A Dose Escalation Study of Ibrutinib with Lenalidomide for Relapsed and Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Authors: Pollyea Daniel A. , Coutre Steven , Gore Lia , Adler Nichole , Harris Pamela , Phelps Mitch A. , Johnson Amy J. , Ling YongHua , Li Hao , Gutman Jonathan A , Byrd John C. 
Published: October 2019

Abstract
Introduction: Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is dependent upon dysregulated signaling through the B-cell receptor (BCR) pathway. Bruton’s tyrosine kinase (BTK) mediates BCR signaling, and inhibition of BTK with ibrutinib, a selective, irreversible BTK inhibitor, is effective and well tolerated for patients (pts) with relapsed/refractory CLL/SLL. However, complete remissions (CRs) are infrequent, mechanisms of resistance to single-agent ibrutinib have been identified, and the duration of response beyond 3 years is unknown. Lenalidomide, a multi-functional immunomodulatory agent, is active in CLL/SLL, but limited by tumor flare reactions, which occur secondary to B-cell activation. Ibrutinib and lenalidomide modulate several key overlapping factors involving the CLL tumor microenvironment, and therefore a phase 1 combination study with lenalidomide dose escalation was undertaken.
Methods: The primary objective was to determine the maximum tolerated dose (MTD) of lenalidomide in combination with ibrutinib. Secondary objectives included assessments of efficacy, PK/PD, and other mechanistic correlative studies. A 1-month (cycle 0) period of 420 mg of daily oral ibrutinib was administered as a single agent to decrease BCR signaling and mitigate lenalidomide-associated tumor flare. Beginning with the second month (cycle 1), ibrutinib was given concomitantly with lenalidomide. Four dose escalation cohorts of lenalidomide were planned using a 3+3 design; 2.5, 5, 7.5 and 10 mg. After the 2.5 mg cohort, intra-patient dose escalation was employed: in cohort 2, pts received 2.5 mg in week 1 followed by 5 mg subsequently; pts in cohort 3 received 2.5 mg in week 1, 5 mg in week 2 and 7.5 mg subsequently; pts in cohort 4 will receive 2.5 mg in week 1, 5 mg in week 2, 7.5 mg in week 3 and 10 mg subsequently. Ibrutinib was not dose escalated (420 mg). Pts receive 12 cycles of the combination, after which lenalidomide is discontinued and ibrutinib continues until unacceptable toxicity or disease progression. Eligible pts had relapsed/refractory CLL/SLL with adequate organ and bone marrow function. Pts who relapsed after stem cell transplantation were excluded.
Results: To date, 11 pts were enrolled; 9 are evaluable (1 voluntarily withdrew consent prior to completing 3 cycles, the protocol-defined minimum to be evaluable, and 1 was a screen fail). The median age was 65 (49-81). Eight were male and 8 had CLL. Median Rai stage was 1 (1-4). The median number of prior therapies was 2 (range 1-8); 3 were purine analog resistant. Six had bulky (>5 cm) disease. Two had del(17p13.1) and 4 had del(11q22.3). The median number of cycles completed was 8 (range 1-13).
Adverse events (AEs) were reported according to the NCI CTCAE v4.0. Possibly related grade 1/2 AEs that occurred in >1 patient included: rash (n=4), muscle cramps (n=3) and abdominal discomfort (n=2). Possibly related grade 3 AEs included neutropenia (n=4), lymphocytosis (n=2), neutropenic fever (n=1), anemia (n=1) and thrombocytopenia (n=1). There was 1 possibly related grade 4 AE, neutropenia, which was pre-defined as DLT, in the 7.5 mg lenalidomide cohort. One patient experienced grade 2 tumor pain, thought to be due to a lenalidomide-associated tumor flare reaction. Four pts required a lenalidomide dose reduction, for neutropenia (n=2) and fatigue (n=2). Six required a treatment hold, of either lenalidomide or both agents, for a median 7 days (2-28), for neutropenia (n=2), anemia (n=1), fatigue/diarrhea (n=1), atrial fibrillation (n=1) and to obtain a lymph node biopsy (n=1). Lymphocytosis was noted in 5 pts, peaking at a median of 22.5 days.
The ORR is 100% (9/9), with all responders experiencing PRs. One progressed with Richter’s transformation during cycle 7, 4 months after achieving a PR. All 9 remain alive with a median follow up of 263 days (range 97-391). The 7.5 mg dose cohort is currently being expanded to 6 pts; after the MTD is determined, a 10 patient dose expansion cohort will commence.
Conclusions: Ibrutinib with lenalidomide appears to be well tolerated, although lenalidomide dose reductions were common. Tumor flare reactions were rare. Response assessments at higher dose cohorts of lenalidomide are ongoing. Completed phase 1 data, preliminary data from the expansion cohort and correlative findings will be presented.

Disclosures
Pollyea: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Lenalidomide for CLL/SLL. Byrd:Genentech: Research Funding; Pharmacyclics: Research Funding.