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Chronic Lymphocytic Leukemia

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Ofatumumab

Chlorambucil

Antineoplastic Agents, Alkylating

Alkylating Agents

ofatumumab dose: cycle 1 300mg day 1 and 1000mg day 8, subsequent cycles: 1000mg at day 1 every 28 days; chlorambucil dose: 10mg/m2 PO at days 1-7 every 28 days; duration: minimum of 3 cycles until best response or maximum of 12 treatment cycles

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

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

chlorambucil, tablets

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

ofatumumab (GSK1841157) infusion

Novartis Pharmaceuticals

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

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.

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

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

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

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

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.

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.

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 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 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.

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 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 is defined as the time from randomization until the start of the next-line of treatment.

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..

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.

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.

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.

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.

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.

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.

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.

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) \[No NCT number available for this study; GlaxoSmithKline Document Number RM1998/00449/00\].

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) \[No NCT number available for this study; GlaxoSmithKline Document Number RM1998/00449/00\].

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).

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.

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).

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).

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.

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.

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.

All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of 111 months.

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.

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.

Ofatumumab 1000 mg + Chlorambucil

Total

Ofatumumab + Chlorambucil

Years

Age, Customized

Sex: Female, Male

Race/Ethnicity, Customized

Intent-to-treat (ITT) population: All randomized subjects regardless of whether or not they received study treatment.

Clinical Disclosure Office

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.

Progression-Free Survival (PFS), as Assessed by the Independent Review Committee (IRC)

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.

Number of Participants With the Best Overall Response (OR), as Assessed by the IRC

MRD negative, irrespective of response

MRD negative, with an IRC-assessed CR

ITT population. Only those participants with data available at the indicated time points were analyzed.

Number of Participants Who Were Negative for Minimal Residual Disease (MRD)

Overall Survival

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.

Time to Response, as Assessed by the IRC

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.

Duration of Response (DOR), as Assessed by the IRC

Time to Progression, as Assessed by the IRC

Time to Next Therapy

ECOG (0, 1) at Baseline

ECOG (0, 1) at Cycle 3 Day 1

ECOG (0, 1) 1 Month Follow-up

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.

Number of Participants With Improvement in ECOG Performance Status of 0 or 1

CS present, Baseline, n=226, 221

CS present, Cycle 3 Day 1, n=198, 199

CS present, 1 Month Follow-up, n=198, 200

Number of Participants With Improvement in Constitutional Symptoms (CS)

Safety population: all participants who received at least 1 dose of a study drug. Only participants with post-ofatumumab HAHA Results are included.

Number of Participants With a Human Anti-human Antibody (HAHA) Positive Result

Cmax, Cycle 1 Day 1, n=0, 176

Cmax, Cycle 1 Day 8, n=0, 193

Cmax, Cycle 4 Day 1, n=0, 169

Ctrough, Cycle 1 Day 8, n=0, 99

Ctrough, Cycle 2 Day 1, n=0, 138

Ctrough, Cycle 3 Day 1, n=0, 142

Ctrough, Cycle 4 Day 1, n=0, 147

Ctrough, Cycle 5 Day 1, n=0, 149

Ctrough, Cycle 6 Day 1, n=0, 155

Ctrough, Cycle 9 Day 1, n=0, 56

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 up to 12 cycles.

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 up to 12 cycles in combination with chlorambucil 10 mg/m\^2 orally on Days 1-7 of every 28-day cycle for up to 12 cycles.

Pharmacokinetic (PK) Population: all participants for whom a pharmacokinetic sample was obtained and analyzed.

Cmax and Ctrough of Ofatumumab

Total Plasma Clearance (CL) of Ofatumumab

Cycle 1 Day 1, n=0, 193

Cycle 1 Day 8, n=0, 208

Cycle 4 Day 1, n=0, 183

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.

AUC(0-tau) of Ofatumumab

Vss, Cycle 1 Day 1, n=0, 193

Vss, Cycle 1 Day 8, n=0, 208

Vss, Cycle 4 Day 1, n=0, 183

Volume of Distribution at Steady State (Vss) of Ofatumumab

Plasma Half Life (t1/2) of Ofatumumab

Chlorambucil Cmax/Dose

PAAM Cmax/Dose

Study OMB110911: Ofatumumab + Chlorambucil

Participants with CLL, Non-Hodgkin's lymphoma or other refractory malignancies received three different formulations of a 0.2 mg/kilogram(kg) chlorambucil tablet orally with a two-day interval between drug administration.

Study LEUA1001: Chlorambucil

Chlorambucil/PAAM pharmacokinetic (PK) Population (substudy): all participants for whom a chlorambucil/PAAM sample is obtained and analyzed.

