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| Name | Class |
|---|---|
| Pharmacyclics LLC. | INDUSTRY |
| The Leukemia and Lymphoma Society | OTHER |
| Blood Cancer Research Partnership | OTHER |
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This research study is evaluating a new drug called ibrutinib in combination with the standard drugs fludarabine, cyclophosphamide, and rituximab (FCR) as a possible treatment for Chronic Lymphocytic Leukemia (CLL).
Ibrutinib is a type of drug called a kinase inhibitor. It is believed to block a protein called Bruton's tyrosine kinase (BTK) that helps CLL cells live and grow. By blocking this, it is possible that the study drug will kill cancer cells or stop them from growing. Ibrutinib has been FDA approved for the treatment of CLL patients who have received at least one prior treatment; however, the FDA has not yet approved ibrutinib as the first treatment for previously untreated CLL. Therefore, ibrutinib is still considered to be study drug, which means it is still being studied.
Fludarabine, cyclophosphamide, and rituximab (FCR) are intravenous chemotherapy and antibody drugs that together are a standard chemotherapy regimen used for younger patients with CLL. Although FCR is highly effective, it does not typically lead to cure.
In this research study, the investigators are combining a new treatment for CLL, ibrutinib, with a standard chemotherapy regimen for CLL, FCR, to determine whether this combination (iFCR) is safe and effective for patients with previously untreated CLL.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Ibrutinib | Experimental | - Ibrutinib-
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Ibrutinib | Drug | Oral BTK inhibitor |
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| Measure | Description | Time Frame |
|---|---|---|
| Part I: Participants Who Achieve a Minimal Residual Disease (MRD) Negative Complete Response (CR) in the Bone Marrow at 2 Months Post FCR | To assess the number of participants who achieve an MRD negative complete response at the 2 months post last dose of FCR timepoint by 2008 IW-CLL criteria ( Hallek et. al). Participants will have a bone marrow biopsy procedure 2 months after completing combination therapy (Ibrutinib+ FCR) in tandem with a chest, neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. | 2 months after completing combination therapy |
| Part II: Participants Who Achieve a Minimal Residual Disease (MRD) Negative Complete Response (CR) in the Bone Marrow at 2 Years Post Discontinuation of Ibrutinib After Having Achieved MRD Negative CR at the 2 Months Post FCR Timepoint | Participants will have bone marrow biopsies in tandem with a chest, neck, abdomen and pelvic PET CT scan as clinically indicated after discontinuation of treatment. A central read of the PET CT scan will confirm the radiographic response, and the bone marrow pathology and morphology assessments will confirm morphological response in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008). | 2 years post discontinuation of ibrutinib after 24 months of ibrutinib maintenance |
| Measure | Description | Time Frame |
|---|---|---|
| Overall Response Rate | The objective response rate (ORR) was defined as the proportion of participants achieving CR+CRi+PR, Complete Response with incomplete count recovery (CRi) or partial response (PR) based on 2008 IW-CLL criteria criteria (Hallek et al., 2008). | Response evaluated at 2 months post iFCR. Treatment up to 6 cycles (28 days each). |
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Inclusion Criteria:
Must have a confirmed diagnosis of chronic lymphocytic leukemia or small lymphocytic lymphoma. as per IW-CLL 2008 criteria. Patients must also require therapy for that diagnosis, based on meeting at least one of the following criteria:
evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia (hemoglobin <11.0 g/L) and/or thrombocytopenia (platelets <100 x 10^9/L)
massive (≥ 6 cm below the left costal margin), progressive, or symptomatic splenomegaly
massive nodes (at least 10 cm longest diameter), progressive, or symptomatic lymphadenopathy
progressive lymphocytosis with an increase of more than 50% over a 2-month period or LDT of <6 months. Lymphocyte doubling time may be obtained by linear regression extrapolation of absolute lymphocyte counts obtained at intervals of 2 weeks over an observation period of 2 to 3 months. In subjects with initial blood lymphocyte counts of <30 x 10^9/L, LDT should not be used as a single parameter to define indication for treatment. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL (eg, infections) should be excluded
autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids or other standard therapy
documented constitutional symptoms, defined as 1 or more of the following disease-related symptoms or signs:
unintentional weight loss >10% within 6 months prior to screening
significant fatigue (inability to work or perform usual activities)
fevers >100.5° F or 38.0° C for 2 or more weeks prior to screening without evidence of infection
night sweats for more than 1 month prior to screening without evidence of infection
Patients must meet the following hematologic criteria at screening:
Serum aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 x upper limit of normal (ULN)
Exclusion Criteria:
Concurrent Conditions:
History of other malignancies, except:
Concurrent systemic immunosuppressant therapy (eg, cyclosporine A, tacrolimus, etc., or chronic administration of >20 mg/day of prednisone) within 28 days of the first dose of study drug.
Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.
Recent infection requiring systemic treatment that was completed ≤ 14 days before the first dose of study drug.
Known bleeding disorders (eg, von Willebrand's disease) or hemophilia.
History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
Known history of human immunodeficiency virus (HIV) or active with hepatitis C virus (HCV) or hepatitis B virus (HBV). Patients who are positive for hepatitis B core antibody or hepatitis B surface antigen must have a negative polymerase chain reaction (PCR) result before enrollment. Those who are PCR positive will be excluded.
Any uncontrolled active systemic infection.
Major surgery within 4 weeks of first dose of study drug.
Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator's opinion, could compromise the subject's safety or put the study outcomes at undue risk.
Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization.
Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction.
Lactating or pregnant.
Patients receiving any other study agents
Patients with known CNS involvement
Baseline QTcF >480 ms. NOTE: This criterion does not apply to patients with a left bundle branch block.
Patients who require warfarin or other vitamin K antagonists for anticoagulation (other anticoagulants are allowed after consultation with the Principal Investigator).
Concurrent administration of medications or foods that are strong inhibitors or inducers of CYP3A
Patients with ongoing use of prophylactic antibiotics are eligible as long as there is no evidence of active infection and the antibiotic is not included on the list of prohibited medications
Significant co-morbid condition or disease which in the judgment of the Principal Investigator would place the patient at undue risk or interfere with the study
Unable to receive prophylactic treatment for pneumocystis
Patients with del(17p) confirmed by FISH in ≥20% of cells or on stimulated karyotype3.2.24 Patients with del(17p) confirmed by FISH in ≥20% of cells or on stimulated karyotype
Patients with unmutated IGHV who also have a complex karyotype on a stimulated karyotype
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| Name | Affiliation | Role |
|---|---|---|
| Matthew Davids, MD | Dana-Farber Cancer Institute | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Miami Sylvester Comprehensive Cancer Center | Coral Gables | Florida | 33146 | United States | ||
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38163317 | Derived | Ahn IE, Brander DM, Ren Y, Zhou Y, Tyekucheva S, Walker HA, Black R, Montegaard J, Alencar A, Shune L, Omaira M, Jacobson CA, Armand P, Ng SY, Crombie J, Fisher DC, LaCasce AS, Arnason J, Hochberg EP, Takvorian RW, Abramson JS, Brown JR, Davids MS. Five-year follow-up of a phase 2 study of ibrutinib plus fludarabine, cyclophosphamide, and rituximab as initial therapy in CLL. Blood Adv. 2024 Feb 27;8(4):832-841. doi: 10.1182/bloodadvances.2023011574. | |
| 31208944 |
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The study opened to enrollment on 10/3/2014 and closed to enrollment on 4/24/2018. 58 participants were enrolled at Dana-Farber, 9 at Massachusetts General Hospital, 3 at Beth Israel Deaconess Medical Center, 9 at Duke University, 1 at University of Kansas, 3 at West Michigan Cancer Center, and 2 at University of Miami for a total of 85 enrolled.
