ALBERT

Description: Abstract 1643 Introduction: Ibrutinib is an orally available, irreversible inhibitor of BTK, a downstream protein in the B-cell receptor signaling pathway critical for normal B-cell development. In a phase I study in patients with relapsed B-cell malignancies (Fowler ASH 2010), the overall response rate (ORR) was 43%, with responses observed in patients with relapsed mantle cell (MCL), diffuse large B-cell (DLBCL), follicular (FL), and marginal zone lymphoma (MZL). In a phase II single agent study in MCL (Wang ASH 2011), ORR was 67% with several responding patients remaining on ibrutinib over 1 year. Rituximab (R) and bendamustine is a highly active regimen with ORR ranging from 52–92% in patients with relapsed/refractory NHL. This phase I study was designed to determine the maximum tolerated dose, dose limiting toxicity (DLT), toxicities, and preliminary efficacy of R-bendamustine in combination with ibrutinib in patients with relapsed/refractory NHL. Methods: Eligibility included patients with relapsed/refractory FL, MZL, MCL, transformed NHL, and DLBCL, and patients with previously untreated MCL not candidates for autologous stem cell transplantation (ASCT). ANC ≥1000/mm3, platelets ≥50,000/mm3, and creatinine ≤ 2.0 mg/dL were required at study entry. Prior ASCT, rituximab, bendamustine, and ibrutinib were permitted. Treatment consisted of R 375 mg/m2 day 1, bendamustine 90 mg/m2days 1 and 2, and escalating doses of ibrutinib (280 mg or 560 mg) days 1–28 every 28 days for 6 cycles. Six patients were enrolled at each dose level. Responding patients could continue ibrutinib alone after cycle 6 until disease progression or unacceptable toxicity. Pegfilgrastim was permitted for patients with grade 4 neutropenia during cycles 1–6. Response was assessed after cycles 3 and 6 by International Harmonization Criteria (Cheson, JCO 2007). Results: Eleven patients (9 males) with a median age of 72 (range 45–84) previously treated with a median of 3 prior therapies (range 0–10) were enrolled. Six patients were refractory to their most recent therapy, 4 patients had prior ASCT, 2 patients had received prior bendamustine, and no patients had prior ibrutinib. Other characteristics included stage III-IV disease in 82%, extranodal involvement in 64%, elevated IPI ≥3 in 55%, bulky adenopathy ≥5 cm in 45%, B-symptoms in 45%, and elevated LDH in 36%. Histologies included MCL (n=3), DLBCL (n=3, all germinal center origin by Hans immunohistochemical criteria), transformed NHL (n=2), FL (n=2), MZL (n=1). Nine patients completed two or more cycles of therapy (median 3, range 1–6) with 280 mg of ibrutinib (n=6) and 560 mg of ibrutinib (n=3). Two patients who discontinued therapy prior to completing cycle 1 for progressive disease (PD) at 280 mg and 560 mg of ibrutinib, respectively, were replaced. Six patients continue to receive protocol treatment. The 5 patients off study included the 2 patients with DLBCL and transformed NHL who were replaced for PD prior to completing cycle 1, 2 patients with DLBCL and PD after cycles 3 and 4, and 1 patient with MCL receiving 280 mg ibrutinib with R-bendamustine who discontinued due to grade 3 neutropenia lasting 〉 14 days after cycle 4. No DLTs have been observed. Grade 3–4 events included lymphopenia (64%), neutropenia (27%), thrombocytopenia (18%), pancreatitis (9%), vomiting (9%), shingles (9%), and rash (9%). Dose reductions from 280 mg ibrutinib to 140 mg were required in 3 patients for grade 3 thrombocytopenia, pancreatitis, and rash. Bendamustine dose reductions to 60 mg/m2were required in 1 patient for grade 3 thrombocytopenia. ORR was 38% in 8 evaluable patients, with 3 patients currently receiving protocol treatment who have not yet undergone restaging scans. Responses included 2 complete responses and 1 partial response in the 3 patients with MCL. Conclusions: Combined ibrutinib with R-bendamustine appears well tolerated without unexpected toxicity and with preliminary activity in patients with previously untreated and relapsed MCL. Three additional patients will be accrued to the 560 mg dose level and expansion cohorts examining this combination specifically in patients with FL, DLBCL, and MCL are planned. Disclosures: Blum: Pharmacyclics: Research Funding. Off Label Use: Ibrutinib is not approved for the treatment of NHL. Jaglowski:Pharmacyclics: Research Funding. Maddocks:Pharmacyclics: Research Funding. Byrd:Pharmacyclics: Research Funding.

