Leukaemia, Lymphoblastic Clinical Trial
Official title:
A Phase II, Open Label, Single Arm, Multicenter Study of Chlorambucil in Japanese Previously Untreated Patients With Chronic Lymphocytic Leukemia
| Verified date | April 2015 |
| Source | GlaxoSmithKline |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | Japan: Pharmaceuticals and Medical Devices Agency |
| Study type | Interventional |
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.
| Status | Completed |
| Enrollment | 5 |
| Est. completion date | November 2014 |
| Est. primary completion date | November 2014 |
| Accepts healthy volunteers | No |
| Gender | Both |
| Age group | 20 Years and older |
| Eligibility |
Inclusion Criteria: - Diagnosis of CLL defined by:Circulating B lymphocytes =5,000 /µL AND Flow cytometry confirmation of immunophenotype with CD5, CD19, CD20, and CD23 prior to Visit 2. - Considered inappropriate for fludarabine-based therapy. - Active disease and indication for treatment based on the IWCLL updated NCI-WG guidelines defined by presenting at least any one of the following conditions: Evidence of progressive marrow failure as manifested by development or worsening of anemia and/or thrombocytopenia. Massive (i.e. at least 6 cm below the left costal margin) or progressive or symptomatic splenomegaly. Massive nodes (i.e. at least 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy. Progressive lymphocytosis with an increase of more than 50% over a two month period or an lymphocyte doubling time of less than 6 months. A minimum of any one of the following disease-related symptoms must be present: a) Unintentional weight loss =10% within the previous six months; b) Fevers >38.0°C for = 2 weeks without evidence of infection; or c) Night sweats for more than 1 month without evidence of infection - Not been previously treated for CLL (prior autoimmune hemolytic anemia treatment with corticosteroids permitted). - ECOG Performance Status of 0-2. - QTc <450 msec or QTc <480 msec for patients with bundle branch block The QTc is the QT interval corrected for heart rate according to either Bazett's formula (QTcB) or to Fridericia's formula (QTcF), machine or manual overread, for males and females. The specific formula that will be used in a protocol should be determined prior to initiation of the study, and the formula used to determine inclusion and discontinuation should be the same throughout the study. The QTc should be based on single or averaged QTc values of triplicate electrocardiograms (ECGs) obtained over a brief recording period. - Life expectancy of at least 6 months, in the opinion of the investigator. - Age = 20 years - Signed written informed consent prior to performing any study-specific procedures (the results of other procedures predating the informed consent can be used). Exclusion Criteria: - Prior immuno- or chemotherapy for CLL or small lymphocytic lymphoma (SLL) with any agent except corticosteroids used to treat autoimmune hemolytic anemia. - Previous autologous or allogeneic stem cell transplantation. - Active autoimmune hemolytic anemia (AIHA) requiring corticosteroid therapy >100 mg/day equivalent to hydrocortisone, or chemotherapy. - Known transformation of CLL (e.g. Richter). - Known CNS involvement of CLL. - Chronic or current active infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment such as, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis, tuberculosis and active Hepatitis C. - Other past or current malignancy. Subjects who have been free of malignancy for at least 5 years, or have a history of completely resected non-melanoma skin cancer, or successfully treated in situ carcinoma are eligible. - Clinically significant cardiac disease including unstable angina, acute myocardial infarction within 6 months prior to screening, congestive heart failure, and arrhythmia requiring therapy, with the exception of extra systoles or minor conduction abnormalities. - History of significant cerebrovascular disease or event with significant symptoms or sequelae. - Glucocorticoid use, unless given in doses = 100 mg/day hydrocortisone (or equivalent dose of other glucocorticoid) for <7 days for exacerbations other than CLL (e.g. asthma). - Known HIV positive. - Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. In addition, if negative for HBsAg but HBcAb and/or HBsAb positive, an HBV DNA test will be performed, and if positive the subject will be excluded. - Screening laboratory values: Creatinine >2.0 times upper normal limit (unless normal creatinine clearance). Total bilirubin > 2.0 times upper normal limit (unless due to Gilbert's syndrome). Alanine aminotransferase (ALT) > 3.0 times upper normal limit. - Treatment with any known non-marketed drug substance or experimental therapy within 5 terminal half lives or 4 weeks prior to Visit 1, whichever is longer, treatment with any anti-CD20 monoclonal antibody within 3 months of Visit 1, or participation in any other interventional clinical study. - Known or suspected inability to comply with study protocol. - Lactating women, women with a positive pregnancy test within 7 days prior to administration of the investigational product or women (of childbearing potential) as well as men with partners of childbearing potential, who are not willing to use adequate contraception from study start through one year following last treatment dose. Adequate contraception is defined as oral hormonal birth control, intrauterine device, and male partner sterilization (if male partner is sole partner for that subject) and the double barrier method (condom or occlusive cap plus spermicidal agent). |
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
| Country | Name | City | State |
|---|---|---|---|
| Japan | GSK Investigational Site | Aichi | |