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| ID | Title | Description |
|---|---|---|
| FG000 | FCR +420mg Ibrutinib Daily | Patients received oral agent ibrutinib daily on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day ibrutinib run in, then will continue daily dosing.Fludarabine, cyclophosphamide, rituximab (FCR) will be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients will receive ibrutinib monotherapy indefinitely unless they are found to be minimal residual disease(MRD) negative in the bone marrow at the 24 months of ibrutinib maintenance timepoint, at which point they will discontinue ibrutinib to undergo active disease monitoring. If during active monitoring they develop MRD positivity in the blood, they may resume ibrutinib monotherapy. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities |
| 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 | Jul 11, 2017 |
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| Fludarabine | Drug | IV purine analogue chemotherapy agent |
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| Cyclophosphamide | Drug | IV alkylator chemotherapy agent |
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| Rituximab | Drug | IV anti-CD20 monoclonal antibody |
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| Complete Response Rate (CRR) | CRR defined as the proportion of participants achieving complete response. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008). | Response evaluated at 2 months post iFCR. Treatment up to 6 cycles (28 days each). |
| Partial Response Rate (PRR) | PRR defined as the proportion of participants achieving partial response. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008). | Response evaluated at 2 months post iFCR. Treatment up to 6 cycles (28 days each). |
| Median Progression-Free Survival (PFS) | Progression-free survival based on the Kaplan-Meier method is defined as the duration between randomization and documented disease progression (PD) or death, or is censored at time of last dsease assessment. | Disease will be evaluated through imaging cycle 3-6 day 1, and In long-term follow-up, after removal or until participant withdrawal, death, or removal from study. Median follow-up is: 63.24 months (range: 6.83-95.8). |
| Median Overall Survival (OS) | Overall Survival (OS) based on the Kaplan-Meier method is defined as the time from study entry to death or censored at date last known alive. | Median follow-up is: 63.24 months (range: 6.83-95.8). |
| Rate of MRD Negative CR After 3 Cycles of iFCR | To determine the rate of minimal residual disease negative complete response (MRD negative CR) in the bone marrow after 3 cycles of ibrutinib + FCR. Participants will have a bone marrow biopsy procedure after completing 3 cycles in tandem with a chest, neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008) | After 3 cycles of iFCR for each patient completing 3 cycles |
| 1-year Combined Response With MRD From Bone Marrow | Combined response with MRD from bone marrow reported as the MRD-negative CR. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008) | at 1 year |
| Number of Participants Who Convert From Bone Marrow MRD Negative PR to Bone Marrow MRD Negative CR After 1 Year of Ibrutinib Maintenance | To determine the rate of minimal residual disease negative complete response (MRD negative CR) in the bone marrow at 12 months from start of therapy, participants will have a bone marrow biopsy procedure at the 1 year timepoint after completing combination therapy (ibrutinib + FCR) in tandem with a chest, neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008) | 12 months ( 1year) after starting therapy |
| Number of Participants Who Convert From Bone Marrow MRD Negative PR to Bone Marrow MRD Negative CR After 2 Years on Treatment | MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)- Bone marrow biopsies will be performed at baseline, after cycle 3, 2 months post FCR, at 1 year and 2 years of ibrutinib maintenance, and as clinically indicated thereafter- Participants will have a bone marrow biopsy procedure 24 months after completing combination therapy (Ibrutinib+ FCR) in tandem with a chest, neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. | 2 years (24 months) from start of therapy |
| Median Time to Bone Marrow MRD Negativity | MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)- | Bone marrow biopsies will be performed at baseline, after cycle 3, 2 months post FCR, at 1 year and 2 years of ibrutinib maintenance, and as clinically indicated thereafter |
| Participants Who Convert From Bone Marrow MRD Negativity to MRD Positivity in Participants Who Discontinue Ibrutinib | .MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008) | Response evaluated at 2 months post iFCR. Treatment up to 6 cycles (28 days each). |
| University of Miami Sylvester Comprehensive Cancer Center |
| Deerfield Beach |
| Florida |
| 33442 |
| United States |
| Unversity of Miami Sylvester Comprehensve Cancer Center | Miami | Florida | 33136 | United States |
