Pharmacodynamic Impact Research Articles

At-Home Administration of Gantenerumab by Care Partners to People with Early Alzheimer's Disease: Feasibility, Safety and Pharmacodynamic Impact.

Monoclonal antibodies that target amyloid-beta and remove amyloid plaques can slow cognitive and functional decline in early Alzheimer's disease. Gantenerumab is a subcutaneously administered fully-human anti-amyloid-beta monoclonal antibody with highest affinity for aggregated amyloid-beta. Since the phase 3 GRADUATE trials did not meet the primary endpoint (change from baseline to Week 116 in Clinical Dementia Rating scale - Sum of Boxes), development of gantenerumab in sporadic Alzheimer's disease was stopped and all ongoing trials were terminated early due to sponsor decision. Subcutaneous administration at the clinic or at home by care partner would be an important option for other therapies in this class in order to increase flexibility and reduce overall burden. The insights obtained from the experience with gantenerumab home administration by care partner in the phase 2 GRADUATION trial will serve to guide the ongoing efforts with other anti-amyloid-beta antibodies. To evaluate the pharmacodynamic effects on brain amyloid load of once weekly subcutaneous administration of gantenerumab and the safety and feasibility of home administration by care partners. Phase 2, open-label, single arm study. Multicenter trial conducted in 33 sites in 8 countries from November 2020 to March 2023. Participants aged 50 to 90 with early symptomatic Alzheimer's disease (mild cognitive impairment/mild dementia due to Alzheimer's disease), and evidence of amyloid positron emission tomography positivity. Participants could receive up to 255 mg gantenerumab once-weekly, administered subcutaneously at site or at home by healthcare professionals or non-healthcare-professional care partners. The primary endpoint was the change from baseline to Week 52 and to Week 104 in brain amyloid load as measured by PET centiloid levels. The secondary endpoints were responses to the home administration questionnaire, plasma concentrations and safety. The overall number of participants enrolled was 192, with a mean (standard deviation) amyloid PET load at baseline of 101.80 (29.80) centiloids. At the time of early study termination by sponsor, 149 participants had valid Week 52 amyloid PET data (primary endpoint), and 12 participants had an early termination PET within the pre-defined time range of Week 104. The mean change in amyloid PET from baseline to Week 52 and Week 104 was -26.19 centiloids (range: -75.6-15.8; n=149) and -35.48 centiloids (range: -63.2--7.0; n=12), respectively. Responses to the home administration questionnaire at Week 52 (n=148) indicated that the majority of care partners (88-97%) considered administration of study drug at home easy (30.4%) or very easy (57.4%), and convenient (25.7%) or very convenient (70.9%). Care partners felt confident (31.1%) or very confident (62.2%) and satisfied (29.7%) or very satisfied (64.9%) with giving the injection at home. Responses by care partners at Week 36 (n=72), Week 76 (n=126) and Week 104 (n=29) and participant (patient) assessment of convenience and satisfaction at these time points were similar. There were no new safety findings associated with gantenerumab administered subcutaneously once weekly at 255 mg or safety issues associated with at-home injections by non-healthcare professional care partners. Once-weekly subcutaneous home administration of the anti-amyloid-beta antibody gantenerumab by non-healthcare-professional care partners to participants with early Alzheimer's disease was feasible, safe, well tolerated, and considered as a convenient option by both the care partners and participants with Alzheimer's disease. Although gantenerumab's development has been stopped due to lack of efficacy, this approach has the potential to reduce the frequency of hospital/outpatient clinic visits required for treatment with other anti-amyloid-β antibodies and can increase flexibility of drug administration for people living with Alzheimer's disease and their families.

Development of Oral Azacitidine with Cedazuridine for Myelodysplastic Syndrome (MDS) and Myeloproliferative Neoplasms (MPN) Including CMML (Chronic Myelomonocytic Leukemia) By Targeting Pharmacokinetic AUC Equivalence Vs Subcutaneous Azacitidine

