A Phase 1 Study of Lenalidomide and Ibrutinib in Combination With Rituximab in Relapsed and Refractory CLL and SLL
Overview
- Phase
- Phase 1
- Intervention
- Biospecimen Collection
- Conditions
- Recurrent Chronic Lymphocytic Leukemia
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 12
- Locations
- 3
- Primary Endpoint
- Recommended phase II dose of lenalidomide and ibrutinib with rituximab based on the maximum tolerated dose and the assessment of any clinically relevant toxicity
- Status
- Active, not recruiting
- Last Updated
- 19 days ago
Overview
Brief Summary
This phase I trial studies the side effects and best dose of lenalidomide when given together with ibrutinib and rituximab in treating patients with chronic lymphocytic leukemia or small lymphocytic lymphoma that has come back (relapsed), has not responded well to prior treatments (refractory), has spread to other parts of the body (metastatic), or cannot be removed by surgery. Biological therapies, such as lenalidomide, use substances made from living organisms that may stimulate or suppress the immune system in different ways and stop cancer cells from growing. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Rituximab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. Giving lenalidomide together with ibrutinib and rituximab may kill more cancer cells.
Detailed Description
PRIMARY OBJECTIVE: I. To determine the recommended phase II doses of lenalidomide and ibrutinib for combination with rituximab in previously treated chronic lymphocytic leukemia and small lymphocytic lymphoma. SECONDARY OBJECTIVES: I. To determine the safety and tolerability of the combination of lenalidomide, ibrutinib and rituximab in previously treated chronic lymphocytic leukemia and small lymphocytic lymphoma. II. To describe any preliminary evidence of antitumor activity of the combination of lenalidomide, rituximab and ibrutinib in previously treated chronic lymphocytic leukemia and small lymphocytic lymphoma as defined by response rate, duration of response, and progression-free survival. III. To observe and record anti-tumor activity. OUTLINE: This is a dose-escalation study of lenalidomide. Patients receive rituximab intravenously (IV) on day 1 (up to 6 cycles), lenalidomide orally (PO) once daily (QD) on days 1-21 (up to 12 cycles), and ibrutinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo electrocardiogram (ECG) on screening and computed tomography (CT) scan or magnetic resonance imaging (MRI), bone marrow biopsy and blood sample collection throughout the study. After completion of study treatment, patients are followed up at 30 days and every 6 months for 10 years.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients must have histologically confirmed malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective; previously treated, pathologically confirmed chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) that requires as per the National Cancer Institute (NCI) Working Group Guidelines for the treatment of CLL; the diagnosis of CLL is defined by the presence of 5 x 10\^9 clonal B-lymphocytes/L in the peripheral blood; clonality of the lymphocyte population is established with flow cytometry and the demonstration of the following surface markers: CD5, CD23, CD19, CD20 and the presence of either kappa or lambda immunoglobulins; the diagnosis of SLL may be made with the demonstration of \< 5 x 10\^9 clonal B-lymphocytes/L in the peripheral blood, with the clinical or radiographic features of enlarged lymph nodes or organomegaly, and the demonstration of SLL cells in the lymph node biopsy; institutional flow cytometry or immunohistochemistry must confirm CD20 antigen expression; patients may not have had a history of Richter's transformation
- •No prior systemic therapy for CLL or SLL including chemotherapy or immunotherapy (e.g., monoclonal antibody-based therapy), radiation therapy, within 4 weeks of enrollment; no prior carmustine (BCNU) or mitomycin C within 6 weeks of enrollment; no radioimmunotherapy within a year of enrollment; no corticosteroids administered within 2 weeks prior to study entry, except for maintenance therapy (=\< prednisone 20 mg daily or equivalent) for a non-malignant disease
- •Patients may have had a prior autologous stem cell transplant; no prior history of allogeneic stem cell transplant
- •Patients may have received prior lenalidomide as long as it has been at least two years since exposure and the patient may not have experienced a progression while receiving lenalidomide previously
- •No Bruton's tyrosine kinase inhibitor at any point prior to enrollment
- •No history of allergic reactions attributed to compounds of similar chemical or biologic composition to ibrutinib, lenalidomide or rituximab or hypersensitivity to murine proteins or to any component of rituximab
- •Measurable disease must be present either on physical examination or imaging studies; non-measurable disease alone is not acceptable; any tumor mass \> 1 cm is acceptable; lesions that are considered non-measurable include the following:
- •Bone lesions (lesions if present should be noted)
- •Pleural/pericardial effusion
- •Lymphangitis cutis/pulmonis
