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This single arm, open-label study will assess the safety and efficacy of low dose fludarabine and cyclophosphamide in combination with standard dose MabThera/Rituxan (rituximab) as primary therapy in elderly patients (>/= 65 years) with chronic lymphocytic leukemia. Patients will receive six 28-day cycles of treatment with Mabthera/Rituxan (375 mg/m2 intravenously [iv] Day 0 of cycle 1, 500 mg/m2 iv Day 1 of cycles 2-6), fludarabine (12.5 mg/m2/d iv Days 1-3, cycles 1-6) and cyclophosphamide (150 mg/m2/d iv Days 1-3, cycles 1-6). Anticipated time on study treatment is 6 months, with a 30-month follow-up period.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Rituximab plus Fludarabine and Cyclophosphamide | Experimental | Elderly participants with chronic lymphocytic leukemia (CLL) will receive combination treatment with low-dose fludarabine and cyclophosphamide combined with standard-dose of rituximab for 6 months. Treatment is followed by a follow up period of 36 months. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Cyclophosphamide | Drug | 150 milligrams per square meter (mg/m^2) intravenously (IV) on Days 1-3 of each 28-day cycle for 6 cycles |
|
| Measure | Description | Time Frame |
|---|---|---|
| Overall Response Rate | Overall response rate was defined as the percentage of participants with a complete response (CR) or a partial response (PR) according to National Cancer Institute - Working Group [NCI-WG] guidelines. CR: no clonal B lymphocytes in peripheral blood, no significant lymphadenopathy, liver and spleen normal size, no disease symptoms, blood counts: absolute neutrophil count (ANC) >1,500/microliter (mcL), platelets > 100,000/mcL, hemoglobin > 11.0 grams/deciliter (g/dL), normocellular bone marrow. PR: >/= 50% decrease in clonal B lymphocyte count, >/= 50% reduction in lymphadenopathy, >/= 50% reduction of liver or spleen enlargement and ANC >1,500/mcL, platelets > 100,000/mcL, hemoglobin > 11.0 g/dL OR >/= 50% increase in ANC, platelets or hemoglobin. | Up to 42 months |
| Measure | Description | Time Frame |
|---|---|---|
| Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. Preexisting conditions which worsen during a study are also considered as adverse events. An SAE is any experience that suggests a significant hazard, contraindication, side effect, or precaution, and fulfills any of the following criteria: fatal (resulted in death), life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was medically significant or required intervention to prevent any of the other outcomes listed here. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Clinical Trials | Hoffmann-La Roche | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Haemek Medical Center; Hematology Department | Afula | 18101 | Israel | |||
| Soroka Medical Center; Hematology Deptartment |
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| ID | Title | Description |
|---|---|---|
| FG000 | Rituximab Plus Fludarabine and Cyclophosphamide | Elderly participants with chronic lymphocytic leukemia (CLL) received combination treatment with low-dose fludarabine and cyclophosphamide combined with standard-dose of rituximab for 6 months. Treatment was followed by a follow up period of 36 months. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | May 7, 2014 |
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| Fludarabine | Drug | 12.5 mg/m^2 IV on Days 1-3 of every 28-day cycle for 6 cycles |
|
| Rituximab | Drug | 375 mg/m^2 IV Day 0 of Cycle 1, 500 mg/m^2 IV Day 1 of Cycles 2-6. Each cycle was 28 days. |
|
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| Up to 53 months |
| Percentage of Participants With Neutropenic Fever, Infection, >/= Grade 3 Drug-Related Neutropenia, >/= Grade 3 Drug-Related Thrombocytopenia, Hospitalizations | Up to 53 months |
| Hospitalization Days | Up to 53 months |
| Progression-free Survival (PFS) | PFS was defined as the interval from the first study drug treatment day to the first sign of disease progression according to NCI-WG guidelines. Progressive disease (PD): Any new lesion, any disease symptoms, >/=50% increase in lymphadenopathy, splenomegaly, hepatomegaly, >/= 50% increase in the number of circulating clonal B lymphocytes, decrease of hemoglobin levels by > 2.0 g/dL, >/= 50% decrease of platelet counts, increase of lymphocytes in bone marrow to more than 30% from normal. | Up to 53 months |