Introduction/ Background: Hypomethylating agents (HMAs) such as azacitidine (AZA) and decitabine (DEC) are FDA-approved for patients with MDS/CMML and acute myeloid leukemia (AML). Treatment is generally administered parenterally as a daily injection or infusion over 5-7 days per four-week cycle. The oral fixed-dose combination of decitabine with cedazuridine, ASTX727, was approved by regulators in the USA and Canada for patients with MDS and CMML based upon the demonstration of biologically equivalent pharmacokinetics (PK) area under the curve (AUC) vs IV decitabine. ASTX030 is a combination of AZA and cedazuridine (CED), a cytidine deaminase inhibitor (CDAi), which enables oral AZA to achieve systemic AUC similar to that of parenteral (subcutaneous) AZA. Development and approval of an oral AZA providing equivalent PK exposure to the parenteral therapy has the potential to markedly reduce the treatment burden associated with parenteral treatment. This Phase I trial is designed to determine the dose combination for oral AZA plus CED to replicate SC AZA AUC exposures in subjects with MDS and MDS/MPN, including CMML. Methods: Adult patients with confirmed MDS, CMML, and other MDS/MPN or AML who are candidates to receive benefit from single agent AZA were enrolled in this open label Phase 1 trial. In addition to assessing safety and efficacy of each combination, the primary PK endpoint was to achieve oral AZA PK AUC 0-24 equivalence versus subcutaneous AZA (at the approved dose of 75 mg/m 2 over the span of 7 days). In the first cycle, patients received oral AZA alone on Day -3, followed by SC AZA at 75 mg/m 2 on Day 1. Subsequently, oral ASTX030 (combination of AZA with CED) was given at varying dose combinations of AZA and CED for each cohort. After cycle 1, patients received oral ASTX030 on Days 1-7 for each 28-day cycle. Dose levels for cohorts in escalation were determined by the data safety and review committee based on safety and PK results. Pharmacodynamic (PD) impact was assessed by changes in LINE-1 DNA methylation in peripheral blood cells. Clinical response assessments were based upon International Working Group (IWG) 2006 criteria for MDS patients and IWG 2015 criteria for MDS/MPN and CMML patients. Results: As of 05 JUL 2023, 65 patients were treated across 8 different dose combinations, with ≥6 patients per cohort. The median age was 72 years old (range 26-87), 36.9% (n=24) were female, 6.2% (n=4), had previously received HMA treatment (unlimited). Of the enrolled patients, 69% (n=45) had MDS, 25%(n=16) had CMML, and 6% (n=4) had MDS/MPN (other). Evaluated dose levels for AZA ranged from 60-136mg and CED dose ranged from 20-100 mg. In cohorts 1-2, tablet formulation was tested first (AZA ranging 80-100mg with CED ranging 80-100mg). Starting with cohort 3, capsule formulation was introduced for AZA to optimize the interaction effect of CDA inhibition by CED. In both tablet and capsule formulation, grade ≥3 AE's (regardless of causality) were observed in 75.9% of patients. The most common Grade ≥3 AE's regardless of relation to drug were leukopenia (25%), thrombocytopenia (20%), and anemia (20%). Gastrointestinal toxicity were similar (for example, nausea 70% ASTX030 vs 71% SC AZA) to those reported for SC AZA (VIDAZA USPI)). No dose limiting toxicity was observed in any of the cohorts. The CED dose of 20 mg resulted in ~100% bioavailability for AZA, suggesting inhibition in a linear range. LINE-1 demethylation results were similar to those reported historically with SC AZA. Although a clinical response comparable to SC AZA was observed, the immature nature of the data requires continued analysis to yield results on treatment efficacy. Conclusion: ASTX030 successfully achieved the primary endpoint of PK equivalence versus SC AZA based on total cycle AUC. The dose combinations evaluated were well tolerated, and the safety profile similar to that of SC AZA, with no unique AE's. LINE-1 demethylation and clinical response confirm the clinical activity of ASTX030. Phase 1B dose expansion for the ASTX030 study at the recommended dose combination of 144mg AZA with 20mg CED will begin soon to confirm PK equivalence for this dose level. An orally bioequivalent AZA based HMA offers significant opportunity for novel combinations and improved convenience for patients with high grade myeloid malignancy.

Red Blood Cell Deformability and Morphological Dynamic Sickling As a Metric to Monitor Pharmacodynamic Response to Voxelotor