Description: Abstract 3904 Background: Navitoclax (ABT-263), a novel, orally bioavailable, small molecule, binds with high affinity (Ki ≤1nM) to Bcl-2, Bcl-xL, and Bcl-w, promoting apoptosis. In vitro, navitoclax shows potent targeted cytotoxicity (EC50≤1 μM) against T and B lymphoid malignancies that overexpress Bcl-2. In preclinical models of B-cell lymphoma, navitoclax enhanced efficacy of rituximab (R) when used alone or in combination with chemotherapy. Based on phase 1 trial data, oral navitoclax monotherapy was well-tolerated and had anti-tumor activity in patients (pts) with chronic lymphocytic leukemia (CLL). Thrombocytopenia was the dose-limiting toxicity (DLT). We examined whether navitoclax could be used safely in combination with fludarabine/cyclophosphamide/rituximab (FCR) or bendamustine/rituximab (BR) for treatment of pts with CLL. Methods: This ongoing, phase 1 dose-escalation study is evaluating the safety and pharmacokinetics (PK) of oral navitoclax used in combination with FCR (Arm A) or BR (Arm B) for treatment of pts with relapsed/refractory CLL. Secondary objectives are efficacy endpoints (PFS, ORR, TTP, OS, duration of response). Eligible pts had measurable disease, ECOG performance score ≤1, ANC ≥1000/μL, platelets ≥100,000/mm3, and hemoglobin ≥9.0 g/dL. Preliminary results are reported. Enrolled pts (6 pts/cohort) were assigned to Arm A or Arm B based on physician preference. In both arms, R was 375 mg/m2 on Day 1 of Cycle 1; and 500 mg/m2 on Day 2 of Cycle 2 and on Day 1 of subsequent 28-day cycles. In Arm A, F 25 mg/m2 and C 175 mg/m2 were dosed on Days 2–4 in Cycles 1 and 2, and on Days 1–3 in subsequent cycles. In Arm B, B was dosed at 70 mg/m2 on Days 2 and 3 of Cycles 1 and 2, and on Days 1 and 2 in subsequent cycles. Oral navitoclax was administered once daily (starting dose of 110 mg) pre-chemotherapy on Days 3–5 of Cycle 1 and Days 1–3 of subsequent cycles. Dose escalation decisions were made independently in each arm via a continuous reassessment method, and the objective was to identify a dose of navitoclax in combination with chemotherapy in which 20%) navitoclax-related AEs of any grade were nausea (73%), fatigue (50%), neutropenia (50%), cough (39%), vomiting (35%), chills (31%), diarrhea (31%), constipation (27%), headache (27%), anemia (23%), and thrombocytopenia (23%). The most common (〉19%) grade 3/4 navitoclax-related AE was neutropenia (35%) and thrombocytopenia (19%); but only 2 of the latter pts had hemorrhagic events (Grade 1 epistaxis) unlikely related to navitoclax. Of the 28 pts evaluated for safety, 6 remain active and 22 discontinued (DC); 1 due to AE, 1 due to AE and progressive disease (PD), 3 due to PD, 6 withdrew consent, 3 due to physician discretion, 4 completed therapy, 2 proceeded to transplant, and 2 due to toxicity. Preliminary best anti-tumor responses were assessed in 20 pts. Of the 16 pts assessed in Arm B (BR), 6 achieved complete responses (CR), 7 partial responses (PR), 2 stable disease (SD) and 1 with PD. The ORR was 81% (13/16). In this arm, 3/5 pts with 17p deletion achieved PR. Of the 4 pts assessed in Arm A (FCR), 2 achieved PR, 1 SD and 1 with PD. Preliminary PK results suggest that there is no apparent PK interaction between navitoclax and bendamustine. Conclusions: The combination of navitoclax with BR appears well-tolerated and to have anti-tumor activity. The maximum tolerated dose of navitoclax has been reached at 250 mg for Arm B, but not for Arm A where escalation continues. To date, we have not observed unacceptable myelotoxicity when this bcl-2 antagonist was used in combination with standard cytotoxic chemo-immunotherapy regimens for treatment of pts with CLL. Disclosures: Kipps: Igenica: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Abbott Industries: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; GSK: Research Funding; Gilead Sciences: Consultancy, Research Funding; Amgen: Research Funding. Off Label Use: R05429083 is a novel humanized antibody direct against the standard region of CD44. R05429083 is currently intensive pre-clinical studies and fist dosing of cancer patients has started in Europe in 2011. Swinnen:Abbott Laboratories: Research Funding. Yang:Abbott Laboratories: Employment. Cui:Abbott Laboratories: Employment, Stock Holder at Abbott Laboratories. Busman:Abbott Laboratories: Employment, Owns Abbott Laboratories Stock. Enschede:Abbott Laboratories: Employment, Owns Abbott Laboratories Stock. Humerickhouse:Abbott Laboratories: Employment, Owns Abbott Laboratories Stock.

