Idelalisib and Ofatumumab in Treating Patients with Previously Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
This phase II trial studies how well giving idelalisib and ofatumumab together works in treating patients diagnosed with chronic lymphocytic leukemia or small lymphocytic lymphoma who have not received any previous treatment. Idelalisib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as ofatumumab, may find cancer cells by identifying a protein on the surface of the cells and help kill them. Giving idelalisib and ofatumumab together may help stop the growth of disease in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma.
Inclusion Criteria
- Subjects must have CLL/SLL, as documented by a history at some point in time of an absolute peripheral blood B cell count > 5000/ul, with a monoclonal B cell population co-expressing cluster of differentiation (CD)19, CD5, and CD23, or if CD23 negative, then documentation of the absence of t(11;14) or cyclin D1 overexpression; alternatively patients with lymphadenopathy in the absence of circulating disease will also be eligible for this study if lymph node biopsy or bone marrow biopsy establishes the diagnosis of CLL with the above immunophenotype
- Participants must have measurable disease (lymphocytosis > 5,000/ul, or palpable or CT measurable lymphadenopathy > 1.5 cm, or bone marrow involvement > 30%)
- Subjects must not have received any prior systemic therapy for CLL and currently have an indication for treatment as defined by the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 guidelines: * Massive or progressive splenomegaly; OR * Massive lymph nodes, nodal clusters, or progressive lymphadenopathy; OR * Grade 2 or 3 fatigue; OR * Fever >= 100.5 degrees Fahrenheit or night sweats for greater than 2 weeks without documented infection; OR * Presence of weight loss >= 10% over the preceding 6 months; OR * Progressive lymphocytosis with an increase of >= 50% over a 2-month period or an anticipated doubling time of less than 6 months; OR * Evidence of progressive marrow failure as manifested by the development of or worsening of anemia and or thrombocytopenia
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2
- Creatinine < 2.0 times institutional upper normal limit
- Total bilirubin < 1.5 times institutional upper normal limit (unless due to disease involvement of liver, hemolysis or a known history of Gilbert’s disease)
- Alanine aminotransferase (ALT) < institutional upper normal limit
- Alkaline phosphatase < 2.5 times institutional upper normal limit (unless due to disease involvement of the liver or bone marrow)
- Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; females of childbearing potential must agree to use a protocol-recommended method of contraception during heterosexual intercourse from the screening visit throughout the study and for 30 days from the last dose of idelalisib; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
- Ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria
- Participants who have had any prior systemic therapy for CLL, or chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) for some other indication prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
- Participants may not be receiving any other study agents
- Participants with known brain metastases should be excluded from this clinical trial
- History of severe allergic reactions attributed to compounds of similar chemical or biologic composition to ofatumumab or idelalisib
- Subjects who have current active hepatic or biliary disease (with exception of participants with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment)
- Treatment with any known non-marketed drug substance or experimental therapy within 5 terminal half-lives or 4 weeks prior to enrollment, whichever is longer, or currently participating in any other interventional clinical study
- Other past or current malignancy that could interfere with the interpretation of outcome; subjects who have been free of active malignancy for at least 2 years, or have a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma, or whose malignancy will not interfere with the interpretation of study results, are eligible
- Chronic or current infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment such as, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis, tuberculosis and active hepatitis C
- History of significant cerebrovascular disease in the past 6 months or ongoing event with active symptoms or sequelae
- Confirmed human immunodeficiency virus (HIV) positive whether or not on antiretroviral therapy
- Clinically significant cardiac disease including unstable angina, acute myocardial infarction within six months prior to randomization, congestive heart failure (New York Heart Association [NYHA] III-IV), and arrhythmia unless controlled by therapy, with the exception of extra systoles or minor conduction abnormalities
- Significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease which in the opinion of the investigator may represent a risk for the participant
- Positive serology for hepatitis B (HB) defined as a positive test for HB surface antigen (HBsAg); in addition, if negative for HBsAg but HB core antibody (HBcAb) positive (regardless of HB surface antibody [HBsAb] status), a HB deoxyribonucleic acid (DNA) test will be performed and if positive the subject will be excluded * If HB virus (HBV) DNA is negative, subject may be included but must undergo HBV DNA polymerase chain reaction (PCR) testing at least every 2 months from the start of treatment until 12 months post treatment; prophylactic antiviral therapy may be initiated at the discretion of the investigator
- Positive serology for hepatitis C (HC) defined as a positive test for HC antibody (HepC Ab), in which case reflexively perform an HC recombinant immunoblot assay (RIBA) or hepatitis C viral load to confirm the result; if the confirmatory test is negative the subject will be eligible
- Pregnant or lactating women; women of childbearing potential must have a negative pregnancy test at screening; breastfeeding should be discontinued if the mother is treated on this study with idelalisib and ofatumumab
- Women of childbearing potential, including women whose last menstrual period was less than one year prior to screening, unable or unwilling to use adequate contraception from study start to 30 days after the last dose of protocol therapy; adequate contraception is defined as hormonal birth control, intrauterine device, double barrier method or total abstinence
- Male subjects unable or unwilling to use adequate contraception methods from study start to 30 days after the last dose of protocol therapy
- Participants using concomitant corticosteroids are allowed as long as the subject is on the equivalent of 20 mg/day or less of prednisone and has been on a stable dose for at least two weeks prior to initiating therapy
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT02135133.