The recent introduction of new therapies, such as hemoglobin (Hb) oxygen affinity modifiers, fetal Hb (HbF) inducers, and gene therapy (replacement of HbS with non-sickling Hb), that affect the Hb polymerization rate for sickle cell disease (SCD), highlight the need for new metrics to assess changes in sickling characteristics as therapeutic response. Primary outcomes in clinical trials often focus on indirect clinical improvement i.e. decrease in vaso-occlusive events (VOC), Hb increase, fatigue and pain score. There is currently a lack of direct biomarkers to assess the pharmacodynamic impact of these therapies. Two methods have been developed to assess downstream Hb polymerization, LoRRca (oxygenscan), a commercial oxygen gradient ektacytometry that measures deformability as a function of oxygen tension (pO 2), and dynamic sickling assay (DSA), an enzymatic oxygen scavenging system that directly assesses morphological sickling. In the present study, we investigate the relationship between red blood cell (RBC) deformability and kinetics of sickling morphology after a treatment with different doses of voxelotor (GBT440, Global Blood Therapeutics), the only FDA approved Hb oxygen modifier. Blood samples from eight SCD patients were collected following the IRB #041718MP2E & IRB #Pro00066220 protocols. RBCs were incubated with voxelotor at five different doses based on sample hematocrit (Hct): 25% (0.32 ± 0.06 mM), 50% (0.65 ± 0.11 mM), 75% (0.97 ± 0.17 mM), 100% (1.29 ± 0.23 mM) and 125% (1.62 ± 0.28 mM), or with an equal volume of DMSO-containing buffer (vehicle). Oxygenscan is performed (LoRRca, RR Mechatronics, The Netherlands) as per manufacturer's instructions. The following parameters are calculated: i) elongation index (EImin), measured at minimum RBC deformability, ii) point of sickling (PoS), the pO 2 at which RBC deformability decreases below 5% of EImax during deoxygenation and iii) ΔEI, the difference between EImin and EImax. DSA uses an enzymatic reaction that allows for tight control of the rate and depth of hypoxia, resulting in RBC morphological changes observed through time-lapse photography. Sickling profiles were constructed to represent: i) morphological points of sickling at 50% of induced fraction (mPoS i@50%), ii) rate of sickling at 50% of induced fraction (rate i@50%) and iii) area under the curve at 15 minutes (AUC 15). Paired t-test analysis of the LoRRca elongation curves show a significant dose response in Elmin (Vehicle: 0.16 ± 0.16; 25%: 0.20 ± 0.16, p=0.0033; 50%: 0.23 ± 0.15, p=0.0001; 75%: 0.27 ± 0.15, p=0.0004; 100%: 0.30 ± 0.14, p=0.0009; 125%: 0.35 ± 0.13, p=0.0015), ΔEl (Vehicle: 0.26 ± 0.11; 25%: 0.22 ± 0.11, p=0.0016; 50%: 0.18 ± 0.11, p=0.0003; 75%: 0.15 ± 0.08, p=0.0002; 100%: 0.11 ± 0.06, p=0.0004; 125%: 0.09 ± 0.07, p=0.0011) and PoS (Figure 1; Vehicle: 35 ± 11 mmHg; 25%: 32 ± 6, p=0.0092; 50%: 28 ± 7, p=0.0038; 75%: 25 ± 6, p<0.0001; 100%: 17 ± 5, p=0.0007; 125%: 14 ± 4, p=0.0015). These findings indicate improvements in RBC deformability under hypoxic conditions when the drug is present. Furthermore, paired t-test of DSA data showed a significant dose response with AUC 15 (Vehicle: 958 ± 104; 25%: 909 ± 105, p=0.0061; 50%: 845 ± 146, p=0.0004; 75%: 768 ± 194, p=0.0014; 100%: 672 ± 179, p<0.0001; 125%: 623 ± 192, p=0.0002), rate i@50% (Vehicle: 0.87 ± 0.26; 25%: 0.77 ± 0.30, p=0.1236; 50%: 0.61 ± 0.29, p=0.0003; 75%: 0.33 ± 0.13, p<0.0001; 100%: 0.28 ± 0.10, p<0.0001; 125%: 0.25 ± 0.09, p=0.0004) and mPoS i@50% (Figure 2; Vehicle: 4.4 ± 0.7 minutes; 25%: 4.7 ± 0.9, p=0.0260; 50%: 5.0 ± 1.2, p=0.0407; 75%: 5.9 ± 1.7, p=0.0082; 100%: 7.0 ± 1.6, p=0.0002; 125%: 7.8 ± 1.8, p=0.0004). These results indicate a delay in morphological sickling due to drug treatment. Based on the results of our study there is a dose-dependent decrease in RBC deformability and in the kinetics of morphologic sickling based of DSA following voxelotor treatment. These two methods have demonstrated a comparable ability to assess downstream therapeutic effects on delaying/inhibiting HbS polymerization. The combination of these two unique properties, RBC deformability and morphology change, can possibly provide a comprehensive approach to describe the cellular level of phenotypes, which may predict SCD severity. With further development these complementary assays have the potential to become important tools for drug development and monitoring response to SCD therapies.

Abstract 3077: Pharmacological profiling of KSHN001034 - A novel prodrug of Fulvestrant with improved efficacy