| University of Kansas Cancer Center | Westwood | Kansas | 66205 | United States |
| Massachusetts General Hospital | Boston | Massachusetts | 02114 | United States |
| Beth Israel Deaconess Medical Center | Boston | Massachusetts | 02215 | United States |
| Dana Farber Cancer Institute | Boston | Massachusetts | 02215 | United States |
| West Michigan Cancer Center | Kalamazoo | Michigan | 49007 | United States |
| Duke University Medical Center | Durham | North Carolina | 27710 | United States |
| Derived |
| Davids MS, Brander DM, Kim HT, Tyekucheva S, Bsat J, Savell A, Hellman JM, Bazemore J, Francoeur K, Alencar A, Shune L, Omaira M, Jacobson CA, Armand P, Ng S, Crombie J, LaCasce AS, Arnason J, Hochberg EP, Takvorian RW, Abramson JS, Fisher DC, Brown JR; Blood Cancer Research Partnership of the Leukemia & Lymphoma Society. Ibrutinib plus fludarabine, cyclophosphamide, and rituximab as initial treatment for younger patients with chronic lymphocytic leukaemia: a single-arm, multicentre, phase 2 trial. Lancet Haematol. 2019 Aug;6(8):e419-e428. doi: 10.1016/S2352-3026(19)30104-8. Epub 2019 Jun 14. |
| COMPLETED |
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| NOT COMPLETED |
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Age greater than or equal to 18 years and less than or equal to 65 with no prior CLL directed therapy that was instituted due to patient previously meeting IWCLL 2008 criteria for treatment
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| ID | Title | Description |
|---|---|---|
| BG000 | FCR+ 420 mg Ibrutinib daily | Patients received oral agent ibrutinib daily on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day ibrutinib run in, then will continue daily dosing.Fludarabine, cyclophosphamide, rituximab (FCR) will be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients will receive ibrutinib monotherapy indefinitely unless they are found to be minimal residual disease(MRD) negative in the bone marrow at the 24 months of ibrutinib maintenance timepoint, at which point they will discontinue ibrutinib to undergo active disease monitoring. If during active monitoring they develop MRD positivity in the blood, they may resume ibrutinib monotherapy. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities |
| Units | Counts |
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| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||||
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| Age, Categorical | Participants were eligible if their age was greater than or equal to 18 years and less than or equal to 65 | Count of Participants | Participants |
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| Age, Continuous | Median | Full Range | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Enrolled in the United States of America | Count of Participants | Participants |
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| 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 | ||||||||||||||||||||
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| Primary | Part I: Participants Who Achieve a Minimal Residual Disease (MRD) Negative Complete Response (CR) in the Bone Marrow at 2 Months Post FCR | To assess the number of participants who achieve an MRD negative complete response at the 2 months post last dose of FCR timepoint by 2008 IW-CLL criteria ( Hallek et. al). Participants will have a bone marrow biopsy procedure 2 months after completing combination therapy (Ibrutinib+ FCR) in tandem with a chest, neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. | No prior CLL-directed therapy that was instituted due to patient previously meeting IWCLL 2008 criteria for treatment- Age greater than or equal to 18 years and less than or equal to 65 and must require therapy by standard IW-CLL 2008 criteria with adequate renal, hepatic, and hematologic function | Posted | Count of Participants | Participants | 2 months after completing combination therapy |
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| Primary | Part II: Participants Who Achieve a Minimal Residual Disease (MRD) Negative Complete Response (CR) in the Bone Marrow at 2 Years Post Discontinuation of Ibrutinib After Having Achieved MRD Negative CR at the 2 Months Post FCR Timepoint | Participants will have bone marrow biopsies in tandem with a chest, neck, abdomen and pelvic PET CT scan as clinically indicated after discontinuation of treatment. A central read of the PET CT scan will confirm the radiographic response, and the bone marrow pathology and morphology assessments will confirm morphological response in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008). | Not Posted | Dec 2025 | 2 years post discontinuation of ibrutinib after 24 months of ibrutinib maintenance | Participants | ||||||||||||||||||||||||||||||