Description: Abstract 2456 The cyclin-dependent kinase inhibitor flavopiridol has been shown to be a highly effective therapy in patients (pts) with relapsed or refractory CLL, and we have shown in vitro that flavopiridol induces apoptosis independent of the p53 pathway. Here we analyze the results of two early single-agent flavopiridol trials at our institution, OSU 0055 and OSU 0491, to study the effect of poor risk cytogenetic abnormalities on overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). 112 pts are included in this analysis; 49 from the phase I and 63 from the phase II study. Data from the two trials were combined for all analyses. Specific genetic abnormalities were identified by fluorescence in situ hybridization, and complexity was determined by stimulated karyotype analysis. Dohner's hierarchical classification was used to group the pts into those with del (17p), those with del (11q) and those with other cytogenetic abnormalities or normal cytogenetics. Using this classification, 40 pts (37%) had del (17p), 37 (33%) had del (11q), and 35 (31%) had neither of these abnormalities. These groups were not significantly different in terms of age, sex, Rai stage, or percent fludarabine-refractory. The median number of prior treatments was 4 (range 1–11) and did not differ among cytogenetic groups (p=0.21). The presence of bulky adenopathy (≥5 cm) was significantly different among the groups (p=0.01). 89% of pts with del (11q) had bulky disease, while only 60% with del (17p) and 77% of pts without these abnormalities had bulky disease. Complex cytogenetics (≥3 abnormalities) were much more likely in pts with del (17p), where 63% possessed a complex karyotype, as opposed to 32% of pts with del (11q) and 26% of pts with other abnormalities (p=0.003). The ORR was 47%, and was not significantly different among the cytogenetic groups (p=0.17). ORR for pts with del (17p) was 48%, for pts with del (11q) was 57%, and for those without these cytogenetic abnormalities was 34%. The overall median PFS was 10 months (mo.). While the estimated medians were slightly higher in pts with poor risk cytogenetics, 10 mo. for both del (17p) and del (11q) groups, and 8 mo. for pts without these abnormalities, the risk of progression changed significantly over time and by 24 mo., the estimated PFS for pts with del (17p), del (11q), and other cytogenetics was respectively, 4%, 5%, and 24%. Overall median OS was 28 mo. and was not significantly different among the groups (20 mo. for del (17p), 36 mo. for del (11q), and 26 mo. for pts without these abnormalities; p=0.13). Multivariable models were fit for ORR, PFS, and OS, which included cytogenetic group, treatment schedule, age, Rai stage, number of prior treatments, bulky adenopathy and presence of complex karyotype. With respect to ORR, odds of response were not significantly different among the cytogenetic groups (p=0.21), and notably, complex karyotype was not a significant predictor of ORR (p=0.15). Since similar patterns of PFS were observed for pts with del (17p) and del (11q), these groups were combined and the risk of progression relative to pts without these abnormalities were allowed to change over time. Although cytogenetic group was not statistically significant (p=0.07), it should be noted that the risk of progression tended to be lower for pts with del (17p)/del (11q) in the first six months and then increased with follow-up as compared to pts without these abnormalities (hazard ratio (HR) 0.7 at 3 mo., 1.1 at 6 mo., 1.5 at 12 mo. and 2.2 at 24 mo.). The only independent predictor of shorter PFS was the presence of bulky adenopathy (HR=2.0, 95% confidence interval (CI) 1.1–3.7). While some differences were observed in PFS, OS was not significantly different among the cytogenetic groups when controlling for other variables (p=0.24) but was impacted (p=0.005) by the number of prior treatments (HR=1.2, 95% CI 1.1–1.3). Collectively, these data show that pts with cytogenetically high-risk disease who are treated with flavopiridol have a high ORR that is not significantly different from those without these cytogenetic abnormalities. While there may be differences with respect to PFS that are being evaluated further, OS did not differ among cytogenetic groups. Flavopiridol is thus an attractive agent to study in the first-line setting for pts with poor-risk cytogenetic abnormalities, as well as to use in further single agent and combination studies in relapsed or refractory disease. Disclosures: Grever: Sanofi Aventis: Dr. Grever is on the use patent for flavopiridol. This patent has not been awarded and has no monetary value at this time. Byrd: Sanofi Aventis: Dr. Byrd is on the use patent for flavopiridol. This patent has not been awarded and has no monetary value at this time.

Description: 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.