Abstract Purpose: KSHN001034, a Fulvestrant (FLV) prodrug, was developed to enhance solubility and achieve higher FLV plasma exposures. Currently, Faslodex® (500 mg) intramuscular depot achieves a steady-state plasma concentration of 24-28 ng/mL in humans translating to efficacy. However, it achieves insufficient estrogen receptor (ER) blockade due to suboptimal pharmacokinetic (PK) exposures. KSHN001034 was studied in the MCF-7 xenograft model to evaluate the pharmacodynamic impact of increased FLV exposure. Methods: Higher strength formulations of KSHN001034 were prepared and 150 mg/mL FLV equivalent (eq.) strength was selected based on PK studies of KSHN001034 and Faslodex® in beagle dogs and cynomolgus monkeys. The MCF-7 xenograft study was executed in comparison with FLV where treatment was initiated with an average tumor volume (TV) of ~160 mm3 or ~450 mm3. KSHN001034 or Faslodex® were dosed at 1mg/mouse, and 5mg/mouse either alone or in combination with oral Palbociclib 50mg/kg, QD for 28 days. The plasma as well as brain concentrations (KSHN001034, FLV) and ER expression in tumor tissue were assessed at the end of the study. The toxicity studies were conducted on rats (50, 100, 250 mg/kg) and dogs (15, 30, 75 mg/kg), respectively, using 1x, 2x, and 5x eq. clinical dose of FLV. Results: Single dose PK in dogs and monkeys generated ~2.5-fold higher FLV AUC from KSHN001034 compared to Faslodex®. In the xenograft study, Faslodex® 1mg/mouse treatment in low tumor burden resulted in inhibition of tumor progression (Day 0: 160.8 vs. Day 28: 180.6 mm3) whereas KSHN001034 displayed regression (Day 0: 160.8 vs. Day 28: 143.5 mm3) due to improved FLV exposures. The brain FLV concentration (~60ng/g) post KSHN001034 dosing was observed versus BLQ after Faslodex®. The xenograft study with high tumor burden emphasized the impact of higher FLV release from KSHN001034. The results showed a >30% decrease in initial TV with KSHN001034 in 2-5 days which was not observed even after 28 days of Faslodex® treatment. Also, KSHN001034 showed significantly higher tumor regression in all treated animals compared to Faslodex® (100% vs. 62.5% animals). The safety studies established a rat dose of 250 mg/kg (2.5 g human eq.) and a dog dose of 30 mg/kg (1.0 g human eq.) as the maximum tolerated dose of FLV eq. KSHN001034. Repeat-dose 28 days toxicity studies currently underway in rodent and non-rodent species. Conclusion: Higher FLV exposures with KSHN001034 resulted in improved tumor control, addressing a significant unmet need to slow disease progression as well as its potential in window-of-opportunity trials. Citation Format: Parva Purohit, Heta Pandya, Vishal Unadkat, Sandip Mehta, Ketan Variya, Sonam Sinha, Mahesh Barmade, Vamsi Krishna, Ganesh Sangle. Pharmacological profiling of KSHN001034 - A novel prodrug of Fulvestrant with improved efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3077.

The Frail Elderly Patient and the Need for a Video Store on Regional Anaesthesia Blocks

The Frail Elderly Patient and the Need for a Video Store on Regional Anaesthesia Blocks

A Quantitative Method for the Study of HIV-1 and Mycobacterium tuberculosis Coinfection.

Mycobacterium tuberculosis and human immunodeficiency virus-1 (HIV-1) syndemic interactions are a major global health concern. Despite the clinical significance of coinfection, our understanding of the cellular pathophysiology and the therapeutic pharmacodynamic impact of coinfection is limited. Here, we use single-round infectious HIV-1 pseudotyped viral particles expressing green fluorescent protein alongside M. tuberculosis expressing mCherry to study pathogenesis and treatment. We report that HIV-1 infection inhibited intracellular replication of M. tuberculosis and demonstrate the therapeutic activity of antiviral treatment (efavirenz) and antimicrobial treatment (rifampicin). The described method could be applied for detailed mechanistic studies to inform the development of novel treatment strategies.

CTNI-23. PRELIMINARY SAFETY AND PHARMACOKINETICS DATA FOR A PHASE 1B TRIAL OF TELAGLENASTAT IN COMBINATION WITH RADIATION THERAPY AND TEMOZOLOMIDE IN PATIENTS WITH IDH-MUTANT GRADE 2/3 ASTROCYTOMA (NCI-10218)

Abstract IDH mutant gliomas depend on glutaminase for glutamate/glutathione generation from glutamine because R-2-hydroxyglutarate inhibits branched chain amino acid transaminase mediated glutamate biosynthesis. Telaglenastat (CB-839 HCl) is a potent glutaminase-1 specific inhibitor which depletes tumor glutamate in orthotopic IDH mutant glioma PDX models and extends survival in these orthotopic models when added to radiation/temozolomide. NCI-10218 (NCT03528642) is a phase I clinical trial investigating the safety and tolerability of telaglenastat administered orally concurrently with standard doses of radiation (50.4 Gy, grade 2; 59.4 Gy, grade 3) and temozolomide (75 mg/m2 orally daily) in patients (age 16+) with previously untreated IDH mutant grade 2/3 astrocytoma. Telaglenastat dose was escalated in cohorts (400-800 mg twice daily) based on a standard 3 + 3 design to determine the recommended phase 2 dose (RP2D). Toxicities were graded per CTCAE v5.0. An expansion cohort additionally incorporated a seven-day run-in of telaglenastat monotherapy at RP2D prior to radiation to evaluate the pharmacodynamic impact of telaglenastat on plasma and tumor metabolites. 23 patients with IDH mutant astrocytoma (WHO grade 2, n = 5; WHO grade 3, n = 18) were accrued between December 2018 and January 2022 (Dose Escalation: 16; Dose Expansion: 7). Median age was 32 years (range 23-69 years). 61% were male and 70% were ECOG 0. No dose-limiting toxicities were observed. Grade 3/4 adverse events (independent of attribution) included: lymphopenia (3), neutropenia (2), leukocytosis (2), alanine transaminase elevation (2), thrombocytopenia (1), leukopenia (1), maculopapular rash (1), hyperglycemia (1), hyponatremia (1). The RP2D of concurrent telaglenastat was defined as 800 mg twice daily. Following peak absorption on Day 15 at RP2D, the mean (%CV) terminal elimination half-life in the plasma was 4.2 (53.5%) hours (range 2.1-7.1 hours). The Cmax, Tmax, oral clearance, and AUC were 1496 ng/mL, 4.0 hr, 93.6 L/hr/m2, and 7430 ng/mL*hr, respectively.