| Secondary | Overall Response Rate | The objective response rate (ORR) was defined as the proportion of participants achieving CR+CRi+PR, Complete Response with incomplete count recovery (CRi) or partial response (PR) based on 2008 IW-CLL criteria criteria (Hallek et al., 2008). | Posted | Number | proportion of participants | Response evaluated at 2 months post iFCR. Treatment up to 6 cycles (28 days each). |
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| Secondary | Complete Response Rate (CRR) | CRR defined as the proportion of participants achieving complete response. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008). | Posted | Number | proportion of participants | Response evaluated at 2 months post iFCR. Treatment up to 6 cycles (28 days each). |
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| Secondary | Partial Response Rate (PRR) | PRR defined as the proportion of participants achieving partial response. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008). | Posted | Number | proportion of participant | Response evaluated at 2 months post iFCR. Treatment up to 6 cycles (28 days each). |
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| Secondary | Median Progression-Free Survival (PFS) | Progression-free survival based on the Kaplan-Meier method is defined as the duration between randomization and documented disease progression (PD) or death, or is censored at time of last dsease assessment. | Posted | Median | 95% Confidence Interval | months | Disease will be evaluated through imaging cycle 3-6 day 1, and In long-term follow-up, after removal or until participant withdrawal, death, or removal from study. Median follow-up is: 63.24 months (range: 6.83-95.8). |
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| Secondary | Median Overall Survival (OS) | Overall Survival (OS) based on the Kaplan-Meier method is defined as the time from study entry to death or censored at date last known alive. | Posted | Median | 95% Confidence Interval | months | Median follow-up is: 63.24 months (range: 6.83-95.8). |
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| Secondary | Rate of MRD Negative CR After 3 Cycles of iFCR | To determine the rate of minimal residual disease negative complete response (MRD negative CR) in the bone marrow after 3 cycles of ibrutinib + FCR. Participants will have a bone marrow biopsy procedure after completing 3 cycles in tandem with a chest, neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008) | Posted | Count of Participants | Participants | After 3 cycles of iFCR for each patient completing 3 cycles |
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| Secondary | 1-year Combined Response With MRD From Bone Marrow | Combined response with MRD from bone marrow reported as the MRD-negative CR. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008) | Posted | Count of Participants | Participants | at 1 year |
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| Secondary | Number of Participants Who Convert From Bone Marrow MRD Negative PR to Bone Marrow MRD Negative CR After 1 Year of Ibrutinib Maintenance | To determine the rate of minimal residual disease negative complete response (MRD negative CR) in the bone marrow at 12 months from start of therapy, participants will have a bone marrow biopsy procedure at the 1 year timepoint after completing combination therapy (ibrutinib + FCR) in tandem with a chest, neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008) | Posted | Count of Participants | Participants | 12 months ( 1year) after starting therapy |
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| Secondary | Number of Participants Who Convert From Bone Marrow MRD Negative PR to Bone Marrow MRD Negative CR After 2 Years on Treatment | MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)- Bone marrow biopsies will be performed at baseline, after cycle 3, 2 months post FCR, at 1 year and 2 years of ibrutinib maintenance, and as clinically indicated thereafter- Participants will have a bone marrow biopsy procedure 24 months after completing combination therapy (Ibrutinib+ FCR) in tandem with a chest, neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. | Posted | Count of Participants | Participants | 2 years (24 months) from start of therapy |
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| Secondary | Median Time to Bone Marrow MRD Negativity | MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)- | Posted | Median | Full Range | months | Bone marrow biopsies will be performed at baseline, after cycle 3, 2 months post FCR, at 1 year and 2 years of ibrutinib maintenance, and as clinically indicated thereafter |
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| Secondary | Participants Who Convert From Bone Marrow MRD Negativity to MRD Positivity in Participants Who Discontinue Ibrutinib | .MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008) | Posted | Count of Participants | Participants | Response evaluated at 2 months post iFCR. Treatment up to 6 cycles (28 days each). |
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Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email.
Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
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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 | FCR+Ibrutinib 420mg Daily | Patients received oral agent ipilimumab daily on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day ipilimumab run in, then will continue daily dosing. Fludarabine, cyclophosphamide, rituximab (FCR) will be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients will receive ibrutinib monotherapy indefinitely unless they are found to be minimal residual disease(MRD) negative in the bone marrow at the 24 months of ibrutinib maintenance timepoint, at which point they will discontinue ibrutinib to undergo active disease monitoring. If during active monitoring they develop MRD positivity in the blood, they may resume ibrutinib monotherapy. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities | 1 | 85 | 24 | 85 | 85 | 85 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Aspartate Aminotransferase Increased | Investigations | CTCAE (4.0) | Systematic Assessment |
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| Lipase Increased | Investigations | CTCAE (4.0) | Systematic Assessment |
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| Alanine Amintransferase Increased | Investigations | CTCAE (4.0) | Systematic Assessment |
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| Appendicitis | Infections and infestations | CTCAE (4.0) | Systematic Assessment |
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| Anaplasmosis | Infections and infestations | CTCAE (4.0) | Systematic Assessment |
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| Pneumatosis | Gastrointestinal disorders | CTCAE (4.0) | Systematic Assessment |
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| Hypoglycemia | Metabolism and nutrition disorders | CTCAE (4.0) | Systematic Assessment |
| |
| Spondylosis | Musculoskeletal and connective tissue disorders | CTCAE (4.0) | Systematic Assessment |
| |
| Non-Cardiac Chest Pain | Cardiac disorders | CTCAE (4.0) | Systematic Assessment |
| |
| Atrial Fibrillation | Cardiac disorders | CTCAE (4.0) | Systematic Assessment |
| |
| Pneumocystis Jivrocii Pneumonia | Infections and infestations | CTCAE (4.0) | Systematic Assessment |
| |
| Secondary Malignancy- Myelodysplastic Syndrome | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | CTCAE (4.0) | Systematic Assessment |
| |
| Sudden Death | General disorders | CTCAE (4.0) | Systematic Assessment |
| |
| Depression | Psychiatric disorders | CTCAE (4.0) | Systematic Assessment |
| |
| Cholecystitis | Hepatobiliary disorders | CTCAE (4.0) | Systematic Assessment |
| |
| Respiratory Syncytial Virus | Infections and infestations | CTCAE (4.0) | Systematic Assessment |
| |
| Appendiceal Mucocele | Infections and infestations | CTCAE (4.0) | Systematic Assessment |
| |
| Sepsis | Infections and infestations | CTCAE (4.0) | Systematic Assessment | MRSA; Septic Shock |
|
| Hemophagocytic lymphohistiocytosis | Immune system disorders | CTCAE (4.0) | Systematic Assessment |
| |
| Febrile Neutropenia | Infections and infestations | CTCAE (4.0) | Systematic Assessment |
| |
| Cellulitis | Infections and infestations | CTCAE (4.0) | Systematic Assessment |
| |
| Diarrhea | Gastrointestinal disorders | CTCAE (4.0) | Systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Rash acneiform | Skin and subcutaneous tissue disorders | CTCAE 4.0 | Systematic Assessment |
| |
| Aspartate aminotransferase increased | Investigations | CTCAE 4.0 | Systematic Assessment |