Dose-normalized Cmax of Chlorambucil and Phenylacetic Acid Mustard (PAAM)

Chlorambucil AUC(0-6)/Dose

Chlorambucil AUC(0-inf)/Dose

PAAM AUC(0-6)/Dose

Dose-normalized AUC(0-6) and AUC(0-inf) of Chlorambucil and Dose-normalized AUC(0-6) of Phenylacetic Acid Mustard (PAAM)

P1, Cycle 4 Day 1, QLQC30 GHS/QoL score, n=139,159

P1, Cycle 7 Day 1, QLQC30 GHS/QoL score, n=52, 55

P1,Cycle 4 Day 1,QLQCLL16 fatigue score, n=145,163

P1, Cycle 7 Day 1,QLQCLL16 fatigue score, n=55,57

P2,1 month FU, QLQC30 GHS/QoL score, n=118, 150

P2, 6 month FU, QLQC30 GHS/QoL score, n=83, 129

P2, 12 month FU, QLQC30 GHS/QoL score, n=48, 96

P2, 1 month FU, QLQCLL16 fatigue score, n=121, 152

P2, 6 month FU, QLQCLL16 fatigue score, n=85, 131

P2, 12 month FU, QLQCLL16 fatigue score, n=51, 95

Change From Baseline in Health Related Quality of Life (HRQOL)

Any AE

Any SAE

Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)

Any AE, Grade 3

Any AE, Grade 4

Any AE, Grade 5

Any SAE, Grade 3

Any SAE, Grade 4

Any SAE, Grade 5

Number of Participants With AEs and SAEs of Maximum Severity of Grade 3 or Higher

Number of Participants With at Least One Grade 3/Grade 4 Myelosuppression (Anemia, Neutropenia, and Thrombocytopenia)

Number of Participants With Autoimmune Hemolytic Anaemia (AIHA) Disease

No transfusions

At least one transfusion

Number of Participants Who Received no Transfusion or at Least One Transfusion During the Study

IgA, n=175, 186

IgG, n=175, 186

IgM n=175, 186

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.

Mean Change From Baseline in the Immunoglobulin (Ig) Antibodies IgA, IgG, and IgM

Overall Study

Lymphoma

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Lymphosarcoma

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

chlorambucil dose: 10mg/m2 PO at days 1-7 every 28 days; duration: minimum of 3 cycles until best response or maximum of 12 treatment cycles

GSK Clinical Trials

This study is an open-label, single arm, phase II study of chlorambucil in subjects with previously untreated CLL.

The primary objective is to evaluate the response to chlorambucil in Japanese subjects with previously untreated CLL.

Secondary objectives are to evaluate efficacy, safety and pharmacokinetics of chlorambucil in Japanese subjects.

This study is an open-label, single arm, phase II study of chlorambucil in subjects with previously untreated CLL.

The primary objective is to evaluate the response to chlorambucil in Japanese subjects with previously untreated CLL.

Secondary objectives are to evaluate efficacy, safety and pharmacokinetics of chlorambucil in Japanese subjects.

Chlorambucil is an effective and well-tolerated chemotherapeutic agent currently approved for treatment of chronic lymphocytic leukemia (CLL) in the United States of America (US), European Union (EU) and other countries globally but not in Japan. Other more aggressive treatment options such as a combination of fludarabine (F) and cyclophosphamide are available, but are associated with significantly greater toxicities. The addition of ofatumumab to chlorambucil offers potentially a more effective therapy, with limited additional toxicity.

Study OMB110911 has been conducted mainly in the US and EU to evaluate progression-free survival (PFS) and overall response (OR) in subjects with previously untreated CLL with ofatumumab in combination with chlorambucil versus (vs.) chlorambucil monotherapy.

The objective of this study is to evaluate overall response of chlorambucil in Japanese subjects with previously untreated CLL.

A Phase II, Open Label, Single Arm, Multicenter Study of Chlorambucil in Japanese Previously Untreated Patients With Chronic Lymphocytic Leukemia

According to the criteria based on the 2008 revision of the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) of the National Cancer Institute-Sponsored Working Group Guidelines (NCI-WG), participants with complete remission (CR), nodular partial remission (nPR), complete remission-incomplete (CRi) and partial remission (PR) were classified as responders, while stable disease (SD) and progressive disease (PD) were classified as non-responders. Participants with unknown or missing responses were considered as non-responders. Assessment was completed by the Investigator, Independent Review Committee (IRC), and IRC with Computed Tomography (CT).

OR is defined as the number of participants achieving either a confirmed CR or PR. Assessment was completed by the Investigator, IRC, and IRC with CT. 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.

