A Phase II Study of Ibrutinib in Combination With Fludarabine, Cyclophosphamide, and Rituximab (iFCR) in Previously Untreated, Younger Patients With Chronic Lymphocytic Leukemia
Overview
- Phase
- Phase 2
- Intervention
- Ibrutinib
- Conditions
- Chronic Lymphocytic Leukemia
- Sponsor
- Dana-Farber Cancer Institute
- Enrollment
- 85
- Locations
- 8
- Primary Endpoint
- Part I: Participants Who Achieve a Minimal Residual Disease (MRD) Negative Complete Response (CR) in the Bone Marrow at 2 Months Post FCR
- Status
- Active, not recruiting
- Last Updated
- 6 months ago
Overview
Brief Summary
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).
Detailed Description
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.
Investigators
Matthew S. Davids, MD
Principal Investigator
Dana-Farber Cancer Institute
Eligibility Criteria
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
Exclusion Criteria
- •Concurrent Conditions:
- •History of other malignancies, except:
- •Malignancy treated with curative intent and with no known active disease present for ≥ 3 years before the first dose of study drug and felt to be at low risk for recurrence by treating physician.
- •Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
- •Adequately treated carcinoma in situ without evidence of disease.
- •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.
Arms & Interventions
Ibrutinib
\- Ibrutinib- * Oral, daily during each cycle * fludarabine-administered at standard dosing for up to 6 cycles * cyclophosphamide-administered at standard dosing for up to 6 cycles * rituximab-administered at standard dosing for up to 6 cycles
Intervention: Ibrutinib
Ibrutinib
\- Ibrutinib- * Oral, daily during each cycle * fludarabine-administered at standard dosing for up to 6 cycles * cyclophosphamide-administered at standard dosing for up to 6 cycles * rituximab-administered at standard dosing for up to 6 cycles
Intervention: Fludarabine
Ibrutinib
\- Ibrutinib- * Oral, daily during each cycle * fludarabine-administered at standard dosing for up to 6 cycles * cyclophosphamide-administered at standard dosing for up to 6 cycles * rituximab-administered at standard dosing for up to 6 cycles
Intervention: Cyclophosphamide
Ibrutinib
\- Ibrutinib- * Oral, daily during each cycle * fludarabine-administered at standard dosing for up to 6 cycles * cyclophosphamide-administered at standard dosing for up to 6 cycles * rituximab-administered at standard dosing for up to 6 cycles
Intervention: Rituximab
Outcomes
Primary Outcomes
Part I: Participants Who Achieve a Minimal Residual Disease (MRD) Negative Complete Response (CR) in the Bone Marrow at 2 Months Post FCR
Time Frame: 2 months after completing combination therapy
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.
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
Time Frame: 2 years post discontinuation of ibrutinib after 24 months of ibrutinib maintenance
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).
Secondary Outcomes
- Partial Response Rate (PRR)(Response evaluated at 2 months post iFCR. Treatment up to 6 cycles (28 days each).)
- Overall Response Rate(Response evaluated at 2 months post iFCR. Treatment up to 6 cycles (28 days each).)
- Rate of MRD Negative CR After 3 Cycles of iFCR(After 3 cycles of iFCR for each patient completing 3 cycles)
- 1-year Combined Response With MRD From Bone Marrow(at 1 year)
- Complete Response Rate (CRR)(Response evaluated at 2 months post iFCR. Treatment up to 6 cycles (28 days each).)
- Median Overall Survival (OS)(Median follow-up is: 63.24 months (range: 6.83-95.8).)
- Number of Participants Who Convert From Bone Marrow MRD Negative PR to Bone Marrow MRD Negative CR After 1 Year of Ibrutinib Maintenance(12 months ( 1year) after starting therapy)
- Participants Who Convert From Bone Marrow MRD Negativity to MRD Positivity in Participants Who Discontinue Ibrutinib(Response evaluated at 2 months post iFCR. Treatment up to 6 cycles (28 days each).)
- Median Progression-Free Survival (PFS)(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).)
- Number of Participants Who Convert From Bone Marrow MRD Negative PR to Bone Marrow MRD Negative CR After 2 Years on Treatment(2 years (24 months) from start of therapy)
- Median Time to Bone Marrow MRD Negativity(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)