This phase I/Ib trial investigates the side effects of CC-486 and how well it works in combination with lenalidomide and obinutuzumab in treating patients with CD20 positive B-cell lymphoma that has come back (recurrent) or has not responded to treatment (refractory). Chemotherapy drugs, such as CC-486, 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. Lenalidomide is a drug that alters the immune system and may also interfere with the development of tiny blood vessels that help support tumor growth. Therefore, in theory, it may reduce or prevent the growth of cancer cells. Obinutuzumab is a type of antibody therapy that targets and attaches to the CD20 proteins found on follicular lymphoma cells as well as some healthy blood cells. Once attached to the CD20 protein the obinutuzumab is thought to work in different ways, including by helping the immune system destroy the cancer cells and by destroying the cancer cells directly. Giving CC-486 with lenalidomide and obinutuzumab may improve response rates, quality, and duration, and minimize adverse events in patients with B-cell lymphoma.
PRIMARY OBJECTIVE: To assess the safety and toxicity of oral azacitidine (CC-486) in combination with lenalidomide and obinutuzumab. SECONDARY OBJECTIVES: I. To evaluate the efficacy of CC-486 in combination with lenalidomide and obinutuzumab in subjects with relapsed/refractory indolent B-cell lymphoma as assessed by: Ia. Overall response rate: complete response (CR) + partial response (PR) per 2016 Lugano criteria and Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC) criteria. Ib. Duration of response (DOR): will be calculated from time of initial response assessment demonstrating at least PR until disease response assessment that demonstrates progressive disease. Ic. Time to response (TTR): calculated as time from registration to first disease response assessment that demonstrates at least PR. Id. Progression-free survival (PFS): Patients are considered a failure for this endpoint if they die or if they relapse/progress or receive additional anti-lymphoma therapy. Ie. Determine the recommended phase 2 dose (RP2D).
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
8
University of California Davis Comprehensive Cancer Center
Sacramento, California, United States
Incidence of adverse events (AEs)
Safety summaries will include tabulations in the form of tables and listings. The frequency (number and percentage) of treatment-emergent AEs will be reported. The frequency of treatment-emergent AEs requiring discontinuation of study drug or dose reductions will be reported. Additional AE summaries will include AE frequency by AE severity and by relationship to study drug. Toxicity data by type and severity will be summarized by frequency tables. Per-treated analysis will be performed to include any patient who received the treatment regardless of the eligibility nor the duration or dose of the treatment received.
Time frame: Up to 30 days post-last dose
Complete response rate
Response will be assessed based on Cheson, Lugano classification 2016. The number and percentage of subjects with a complete response at 120 weeks will be tabulated.
Time frame: At 48 weeks
Overall response rate (ORR) (complete response + partial response)
Will be assessed by the investigator based on Cheson, Lugano classification 2016. The number and percentage of subjects with an ORR will be tabulated. The best ORR will be recorded.
Time frame: Up to 2 years
Duration of response
Kaplan-Meier methodology will be used to estimate event-free curves, median, and 95% confidence interval. Comparison by important subgroups will be made using the log-rank test.
Time frame: From the time by which measurement criteria for complete response or partial response, whichever is recorded first, is met until death or the first date by which progressive disease is documented, assessed up to 2 years
Time to response
Comparison by important subgroups will be made using the log-rank test. Will be estimated using the product-limit method of Kaplan and Meier.
Time frame: From registration to first disease response assessment that demonstrates at least partial response, assessed up to 2 years
Progression-free survival
Kaplan-Meier methodology will be used to estimate event-free curves, median, and 95% confidence interval. Comparison by important subgroups will be made using the log-rank test.
Time frame: From the date of first dose (cycle 1, day 1) to the date of first documented progression or death, assessed up to 2 years.
Recommended phase 2 dose
The maximum tolerated dose (MTD) will be defined as the highest dose of CC-486 tested in which fewer than 33% of patients experience a dose-limiting toxicity and at least 6 patients have been treated at that dose. The MTD will be the recommended phase 2 dose, provided that other safety considerations are acceptable.
Time frame: Up to 35 days
Time to next treatment
Kaplan-Meier methodology will be used to estimate event-free curves, median, and 95% confidence interval. Comparison by important subgroups will be made using the log-rank test.
Time frame: From the end of cycle 24 (each cycle is 28 days) to the date of first documented new anti-lymphoma treatment, assessed up to 2 years.
Event-free survival
Kaplan-Meier methodology will be used to estimate event-free curves, median, and 95% confidence interval. Comparison by important subgroups will be made using the log-rank test.
Time frame: From the date of first dose (cycle 1, day 1) to the date of first documented progression, transformation to diffuse large B-cell lymphoma, initiation of new anti-lymphoma treatment, or death, assessed up to 2 years.
Overall survival
Kaplan-Meier methodology will be used to estimate event-free curves, median, and 95% confidence interval. Comparison by important subgroups will be made using the log-rank test.
Time frame: From the date of first dose (cycle 1, day 1) to the date of death regardless of cause, assessed up to years.
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