Ibrutinib and Rituximab Compared With Fludarabine Phosphate, Cyclophosphamide, and Rituximab in Treating Patients With Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
Condition: Anemia; Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma
MeSH terms: Lymphoma; Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell
Intervention: Cyclophosphamide; Fludarabine Phosphate; Ibrutinib; Laboratory Biomarker Analysis; Pharmacogenomic Study; Quality-of-Life Assessment; Rituximab
Intervention description: Given IV; Given IV; Given PO; Correlative studies; Correlative studies; Ancillary studies; Given IV
Intervention MeSH terms: Cyclophosphamide; Rituximab; Fludarabine; Fludarabine phosphate; Antineoplastic Agents, Immunological; Antibodies; Immunoglobulins; Antibodies, Monoclonal
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 529.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No

Summary:

      This phase III trial studies ibrutinib and rituximab to see how well they work compared to
      fludarabine phosphate, cyclophosphamide, and rituximab in treating patients with untreated
      chronic lymphocytic leukemia or small lymphocytic lymphoma. Ibrutinib may stop the growth of
      cancer cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such
      as fludarabine phosphate and cyclophosphamide, 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. Rituximab is a monoclonal antibody. It binds to a protein called CD20,
      which is found on B cells (a type of white blood cell) and some types of cancer cells. This
      may help the immune system kill cancer cells. It is not yet known whether fludarabine
      phosphate, cyclophosphamide, and rituximab may work better than ibrutinib and rituximab in
      treating patients with untreated chronic lymphocytic leukemia or small lymphocytic lymphoma.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Diagnosis of CLL according to the National Cancer Institute (NCI)/Internal Workshop on
             Chronic Lymphocytic Leukemia (IWCLL) criteria or small lymphocytic lymphoma (SLL)
             according to the World Health Organization (WHO) criteria; this includes previous
             documentation of:

               -  Biopsy-proven small lymphocytic lymphoma or

               -  Diagnosis of CLL according to the NCI/IWCLL criteria as evidenced by all of the
                  following:

                    -  Peripheral blood lymphocyte count of greater than 5 x 10^9/L

                    -  Immunophenotype consistent with CLL defined as:

                         -  The predominant population of lymphocytes share both B-cell antigens
                            (cluster of differentiation [CD]19, CD20 [typically dim expression], or
                            CD23) as well as CD5 in the absence of other pan-T-cell markers (CD3,
                            CD2, etc)

                         -  Clonality as evidenced by kappa or lambda light chain restriction
                            (typically dim immunoglobulin expression)

               -  Negative FISH analysis for t(11;14)(immunoglobulin heavy locus [IgH]/cyclin D1
                  [CCND1]) on peripheral blood or tissue biopsy (e.g. marrow aspirate) or negative
                  immunohistochemical stains for cyclin D1 staining on involved tissue biopsy (e.g.
                  marrow aspirate or lymph node biopsy)

          -  No prior chemotherapy, Bruton's tyrosine kinase (BTK) inhibitor therapy, or monoclonal
             anti-body therapy for treatment of CLL or SLL

          -  Has met at least one of the following indications for treatment:

               -  Evidence of progressive marrow failure as manifested by the development of
                  worsening anemia (hemoglobin [Hg] < 11 g/dl) and/or thrombocytopenia (platelets <
                  100 x 10^9/L)

               -  Symptomatic or progressive lymphadenopathy, splenomegaly, or hepatomegaly

               -  One or more of the following disease-related symptoms:

                    -  Weight loss >= 10% within the previous 6 months

                    -  Grade 2 or 3 fatigue attributed to CLL

                    -  Fevers > 100.5 Fahrenheit (F) for 2 weeks without evidence of infection

                    -  Clinically significant night sweats without evidence of infection

               -  Progressive lymphocytosis (not due to the effects of corticosteroids) with an
                  increase of > 50% over a two-month period or an anticipated doubling time of less
                  than six months

          -  ECOG performance status between 0-2

          -  Life expectancy of >= 12 months

          -  Ability to tolerate FCR based therapy

          -  No deletion of 17p13 on cytogenetic analysis by FISH

          -  Glomerular filtration rate (GFR) > 40 mL/minute as calculated by the Cockcroft-Gault
             formula (obtained =< 14 days prior to registration)

          -  Total bilirubin =< 2.5 x upper limit of normal (ULN) (obtained =< 14 days prior to
             registration) unless due to Gilbert's disease; for those with a total bilirubin > 2.5
             x ULN, a direct bilirubin should be performed and must be < 1.5 mg/dL for Gilbert's to
             be diagnosed

