| June 24, 2013
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| June 26, 2013
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| September 30, 2019
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| December 30, 2019
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| April 4, 2024
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| December 9, 2013
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| August 7, 2018 (Final data collection date for primary outcome measure)
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| Progression Free Survival (PFS) [ Time Frame: Time from study entry to the time of documented disease progression or death. The analysis was event driven, performed at 2.5 years after the last patient enrolled;up to 4 years. ] The Kaplan-Meier method will be used to estimate the progression free survival distributions for each arm, with median estimates provided. Progression is defined as any one of the following: an increase in number of blood lymphocytes by >= 50% with >= 5000 B lymphocytes/mL in patients on Arm A or those on Arms 2 or 3 no longer receiving ibrutinib, >= 50% increase in the products of at least 2 lymph nodes on 2 consecutive determination 2 weeks apart, >= 50% increase in the size of the liver/spleen, transformation to a more aggressive histology, progression of any cytopenia (i.e. decrease of Hb levels > 2g/dL). Progression free survival time will be the time to either progression or death whichever occurs first.
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| PFS [ Time Frame: Time from study entry to the time of documented disease progression or death, assessed up to 2 years ] Log-rank statistics will be used to compare the PFS distributions of the different treatment arms. The methods of Kaplan and Meier will be used to estimate PFS for the treatment arms. For each of the planned comparisons, we will assess the corresponding hazard ratios, 2-year PFS estimates, and PFS medians along with their 95% confidence intervals.
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- Progression Free Survival (PFS) Rate at 2 Years [ Time Frame: Time from study entry to the time of documented disease progression or death, assessed up to 2 years ]
The Kaplan-Meier method will be used to estimate the rate of progression free survival at 2 years in each treatment arm. Progression is defined as any one of the following: an increase in number of blood lymphocytes by >= 50%, >= 50% increase in the products of at least 2 lymph nodes on 2 consecutive determination 2 weeks apart, >= 50% increase in the size of the liver/spleen, transformation to a more aggressive histology, progression of any cytopenia (i.e. decrease of Hb levels > 2g/dL). Progression free survival time will be the time to either progression or death whichever occurs first.
- Overall Survival (OS) at 2 Years [ Time Frame: From the date of registration to the date of death, assessed up to 2 years ]
The Kaplan-Meier method will be used to estimate the rate of overall survival at 2 years in each treatment arm. OS will be measured from the date of registration to the date of the event (i.e., death) or the date of last follow-up to evaluate that event. Patients who are event-free at their last follow-up evaluation will be censored at that time point.
- Duration of Response (DOR) (Complete Response [CR], CCR, Nodular Partial Response [nPR], Partial Response [PR], and PRL) [ Time Frame: From the date of first response until progression or death, performed at 2.5 years after the last patient enrolled; up to 4 years. ]
The Kaplan-Meier method will be used to estimate median DOR. DOR is the time from first objective status to progression or death. CR requires all of the following: absence of lymphadenopathy > 1.5 cm on physical exam/CT scan, no hepatomegaly/splenomegaly on physical exam, no clonal B-cells in the blood, Normal CBC, bone marrow aspirate & biopsy must be normocellular for age. PR requires >= 50% decrease in peripheral lymphocyte count from pre-treatment value, >= 50% reduction in lymphadenopathy, and/or ≥ 50% reduction in splenomegaly/hepatomegaly. CR with exception of having bone marrow lymphoid CLL nodules will be considered a nodular PR (nPR). CR with exception of not having a bone marrow biopsy performed will be considered a clinical CR (CCR). PR with the exception of having less than a 50% reduction in peripheral lymphocyte count will be considered a PR except persistent lymphocytosis (PRL).
- Percentage of Patients Achieving Any Response to Treatment (Overall Response Rate [ORR] [Complete Response [CR], CCR, Nodular Partial Response [nPR], Partial Response [PR], and PRL]) [ Time Frame: Performed at 2.5 years after the last patient enrolled;up to 4 years. ]
Complete response (CR) requires all of the following: absence of lymphadenopathy >1.5 cm on physical exam/CT scan, no hepatomegaly/splenomegaly on physical exam, no clonal B-cells in the blood, Normal CBC, bone marrow aspirate & biopsy must be normocellular for age. Partial response (PR) requires >= 50% decrease in peripheral lymphocyte count from pre-treatment value, >= 50% reduction in lymphadenopathy, and/or ≥ 50% reduction in splenomegaly/hepatomegaly. CR with exception of having bone marrow lymphoid CLL nodules will be considered a nodular PR (nPR). CR with exception of not having a bone marrow biopsy performed will be considered a clinical CR (CCR). PR with the exception of having less than a 50% reduction in peripheral lymphocyte count will be considered a PR except persistent lymphocytosis (PRL).Overall response rate and corresponding exact binomial 95% CI provided.
