Summary Aims Three single‐dose and one multiple‐dose phase I studies were conducted in subjects with primary hypercholesterolemia to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of bococizumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. Methods The dosing schedules for hypercholesterolemic subjects randomized in the four phase I studies were (1) ascending, single, intravenous (IV) bococizumab (0.3, 1, 3, 6, 12, or 18 mg/kg), or placebo (N = 48; baseline low‐density lipoprotein cholesterol [LDL‐C] ≥130 mg/dL); (2) single, IV bococizumab (0.5 or 4 mg/kg; no placebo) added to ongoing atorvastatin 40 mg/day (N = 24); (3) single, fixed, subcutaneous (SC) bococizumab (100 or 200 mg), or IV bococizumab (200 mg; no placebo; N = 49; baseline LDL‐C ≥130 mg/dL); and (4) weekly IV bococizumab (0.25, 0.5, 1, or 1.5 mg/kg) or placebo for 4 weeks (N = 67; baseline LDL‐C ≥130 mg/dL). Results Bococizumab pharmacokinetics were well characterized following single IV or SC doses and following multiple IV doses. Exposure to single‐dose bococizumab increased slightly greater than dose‐proportionally and clearance decreased with increasing dose. In the single‐dose studies, maximal mean percent reductions from baseline in LDL‐C ranged from 43% (0.3 mg/kg) to 84% (18 mg/kg) in bococizumab‐treated subjects, compared with 2% for placebo. For the multiple‐dose study, maximal reductions in LDL‐C ranged from 55% (0.25 mg/kg) to 66% (1 mg/kg) in bococizumab‐treated subjects, compared with 9% for placebo. In all studies, adverse events were infrequent, transient, and not dose‐related. Conclusions Bococizumab was generally safe and well tolerated. Bococizumab lowered LDL‐C levels substantially in all four studies.

Azetidine and piperidine derived organozinc species have been prepared from the corresponding azacycloalkyl iodides by direct Zn insertion. They have been shown to readily undergo Pd (0) mediated cross-coupling reactions and to transmetallate with CuCN.2LiCl.During the course of our studies towards new agents for the treatment of asthma we became interested in preparing 3-(2-pyridyl) azetidines 1 .3-Aryl azetidines are generally synthesised by reduction of 3-aryl azetidine-2-ones 2 or base-mediated ring closure of the appropriate N-Oditosyl-2-aryl-3-amino-propan-1-ols 3 . However, both routes rely on non-readily accessible 2-aryl-2-cyanoacetates and require the use of reagents which might not be suitable for substrates containing sensitive functionalities.Due to their high functional group tolerance, organozinc reagents are attractive intermediates in C-C bond formation reactions 4 , and we chose to investigate the convergent synthesis of 3-(2-pyridyl) azetidines by the Pd (0) -mediated cross-coupling of an azetidinyl zincate reagent with a 2-halopyridine. Previously Knochel 5 had shown that Zn insertion into the C-I bond of an acyclic ß-iodocarbamate was possible, although it was not clear at the outset of our work whether a similar reaction could be performed with cyclic substrates. Consequently, we targeted the synthesis of the Boc-protected iodo-azetidine 1 and examined its metallation with Zn. We felt that, if successful, this approach would also allow access to a variety of 3-aryl azetidines (Scheme 1). Scheme 1The synthesis of 1 was achieved starting with N-benzhydrylazetidinyl-3 mesylate 6 (Scheme 2). Removal of the benzhydryl group with α-chloroethyl chloroformate (ACE-Cl) followed by Boc-protection afforded N-Boc-azetidinyl-3 mesylate which reacted with KI in DMSO at elevated temperature to give 1 in good yield. We were then pleased to find that Zn insertion into the C-I bond of 1 could be achieved following the procedure described by Knochel 7 . Formation of the organozinc species 2 was followed by TLC and was complete after 45 min. at room temperature. This was confirmed by quenching the reaction mixture with aqueous NH 4 Cl followed by 1 H NMR analysis of the crude organic phase showing N-Boc-azetidine as the main product. To our knowledge, Zn insertion into azacycloakyl iodides is unprecedented. Having established that we could easily prepare the organozinc reagent 2, our attention was then directed to demonstrating that it could undergo Pd (0) mediated cross-coupling reactions.Thus, 2-bromopyridine was added to a freshly prepared solution of 2 in THF and the mixture was heated at 65°C in the presence of Pd 2 (dba) 3 and P(2-furyl) 3 8 for 2 h. Using this procedure N-Boc-3-(2-pyridyl)azetidine 3 was isolated in 63% yield after chromatography.Removal of the Boc protecting group from 3 under standard acidic conditions gave 3-(2-pyridyl) azetidine dihydrochloride 4 in quantitative yield (Scheme 3) . Scheme 3Using this methodology we were then able to synthesise various 3-aryl-N-Boc-azetidines 9 and the...