Progression-free survival (PFS) is defined as the time from the start of treatment of investigational product until the first documented sign of PD or death due to any cause. PD requires at least one of the following: lymphadenopathy, appearance of any new lesion such as enlargerd lymph nodes (\>1.5 cm) spleen or liver or other infiltrates or an increase by 50% or more in the greatest diameter of any previous site; an increase by 50% or more in the previously noted enlargement of the liver or spleen, an increase by 50% or more in the numbers of blood lymphocytes with at least 5000 lymphocytes per microliter, transformation to a more aggressive histology, or occurrence of cytopenia attributable to chronic lymphocytic leukaemia. 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.

Overall survival is defined as time from the start of treatment until death due to any cause. Participants who had not died were censored at the date of last contact.

Time to response is defined as time from the start of treatment until the first response (CR/PR). Time to Response analyses was restricted to the subgroup of the population who experienced an overall response (CR/ nPR/CRi/PR) during the study. 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.

Duration of response is defined as the time from the initial response (CR or PR) until progression or death. 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 to next CLL therapy is defined as the time from start of treatment until the first administration of the next CLL treatment other than chlorambucil administrations scheduled in this study. Time to next CLL therapy was restricted to the subgroup of the population who receive a next CLL therapy after experiencing disease progression.

ECOG PS is a scale to assess disease progression, extent to which disease affects the daily living abilities and determines appropriate treatment and prognosis. It is scored on a scale of 0 to 5 as, 0 (fully active), 1 (restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature), 2 (ambulatory and capable of all self cares but unable to carry out any work activities, Up and about \> 50% of waking hours), 3 (capable of only limited self cares, confined to bed or chair \> 50% of waking hours), 4 (completely disabled, cannot carry on any self cares, totally confined to bed or chair), 5 (death). Improvement is defined as decrease from baseline by at least one step on the ECOG performance status scale (yes/no). Baseline was last pre-dose assessment performed on Cycle 1 Day 1(C1 D1). When C1 D1 was missing, the last assessment performed prior to pre-dose C1 D1 was used. It was performed on Day 1 of each cycle and follow-up (FU).

The number of participants with no B-symptoms (no night sweat, no weight loss, no fever and no extreme fatigue) and the number of participants with at least one of the B-symptoms are summarized by assessment time. The presence of the B-symptoms was assessed at Baseline, Day 1 of each treatment cycle and follow-up (FU). Baseline was the last pre-dose assessment performed at C1 D1.

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 whether or not considered related to the medicinal product. A SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, is a congenital anomaly/birth defect or is associated with protocol specified liver injury and impaired liver function or is any protocol specific AEs.

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 whether or not considered related to the medicinal product. Non-hematologic AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 (NCI CTCAE V4.03): Grade 0, none; Grade 1, mild; Grade 2, moderate; Grade 3, severe or medically significant; Grade 4, life-threatening consequences; Grade 5, death related to AE

Number of participants with a Grade 3 or Grade 4 adverse event of infection or myelosuppression (anemia, neutropenia, and thrombocytopenia) are presented. Myelosuppression is defined as the decrease in the ability of the bone marrow to produce blood cells. AEs were graded according to NCI common terminology criteria for adverse events (CTCAE) grade, version 3.0 (1, mild; 2, moderate; 3, severe; 4, life-threatening/disabling; 5, death).

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.Peripheral samples were collected for the analysis of IgA, IgG, and IgM at Baseline and 28 days after Day 1 of the last treatment cycle (FU 1-PDFU 1) for all participants, and 168 days after day of FU 1-PDFU 1 for participants with CR, PR, and SD. Baseline was the last pre-dose assessment performed on Cycle 1-Day 1. The the last assessment performed prior to pre-dose Cycle 1-Day 1 was used if Cycle 1-Day 1 was missing. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

MRD refers to the small number of leukemic cells that remain in the participant during treatment or after treatment at the time the participant achieved a confirmed CR and in whom bone marrow test was performed. A bone marrow sample was examined by flow cytometry (Cluster of differentiation \[CD\]5, CD19, CD20, and CD23). MRD positive is defined as more than one CLL cell per 10000 leukocytes.

Blood samples were collected at the Baseline (Day 1 of Cycle 1) visit for prognostic biomarker Beta 2 microglobulin measurements.

Peripheral samples were collected for the analysis of complement CH50 at Baseline (Day 1 of Cycle 1) and after completion of Cycle 4 (Day 85).