- Percentage of Patients Achieving a Biopsy-proven Complete Response (CR) [ Time Frame: Performed at 2.5 years after the last patient enrolled; up to 4 years. ]
Complete response (CR) requires all of the following: absence of lymphadenopathy > 1.5 cm on physical exam/CT scan, no hepatomegaly or splenomegaly on physical exam, no clonal B-cells in the blood, Normal CBC, bone marrow aspirate and biopsy must be normocellular for age. Complete response rate and corresponding exact binomial 95% confidence intervals provided.
- Percentage of Patients Achieving Complete (CR and CCR) or Nodular Partial Response (nPR) [ Time Frame: Performed at 2.5 years after the last patient enrolled; up to 4 years. ]
Complete response (CR) requires all of the following: absence of lymphadenopathy > 1.5 cm on physical exam/CT scan, no hepatomegaly or splenomegaly on physical exam, no clonal B-cells in the blood, Normal CBC, bone marrow aspirate and biopsy must be normocellular for age. CR with exception of having bone marrow lymphoid CLL nodules will be considered a nodular PR (nPR). CR with exception of not having a bone marrow biopsy performed will be considered a clinical CR (CCR). Response rate and corresponding exact binomial 95% confidence intervals provided.
- Percentage of Patients Who Attain Minimal Residual Disease (MRD) Negative Status [ Time Frame: Cycle 9 Day 1 Evaluation ]
Estimated using the number of patients who achieve minimal residual disease divided by the total number randomized to that treatment arm. Corresponding exact binomial 95% confidence intervals for MRD rates will be calculated.
- The Rate of Grade 3, 4, or 5 Treatment-related Non-hematologic Adverse Events (Toxicities) [ Time Frame: Performed at 2.5 years after the last patient enrolled; up to 4 years. ]
The rate of grade 3, 4, or 5 treatment-related non-hematologic adverse events (toxicities) by arm; excludes adverse events occurring post-crossover for patients in Arm A
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- OS [ Time Frame: Up to 2 years ]
The Kaplan-Meier method will be used to estimate OS distributions in this CLL population.
- Time to progression [ Time Frame: Up to 2 years ]
The Kaplan-Meier method will be used to estimate time to progression distributions in this CLL population.
- Duration of response (CR, nPR, and PR) [ Time Frame: From the date at which the patient's objective status is first noted to be a response to the date that progression or death is documented (if one has occurred) or to the date of last follow-up, assessed up to 2 years ]
The Kaplan-Meier method will be used to estimate the duration of response in the CLL population.
- ORR (PR +nPR+ CR) [ Time Frame: Up to 2 years ]
- Change in MRD status [ Time Frame: Baseline to 2 years ]
Hazard ratios and 95% confidence intervals for MRD negative versus positive patients will be calculated for PFS and OS.
- Frequency and severity of adverse events and tolerability per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: Up to 2 years post-treatment ]
The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns.
- Change in geriatric functional status [ Time Frame: Up to 2 years ]
Assessed using assessed by the Older Americans' Resources and Services Multidimensional Functional Assessment Questionnaire, Activities of Daily Living, Medical Outcomes Study physical functioning, Karnofsky performance status rated by a health care professional, Karnofsky performance status rated by the patient, timed "Up and Go", and number of falls in the last six months.
- Change in quality of life [ Time Frame: Baseline to up to 2 years ]
Assessed by the Self Assessment Measure-Patient Questionnaire, European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 Questionnaire, the Health Care Professional Questionnaire, and the Geriatric Quality of Life Outcomes
- Correlative markers (cytogenetics, FISH abnormalities, IgVH mutational status, ZAP-70 methylation status) related to outcomes or response [ Time Frame: Baseline ]
The correlative markers will be summarized quantitatively and graphically between treatment arms.
- Change in gene expression profiling, mRNA and miR expression [ Time Frame: Baseline to up to 2 years ]
- Relationship between the FCGR3A SNP (rs396991) and response [ Time Frame: After 168 days (6 courses) of treatment ]
The response phenotype will be quantified using MRD negativity status.
