David Michael Johnson

Idelalisib, a selective inhibitor of phosphatidylinositol 3-kinase-δ, as therapy for previously treated indolent non-Hodgkin lymphoma

Idelalisib (GS-1101, CAL-101), an oral inhibitor of phosphatidylinositol 3-kinase-δ, was evaluated in a phase I study in 64 patients with relapsed indolent non-Hodgkin lymphoma (iNHL). Patients had a median (range) age of 64 (32-91) years, 34 (53%) had bulky disease (≥1 lymph nodes ≥5 cm), and 37 (58%) had refractory disease. Patients had received a median (range) of 4 (1-10) prior therapies. Eight dose regimens of idelalisib were evaluated; idelalisib was taken once or twice daily continuously at doses ranging from 50 to 350 mg. After 48 weeks, patients still benefitting (n = 19; 30%) enrolled into an extension study. Adverse events (AEs) occurring in 20% or more patients (total%/grade ≥3%) included diarrhea (36/8), fatigue (36/3), nausea (25/3), rash (25/3), pyrexia (20/3), and chills (20/0). Laboratory abnormalities included neutropenia (44/23), anemia (31/5), thrombocytopenia (25/11), and serum transaminase elevations (48/25). Twelve (19%) patients discontinued therapy due to AEs. Idelalisib induced disease regression in 46/54 (85%) of evaluable patients achieving an overall response rate of 30/64 (47%), with 1 patient having a complete response (1.6%). Median duration of response was 18.4 months, median progression-free survival was 7.6 months. Idelalisib is well tolerated and active in heavily pretreated, relapsed/refractory patients with iNHL. These trials were registered at clinicaltrials.gov as NCT00710528 and NCT01090414.

A phase 2 study of idelalisib plus rituximab in treatment-naïve older patients with chronic lymphocytic leukemia

Idelalisib is a first-in-class oral inhibitor of PI3Kδ that has shown substantial activity in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). To evaluate idelalisib as initial therapy, 64 treatment-naïve older patients with CLL or small lymphocytic leukemia (median age, 71 years; range, 65-90) were treated with rituximab 375 mg/m(2) weekly ×8 and idelalisib 150 mg twice daily continuously for 48 weeks. Patients completing 48 weeks without progression could continue to receive idelalisib on an extension study. The median time on treatment was 22.4 months (range, 0.8-45.8+). The overall response rate (ORR) was 97%, including 19% complete responses. The ORR was 100% in patients with del(17p)/TP53 mutations and 97% in those with unmutated IGHV. Progression-free survival was 83% at 36 months. The most frequent (>30%) adverse events (any grade) were diarrhea (including colitis) (64%), rash (58%), pyrexia (42%), nausea (38%), chills (36%), cough (33%), and fatigue (31%). Elevated alanine transaminase/aspartate transaminase was seen in 67% of patients (23% grade ≥3). The combination of idelalisib and rituximab was highly active, resulting in durable disease control in treatment-naïve older patients with CLL. These results support the further development of idelalisib as initial treatment of CLL. This study is registered at ClinicalTrials.gov as #NCT01203930.

Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins

Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.

Abstract 408: ACP-196, an orally bioavailable covalent selective inhibitor of Btk, modulates the innate tumor microenvironment, exhibits antitumor efficacy and enhances gemcitabine activity in pancreatic cancer

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Pancreatic ductal adenocarcinoma exists in a complex desmoplastic microenvironment that provides stromal support for tumor growth and conceals the tumor from immune surveillance. Tumor-associated stroma comprises a mix of fibroblasts, immunosuppressive T regulatory cells (Tregs), myeloid suppressive monocytes (MDSCs) and tumor-associated macrophages (TAMs) that promote tumor growth and restrain immune-mediated tumor cell killing. The targeting of immune infiltrates may impair stromal support and enhance immune-mediated killing of pancreatic cancer cells. Brutons tyrosine kinase (Btk) is a nonreceptor enzyme in the Tec kinase family expressed among cells of hematopoietic origin including B cells, myeloid cells, mast cells and platelets, but not T cells, where it regulates multiple cellular processes. Here we describe an unexpected finding of ACP-196, a potent, novel, second generation Btk inhibitor with improved selectivity and target coverage that binds covalently to a cysteine residue (Cys481) in the front position of the ATP-binding pocket. In an orthotopic mouse model of pancreatic cancer, KPC derived pancreatic cancer cells (KrasG12D; Trp53R172H; Pdx1-Cre) were injected into the pancreases. Vehicle, single agent ACP-196 (15 mg/kg/BID, gavage), single agent gemcitabine (50 mg/kg, IV) and combination ACP-196 with gemcitabine were evaluated for efficacy. By 4 weeks of treatment, mice in the vehicle group showed signs of health deterioration and all mice were euthanized, tumors were collected and measured. Relative to the vehicle treatment, ACP-196 monotherapy resulted in a >2-fold reduction in tumor growth compared with less than a 2-fold reduction with gemcitabine alone. The combination of ACP-196 and gemcitabine resulted in a further reduction in tumor growth when compared to each single agent. Interestingly, analysis of tumor tissues showed that single agent ACP-196 inhibited immunosuppressive populations of TAMs and MDSCs. Surprisingly, Treg populations were also reduced with a robust expansion of CD8+ T cells in the tumors. None of these effects were observed with gemcitabine alone. Although Btk is not expressed in T cells, this finding maybe the result of inhibiting the MDSC and TAM populations within the tumor microenvironment, a mechanism of action which is currently under investigation. Taken together, these data identify Btk as a novel target for modulating tumor immune escape and suggest that pharmacologic targeting of suppressive myeloid cells by ACP-196 induces therapeutic benefit. ACP-196 is currently being evaluated in clinical trials including frontline and salvage pancreatic cancer. Citation Format: Brian J. Lannutti, Michael Gulrajani, Fanny Krantz, Elena Bibikova, Todd Covey, Katti Jessen, Wayne Rothbaum, David M. Johnson, Roger Ulrich. ACP-196, an orally bioavailable covalent selective inhibitor of Btk, modulates the innate tumor microenvironment, exhibits antitumor efficacy and enhances gemcitabine activity in pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 408. doi:10.1158/1538-7445.AM2015-408