Infinity Pharmaceuticals (United States)

Abstract Inhibitors of Bruton’s Tyrosine Kinase (BTKi) and phosphoinositide 3-kinase (PI3Ki) have significantly improved therapy of chronic lymphocytic leukemia (CLL). However, the emergence of resistance to BTKi has introduced an unmet therapeutic need. Here we demonstrate in vitro and in vivo the essential roles of PI3K-δ for CLL B-cell survival and migration and of PI3K-γ in T-cell migration and macrophage polarization; and more efficacious inhibition in CLL-cell burden by dual inhibition of PI3K-δ,γ. We also report an ibrutinib-resistant CLL case, whose clone exhibited BTK and PLCγ2 mutations, responded immediately to single agent duvelisib with a redistribution lymphocytosis followed by a partial clinical remission associated with subsequent modulation of T and myeloid cells. CLL samples from patients progressed on ibrutinib were also responsive to duvelisib in patient-derived xenografts irrespective of BTK mutations. Our data support dual inhibition of PI3K-δ,γ as a valuable approach for therapeutic interventions, including patients refractory to BTKi.

Abstract The duration of natural immunity in response to SARS-CoV-2 is a matter of some debate in the literature at present. For example, in a recent publication characterizing SARS-CoV-2 immunity over time, the authors fit pooled longitudinal data, using fitted slopes to infer the duration of SARS-CoV-2 immunity. In fact, such approaches can lead to misleading conclusions as a result of statistical model-fitting artifacts. To exemplify this phenomenon, we reanalyzed one of the markers (pseudovirus neutralizing titer) in the publication, using mixed-effects modeling, a methodology better suited to longitudinal datasets like these. Our findings showed that the half-life was both longer and more variable than reported by the authors. The example selected by us here illustrates the utility of mixed-effects modeling in provide more accurate estimates of the duration and heterogeneity of half-lives of molecular and cellular biomarkers of SARS-CoV-2 immunity.

From the Department of Medicine (Medical Oncology), Yale School of Medicine, New Haven, CT. Conflicts of Interest and Source of Funding: S.B.G. is a consultant to AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Genentech, Spectrum, Amgen, Blueprint Medicine, Sanofi-Genzyme, and Daiichi Sankyo, and receives research funding from AstraZeneca and Boehringer-Ingelheim. R.S.H. is a consultant to Abbvie Pharmaceuticals, ARMO Biosciences, AstraZeneca, Biodesix, Bolt Biotherapeutics, Bristol-Myers Squibb, Cybrexa, Eli Lilly and Company, EMD Serono, Genentech/Roche, Genmab, Halozyme, Heat Biologics, IMAB Biopharma, Immunocore, Infinity Pharmaceuticals, Loxo Oncology, Merck and Company, Mirati Therapeutics, Nektar, Neon Therapeutics, NextCure, Novartis, Oncternal Therapeutics, Pfizer, Sanofi, Seattle Genetics, Shire PLC, Spectrum Pharmaceuticals, Symphogen, Takeda, Tesaro, Tocagen, and WindMIL Therapeutics; receives research support from AstraZeneca, Eli Lilly and Company, Genentech/Roche, Merck and Company; and is a board member (nonexecutive/independent) at Junshi Pharmaceuticals. Reprints: Sarah B. Goldberg, MD, Yale School of Medicine, 333 Cedar St, FMP-130, New Haven, CT 06510. E-mail: [email protected].

A hallmark of prostate cancer progression is dysregulation of lipid metabolism via overexpression of fatty acid synthase (FASN), a key enzyme in de novo fatty acid synthesis. Metastatic castration-resistant prostate cancer (mCRPC) develops resistance to inhibitors of androgen receptor (AR) signaling through a variety of mechanisms, including the emergence of the constitutively active AR variant V7 (AR-V7). Here, we developed an FASN inhibitor (IPI-9119) and demonstrated that selective FASN inhibition antagonizes CRPC growth through metabolic reprogramming and results in reduced protein expression and transcriptional activity of both full-length AR (AR-FL) and AR-V7. Activation of the reticulum endoplasmic stress response resulting in reduced protein synthesis was involved in IPI-9119-mediated inhibition of the AR pathway. In vivo, IPI-9119 reduced growth of AR-V7-driven CRPC xenografts and human mCRPC-derived organoids and enhanced the efficacy of enzalutamide in CRPC cells. In human mCRPC, both FASN and AR-FL were detected in 87% of metastases. AR-V7 was found in 39% of bone metastases and consistently coexpressed with FASN. In patients treated with enzalutamide and/or abiraterone FASN/AR-V7 double-positive metastases were found in 77% of cases. These findings provide a compelling rationale for the use of FASN inhibitors in mCRPCs, including those overexpressing AR-V7.