PRIMARY OBJECTIVES:
I. To determine the overall response rate (ORR) of ofatumumab and idelalisib in previously untreated chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) participants in need of therapy.
SECONDARY OBJECTIVES:
I. To determine the complete remission (CR) rate and progression-free survival (PFS) of ofatumumab and idelalisib.
II. To determine the ORR, CR rate and rate of nodal partial remission (PR) with lymphocytosis for idelalisib given alone for two months of therapy to previously untreated participants.
III. To determine the rate of lymphocytosis with idelalisib in previously untreated participants.
IV. To assess the safety of idelalisib in untreated participants and in combination with ofatumumab.
V. To determine whether clinical response correlates with known CLL molecular prognostic factors including fluorescent in situ hybridization (FISH), immunoglobin heavy change variable regions (IGHV), zeta-chain-associated protein kinase 70 (ZAP-70).
VI. To determine whether the use of computed tomography (CT) scans in response assessment improves the predictive power of ORR for progression-free survival or time to next treatment.
VII. To determine whether serum ofatumumab and/or idelalisib levels in vivo predict response.
VIII. To assess whether initial treatment with idelalisib alters the cell surface marker phenotype of circulating CLL cells.
IX. To assess whether in vivo treatment with idelalisib alters CLL cell sensitivity to therapy with antibodies or other kinase inhibitors.
X. To assess pharmacodynamic markers of phosphoinositide 3-kinase (PI3 kinase) inhibition including protein kinase B (AKT) phosphorylation, production of T cell chemokines and response to C-X-C chemokine receptor type 4/5 (CXCR 4/5).
XI. To determine whether response or resistance correlates with genetic alterations in phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) or phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit delta (PIK3CD) or other genes.
XII. To determine the influence of idelalisib treatment on intrinsic innate immune suppression and on regulatory T cells.
XIII. To identify predictors of response and resistance to idelalisib through biochemical and genetic analysis of the PI3 kinase (PI3K) pathway.
XIV. To assess the clonal dynamics of CLL in peripheral blood versus (vs) bone marrow, and during therapy with idelalisib.
OUTLINE: (Closed to enrollment and discontinuing administration of idelalisib to patients previously enrolled as of 3/11/16)
SINGLE-AGENT IDELALISIB AND COMBINATION INDUCTION THERAPY: Patients receive idelalisib orally (PO) twice daily (BID) continuously. Beginning on day 57, patients also receive ofatumumab intravenously (IV) over approximately 4-4.6 hours once weekly on days 64, 71, 78, 85, 92, 99, and 106 (courses 3-4) and then once monthly in weeks 20, 24, 28, and 32 (courses 5-8). Treatment repeats every 28 days (49 days in course 4) for up to 8 courses in the absence of disease progression or unacceptable toxicity.
IDELALISIB POST-INDUCTION THERAPY: Patients achieving CR may continue to receive idelalisib PO BID. Courses with idelalisib repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 or 6 months for up to 12 months, and then periodically for up to 10 years.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationDana-Farber Harvard Cancer Center
Principal InvestigatorJennifer Ruth Brown
- Primary ID13-309
- Secondary IDsNCI-2014-01554, IN-US-312-1237
- ClinicalTrials.gov IDNCT02135133