| |
| Hyponatremia | Metabolism and nutrition disorders | CTCAE 4.0 | Systematic Assessment |
| |
| Pain in extremity | Musculoskeletal and connective tissue disorders | CTCAE 4.0 | Systematic Assessment |
| |
| Headache | Nervous system disorders | CTCAE 4.0 | Systematic Assessment |
| |
| Skin/subcutaneous tissue disorders; Other, specify | Skin and subcutaneous tissue disorders | CTCAE 4.0 | Systematic Assessment |
| |
| Lymphocyte count increased | Investigations | CTCAE 4.0 | Systematic Assessment |
| |
| Myalgia | Musculoskeletal and connective tissue disorders | CTCAE 4.0 | Systematic Assessment |
| |
| Leukocytosis | Blood and lymphatic system disorders | CTCAE 4.0 | Systematic Assessment |
| |
| Upper respiratory infection | Infections and infestations | CTCAE 4.0 | Systematic Assessment |
| |
| Vomiting | Gastrointestinal disorders | CTCAE 4.0 | Systematic Assessment |
| |
| Alanine aminotransferase increased | Investigations | CTCAE 4.0 | Systematic Assessment |
| |
| Fever | General disorders and administration site conditions | CTCAE 4.0 | Systematic Assessment |
| |
| Hyperkalemia | Metabolism and nutrition disorders | CTCAE 4.0 | Systematic Assessment |
| |
| Insomnia | Psychiatric disorders | CTCAE 4.0 | Systematic Assessment |
| |
| Blood bilirubin increased | Investigations | CTCAE 4.0 | Systematic Assessment |
| |
| Gastroesophageal reflux disease | Gastrointestinal disorders | CTCAE 4.0 | Systematic Assessment |
| |
| Hypokalemia | Metabolism and nutrition disorders | CTCAE 4.0 | Systematic Assessment |
| |
| Nasal congestion | Respiratory, thoracic and mediastinal disorders | CTCAE 4.0 | Systematic Assessment |
| |
| Hypophosphatemia | Metabolism and nutrition disorders | CTCAE 4.0 | Systematic Assessment |
| |
| Back pain | Musculoskeletal and connective tissue disorders | CTCAE 4.0 | Systematic Assessment |
| |
| Dry skin | Skin and subcutaneous tissue disorders | CTCAE 4.0 | Systematic Assessment |
| |
| Hypoglycemia | Metabolism and nutrition disorders | CTCAE 4.0 | Systematic Assessment |
| |
| Hypomagnesemia | Metabolism and nutrition disorders | CTCAE 4.0 | Systematic Assessment |
| |
| Anxiety | Psychiatric disorders | CTCAE 4.0 | Systematic Assessment |
| |
| Dizziness | Nervous system disorders | CTCAE 4.0 | Systematic Assessment |
| |
| Edema limbs | General disorders and administration site conditions | CTCAE 4.0 | Systematic Assessment |
| |
| Palpitations | Cardiac disorders | CTCAE 4.0 | Systematic Assessment |
| |
| Bone pain | Musculoskeletal and connective tissue disorders | CTCAE 4.0 | Systematic Assessment |
| |
| Rash maculo-papular | Skin and subcutaneous tissue disorders | CTCAE 4.0 | Systematic Assessment |
| |
| Alkaline phosphatase increased | Investigations | CTCAE 4.0 | Systematic Assessment |
| |
| Dyspepsia | Gastrointestinal disorders | CTCAE 4.0 | Systematic Assessment |
| |
| Pruritus | Skin and subcutaneous tissue disorders | CTCAE 4.0 | Systematic Assessment |
| |
| Creatinine increased | Investigations | CTCAE 4.0 | Systematic Assessment |
| |
| Hypoalbuminemia | Metabolism and nutrition disorders | CTCAE 4.0 | Systematic Assessment |
| |
| Lung infection | Infections and infestations | CTCAE 4.0 | Systematic Assessment |
| |
| Musculoskeletal and connective tissue disorder - Other, specify | Musculoskeletal and connective tissue disorders | CTCAE 4.0 | Systematic Assessment |
| |
| Pain | General disorders and administration site conditions | CTCAE 4.0 | Systematic Assessment |
| |
| Abdominal pain | Gastrointestinal disorders | CTCAE 4.0 | Systematic Assessment |