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| Geriatric Functional Status (Optional) [ Time Frame: Performed at 2.5 years after the last patient enrolled ] Assessed using the Older Americans' Resources and Services Multidimensional Functional Assessment Questionnaire, Activities of Daily Living, Medical Outcomes Study physical functioning, Karnofsky performance status rated by a health care professional, Karnofsky performance status rated by the patient, timed "Up and Go", and number of falls in the last six months.
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| Not Provided
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| Rituximab and Bendamustine Hydrochloride, Rituximab and Ibrutinib, or Ibrutinib Alone in Treating Older Patients With Previously Untreated Chronic Lymphocytic Leukemia
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| A Randomized Phase III Study of Bendamustine Plus Rituximab Versus Ibrutinib Plus Rituximab Versus Ibrutinib Alone in Untreated Older Patients (>/= 65 Years of Age) With Chronic Lymphocytic Leukemia (CLL)
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| This randomized phase III trial studies rituximab with bendamustine hydrochloride or ibrutinib to see how well they work compared to ibrutinib alone in treating older patients with previously untreated chronic lymphocytic leukemia. Monoclonal antibodies, such as rituximab, may block cancer growth in different ways by targeting certain cells. Drugs used in chemotherapy, such as bendamustine hydrochloride, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. It is not yet known whether rituximab with bendamustine hydrochloride may work better than rituximab and ibrutinib or ibrutinib alone in treating chronic lymphocytic leukemia.
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PRIMARY OBJECTIVE:
I. To determine whether progression free survival (PFS) is superior after therapy with bendamustine hydrochloride (bendamustine) in combination with rituximab, ibrutinib alone, or ibrutinib in combination with rituximab in patients age 65 or older with previously untreated chronic lymphocytic leukemia (CLL).
SECONDARY OBJECTIVES:
I. To determine 2-year PFS in each of the three treatment arms. II. To determine which treatment arm produces superior overall survival (OS). III. To determine the complete response (CR) rate, complete and nodular partial response (CR/nPR) rate, and overall response (PR+nPR+CR) rate (ORR) among the three treatment arms and compare these arms.
IV. To determine the impact of minimal residual disease (MRD)-negative disease at time of CR documentation and at 2 years on PFS and OS in each of the treatment arms.
V. To determine duration of response after each of the three treatments and compare these treatment arms.
VI. To determine toxicity and tolerability of the three treatment regimens. VII. To determine response and PFS of patients initially on the bendamustine in combination with rituximab arm who cross over to ibrutinib.
OTHER PRE-SPECIFIED OBJECTIVES:
I. To determine whether baseline cytogenetic markers, Zap-70 methylation, IgVH mutational status, or select deoxyribonucleic acid (DNA) mutations predict outcomes or time to response in these three arms.
II. To determine whether local fluorescence in situ hybridization (FISH) results for del(11q22.3) and del(17p13.1) are consistent with central analysis.
III. To determine whether baseline micro ribonucleic acid (RNA) and gene expression markers are correlated with clinical outcomes of interest (e.g. progression-free and alive at 2 years versus not), as well as to explore changes in microRNA expression from baseline to post-treatment time points, with a focus on those with persistent lymphocytosis and relapse.
IV. To determine whether eradication of MRD predicts longer duration of response with standard therapy and ibrutinib-based regimens.
V. To describe the baseline functional status, comorbid medical conditions, and number of medications of older CLL patients who meet criteria for therapy.
VI. To determine how functional status changes with therapy using baseline to 3-month evaluation and end-of-study/2-year evaluation; to determine whether this change is different among the treatment groups.
VII. To determine whether geriatric assessment variables known to be associated with chemotherapy toxicity in other disease groups can also predict therapy-associated toxicity in the CLL population.
VIII. To assess whether the FCGR3A polymorphism (rs396991) is correlated with depth of response (MRD status) to ibrutinib plus rituximab after 6 cycles, with secondary endpoints CR rate, rapidity of response, and progression-free survival (PFS).
IX. To assess whether C1QA polymorphism (rs172378) is correlated with MRD status, CR rate, rapidity of response, and PFS.
OUTLINE: Patients are randomized to 1 of 3 treatment arms.
ARM I: Patients receive rituximab intravenously (IV) on day 1 (day 0 course 1) and bendamustine hydrochloride IV over 30 minutes on days 1-2. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients experiencing disease progression may crossover to Arm II.
