Dinaciclib (SCH 727965) and Ofatumumab for the Treatment of Relapsed and Refractory (R/R) Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL): Results of a Phase 1b/2 Study
Authors: Jones Jeffrey Alan , Geyer Susan , Andritsos Leslie A. , Awan Farrukh , Flynn Joseph M , Maddocks Kami J. , Bingman Anissa , Johnson Amy J. , Heerema Nyla A. , Brookfield Cathy , Byrd John C. , Grever Michael R. 
Published: October 2019

Abstract
BACKGROUND: Despite recent advances in the treatment of relapsed/refractory (R/R) CLL/SLL, patients (pts) with genetically high-risk disease, particularly complex abnormal karyotype and deletion(17p), continue to demonstrate inferior survival. Dinaciclib, a selective inhibitor of cyclin-dependent kinases (CDKs), has demonstrated activity in high-risk CLL/SLL. In an effort to improve response rates and reduce the risk for hyperacute tumor lysis syndrome (TLS), we conducted a NCI-sponsored phase 1b/2 study (NCI 9268) to characterize the safety and efficacy of dinaciclib when given in combination with the anti-CD20 monoclonal antibody ofatumumab.
METHODS: Pts with CLL/SLL R/R after ≥1 prior therapy, age ≥ 18 years, ECOG ≤ 2, and retained end-organ function received ofatumumab according to the approved dose and schedule (weekly x 8, monthly x 4) starting on Cycle 1 Day 1. Dinaciclib was administered as a 2-hour infusion on days 1, 8, and 15 of a 28-day cycle beginning on Cycle 2 Day 1 and continued for up to 6 cycles. Pts could then continue single-agent dinaciclib indefinitely at MD discretion. During the phase 1b portion of the study, 3 pts were treated with 7 mg/m2 on Day 1 escalated to 10 mg/m2 on Day 8 (DL1); 3 additional phase 1b pts and all pts enrolled to the phase 2 were escalated to 14 mg/m2on Day 15 (DL2). All pts received aggressive hydration and pre-medication prior to dinaciclib to prevent TLS, peg-filgrastim on Day 16 of Cycles 2-7, and required antimicrobial prophylaxis (val-/acyclovir, ciprofloxacin, and TMP/SMX). Response was assessed with CT imaging according to IWCLL 2008 criteria at the end of cycle 1, after odd-numbered cycles, and every 3 months during follow-up.
RESULTS: As of 30 July 2014, 36 pts (DL1 n = 4; DL2 n=32) have been treated: median age 62.5 years (range 35-80), 13 (36%) female, ECOG ≤1 in 32 (89%), and median number prior therapies was 2 (range 1-5). Del (17p) was present in 25 pts (69%), del (11q) in 16 (44%), and complex abnormal karyotype in 15 (42%). No dose limiting toxicities were observed in the phase 1b portion of the study. The most common grade ≥ 3 adverse events (without regard to attribution) included hyperglycemia in 5 pts (16%), hypocalcemia in 4 (13%), hypophosphatemia in 13 (41%), leukopenia in 12 (37%), anemia in 11 (34%), and thrombocytopenia in 9 (28%). Neutropenia was common (18% grade 3, 47% grade 4), but grade ≥ 3 infections were rare (1 pleural, 5 lung, 2 sepsis). Only 1 pt with highly proliferative disease refractory to both ibrutinib and IPI-145 developed TLS, which was further complicated by grade 5 sepsis. Pts have received a median 4 cycles (range 1-12), and 4 pts (11%) remain on treatment. Reasons for discontinuation are listed in the table. Best protocol response of partial response was recorded for 12 pts (33%), and an additional 20 (56%) patients achieved stable disease. Responses were observed in all genetic subgroups and deepened with continued dinaciclib treatment (see table). Estimated median PFS was 10.4 months (95%CI 8.2-12.2 months) and median overall survival (OS) had not been reached (95%CI 13.2-NR).
CONCLUSIONS: Dinaciclib can be safely administered with ofatumumab to pts with R/R CLL/SLL. Serious non-hematologic adverse events are infrequent, and supportive measures help limit infectious complications. Initiating treatment with ofatumumab, stepwise dose escalation of dinaciclib, and rigorous prophylaxis abrogate the risk for TLS. These results confirm the activity of dinaciclib in a population enriched for genetically high-risk CLL/SLL. Responses improved with continued therapy, and discontinuation prior to best response likely impacted observed response rates. Further study of dinaciclib in combination with novel monoclonal antibodies and/or other kinase inhibitors is warranted, particularly in genetically high-risk disease.
Table Reason for Discontinuation n=36 (%) Completed planned therapy 13 (41) Adverse event/complication 6 (19) Disease progression 6 (19) Alternative therapy 3 (9) Death on study 2 (6) Other 2 (6) Best Protocol Response to Date n=36 (%) PR 12 (33) SD 20 (56) PD 2 (6) IE 1 (3) Cycle 2 Response n=34 (%)* PR 0 SD 32 (94%) PD 2 (6) Cycle 4 Response n=23 (%) PR 5 (22) SD 18 (78) PD 0 Cycle 6 Response n=15 (%) PR 11 (73) SD 4 (27) PD 0 *1 pt with probable PD discontinued during Cycle 1

Disclosures
Off Label Use: Dinaciclib is an investigational agent made available through NCI/CTEP. Awan:Boehringer Ingelheim: Consultancy; Lymphoma Research Foundation: Research Funding. Maddocks:Pharmacyclics, Seattle Genetics, MorphoSys: Advisory Board Other, Research Funding. Byrd:Pharmacyclics: Research Funding.