Abstract 2034: Spatial transcriptomics identifies unique pharmacodynamic effects of checkpoint inhibitor treatment on the tumor microenvironment in NSCLC

Abstract Background: Immune checkpoint inhibitor (ICI) therapy has improved outcomes in non-small cell lung cancer (NSCLC), particularly in patients with high tumor infiltrating lymphocytes (TILs). Identifying the pharmacodynamic (PD) impact of ICI on immune cells in the tumor microenvironment (TME) can inform therapeutic development for patients with progressive disease. We sought to identify PD changes in the TME from patients before and after ICI therapy using a spatial transcriptomics platform that allows highly multiplexed profiling of 1,800 genes (Nanostring Digital Spatial Profiler [DSP]). Methods: Formalin fixed, paraffin embedded (FFPE) tumor tissue from 22 patients was sourced commercially. Patients were treated with neoadjuvant chemotherapy, then underwent a surgical tumor resection. After surgery an adjuvant chemotherapy was administered until progression; patients then received monotherapy ICI (nivolumab or pembrolizumab). Once progressed on ICI, another resection was performed. Patients were then treated with chemotherapy and followed until progression and/or death. The DSP technology was used to independently profile RNA from PanCK+ (tumor) and PanCK- (stroma) regions in the tissue based on fluorescence staining. Six circular regions of 600μm in diameter were selected for analysis using the GeoMx instrument; each area contained CD3+ cells. Additionally, immunohistochemistry for PDL1 and CD3 was performed, images were scored by a pathologist and analyzed with digital pathology algorithms. Results: Spatial transcriptomic analysis of pre- vs post-ICI treatment in stroma revealed significant increases in T cell genes (CD3E, TCRB, NKG7), T-cell activation markers (CD69, IFNG, OX40, GZMB, ICOS), costimulatory signaling (CD28, CD80, CD86), and immune checkpoints (CTLA4, TIGIT). Ayers et al., JCI 2017 identified 28 genes predictive of ICI response, 12 were significantly upregulated in the stroma post-ICI (26 were present in the DSP panel). We identified genes in the pre-ICI stromal microenvironment that were highly expressed in patients with partial response to ICI, the most significant genes were involved in immune regulation (IFIT1) and extracellular matrix remodeling (MMP3). In contrast, stromal genes highly expressed in patients with progressive disease were associated with T-cell maintenance (ETS1, IL7R, CCL19). Conclusions: In this study we used spatial transcriptomics to profile tissue regions where T-cells were in close proximity to tumor cells (microns). This focused, local PD analysis confirmed activated T-cells are present post-ICI. Ongoing studies in a larger cohort will be used to identify tumoral mechanisms of resistance and immune dysfunction to inform future therapeutics and combinations. Citation Format: Li Fan, Omar Jabado, Nora Pencheva, Patricia Coutinho de Souza, Brandon Higgs, Angelo Harris, Patrick Franken, Anantharaman Muthuswamy, Maria Jure-Kunkel, Suzana Couto, Kate Sasser, Mark Fereshteh. Spatial transcriptomics identifies unique pharmacodynamic effects of checkpoint inhibitor treatment on the tumor microenvironment in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2034.

Biosimilar Pegfilgrastim-cbqv Demonstrated Similar Immunogenicity to Pegfilgrastim in Healthy Subjects Across Three Randomized Clinical Studies.