To develop recommendations for clinical trial reporting that address the unique efficacy, toxicity, and combination and sequencing aspects of immuno-oncology (IO) treatments. ASCO and the Society for Immunotherapy of Cancer (SITC) convened a working group that consisted of practicing medical oncologists, immunologists, clinical researchers, biostatisticians, and representatives from industry and government to develop Trial Reporting in Immuno-Oncology (TRIO) recommendations. These recommendations are based on expert consensus, given that existing data to support evidence-based recommendations are limited. The TRIO recommendations are intended to improve the reporting of IO clinical trials and thus provide more complete evidence on the relative benefits and risks of an IO therapeutic approach. Given the rapid expansion of the number of IO clinical trials and ongoing improvements to the evidence base supporting the use of IO treatments in clinical care, these recommendations will likely need regular revision as the IO field develops.

ObjectiveThis study was conducted to characterize the effects of food on single-dose pharmacokinetics (PK) of the investigational Aurora A kinase inhibitor alisertib (MLN8237) in patients with advanced solid tumors.MethodsFollowing overnight fasting for 10 h, a single 50 mg enteric-coated tablet (ECT) of alisertib was administered under either fasted (alisertib with 240 mL of water) or fed (high-fat meal consumed 30 min before receiving alisertib with 240 mL of water) conditions using a two-cycle, two-way crossover design. Patients on both arms were not allowed food for 4 h post-dose. Water was allowed as desired, except for 1 h before and after alisertib administration.ResultsTwenty-four patients were enrolled and 14 patients were PK-evaluable (ten patients were not PK-evaluable due to insufficient data). Following a single oral dose of alisertib, median tmax was 6 h and 3 h under fed and fasted conditions, respectively. The geometric mean ratio of AUCinf (fed- vs. fasted-state dosing) was 0.94 [90 % confidence interval (CI) 0.68–1.32]. The geometric mean Cmax under fed conditions was 84 % of that under fasted conditions (90 % CI 66–106). Alisertib was generally well-tolerated; most common drug-related grade 3/4 adverse events included neutropenia (50 %), leukopenia (38 %), and thrombocytopenia (21 %).ConclusionsSystemic exposures achieved following a single 50 mg dose of alisertib administered as an ECT formulation after a high-fat meal are similar to those observed in the fasted state. Alisertib 50 mg ECT can be administered without regard for food.ClinicalTrials.gov IdentifierNCT00962091.