| Quality of Life (QoL): Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) Questionnaire | The FACIT-F questionnaire consists of 13 questions with a total score range of 0 to 52 with 0 indicating a better outcome and 52 indicating a worse outcome. | [Visit 1 (Screening, Week 0), at Visits 11 (Week 45) and 14 (Week 80) and at the end of the study (Month 42)] |
| Beersheba |
| 8410101 |
| Israel |
| Rambam Medical Center; Heamatology & Bone Marrow Transplantation | Haifa | 3109601 | Israel |
| Bnei-Zion Medical Center; Hematology Dept | Haifa | 3339419 | Israel |
| Shaare Zedek Medical Center; Hematology Dept. | Jerusalem | 9103102 | Israel |
| Hadassah Ein Karem Hospital; Haematology | Jerusalem | 9112001 | Israel |
| Meir Medical Center; Internal Dept A | Kfar Saba | 44281 | Israel |
| Western Galilee Hospital - Nahariya | Nahariya | 22100 | Israel |
| Beilinson Medical Center; Haematology | Petah Tikva | 49100 | Israel |
| Kaplan Medical Center | Rehovot | 7661041 | Israel |
| ASSAF Harofe; Department of Hematology | Rishon LeZiyyon | 70300 | Israel |
| Ichilov Sourasky Medical Center; Heamatology | Tel Aviv | 6423906 | Israel |
| COMPLETED |
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| NOT COMPLETED |
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Intent-to-Treat (ITT) population included all enrolled participants.
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| ID | Title | Description |
|---|---|---|
| BG000 | Rituximab Plus Fludarabine and Cyclophosphamide | Elderly participants with chronic lymphocytic leukemia (CLL) received combination treatment with low-dose fludarabine and cyclophosphamide combined with standard-dose of rituximab for 6 months. Treatment was followed by a follow up period of 36 months. |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
| |||||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| ||||||||||||||||||
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Overall Response Rate | Overall response rate was defined as the percentage of participants with a complete response (CR) or a partial response (PR) according to National Cancer Institute - Working Group [NCI-WG] guidelines. CR: no clonal B lymphocytes in peripheral blood, no significant lymphadenopathy, liver and spleen normal size, no disease symptoms, blood counts: absolute neutrophil count (ANC) >1,500/microliter (mcL), platelets > 100,000/mcL, hemoglobin > 11.0 grams/deciliter (g/dL), normocellular bone marrow. PR: >/= 50% decrease in clonal B lymphocyte count, >/= 50% reduction in lymphadenopathy, >/= 50% reduction of liver or spleen enlargement and ANC >1,500/mcL, platelets > 100,000/mcL, hemoglobin > 11.0 g/dL OR >/= 50% increase in ANC, platelets or hemoglobin. | Efficacy analysis population included all participants who received rituximab during the study. | Posted | Number | 95% Confidence Interval | percentage of participants | Up to 42 months |
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| |||||||||||||||||||||||||
| Secondary | Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. Preexisting conditions which worsen during a study are also considered as adverse events. An SAE is any experience that suggests a significant hazard, contraindication, side effect, or precaution, and fulfills any of the following criteria: fatal (resulted in death), life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was medically significant or required intervention to prevent any of the other outcomes listed here. | The safety population included all enrolled participants. | Posted | Number | percentage of participants | Up to 53 months |
|
| |||||||||||||||||||||||||||
| Secondary | Percentage of Participants With Neutropenic Fever, Infection, >/= Grade 3 Drug-Related Neutropenia, >/= Grade 3 Drug-Related Thrombocytopenia, Hospitalizations | The safety population included all enrolled participants. | Posted | Number | percentage of participants | Up to 53 months |
|
| ||||||||||||||||||||||||||||