IntroductionBiologic therapeutics can trigger immune responses in patients. As part of the totality of evidence that is required for regulatory approval of biosimilars, immunogenicity similarity must be assessed in the clinical programs. Pegfilgrastim-cbqv (UDENYCA®) is a pegfilgrastim biosimilar approved in the USA and European Union. This article demonstrates the similar immunogenicity of pegfilgrastim-cbqv compared with its reference product, pegfilgrastim (Neulasta®).MethodsThe immunogenicity of pegfilgrastim-cbqv was assessed in three clinical studies in healthy subjects (one specifically designed to evaluate immunogenicity similarity and two studies to assess pharmacokinetics and pharmacodynamics bioequivalence) using a tiered approach, in which plasma samples were tested for the presence of antidrug antibodies (ADAs) as well as ADA binding-specificity, titer and neutralizing activity. To assess the clinical impact of ADAs, pharmacokinetics, pharmacodynamics and safety profiles were compared between ADA-positive and -negative subjects.ResultsThese studies demonstrated similar immunogenicity of pegfilgrastim-cbqv and pegfilgrastim. The small differences in ADA incidence between treatment groups observed in the immunogenicity study were driven by non-neutralizing, low-titer, polyethylene glycol (PEG)-reactive ADAs, which are commonly present in healthy subjects. No treatment-emergent neutralizing antibodies (NAbs) were detected in either treatment group, and there was no apparent impact of ADAs on pharmacokinetics, pharmacodynamics or safety.ConclusionPegfilgrastim-cbqv has similar immunogenicity to pegfilgrastim. The presented immunogenicity, pharmacokinetics, pharmacodynamics and safety data support the overall demonstration of no clinically meaningful differences between pegfilgrastim-cbqv and pegfilgrastim.Clinical Trial RegistrationNCT02418104 (CHS-1701-04, April 2015), NCT02650973 (CHS-1701-05, February 2016) and NCT02385851 (CHS-1701-03, March 2015).Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-021-02024-x.

Subchronic toxicity of the pulmonary hypertension model due to low-dose monocrotaline in rats

Context: The study of pulmonary hypertension is mainly based on an experimental model that induces this condition using monocrotaline. Even though this model has been in use for decades, the toxic effect of low dose monocrotaline in other systems is not well described. Aims: To evaluate the renal and hepatic effects of monocrotaline in order to be able to better predict the pharmacodynamic impact that it could have. Methods: Two groups of rats were used, the first one received monocrotaline following pulmonary hypertension protocol (30 mg/kg) and the second one received saline 0.9%. At day 60 blood from the vena cava was obtained and liver and kidney were extracted for histologic exam. Fulton index (right ventricle hypertrophy measurement) was used to confirm pulmonary hypertension. Results: The monocrotaline group presents focal interstitial lymphoid infiltration and regeneration foci in the kidney as well as venous congestion of the liver in some of the animals, these changes were not found in the control group. Kidney and liver function tests showed no significant differences. These results show that low-dose monocrotaline model for pulmonary hypertension generates changes on liver and kidney; however, these alterations were not consistent, making it a viable model for evaluating new drugs in this condition. Conclusions: The present study demonstrates that the low dose of monocrotaline (30 mg/kg) in animals exposed for 60 days does not cause consistent changes in liver and kidney; there were findings in some animals that could be caused by cardiovascular changes generated by pulmonary hypertension.

Abstract 2400: K01401-020 is a novel anti-VISTA antibody for cancer treatment: Pharmacodynamic impact on non-human primates and human immune system

Abstract VISTA (V-domain Ig suppressor of T cell activation), also known as PD-1 homolog (PD-1H), is a transmembrane protein which is highly expressed in myeloid cells such as neutrophils, monocytes, macrophages, and dendritic cells, and at low levels on naive CD4, CD8 and regulatory T-cells. VISTA is also expressed in cancer cells in some patient subsets (Villarroel-Espindola, 2017; Böger, 2017; Liao, 2018). VISTA is functionally described as a negative checkpoint regulator of immune response. Hence, VISTA blockade increases proliferation when T cells are stimulated with VISTA expressing myeloid antigen presenting cells (Wang et al, 2011). Immune suppression by VISTA-positive cells has been hypothesized in the primary or acquired resistance to cancer immunotherapy (Kakhavand, 2017); and even a negative impact of VISTA on immune response has been functionally demonstrated in prostate cancer samples from patients having received prior immunotherapy (Gao, 2017). Here we show that VISTA RNA and protein are expressed in lung cancer samples. We also show by using bioinformatics, that VISTA expression is linked to the higher myeloid infiltrated tumors and can also be found in tumor cells. K01401-020 is novel monoclonal, humanized IgG antibody that binds to cynomolgus monkey and human-VISTA (hVISTA) with a high affinity (Kd ~0.1 nM). The antibody binds to VISTA extracellular domain and blocks its associated function. The pharmacology of K01401-020 was studied in a series of in vitro (ex vivo) experiments with human blood cells, and in vivo studies in non-human primates. Peripheral Blood Mononuclear cells (PBMCs) from several couples of human donors were mixed together in a Mixed Lymphocyte Reaction (MLR) setting, which showed that K01401-020 stimulated IFNg release after 5 days of culture. K01401-020 stimulates NK cells to proliferate and induces activating cytokines by NK cells and monocytes, contributing to T cell activation. PDL1 expression is also clearly induced on myeloid cells by K01401-020, suggesting that combination therapy with anti-PD1/L1 may be required to optimize the anti-tumor efficacy. In non-human primates, preliminary results show that both K01401-020 monotherapy, given weekly at 3 dose levels for 4 weeks and anti-VISTA antibody combination with anti-PD1 antibody (pembrolizumab) were well tolerated. Pharmacodynamic exploration using peripheric blood sampling demonstrated full VISTA occupation by the antibody, and notably, dendritic cell activation. K01401-020 antibody drug is thus expected to increase global and specific anti-tumor immune response in situations where VISTA is expressed in cancer patients and may be synergistic with anti-PD1/L1 antibodies. Citation Format: Noureddine Loukili, Isabelle Vandenberghe, Olivier Delfour, Françoise Fraboul, Eric Chetaille, Francisco Cruzalegui, Nathalie Corvaïa, Pierre J. Ferré. K01401-020 is a novel anti-VISTA antibody for cancer treatment: Pharmacodynamic impact on non-human primates and human immune system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2400.

