A Phase I/Randomized Phase II Trial of Idelalisib, Lenalidomide and Rituximab in Patients With Relapsed/Refractory Mantle Cell Lymphoma
Outline: This is a phase I, dose-escalation study followed by a phase II study.
The phase I treatment plan includes the following:
1. Lenalidomide will be tested at sequential dose levels in a standard 3+3 design.
1. Dose Level 0 = 15mg/day for days 1-21 every 28 days
2. Dose Level 1 = 20mg/day for days 1-21 every 28 days and
3. Dose Level 2 = 25mg/day for days 1-21 every 28 days.
Patients can continue lenalidomide for up to 48 weeks (12 cycles) of treatment.
2. Idelalisib will be orally administered starting at Dose Level 1 (150 mg twice daily)
for continuous 28-day cycles until progression, intolerence, or patient/physician
3. Rituximab will be administered intravenously at 375 mg/m2 for cycle 1 (ie, cycle 1, day
1, day 8, day 15, day 22) and then on day 1 of cycles 4,6,8,10. There will be no dose
reductions or escalations of rituximab.
Patients are randomized to 1 of 2 treatment arms in the Phase II treatment plan described in
the "Arms" section. The primary and secondary objectives for this study are:
1. Phase I Primary Objective: To determine the safety and tolerability of the combination
of lenalidomide and rituximab with idelalisib in sequential dose cohorts.
2. Phase II Primary Objective: To determine the progression-free survival (PFS) of the
combination of lenalidomide and rituximab, with or without idelalisib in a randomized
phase II design.
3. Phase II Secondary Objectives:
1. To determine the overall response rate (ORR), complete response rate (CR), and
overall survival (OS) of the combination of lenalidomide and rituximab, with or
without idelalisib in a randomized phase II design.
2. To determine the prognostic and/or predictive significance of proliferation
markers and cell cycle components in patients with relapsed/refractory mantle cell
lymphoma (MCL) treated with idelalisib and lenalidomide.
3. To determine whether phosphorylated protein kinase B (pAKT) expression levels are
correlated with response to idelalisib plus lenalidomide.
4. To determine whether notch homolog 1, translocation-association (NOTCH1)
intracellular domain (ICD) immunohistochemistry (IHC) correlates with mutation and
outcome in MCL patients treated with idelalisib and lenalidomide.
5. To determine whether sex determining region Y-box 11 (SOX11) expression correlates
with response in patients with relapsed/refractory MCL treated with idelalisib and
6. To correlate cereblon (CRBN) expression with response in patients with
relapsed/refractory MCL treated with idelalisib and lenalidomide.
7. To evaluate several plasma cytokines and correlate observed changes to objective
Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Maximum tolerated dose (MTD) of idelalisib and lenalidomide, determined according to incidence of dose-limiting toxicity (DLT) graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (Phase I)
Sonali Smith, M.D.
University of Chicago
United States: Food and Drug Administration