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2612 Background: Therapeutic vaccines targeting PC-associated antigens represent attractive approaches in combination with immune checkpoint inhibitors (ICI). Safety/antitumor activity of PF-06753512 (PrCa VBIR) was evaluated in a phase I, dose-escalation and expansion study in patients (pts) with BCR prior to ADT and in pts with mCRPC either prior to or after failure of novel hormone therapy. PrCa VBIR consists of: 1) priming immunization with a replication-deficient adenoviral vector (AdC68) expressing PSA, prostate-specific membrane antigen and prostate stem cell antigen; 2) boosts with plasmid DNA (pDNA) encoding the same antigens by IM electroporation; 3) ICI given subcutaneously, including anti CTLA-4 antibody tremelimumab (TRM) and anti PD-1 antibody sasanlimab (SSL). Methods: AdC68 ± ICI(s) were given on months (mos) 1 and 5 and pDNA ± ICI(s) on mos 2–4 and 6–8. After 8 mos, maintenance pDNA + ICI(s) were given every 1 or 2 mos. In Part A (6 escalation cohorts), pts with mCRPC received AdC68 (4 or 6x10e11 viral particles) + pDNA 5 mg ± ICIs (TRM alone 80 mg; TRM 40 or 80 mg + SSL 130 or 300 mg). In Part B (3 expansion cohorts), pts with mCRPC received AdC68 6x10e11 + pDNA 5 mg + TRM 80 mg + SSL 300 mg; pts with BCR received similar vector and pDNA + TRM 80 mg ± SSL 130 mg. Primary objectives: Assess overall safety (CTCAE v4.03), determine expansion dose. Secondary objectives: Anti-tumor activity (RECIST v1.1, Prostate Cancer Working Group 3, PSA 50 response) and immune response. (Note: Database remains open, some queries pending). Results: As of Sept 15, 2020, 91 pts were treated in dose-escalation (n=38) and expansion (n=53; BCR=35, mCRPC=18). Immune responses (ELISpot) were positive in some pts. Grade (G) 3 or 4 treatment-related adverse events (TRAEs) developed in 38.5% (35/91) of pts. G5 TRAEs occurred in 2 pts (n=1 G4 myasthenia gravis + G5 pulmonary embolism; n=1 G5 myocarditis). irAEs were more frequent in BCR compared to mCRPC. See the table for efficacy data. Conclusions: Vaccination with PrCa VBIR had a manageable safety profile. TRAEs increased when 2 ICIs were given. Some pts with BCR experienced durable PSA-50 responses without ADT; patients with mCRPC had few objective tumor responses, but had prolonged median rPFS. PrCa VBIR appears to stimulate antigen-specific immunity and results in noticeable antitumor activity, particularly in androgen sensitive disease. Clinical trial information: NCT02616185. [Table: see text]

3009 Background: PF-07220060 is a novel potent oral CDK4-selective inhibitor with significant sparing of CDK6. We report the first disclosure of the first-in-human, multicenter trial of PF-07220060 alone or with endocrine therapy (ET). Methods: This Phase 1/2a study in advanced solid tumors was enriched for pts with HR+ HER2- advanced/metastatic breast cancer (HR+/HER2- mBC) who had received ≥2 lines of treatment including ET and CDK4/6 inhibitors (CDK4/6i). Prior fulvestrant and chemotherapy were allowed. Primary objective was to assess safety and tolerability of PF-07220060 alone and in combination with ET. Secondary/exploratory objectives included anti-tumor activity, pharmacokinetics (PK) and pharmacodynamics (PD). Results: At data cut off (Nov 1, 2022), 34 pts with advanced solid tumors received PF-07220060 in monotherapy dose escalation (Part 1A: 100–500 mg BID), and 26 pts with HR+/HER2- mBC in combination (300mg/400mg BID) with letrozole or fulvestrant (Parts 1B + 1C). For pts with HR+/HER2- mBC, median age was 61.5y (range 41–82y), ECOG PS was 0 (38.5% pts) or 1, and median prior lines of systemic therapy (advanced setting) 4.5 (range 1–11); all had prior CDK4/6i, 19 (73.1%) prior fulvestrant and 20 (76.9%) prior chemotherapy. Most frequent all causality treatment-emergent adverse events (TEAEs) with PF-07220060 + ET were diarrhea (50.0%; 0% G3), neutropenia (50.0%; 15.4% G3) and nausea (38.5%; 3.8% G3) with no >G3 TEAEs. A similar safety profile was seen in monotherapy. Dose-limiting toxicities occurred at PF-07220060 500 mg monotherapy BID (n=2 G3 thrombocytopenia) and at 400 mg BID + fulvestrant (n=1 G3 leukopenia/neutropenia). Preliminary PK analyses showed PF-07220060 is rapidly absorbed with dose-dependent increases in exposure. PF-07220060 300 mg BID was selected as the recommended dose for expansion. PD biomarker modulation was seen in tumor (pRB, Ki67 inhibition) and blood (TK1 inhibition). In pts with HR+/HER2- mBC with measurable disease who progressed on prior CDK4/6i+ET (n=21) treated with PF-07220060 (300/400 mg BID) + ET, confirmed RECIST v1.1 responses were observed in 6 (28.6%) pts (1 complete [CR], 5 partial [PR]). Clinical benefit response (CR, PR, or ≥24 wks stable disease) was seen in 11 (52.4%) pts. Median progression-free survival was 24.7 wks (95% CI: 23.1, 47.4). At data cutoff, 8/26 (30.8%) pts with mBC continued PF-07220060 + ET without progression for up to 60+ wks. Updated efficacy, PK, PD, and biomarker data will be presented. Conclusions: PF-07220060 + ET showed efficacy in pts with HR+/HER2- mBC who progressed on prior CDK4/6i+ET. Tolerability of PF-07220060 alone and in combination with ET was encouraging. Dose expansions with PF-07220060 + ET in pts with HR+/HER2- mBC post CDK4/6i and in CDK4/6i naïve pts are ongoing. Clinical trial information: NCT04557449 .