| Japan | GSK Investigational Site | Fukuoka | |
| Japan | GSK Investigational Site | Gunma | |
| Japan | GSK Investigational Site | Miyagi | |
| Japan | GSK Investigational Site | Tokyo | |
| Japan | GSK Investigational Site | Tokyo |
| Lead Sponsor | Collaborator |
|---|---|
| GlaxoSmithKline |
Japan,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | Number of Participants With a Best Response of Either Complete Remission (CR), Nodular Partial Remission (nPR), Complete Remission-incomplete (CRi) or Partial Remission (PR), as Assessed by the Investigator, IRC and IRC With CT | 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). | From the start of treatment until disease progression or death (up to Week 61.1) | No |
| Secondary | Number of Participants With the Best Overall Response (OR), as Assessed by the Investigator, IRC and IRC With 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. | From the start of treatment until disease progression or death (up to Week 61.1) | No |
| Secondary | Progression Free Survival (PFS), as Assessed by the Investigator and the IRC | 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. | From the start of treatment until disease progression or death (up to Week 61.1) | No |
| Secondary | Overall Survival (OS) | 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. | From the start of treatment until death (up to Week 61.1) | No |
| Secondary | Time to Response, as Assessed by the IRC | 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. | From the start of treatment until the first response (CR/PR) (up to Week 61.1) | No |
| Secondary | Duration of Response, as Assessed by the IRC | 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. | From the initial response (CR/PR) until disease progression or death (up to Week 61.1) | No |
| Secondary | Time to Next Chronic Lymphocytic Leukemia (CLL) Therapy | 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. | From the start of treatment until the first administration of the next CLL treatment (up to Week 61.1) | No |
| Secondary | Number of Participants With Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) | 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). | Baseline, Cycle (C) 2-Day (D) 29, C3-D57, C4-D85, C5-D113, C6-D141, C7-D169, C8-D197, C9-D225, FU 1- PDFU 1, FU 85-PDFU 85, and FU 169-PDFU 169 | No |
| Secondary | Number of Participants With no B-symptoms and With at Least One B-symptom Over Time | 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. | Baseline, C2-D29, C3-D57, C4-D85, C5-D113, C6-D141, C7-D169, C8-D197, C9-D225, FU 1-PDFU 1, FU 85-PDFU 85, and FU 169-PDFU 169 | No |
| Secondary | Number of Participants With Any Adverse Events (AE) or Serious Adverse Events (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 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. | From the start of treatment up to Week 61.1 | No |
| Secondary | Number of Participants With Adverse Events by the Indicated Maximum Toxicity Grade | 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 | From the start of treatment up to Week 61.1 | No |
| Secondary | Number of Participants With at Least One Grade 3/Grade 4 Adverse Event of Infection or Myelosuppression (Anemia, Neutropenia, and Thrombocytopenia) | 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). | From the start of treatment up to Week 61.1 | No |
| Secondary | 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.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. | Baseline, FU 1-PDFU 1, FU 85-PDFU 85, and FU 169-PDFU 169 | No |
| Secondary | Number of Participants With Positive Minimal Residual Disease (MRD) | 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. | From the start of treatment up to Week 61.1 | No |
| Secondary | Expression of Beta 2 Microglobulin | Blood samples were collected at the Baseline (Day 1 of Cycle 1) visit for prognostic biomarker Beta 2 microglobulin measurements. | Baseline (Cycle 1 Day 1) | No |
| Secondary | Expression of Complement CH50 | 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). | Baseline, Cycle 1-Day 1, and Cycle 4-Day 85 | No |
| Secondary | Maximum Serum Concentration (Cmax), and Minimum Serum Concentration (Cmin) for Chlorambucil | 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). | Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 1 | No |
| Secondary | Area Under the Serum Concentration-time (AUC) for Chlorambucil | 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). | Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 | No |
| Secondary | Elimination Half-life (t1/2) for Chlorambucil | 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). | Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 | No |
| Secondary | Time of Maximum Serum Concentration (Tmax) for Chlorambucil | 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). | Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 | No |
| Secondary | Maximum Serum Concentration (Cmax), and Minimum Serum Concentration (Cmin) for Phenyl Acetic Acid Mustard | 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). | Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 1 | No |
| Secondary | Area Under the Serum Concentration-time (AUC) for Phenyl Acetic Acid Mustard | 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). | Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 | No |
| Secondary | Elimination Half-life (t1/2) for Phenyl Acetic Acid Mustard | 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). | Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 | No |
| Secondary | Time of Maximum Serum Concentration (Tmax) for Phenyl Acetic Acid Mustard | 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). | Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 | No |