               -  If value is higher due to hepatic involvement by CLL, patient is eligible

          -  Serum glutamic oxaloacetic transaminase (SGOT) (aspartate transaminase [AST])/serum
             glutamate-pyruvate transaminase (SGPT) (alanine transaminase [ALT]) =< 3.0 x the
             institutional ULN (obtained =< 14 days prior to registration)

               -  If value is higher due to hepatic involvement by CLL, patient is eligible

          -  Prothrombin time (PT)/international normalized ratio (INR) < 1.5 ULN and partial
             thromboplastin time (PTT) (activated partial thromboplastin time [aPTT]) < 1.5 X ULN
             (obtained =< 14 days prior to registration)

               -  If value is higher due to hepatic involvement by CLL, patient is eligible

          -  No active hemolytic anemia requiring immunosuppressive therapy or other pharmacologic
             treatment; patients who have a positive Coombs test but no evidence of hemolysis are
             NOT excluded from participation

          -  No current use of corticosteroids; EXCEPTION: low doses of steroids (< 10 mg of
             prednisone or equivalent dose of other steroid) used for treatment of non-hematologic
             medical condition (e.g. chronic adrenal insufficiency) is permitted

          -  No previous use of corticosteroids for autoimmune complications that have developed
             since the initial diagnosis of CLL; prior use of corticosteroids for reasons other
             than treatment of autoimmune complications is allowed

          -  No other active primary malignancy (other than non-melanomatous skin cancer or
             carcinoma in situ of the cervix) requiring treatment or limiting expected survival to
             =< 2 years; NOTE: if there is a history of prior malignancy, they must not be
             receiving other specific treatment (other than hormonal therapy for their cancer)

          -  Able to adhere to the study visit schedule and other protocol requirements

          -  No major surgery within the last 4 weeks (28 days) of first dose of study drug or
             minor surgery within 3 days of first dose of study drug

          -  No radiation therapy =< 4 weeks prior to registration

          -  Patients with human immunodeficiency virus (HIV) infection may be eligible provided
             they meet the following criteria:

               -  CD4-positive cell count >= lower limit of institutional normal

               -  HIV viral load < 10,000 copies HIV ribonucleic acid (RNA)/mL (if not on anti-HIV
                  therapy) OR < 50 copies HIV RNA/mL (if on anti-HIV therapy)

               -  No evidence of hepatitis B or C infection

               -  No evidence of resistant strains of HIV

               -  No history of acquired immune deficiency syndrome (AIDS)-defining condition

          -  Patients must not have any of the following conditions:

               -  Congestive heart failure or New York Heart Association Functional Classification
                  III or IV congestive heart failure

               -  History of myocardial infarction, unstable angina, or acute coronary syndrome
                  within 6 months prior to registration

               -  Recent infections requiring systemic treatment; need to have completed
                  anti-biotic therapy > 14 days before the first dose of study drug

               -  Cerebral vascular accident or intracranial bleed within the last 6 months

               -  Infection with known chronic, active hepatitis C

               -  Serologic status reflecting active hepatitis B or C infection; patients that are
                  positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or
                  hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior
                  to enrollment (PCR positive patients will be excluded)

          -  Patients are not eligible if they require treatment with a strong cytochrome P450
             (CYP) family 3, subfamily A (3A) inhibitor

          -  Patients may not be on any other investigational agents

          -  Patients may not have received warfarin or another vitamin K antagonist in the
             preceding 30 days

          -  Women must not be pregnant or breast-feeding since this study involves an
             investigational agent whose genotoxic, mutagenic, and teratogenic effects on the
             developing fetus and newborn are unknown; female patients of childbearing potential
             must have a negative serum pregnancy test within 2 weeks prior to registration to rule
             out pregnancy; female patients who are of non-reproductive potential are those who are
             post-menopausal by history (i.e. no menses for >= 1 year); OR history of hysterectomy;
             OR history of bilateral tubal ligation; OR history of bilateral oophorectomy)

          -  Women of childbearing potential and sexually active males must be strongly advised to
             use an accepted and effective method of contraception or to abstain from sexual
             intercourse for 90 days after the last dose of study drug

          -  Patient must be able to swallow capsules and not have the following conditions:

               -  Disease significantly affecting gastrointestinal function

               -  Resection of the stomach or small bowel

               -  Symptomatic inflammatory bowel disease

               -  Ulcerative colitis

               -  Partial or complete bowel obstruction

          -  Patient must not be on any other systemic immunosuppressant therapy other than
             corticosteroids within 28 days of the first dose of study drug

          -  Patient must not be vaccinated with live, attenuated vaccines within 4 weeks of first
             dose of study drug

          -  Patient must not have any known bleeding disorders (e.g., von Willebrand's disease) or
             hemophilia

          -  Patient must not have currently active, clinically significant hepatic impairment (>=
             moderate hepatic impairment according to the NCI/Child Pugh)