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).

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. 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).