Exclusion Criteria
- •Chemotherapy =\< 21 days prior to first administration of study treatment and/or monoclonal antibody =\< 6 weeks prior to first administration of study treatment
- •Prior exposure to a Bruton's tyrosine kinase (BTK) inhibitor
- •Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to ibrutinib
- •Patients who received a strong cytochrome P450 (CYP) 3A inhibitor within 7 days prior to the first dose of ibrutinib or patients who require continuous treatment with a strong CYP3A inhibitor
- •Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or an infection requiring systemic antibiotics, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements; recent infections requiring systemic treatment need to have completed therapy \> 14 days before the first dose of study drug
- •Pregnant and breastfeeding women are excluded from this study; pregnant women are excluded in this study because ibrutinib is a tyrosine kinase inhibitor with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with ibrutinib, breastfeeding should be discontinued if the mother is treated with ibrutinib
- •Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are eligible; unless the patient's CD4 count is below the institutional lower limit of normal
- •Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura (ITP) resulting in (or as evidenced by) declining platelet or hemoglobin (Hgb) levels within the 4 weeks prior to first dose of study drug
- •Presence of transfusion-dependent thrombocytopenia
Arms & Interventions
Treatment (lenalidomide, ibrutinib, rituximab)
Patients receive rituximab IV on day 1 (up to 6 cycles), lenalidomide PO QD on days 1-21 (up to 12 cycles), and ibrutinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECG on screening and CT scan or MRI, bone marrow biopsy and blood sample collection throughout the study.
Intervention: Biospecimen Collection
Treatment (lenalidomide, ibrutinib, rituximab)
Patients receive rituximab IV on day 1 (up to 6 cycles), lenalidomide PO QD on days 1-21 (up to 12 cycles), and ibrutinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECG on screening and CT scan or MRI, bone marrow biopsy and blood sample collection throughout the study.
Intervention: Electrocardiogram
Treatment (lenalidomide, ibrutinib, rituximab)
Patients receive rituximab IV on day 1 (up to 6 cycles), lenalidomide PO QD on days 1-21 (up to 12 cycles), and ibrutinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECG on screening and CT scan or MRI, bone marrow biopsy and blood sample collection throughout the study.
Intervention: Ibrutinib
Treatment (lenalidomide, ibrutinib, rituximab)
Patients receive rituximab IV on day 1 (up to 6 cycles), lenalidomide PO QD on days 1-21 (up to 12 cycles), and ibrutinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECG on screening and CT scan or MRI, bone marrow biopsy and blood sample collection throughout the study.
Intervention: Bone Marrow Biopsy
Treatment (lenalidomide, ibrutinib, rituximab)
Patients receive rituximab IV on day 1 (up to 6 cycles), lenalidomide PO QD on days 1-21 (up to 12 cycles), and ibrutinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECG on screening and CT scan or MRI, bone marrow biopsy and blood sample collection throughout the study.
Intervention: Magnetic Resonance Imaging
Treatment (lenalidomide, ibrutinib, rituximab)
Patients receive rituximab IV on day 1 (up to 6 cycles), lenalidomide PO QD on days 1-21 (up to 12 cycles), and ibrutinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECG on screening and CT scan or MRI, bone marrow biopsy and blood sample collection throughout the study.
Intervention: Computed Tomography
Treatment (lenalidomide, ibrutinib, rituximab)
Patients receive rituximab IV on day 1 (up to 6 cycles), lenalidomide PO QD on days 1-21 (up to 12 cycles), and ibrutinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECG on screening and CT scan or MRI, bone marrow biopsy and blood sample collection throughout the study.
Intervention: Rituximab
Treatment (lenalidomide, ibrutinib, rituximab)
Patients receive rituximab IV on day 1 (up to 6 cycles), lenalidomide PO QD on days 1-21 (up to 12 cycles), and ibrutinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECG on screening and CT scan or MRI, bone marrow biopsy and blood sample collection throughout the study.
Intervention: Lenalidomide
Outcomes
Primary Outcomes
Recommended phase II dose of lenalidomide and ibrutinib with rituximab based on the maximum tolerated dose and the assessment of any clinically relevant toxicity
Time Frame: Up to 28 days
Graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Secondary Outcomes
- Overall response rate(From the start of the treatment until disease progression/recurrence or death, assessed up to 10 years)
- Complete response rates(Up to 10 years)
- Progression-free survival(Time from start of treatment to time of progression or relapse or death, whichever occurs first, assessed up to 10 years)
- Incidence of adverse events(Up to 30 days following the last dose of ibrutinib)
- Duration of response(From the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented or death, assessed up to 10 years)