| Secondary | Hospitalization Days | The safety population included all enrolled participants. | Posted | Median | Full Range | days | Up to 53 months |
|
| |||||||||||||||||||||||||||
| Secondary | Progression-free Survival (PFS) | PFS was defined as the interval from the first study drug treatment day to the first sign of disease progression according to NCI-WG guidelines. Progressive disease (PD): Any new lesion, any disease symptoms, >/=50% increase in lymphadenopathy, splenomegaly, hepatomegaly, >/= 50% increase in the number of circulating clonal B lymphocytes, decrease of hemoglobin levels by > 2.0 g/dL, >/= 50% decrease of platelet counts, increase of lymphocytes in bone marrow to more than 30% from normal. | Efficacy analysis population included all participants who received rituximab during the study. | Posted | Median | 95% Confidence Interval | months | Up to 53 months |
|
| ||||||||||||||||||||||||||
| Secondary | Quality of Life (QoL): Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) Questionnaire | The FACIT-F questionnaire consists of 13 questions with a total score range of 0 to 52 with 0 indicating a better outcome and 52 indicating a worse outcome. | Efficacy analysis population included all participants who received rituximab during the study. Participants from the efficacy analysis population, who completed the FACIT-F questionnaire at any time point during the study, were analyzed as indicated at each time point. | Posted | Mean | Standard Deviation | score on a scale | [Visit 1 (Screening, Week 0), at Visits 11 (Week 45) and 14 (Week 80) and at the end of the study (Month 42)] |
|
|
Up to 53 months
The safety population included all enrolled participants.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Rituximab Plus Fludarabine and Cyclophosphamide | Elderly participants with chronic lymphocytic leukemia (CLL) received combination treatment with low-dose fludarabine and cyclophosphamide combined with standard-dose of rituximab for 6 months. Treatment was followed by a follow up period of 36 months. | 2 | 42 | 19 | 42 | 41 | 42 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Febrile neutropenia | Blood and lymphatic system disorders | MedDRA version: 20.1 | Systematic Assessment |
| |
| Leukopenia | Blood and lymphatic system disorders | MedDRA version: 20.1 | Systematic Assessment |
| |
| Thrombocytopenia | Blood and lymphatic system disorders | MedDRA version: 20.1 | Systematic Assessment |
| |
| Diabetes mellitus | Endocrine disorders | MedDRA version: 20.1 | Systematic Assessment |
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| Pancreatitis acute | Gastrointestinal disorders | MedDRA version: 20.1 | Systematic Assessment |
| |
| Chills | General disorders | MedDRA version: 20.1 | Systematic Assessment |
| |
| Pyrexia | General disorders | MedDRA version: 20.1 | Systematic Assessment |
| |
| Herpes zoster | Infections and infestations | MedDRA version: 20.1 | Systematic Assessment |
| |
| Pneumonia | Infections and infestations | MedDRA version: 20.1 | Systematic Assessment |
| |
| Pneumonia bacterial | Infections and infestations | MedDRA version: 20.1 | Systematic Assessment |
| |
| Sepsis | Infections and infestations | MedDRA version: 20.1 | Systematic Assessment |
| |
| Subacute endocarditis | Infections and infestations | MedDRA version: 20.1 | Systematic Assessment |
| |
| Urinary tract infection | Infections and infestations | MedDRA version: 20.1 | Systematic Assessment |
| |
| Compression fracture | Injury, poisoning and procedural complications | MedDRA version: 20.1 | Systematic Assessment |
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| Femoral neck fracture | Injury, poisoning and procedural complications | MedDRA version: 20.1 | Systematic Assessment |
| |
| Squamous cell carcinoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA version: 20.1 | Systematic Assessment |
| |
| Delirium | Psychiatric disorders | MedDRA version: 20.1 | Systematic Assessment |
| |
| Chronic obstructive pulmonary disease | Respiratory, thoracic and mediastinal disorders | MedDRA version: 20.1 | Systematic Assessment |
| |
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDRA version: 20.1 | Systematic Assessment |
| |