Abstract 3870: The addition of CB-839 to temozolomide significantly reduces glioma aspartate and glutamate in an IDH mutated patient derived glioma xenograft model

Abstract Background: IDH mutated gliomas are critically dependent on glutaminase for glutamate biosynthesis. CB-839 is a novel glutaminase-1 inhibitor which has demonstrated efficacy in both genetically engineered and patient derived IDH mutated glioma cells, especially in combination with radiation. These preclinical studies evaluate the pharmacodynamic and pharmacokinetic impact of combining CB-839 with TMZ in patient derived xenograft (PDX) glioma models. Methods: GBM164 is a PDX model derived from an IDH1 mutant, 1p/19q non-codeleted glioma. D- and L-2HG levels in untreated GBM164 tumors were compared to GBM6 tumors (IDH wildtype glioma PDX) by GC/MS. Athymic nude mice bearing GBM164 flank tumors were treated with CB-839 (200 mg/kg PO BID x 9 doses) and/or temozolomide (50 mg/kg PO daily x 5 doses) and sacrificed four hours after the last dose to harvest plasma, normal brain and flank tumor. Tumor metabolomics were assessed by GC/MS. DNA damage signaling in tumors was assessed by Western blotting for KAP1 / Chk1 / Chk2 phosphorylation and H2AX / Rad51. Tumor, plasma and brain pharmacokinetics were assessed by LC/MS/MS. Results: Total 2HG levels in GBM164 were 18-fold higher than GBM6. CB-839 monotherapy reduced tumor glutamate (18% reduction, p = 0.15) and aspartate (30% reduction, p = 0.06) when compared to vehicle, however these changes did not reach statistical significance. The combination of CB-839 and TMZ more significantly reduced both tumor glutamate (30% reduction, p = 0.03) and aspartate (34% reduction, p < 0.001) when compared to TMZ monotherapy. CB-839 did not significantly increase DNA damage compared to vehicle, and the combination of CB-839 and TMZ did not significantly increase DNA damage compared to TMZ monotherapy. The mean tumor: plasma ratios of CB-839 concentrations were 0.68 and 0.58 in mice treated with CB-839 monotherapy and CB-839/TMZ, respectively. The mean brain: plasma ratios of CB-839 concentrations were 0.07 and 0.12 in mice treated with CB-839 monotherapy and CB-839/TMZ, respectively. Conclusion: The addition of CB-839 to TMZ significantly reduces glioma aspartate and glutamate in an IDH1 mutant PDX glioma model, without any impact on DNA damage. Survival studies are in progress to assess the efficacy of CB-839 when used in combination with RT and/or TMZ. Citation Format: Sani Haider Kizilbash, Danielle M. Burgenske, Samuel McBrayer, Sandhya Devarajan, Shiv K. Gupta, Taro Hitosugi, Lihong He, Mark A. Schroeder, Brett L. Carlson, Marina Gelman, Charles A. Kunos, Joel M. Reid, Alex A. Adjei, Jann N. Sarkaria. The addition of CB-839 to temozolomide significantly reduces glioma aspartate and glutamate in an IDH mutated patient derived glioma xenograft model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3870.