| |
| Anorexia | Metabolism and nutrition disorders | CTCAE 4.0 | Systematic Assessment |
| |
| Dyspnea | Respiratory, thoracic and mediastinal disorders | CTCAE 4.0 | Systematic Assessment |
| |
| Febrile neutropenia | Blood and lymphatic system disorders | CTCAE 4.0 | Systematic Assessment |
| |
| Chills | General disorders and administration site conditions | CTCAE 4.0 | Systematic Assessment |
| |
| Gastrointestinal disorders - Other, specify | Gastrointestinal disorders | CTCAE 4.0 | Systematic Assessment |
| |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | CTCAE 4.0 | Systematic Assessment |
| |
| Epistaxis | Respiratory, thoracic and mediastinal disorders | CTCAE 4.0 | Systematic Assessment |
| |
| Hot flashes | Vascular disorders | CTCAE 4.0 | Systematic Assessment |
| |
| Hypertension | Vascular disorders | CTCAE 4.0 | Systematic Assessment |
| |
| Peripheral sensory neuropathy | Nervous system disorders | CTCAE 4.0 | Systematic Assessment |
| |
| Sinusitis | Infections and infestations | CTCAE 4.0 | Systematic Assessment |
| |
| Sore throat | Respiratory, thoracic and mediastinal disorders | CTCAE 4.0 | Systematic Assessment |
| |
| Allergic rhinitis | Respiratory, thoracic and mediastinal disorders | CTCAE 4.0 | Systematic Assessment |
| |
| Atrial fibrillation | Cardiac disorders | CTCAE 4.0 | Systematic Assessment |
| |
| Depression | Psychiatric disorders | CTCAE 4.0 | Systematic Assessment |
| |
| Dry mouth | Gastrointestinal disorders | CTCAE 4.0 | Systematic Assessment |
| |
| Flank pain | Musculoskeletal and connective tissue disorders | CTCAE 4.0 | Systematic Assessment |
| |
| Hyperhidrosis | Skin and subcutaneous tissue disorders | CTCAE 4.0 | Systematic Assessment |
| |
| Hypernatremia | Metabolism and nutrition disorders | CTCAE 4.0 | Systematic Assessment |
| |
| Infusion related reaction | General disorders and administration site conditions | CTCAE 4.0 | Systematic Assessment |
| |
| Investigations - Other, specify | Investigations | CTCAE 4.0 | Systematic Assessment |
| |
| Localized edema | General disorders and administration site conditions | CTCAE 4.0 | Systematic Assessment |
| |
| Metabolism and nutrition disorders - Other, specify | Metabolism and nutrition disorders | CTCAE 4.0 | Systematic Assessment |
| |
| Mucositis oral | Gastrointestinal disorders | CTCAE 4.0 | Systematic Assessment |
| |
| Neck pain | Musculoskeletal and connective tissue disorders | CTCAE 4.0 | Systematic Assessment |
|
Not provided
Not provided
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Matthew Davids, MD | Dana-Farber Cancer Institute | 617-632-6331 | matthew_davids@dfci.harvard.edu |
| May 13, 2020 |
| Prot_SAP_000.pdf |
| ID | Term |
|---|---|
| D015451 | Leukemia, Lymphocytic, Chronic, B-Cell |
| D007938 | Leukemia |
| ID | Term |
|---|---|
| D015448 | Leukemia, B-Cell |
| D007945 | Leukemia, Lymphoid |
| 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 |
Not provided
Not provided
| ID | Term |
|---|---|
| C551803 | ibrutinib |
| C024352 | fludarabine |
| C042382 | fludarabine phosphate |
| D003520 | Cyclophosphamide |
| 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 |
Not provided
Not provided
| Unknown or Not Reported |
|
| Native Hawaiian or Other Pacific Islander |
|
| Black or African American |
|
| White |
|
| More than one race |
|
| Unknown or Not Reported |
|
|
|
|
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| Participants |
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| Participants |
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