ARM II: Patients receive ibrutinib orally (PO) daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
ARM III: Patients receive ibrutinib as in Arm II. Patients receive rituximab IV on days 1, 8, 15, and 22 of course 2 and on day 1 of courses 3-6. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 6 months for up to 10 years.
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| Interventional
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| Phase 3
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Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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- Stage I Chronic Lymphocytic Leukemia
- Stage II Chronic Lymphocytic Leukemia
- Stage III Chronic Lymphocytic Leukemia
- Stage IV Chronic Lymphocytic Leukemia
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- Active Comparator: Arm I (rituximab, bendamustine hydrochloride)
Patients receive rituximab IV on day 1 (day 0 course 1) and bendamustine hydrochloride IV over 30 minutes on days 1-2. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients experiencing disease progression may crossover to Arm II.
Interventions:
- Drug: Bendamustine Hydrochloride
- Other: Laboratory Biomarker Analysis
- Other: Quality-of-Life Assessment
- Biological: Rituximab
- Experimental: Arm II (ibrutinib)
Patients receive ibrutinib PO daily. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions:
- Drug: Ibrutinib
- Other: Laboratory Biomarker Analysis
- Other: Quality-of-Life Assessment
- Experimental: Arm III (ibrutinib, rituximab)
Patients receive ibrutinib as in Arm II. Patients receive rituximab IV on days 1, 8, 15, and 22 of course 2 and on day 1 of courses 3-6. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions:
- Drug: Ibrutinib
- Other: Laboratory Biomarker Analysis
- Other: Quality-of-Life Assessment
- Biological: Rituximab
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- Ruppert AS, Booth AM, Ding W, Bartlett NL, Brander DM, Coutre S, Brown JR, Nattam S, Larson RA, Erba H, Litzow M, Owen C, Kuzma CS, Abramson JS, Little RF, Smith SE, Stone RM, Byrd JC, Mandrekar SJ, Woyach JA. Adverse event burden in older patients with CLL receiving bendamustine plus rituximab or ibrutinib regimens: Alliance A041202. Leukemia. 2021 Oct;35(10):2854-2861. doi: 10.1038/s41375-021-01342-x. Epub 2021 Jul 17.
- Woyach JA, Ruppert AS, Heerema NA, Zhao W, Booth AM, Ding W, Bartlett NL, Brander DM, Barr PM, Rogers KA, Parikh SA, Coutre S, Hurria A, Brown JR, Lozanski G, Blachly JS, Ozer HG, Major-Elechi B, Fruth B, Nattam S, Larson RA, Erba H, Litzow M, Owen C, Kuzma C, Abramson JS, Little RF, Smith SE, Stone RM, Mandrekar SJ, Byrd JC. Ibrutinib Regimens versus Chemoimmunotherapy in Older Patients with Untreated CLL. N Engl J Med. 2018 Dec 27;379(26):2517-2528. doi: 10.1056/NEJMoa1812836. Epub 2018 Dec 1.
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| Active, not recruiting
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| 547
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| 523
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| January 30, 2025
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| August 7, 2018 (Final data collection date for primary outcome measure)
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Inclusion Criteria:
- PRE-REGISTRATION (STEP 0)
- All patients are REQUIRED to be pre-registered to A041202 in order to submit peripheral blood to the Alliance Hematologic Malignancy Biorepository (HEME) for central Zap-70 methylation. This specimen submission is mandatory prior to registration as results will be used for stratification
- REGISTRATION (STEP 1)
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Patients must be diagnosed with CLL in accordance with International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria that includes all of the following:
- >= 5 x 10^9 B lymphocytes (5000/uL) in the peripheral blood
- On morphologic review, the leukemic cells must be small mature lymphocytes, and prolymphocytes must not exceed 55% of the blood lymphocytes
- CLL cells on immunophenotype (performed locally) must reveal a clonal B-cell population, which express the B cell surface markers of CD19 and CD20, as well as the T-cell antigen CD5; patients with bright surface immunoglobulin expression or lack of CD23 expression in > 10% of cells must lack t(11;14) translocation by interphase cytogenetics
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Patients must be intermediate or high-risk Rai stage CLL
- Intermediate risk (formerly Rai stage I/II) is defined by lymphocytosis plus enlarged lymph nodes at any site, with or without hepatomegaly or splenomegaly
- High risk (formerly Rai stage III/IV) is defined by lymphocytosis with or without enlarged nodes and spleen plus disease-related anemia (hemoglobin < 11 g/dL) or thrombocytopenia (platelet count < 100 x 10^9/L) that is not attributable to autoimmune hemolytic anemia or thrombocytopenia
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Patients must meet criteria for treatment as defined by IWCLL 2008 guidelines which includes at least one of the following criteria:
- Age >= 65 years
- Eastern Cooperative Oncology Group (ECOG) performance status 0-2
