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.
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT04578600.
PRIMARY OBJECTIVE:
I. 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).
EXPLORATORY OBJECTIVES:
I. To assess the potential correlation between mutational burden and response to CC-486/lenalidomide/obinutuzumab in patients with relapsed/refractory indolent non-Hodgkin lymphoma (NHL) as assessed by immune monitoring and DNA methylation.
II. To assess response to CC-486/lenalidomide/obinutuzumab in patients that have progressed after treatment with lenalidomide and rituximab (R^2).
III. To assess response to CC-486/lenalidomide/obinutuzumab in patients with relapsed/refractory follicular lymphoma that have progressed within 24 months of initial treatment initiation (POD24).
OUTLINE:
Patients receive azacitidine orally (PO) once daily (QD) on days 1-21, obinutuzumab intravenously (IV) over on days 8, 15, 22, and 29, and lenalidomide PO QD on days 8-28 of cycle 1. Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity. Patients then receive azacitidine PO QD on days 1-21, obinutuzumab IV over on day 1, and lenalidomide PO QD on days 1-21. Cycles repeats every 28 days in the absence of disease progression, unacceptable toxicity, or until stem cell transplant. Patients who achieve stable disease (SD), PR, or CR do not proceed to stem cell transplant may continue treatment for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 4 weeks, every 3 months for 3 assessments, then annually for up to 2 years after last study drug dose or per physician discretion.
Lead OrganizationUniversity of California Davis Comprehensive Cancer Center
Principal InvestigatorJoseph M. Tuscano