Abstract We previously reported interim dose escalation results from this multi-center, open-label Phase 1 clinical trial (NCT01226485) (Bendell et al, EJC 2012). Here, we report the final aggregate safety results and the anti-tumor activity demonstrated by LY2940680, a novel Hh pathway inhibitor, in locally advanced (la) and metastatic (m) BCC. Methods: The primary objective of this study was to determine a recommended Phase 2 dose and regimen of LY2940680 that could be safely administered to patients with advanced cancer, including BCC. Patients deemed eligible for experimental therapy were enrolled in the study and dosed once daily (QD) for 28 day cycles until discontinuation. The maximum tolerated dose (MTD) was determined using a 3+3 dose escalation design. Based on initial anti-tumor activity, a cohort of la/m BCC patients was enrolled. Safety, PK/PD, and tumor response data were collected and analyzed. Results: A total of 84 advanced cancer patients were dosed, including 47 patients with la/m BCC. Median age was 62.5 years (range: 29-89). Advanced cancer patients received escalating doses ranging from 50 mg to 600 mg QD resulting in a MTD of 400 mg QD. The most commonly reported treatment-emergent adverse events (TEAE) possibly related to study drug (>20%) were dysgeusia (Gr 1-2: 46.4%, Gr 3: 2.4%), fatigue (Gr 1-2: 44.0%, Gr 3: 3.6%), nausea (Gr 1-2: 42.9%, Gr 3: 2.4%), muscle spasms (Gr 1-2: 35.7%, Gr 3: 4.8%), decreased appetite (Gr 1-2: 35.7%, Gr 3: 0%), vomiting (Gr 1-2: 29.7%, Gr 3: 2.4%), alopecia (Gr 1-2: 33.3%, Gr 3: 0%), and weight decrease (Gr 1-2: 26.2%, Gr 3: 1.2%). PK analysis showed no clear relationship between exposure (PK) and toxicity. PD marker analysis of Gli-1 mRNA from unaffected skin biopsies suggested all doses were biologically active (inhibition median of 91.7% with interquartile range (80.9-95.7%) in all patients with available pre- and post-treatment biopsies). The most common reasons for treatment discontinuation were progression of disease (n = 43), adverse event (n = 10) and withdrawal by subject (n = 10). All reported clinical responses (per RECIST 1.1) were in patients with la/m BCC. Overall response rate (ORR) for patients with la/m BCC (n = 47) was 46.8% (95% CI: 32.1-61.9%) and clinical benefit rate (CR+PR+SD) was 93.6% (95% CI: 82.5-98.7%). The median duration of response was estimated at 10.2 months (95% CI: 5.6- not estimable). Responses were observed in patients who were Hh treatment naïve (11/16) but also in patients who previously failed Hh therapy (11/31). Conclusion: LY2940680 treatment resulted in an acceptable safety profile in patients with advanced cancer including la/m BCC. Clinical responses were observed in la/m BCC patients naïve to Hh inhibitor treatment and also in those who had failed treatment with other Hh inhibitor agents. This phase 1 study supports further clinical development of LY2940680 in advanced BCC and potentially in other malignancies Citation Information: Bendell J. et al. European Journal of Cancer (EJC) 2012 48(6 Suppl) Abstract 594. Citation Format: Johanna Bendell, Valerie Andre, Alan Ho, Ragini Kudchadkar, Michael Migden, Jeffrey Infante, Ramon Tiu, Celine Pitou, Trevor Tucker, Les Brail, Daniel Von Hoff. LY2940680, a hedgehog (Hh) pathway inhibitor, demonstrates anti-tumor activity in patients with advanced basal cell carcinoma (BCC). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B32.

Anthracyclines are efficient chemotherapy agents. However, their use is limited by anthracycline-induced cardiotoxicity (CT). We investigated the influence of polymorphisms in doxorubicin metabolic and functional pathways on late-onset CT as estimated by echocardiography in 251 childhood acute lymphoblastic leukemia (cALL) patients. Association analyses revealed a modulating effect of two variants: A-1629 T in ABCC5, an ATP-binding cassette transporter, and G894T in the NOS3 endothelial nitric oxide synthase gene. Individuals with the ABCC5 TT-1629 genotype had an average of 8-12% reduction of ejection (EF) and shortening fractions (SF; EF: P<0.0001, and SF: P=0.001, respectively). A protective effect of the NOS3 TT894 genotype on EF was seen in high-risk patients (P=0.02), especially in those who did not receive dexrazoxane (P=0.002). Analysis of an additional cohort of 44 cALL patients replicated the ABCC5 association but was underpowered for NOS3. In summary, we identified two biomarkers that may contribute to cALL anthracycline CT risk stratification.