| Hypoxia | Respiratory, thoracic and mediastinal disorders | MedDRA version: 20.1 | Systematic Assessment |
| |
| Respiratory failure | Respiratory, thoracic and mediastinal disorders | MedDRA version: 20.1 | Systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anemia | Blood and lymphatic system disorders | MedDRA version: 20.1 | Systematic Assessment |
| |
| Leukopenia | Blood and lymphatic system disorders | MedDRA version: 20.1 | Systematic Assessment |
| |
| Neutropenia | Blood and lymphatic system disorders | MedDRA version: 20.1 | Systematic Assessment |
| |
| Thrombocytopenia | Blood and lymphatic system disorders | MedDRA version: 20.1 | Systematic Assessment |
| |
| Constipation | Gastrointestinal disorders | MedDRA version: 20.1 | Systematic Assessment |
| |
| Diarrhea | Gastrointestinal disorders | MedDRA version: 20.1 | Systematic Assessment |
| |
| Nausea | Gastrointestinal disorders | MedDRA version: 20.1 | Systematic Assessment |
| |
| Asthenia | General disorders | MedDRA version: 20.1 | Systematic Assessment |
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| Chills | General disorders | MedDRA version: 20.1 | Systematic Assessment |
| |
| Fatigue | General disorders | MedDRA version: 20.1 | Systematic Assessment |
| |
| Infusion related reaction | General disorders | MedDRA version: 20.1 | Systematic Assessment |
| |
| Edema peripheral | General disorders | MedDRA version: 20.1 | Systematic Assessment |
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| Pyrexia | General disorders | MedDRA version: 20.1 | Systematic Assessment |
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| Pneumonia | Infections and infestations | MedDRA version: 20.1 | Systematic Assessment |
| |
| Urinary tract infection | Infections and infestations | MedDRA version: 20.1 | Systematic Assessment |
| |
| Neutrophil count decreased | Investigations | MedDRA version: 20.1 | Systematic Assessment |
| |
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA version: 20.1 | Systematic Assessment |
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| Musculoskeletal pain | Musculoskeletal and connective tissue disorders | MedDRA version: 20.1 | Systematic Assessment |
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| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA version: 20.1 | Systematic Assessment |
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| Dyspnea | Respiratory, thoracic and mediastinal disorders | MedDRA version: 20.1 | Systematic Assessment |
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| Pruritus | Skin and subcutaneous tissue disorders | MedDRA version: 20.1 | Systematic Assessment |
| |
| Rash | Skin and subcutaneous tissue disorders | MedDRA version: 20.1 | Systematic Assessment |
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The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Medical Communications | Hoffmann-La Roche | 800 821-8590 | genentech@druginfo.com |
| Mar 19, 2018 |
| Prot_SAP_000.pdf |
| ID | Term |
|---|---|
| D015451 | Leukemia, Lymphocytic, Chronic, B-Cell |
| ID | Term |
|---|---|
| D015448 | Leukemia, B-Cell |
| D007945 | Leukemia, Lymphoid |
| D007938 | Leukemia |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D008232 | Lymphoproliferative Disorders |
| D008206 | Lymphatic Diseases |
| D007160 | Immunoproliferative Disorders |
| D007154 | Immune System Diseases |
| D002908 | Chronic Disease |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D003520 | Cyclophosphamide |
| C024352 | fludarabine |
| D000069283 | Rituximab |
| ID | Term |
|---|---|
| D010752 | Phosphoramide Mustards |
| D009588 | Nitrogen Mustard Compounds |
| D009150 | Mustard Compounds |
| D006846 | Hydrocarbons, Halogenated |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D063088 | Phosphoramides |
| D009943 | Organophosphorus Compounds |
| D058846 | Antibodies, Monoclonal, Murine-Derived |
| D000911 | Antibodies, Monoclonal |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
| D007162 | Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |
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| Title | Denominators | Categories | ||||
|---|---|---|---|---|---|---|
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