including 15 graduate students) and 53 nonmembers (including 16 graduate students). There were 17 invited speakers, with three from the USA, five from the EU and five from the UK.Jean Schwarzbauer (Princeton University, USA) opened the meeting by describing her recent findings concerning the events that control fibronectin (Fn) matrix assembly. The assembly of Fn matrix fibrils is influenced by extracellular factors such as availability of Fn and other matrix molecules, and intracellular signalling pathways mediated by integrin receptors. Jean's group has investigated two kinases downstream of integrin receptors, focal adhesion kinase (FAK) and pp60-Src. Mouse fibroblasts lacking FAK were found to assemble reduced amounts of Fn fibrils. Src family kinases phosphorylate FAK, and it was found that fibroblasts without Src family kinases (SYF cells) or wild-type cells treated with an Src inhibitor (PP1) also lack Fn matrix. The extracellular influence of tenascin-C was also discussed. In fibroblasts on a 3D Fn matrix, FAK was constitutively phosphorylated, whereas in the presence of tenascin-C, FAK is transiently activated, and there is a reduction in the assembly of Fn matrix fibrils. Other aspects of integrin-Fn interactions were also described, including the stimulation of Fn matrix formation by dexamethasone in the tumourgenic cell line HT1080.Karl Kadler (University of Manchester) summarized findings on the molecular and cellular basis of collagen fibrillogenesis. The talk focussed on the sorting and secretion of type-I collagen in organ cultures of embryonic chick tendon. It Int.

BackgroundThis phase 1 study evaluated PF-06753512, a vaccine-based immunotherapy regimen (PrCa VBIR), in two clinical states of prostate cancer (PC), metastatic castration-resistant PC (mCRPC) and biochemical recurrence (BCR).MethodsFor dose escalation, patients with mCRPC received intramuscular PrCa VBIR (adenovirus vector and plasmid DNA expressing prostate-specific membrane antigen (PSMA), prostate-specific antigen (PSA), and prostate stem cell antigen (PSCA)) with or without immune checkpoint inhibitors (ICIs, tremelimumab 40 or 80 mg with or without sasanlimab 130 or 300 mg, both subcutaneous). For dose expansion, patients with mCRPC received recommended phase 2 dose (RP2D) of PrCa VBIR plus tremelimumab 80 mg and sasanlimab 300 mg; patients with BCR received PrCa VBIR plus tremelimumab 80 mg (Cohort 1B-BCR) or tremelimumab 80 mg plus sasanlimab 130 mg (Cohort 5B-BCR) without androgen deprivation therapy (ADT). The primary endpoint was safety.ResultsNinety-one patients were treated in dose escalation (mCRPC=38) and expansion (BCR=35, mCRPC=18). Overall, treatment-related and immune-related adverse events occurred in 64 (70.3%) and 39 (42.9%) patients, with fatigue (40.7%), influenza-like illness (30.8%), diarrhea (23.1%), and immune-related thyroid dysfunction (19.8%) and rash (15.4%), as the most common. In patients with mCRPC, the objective response rate (ORR, 95% CI) was 5.6% (1.2% to 15.4%) and the median radiographic progression-free survival (rPFS) was 5.6 (3.5 to not estimable) months for all; the ORR was 16.7% (3.6% to 41.4%) and 6-month rPFS rate was 45.5% (24.9% to 64.1%) for those who received RP2D with measurable disease (n=18). 7.4% of patients with mCRPC achieved a ≥50% decline in baseline PSA (PSA-50), with a median duration of 4.6 (1.2–45.2) months. In patients with BCR, 9 (25.7%) achieved PSA-50; the median duration of PSA response was 3.9 (1.9–4.2) and 10.1 (6.9–28.8) months for Cohorts 5B-BCR and 1B-BCR. Overall, antigen specific T-cell response was 88.0% to PSMA, 84.0% to PSA, and 80.0% to PSCA.ConclusionsPrCa VBIR overall demonstrated safety signals similar to other ICI combination trials; significant side effects were seen in some patients with BCR. It stimulated antigen-specific immunity across all cohorts and resulted in modest antitumor activity in patients with BCR without using ADT.Trial registration numberNCT02616185.

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