Abstract Background: AKT phosphorylation is a widely used pharmacodynamic indicator for Class I PI3K activity in cells and tumors; however, the direct correlation of pAKT with PI3K activity has not been carefully examined. We have developed a novel, direct isoform specific occupancy assay for PI3K to determine if intracellular isoform specific inhibition of PI3K is quantitatively equivalent to inhibition of pAKT formation. Methods: A biotin-conjugated derivative of the irreversible pan-PI3K inhibitor, wortmannin, was synthesized. All four class I PI3K isoforms could be pulled down using this biotin-probe. ATP-competitive PI3K inhibitor binding prevented probe binding in a dose dependent manner, and hence pull-down of PI3K. Inhibition isotherms monitoring the decrease in PI3K pulled down with increasing inhibitor concentrations were generated via western blot with PI3K isoform specific antibodies. The affinity of a given inhibitor against PI3K-β, -δ, and -γ was determined in various cell lines and compared to inhibition of pAKT levels measured by ELISA or western blotting in unstimulated 786.0 cells, IgM-stimulated Raji cells, and C5a-stimulated RAW264.7 cells. Results: We utilized the occupancy assay on these cell lines with compounds that have differential biochemical PI3K isoform inhibition profiles. All of these cell lines significantly express more than one PI3K isoform, with Raji and 786.0 cells expressing PI3K-δ and -β, and RAW264.7 cells expressing PI3K-δ and -γ. In unstimulated 786.0 cells, PI3K-β and PI3K-δ occupancy IC50s were obtained and compared with pAKT IC50s. PI3K-β occupancy IC50s, but not PI3K-δ occupancy IC50s, correlated well with pAKT IC50s, indicating that in 786.0 cells, PI3K-β is the main driver for pAKT formation. Similarly, PI3K-β and PI3K-δ occupancy IC50s were obtained in anti-IgM stimulated Raji cells. Here pAKT IC50s correlated with PI3K-δ, and not PI3K-β occupancy IC50s, indicating that PI3K-δ is the major signaling isoform responding to this stimulus. The PI3K-δ occupancy IC50s were similar in C5a-stimulated RAW264.7 cells, but here the PI3K-γ occupancy IC50 was equivalent to pAKT IC50, confirming that PI3K-γ is the major PI3K signaling isoform downstream of C5a in RAW264.7 cells. Interestingly, PI3K-δ and PI3K-γ occupancy IC50s were similar between stimulated or unstimulated Raji or RAW264.7 cells. Therefore, PI3K occupancy is unaffected by PI3K migration to the cell membrane after stimulation. Conclusions: To our knowledge, this is the first demonstration that occupancy of membrane-recruited Class I PI3K isoforms by PI3K inhibitors directly correlates with the inhibition of pAKT. These results also indicate a predominant PI3K signaling isoform is responsible for downstream pAKT formation in these cell lines, validating them for PI3K isoform specific cell based assays. Citation Format: Lina Gu, Erin Brophy, Erin Murphy, Bonnie Tillotson, Jonathan DiNitto, Louis Grenier, Janid Ali. A novel cellular class I phosphoinositide-3-kinase (PI3K) isoform-specific occupancy assay demonstrates a direct correlation between PI3K isoform activity and phospho-AKT levels. [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 4973. doi:10.1158/1538-7445.AM2015-4973

Abstract PI3K-δ and PI3K-γ isoforms are preferentially expressed in leukocytes where they have distinct and mostly non-overlapping roles in immune cell function and important roles in the biology of B-cell neoplasms. Duvelisib (IPI-145), a potent, orally available, small molecule inhibitor of PI3K-δ and PI3K-γ, was designed to investigate the hypothesis that simultaneous inhibition of these two specific isoforms would demonstrate broad adaptive and innate immune cell inhibitory activity and enhanced efficacy in hematologic malignancies as well as inflammatory and autoimmune diseases. Biochemical, target occupancy, cellular, and whole blood assays indicate that the inhibition of both the PI3K-δ and PI3K-γ isoforms with duvelisib can be accomplished effectively at clinically relevant concentrations. Duvelisib displays single-agent activity across a spectrum of hematologic neoplasm cell lines and potently inhibits the in vitro proliferation of primary human CLL cells. In certain tumor cell lines, the combination of isoform selective PI3K-δ and PI3K-γ inhibitors demonstrated synergy, suggesting that combined inhibition of both PI3K-δ and PI3K-γ results in greater growth suppression than the inhibition of either isoform alone. In addition, a high throughput combination screen demonstrates synergy between duvelisib in combination with multiple classes of approved and investigational compounds in hematologic malignancies represented by a broad panel of tumor cell lines. Duvelisib is currently in late-stage development for the treatment of hematologic malignancies including iNHL and CLL. Inhibition of both the PI3K-δ and PI3K-γ isoforms targets the malignant cells as well as their microenvironment, suggesting a rationale for the favorable response rates reported in iNHL and CLL patients administered duvelisib. Citation Format: Julian Adams. Targeting PI3K-δ and PI3K-γ in hematological malignancies with duvelisib (IPI-145). [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr IA19.