Blood samples for pharmacokinetic (PK) analysis of chlorambucil were collected on Day 1 and Day 4 in Cycle 1, and on Day 1 in Cycle 3. In each sampling, blood samples (2 milliliter \[mL\]/sample) were collected at pre-dose, and 15 minute (min), 30 min, 1 hour (hr), 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr post dosing. Maximum serum concentration (Cmax), minimum serum concentration (Cmin) were determined. Between participants coefficient of variation (%CVb) was calculated according to the following methods: Transformed Data : 100 \* (square root of the exponential \[standard deviation of loge-transformed \]2-1).

Blood samples for PK analysis of chlorambucil were collected on Day 1 and Day 4 in Cycle 1, and on Day 57 in Cycle 3. In each sampling, blood samples (2 mL/sample) were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr post dosing. AUC from time zero up to a definite time t (AUC\[0-t\]), AUC from time zero up to infinity (AUC\[0-inf\]), AUC from time zero up to 6 hours post dose (AUC\[0-6\]), AUC from time zero up to 24 hours post dose (AUC\[0-24\]) were determined. Between participants coefficient of variation (%CVb) was calculated according to the following methods: Transformed Data : 100 \* (square root of the exponential \[standard deviation of loge-transformed \]2-1).

Blood samples for pharmacokinetic (PK) analysis of chlorambucil were collected on Day 1 and Day 4 in Cycle 1, and on Day 57 in Cycle 3. In each sampling, blood samples (2 mL/sample) were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr post dosing. Elimination half-life (t1/2) was determined. Between participants coefficient of variation (%CVb) was calculated according to the following methods: Transformed Data : 100 \* (square root of the exponential \[standard deviation of loge-transformed \]2-1).

Blood samples for pharmacokinetic (PK) analysis of chlorambucil were collected on Day 1 and Day 4 in Cycle 1, and on Day 57 in Cycle 3. In each sampling, blood samples (2 mL/sample) were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr post dosing. Time of maximum serum concentration (tmax) was determined. Between participants coefficient of variation (%CVb) was calculated according to the following methods: Transformed Data : 100 \* (square root of the exponential \[standard deviation of loge-transformed \]2-1).

Blood samples for pharmacokinetic (PK) analysis of chlorambucil and its metabolite phenyl acetic acid mustard were collected on Day 1 and Day 4 in Cycle 1, and on Day 1 in Cycle 3. In each sampling, blood samples (2 milliliter \[mL\]/sample) were collected at pre-dose, and 15 minute (min), 30 min, 1 hour (hr), 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr post dosing. Maximum serum concentration (Cmax), minimum serum concentration (Cmin) were determined. Between participants coefficient of variation (%CVb) was calculated according to the following methods: Transformed Data : 100 \* (square root of the exponential \[standard deviation of loge-transformed \]2-1).

Blood samples for PK analysis of chlorambucil and its metabolite phenyl acetic acid mustard were collected on Day 1 and Day 4 in Cycle 1, and on Day 57 in Cycle 3. In each sampling, blood samples (2 mL/sample) were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr post dosing. AUC from time zero up to a definite time t (AUC\[0-t\]), AUC from time zero up to infinity (AUC\[0-inf\]), AUC from time zero up to 6 hours post dose (AUC\[0-6\]), AUC from time zero up to 24 hours post dose (AUC\[0-24\]) were determined. Between participants coefficient of variation (%CVb) was calculated according to the following methods: Transformed Data : 100 \* (square root of the exponential \[standard deviation of loge-transformed \]2-1).

Blood samples for pharmacokinetic (PK) analysis of chlorambucil and its metabolite phenyl acetic acid mustard were collected on Day 1 and Day 4 in Cycle 1, and on Day 57 in Cycle 3. In each sampling, blood samples (2 mL/sample) were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr post dosing. Elimination half-life (t1/2) was determined. Between participants coefficient of variation (%CVb) was calculated according to the following methods: Transformed Data : 100 \* (square root of the exponential \[standard deviation of loge-transformed \]2-1).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Ofatumumab + Chlorambucil vs Chlorambucil Monotherapy in Previously Untreated Patients With Chronic Lymphocytic Leukemia	NCT00748189	Leukaemia, Lymp...	chlorambucil, t... ofatumumab (GSK...	18 Years -	Novartis
Ofatumumab + Chlorambucil vs Chlorambucil Monotherapy in Previously Untreated Patients With Chronic Lymphocytic Leukemia	NCT00748189	Leukaemia, Lymp...	chlorambucil, t... ofatumumab (GSK...	18 Years -	Novartis
A Phase II, Open Label, Single Arm, Multicenter Study of Chlorambucil in Japanese Previously Untreated Patients With Chronic Lymphocytic Leukemia	NCT01808326	Leukaemia, Lymp...	chlorambucil, t...	20 Years -	GlaxoSmithKline

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