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Patients with active hepatitis B defined by hepatitis B surface antigen positivity or core antibody positivity in the presence of hepatitis B DNA are not eligible for this study; patients with a positive hepatitis B core antibody but with negative hepatitis B DNA may participate, but must have hepatitis serologies and hepatitis B DNA monitored periodically by the treating physician
- Intravenous immunoglobulin (IVIG) can cause a false positive hepatitis B serology; if patients receiving routine IVIG have core antibody or surface antigen positivity without evidence of active viremia (negative hepatitis B DNA) they may still participate in the study, but should have hepatitis serologies and hepatitis B DNA monitored periodically by the treating physician
- Patients with class III or class IV heart failure by New York Heart Association, those with unstable angina, and those with uncontrolled arrhythmia are not eligible
- Patients who have had a myocardial infarction, intracranial bleed, or stroke within the past 6 months are not eligible
- Patients with known human immunodeficiency virus (HIV) are eligible if their CD4 count is >= 350 cells/mm^3 and if they are not taking prohibited CYP-interacting medications
- Patients may not have had major surgery within 10 days of enrollment, or minor surgery within 7 days of enrollment; examples of minor surgery include dental surgery, insertion of a venous access device, skin biopsy, or aspiration of a joint; the decision about whether a surgery is major or minor can be made at the discretion of the treating physician
- Absolute neutrophil count (ANC) >= 1,000/uL unless due to bone marrow involvement
- Aspartate aminotransferase (AST) or alanine aminotransferase (AST) =< 2.5 x upper limits of normal except if due to disease infiltration of the liver
- Bilirubin =< 1.5 x upper limits of normal (unless due to liver involvement, hemolysis, or Gilbert's disease)
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Creatinine clearance >= 40 mL/min
- To be calculated by modified Cockcroft-Gault formula
- Platelet count (untransfused) >= 30,000/uL
Exclusion Criteria:
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Prior treatment
- Patients must not have had prior therapy for CLL (except palliative steroids or treatment of autoimmune complications of CLL with rituximab or steroids)
- Treatment with rituximab and/or high dose corticosteroids for autoimmune complications of CLL must be complete at least 4 weeks prior to enrollment; palliative steroids must be at a dose not higher than 20 mg/day of prednisone or equivalent corticosteroid at the time of registration
- Patients must not be receiving active systemic anticoagulation with heparin or warfarin; patients must be off warfarin therapy for at least 30 days prior to enrollment
- Patients must not have any history of Richter's transformation or prolymphocytic leukemia (prolymphocytes in blood > 55%)
- Patients must not require more than 20 mg prednisone or equivalent corticosteroid daily
- Patients must not have uncontrolled active systemic infection requiring intravenous antibiotics
- Patients must not have continued requirement for therapy with a strong cytochrome P450 3A4/5 (CYP3A4/5) inhibitor or inducer
- Patients must not have a known allergy to mannitol
- Patients must not have prior significant hypersensitivity to rituximab (not including infusion reactions)
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| Sexes Eligible for Study: |
All |
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| 65 Years and older (Older Adult)
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| No
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| Contact information is only displayed when the study is recruiting subjects
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| Canada, United States
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| India
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| NCT01886872
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NCI-2013-01220
NCI-2013-01220 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
ALLIANCE A041202
A041202 ( Other Identifier: Alliance for Clinical Trials in Oncology )
A041202 ( Other Identifier: CTEP )
K23CA178183 ( U.S. NIH Grant/Contract )
R01CA183444 ( U.S. NIH Grant/Contract )
U10CA180821 ( U.S. NIH Grant/Contract )
U10CA031946 ( U.S. NIH Grant/Contract )
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| No
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| Not Provided
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| Not Provided
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| National Cancer Institute (NCI)
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| Same as current
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| National Cancer Institute (NCI)
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| Same as current
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| Not Provided
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| Principal Investigator: |
Jennifer A Woyach |
Alliance for Clinical Trials in Oncology |
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| National Cancer Institute (NCI)
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| January 2024
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