Autoimmune Hemolytic Anaemia (AIHA) Disease | 6 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Autoimmune Hemolytic Anaemia (AIHA) Disease | 4 Participants |
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.
Time frame: Baseline, Cycle 3 Day 1, and 1 month Follow-up
Population: ITT population. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the ITT Population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Chlorambucil | Number of Participants With Improvement in Constitutional Symptoms (CS) | CS present, Baseline, n=226, 221 | 120 Participants |
| Chlorambucil | Number of Participants With Improvement in Constitutional Symptoms (CS) | CS present, Cycle 3 Day 1, n=198, 199 | 44 Participants |
| Chlorambucil | Number of Participants With Improvement in Constitutional Symptoms (CS) | CS present, 1 Month Follow-up, n=198, 200 | 23 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Improvement in Constitutional Symptoms (CS) | CS present, Baseline, n=226, 221 | 118 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Improvement in Constitutional Symptoms (CS) | CS present, Cycle 3 Day 1, n=198, 199 | 33 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Improvement in Constitutional Symptoms (CS) | CS present, 1 Month Follow-up, n=198, 200 | 22 Participants |
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..
Time frame: Baseline, Cycle 3 Day 1, 1 month Follow-up
Population: ITT population. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the ITT Population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Chlorambucil | Number of Participants With Improvement in ECOG Performance Status of 0 or 1 | ECOG (0, 1) at Baseline | 209 Participants |
| Chlorambucil | Number of Participants With Improvement in ECOG Performance Status of 0 or 1 | ECOG (0, 1) at Cycle 3 Day 1 | 184 Participants |
| Chlorambucil | Number of Participants With Improvement in ECOG Performance Status of 0 or 1 | ECOG (0, 1) 1 Month Follow-up | 183 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Improvement in ECOG Performance Status of 0 or 1 | ECOG (0, 1) at Baseline | 200 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Improvement in ECOG Performance Status of 0 or 1 | ECOG (0, 1) at Cycle 3 Day 1 | 189 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Improvement in ECOG Performance Status of 0 or 1 | ECOG (0, 1) 1 Month Follow-up | 191 Participants |
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.
Time frame: From randomization until the 259th PFS event occurred, up to about 49 months
Population: ITT population. Only those participants with data available at the indicated time points were analyzed. OR was according to the International Workshop for Chronic Lymphocytic Leukemia (IWCLL) updated National Cancer Institute-sponsored Working Group (NCI-WG) guidelines. The 95% exact binomial confidence interval is for CR+CRi+nPR+PR.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Chlorambucil | Number of Participants With the Best Overall Response (OR), as Assessed by the IRC | CR | 3 Participants |
| Chlorambucil | Number of Participants With the Best Overall Response (OR), as Assessed by the IRC | CRi | 0 Participants |
| Chlorambucil | Number of Participants With the Best Overall Response (OR), as Assessed by the IRC | nPR | 0 Participants |
| Chlorambucil | Number of Participants With the Best Overall Response (OR), as Assessed by the IRC | PR | 152 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With the Best Overall Response (OR), as Assessed by the IRC | PR | 149 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With the Best Overall Response (OR), as Assessed by the IRC | CR | 27 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With the Best Overall Response (OR), as Assessed by the IRC | nPR | 1 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With the Best Overall Response (OR), as Assessed by the IRC | CRi | 5 Participants |
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.
Time frame: From randomization up to about 111 months
Population: ITT population. Only those participants with data available at the indicated time points were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Chlorambucil | Overall Survival | 84.67 Months |
| Ofatumumab + Chlorambucil | Overall Survival | NA Months |
p-value: 0.36395% CI: [0.65, 1.17]Log Rank
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.
Time frame: Cycle 4 Day 1
Population: PK Population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Ofatumumab + Chlorambucil | Plasma Half Life (t1/2) of Ofatumumab | 445 hours | Geometric Coefficient of Variation 1.05 |
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.
Time frame: From randomization up to about 49 months
Population: ITT population. Only those participants with data available at the indicated time points were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Chlorambucil | Time to Next Therapy | 24.67 Months |
| Ofatumumab + Chlorambucil | Time to Next Therapy | 39.82 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.
Time frame: From randomization up to about 49 months
Population: ITT population. Only those participants with data available at the indicated time points were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Chlorambucil | Time to Progression, as Assessed by the IRC | 13.6 Months |
| Ofatumumab + Chlorambucil | Time to Progression, as Assessed by the IRC | 23.1 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.
Time frame: From randomization uo to about 27 months
Population: ITT population. Time to response was measured using the International Workshop for CLL (IWCLL) updated National Cancer Institute-sponsored Working Group (NCI-WG) guidelines 2008.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Chlorambucil | Time to Response, as Assessed by the IRC | 1.9 Months |
| Ofatumumab + Chlorambucil | Time to Response, as Assessed by the IRC | 1.2 Months |
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.
Time frame: Cycle 4 Day 1
Population: PK Population.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Ofatumumab + Chlorambucil | Total Plasma Clearance (CL) of Ofatumumab | 15.4 Milliliter/hour (mL/h) | Geometric Coefficient of Variation 0.73 |
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.
Time frame: Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 4 Day 1
Population: PK Population. Only those participants available at the indicated time points were assessed. The number of participants assessed at each time point is indicated by n=X,X.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Ofatumumab + Chlorambucil | Volume of Distribution at Steady State (Vss) of Ofatumumab | Vss, Cycle 1 Day 1, n=0, 193 | 7.78 Liters | Geometric Coefficient of Variation 0.55 |
| Ofatumumab + Chlorambucil | Volume of Distribution at Steady State (Vss) of Ofatumumab | Vss, Cycle 1 Day 8, n=0, 208 | 7.77 Liters | Geometric Coefficient of Variation 0.54 |
| Ofatumumab + Chlorambucil | Volume of Distribution at Steady State (Vss) of Ofatumumab | Vss, Cycle 4 Day 1, n=0, 183 | 8.06 Liters | Geometric Coefficient of Variation 0.53 |