Abstract 5711: The impact of combination oral azacitidine (CC-486) + pembrolizumab (PEMBRO) on the immune infiltrate in metastatic melanoma (MM)

Abstract Introduction: Although immune checkpoint inhibitors have improved survival for many with MM, most pts do not respond and median PFS is only 6 months for single agent therapy. Cancers subvert the cellular epigenetic machinery to facilitate immune escape. Epigenetic mechanisms of resistance are potentially reversible by DNA hypomethylating agents (HMA). Based on preclinical models, we hypothesized that CC-486, an oral HMA, will enhance response to PEMBRO in PD-1 naïve pts and reverse resistance in anti-PD-1 refractory pts. The aim of this study is to determine the safety, efficacy, and characterize the pharmacodynamic impact of CC-486 + PEMBRO on immune infiltrates in pts with MM. Experimental: NCT02816021 is an ongoing phase II study of CC-486 + PEMBRO in MM pts who are PD-1 naïve (Arm A) or who have progressed on prior PD-1 directed therapy (Arm B). Pts receive 300mg PO of CC-486 on days 1-14 and 200mg IV of PEMBRO q3 weeks. Serum and tumor biopsies are obtained at baseline, prior to cycles 3 and 5. Immune monitoring studies were performed by the Immunotherapy Platform at MD Anderson. Immune cell phenotyping by CyTOF was performed using 36 metal-conjugated antibodies targeting myeloid and T cell surface markers. FCS files were exported and manually gated for lymphocytes using FlowJo (version 10.1) and subjected to multidimensional phenographic analysis. Results: Thirteen pts (Arm A, n=6; Arm B, n=7) have been enrolled. Two of the 3 pts remaining on study are PD-1 naïve and have received 13 and 8 cycles of CC-496 + PEMBRO with partial responses by RECIST1.1 at 6 months, respectively. One pt on Arm B remains on study with stable disease after 4 cycles. The combination was considered safe after a run-in phase (6 pts/arm treated without DLTs) and the study is open to full accrual. The most common grade 3/4 AEs were leukopenia , neutropenia, vomiting, and diarrhea (2 each) with 1 grade 5 AE unrelated to treatment (hepatic rupture/bleeding due to progressive disease). Serum and tumor biopsies from 6 pts (3 per Arm) were available for interim analysis, with additional samples in process. Of these 6 pts, 1 pt (PD-1 naïve) responded to therapy by RECIST1.1. We evaluated the blood and tumor samples by CyTOF. In the tumor samples, we observed an increase in frequency of T cells in 2 PD-1 naïve patients but did not observe similar changes in PD-1 refractory patients in this small cohort. Similar data was found with immunohistochemistry. These changes were not observed in the blood samples. Conclusion: The regimen CC-486 + PEMBRO is not marrow suppressive and is well tolerated. Changes in the peripheral lymphocyte cell populations upon treatment are not necessarily concordant with changes occurring in the tumor. Analysis of collected samples is ongoing and will be presented at the meeting, and will help corroborate initial findings and yield further insight into the effect of this combination on the immune response. Citation Format: Emily Z. Keung, Isabella C. Glitza, Elizabeth Burton, Rodabe N. Amaria, Sapna P. Patel, Adi Diab, Cassian Yee, Michael K. Wong, Wen-Jen Hwu, Patrick Hwu, Scott E. Woodman, Michael T. Tetzlaff, Nallely Trujillo-Conley, Denai R. Milton, Michael A. Davies, Kunal Rai, Irina Fernandez, Jorge M. Blando, Luis M. Vence, Padmanee Sharma, James P. Allison, Jennifer A. Wargo, Hussein Tawbi. The impact of combination oral azacitidine (CC-486) + pembrolizumab (PEMBRO) on the immune infiltrate in metastatic melanoma (MM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5711.

Randomized open-label crossover assessment of Prograf vs Advagraf on immunosuppressant pharmacokinetics and pharmacodynamics in simultaneous pancreas-kidney patients.

We assessed the pharmacokinetic and pharmacodynamic impact of converting stable simultaneous pancreas-kidney (SPK) recipients from standard tacrolimus (Prograf) to long-acting tacrolimus (Advagraf). In a randomized prospective crossover study, stable SPK recipients on Prograf were assigned to Prograf with 1:1 conversion to Advagraf or vice versa. Demographics, tacrolimus, mycophenolic acid levels, and Cylex CD4+ATP levels were taken at specified intervals in addition to standard blood work. Twenty-one patients, who were a minimum of 1year post-transplant, were entered into the study. No difference in tacrolimus or mycophenolic acid levels was noted between patients who were first assigned to Prograf or Advagraf. Additionally, Cylex levels as well as serum creatinine, lipase, and blood sugar levels were unchanged. There were no episodes of rejection during the 6-month study. It is safe to convert between Prograf and Advagraf 1:1, without major impact on pharmacokinetics or pharmacodynamics in SPK recipients.

Meta-analysis: Risk of hyperhidrosis with second-generation antidepressants.

Our goal was to quantify the risk of hyperhidrosis associated with commonly used antidepressant agents and examine the impact of medication class, pharmacodynamics, and dose on risk of hyperhidrosis. We conducted a PubMed search to identify all double-blind, randomized, placebo-controlled trials examining the efficacy of second-generation antidepressant medications in the treatment of adults with a depressive disorder, anxiety disorders, or obsessive-compulsive disorder. We used a random-effects meta-analysis to examine the pooled risk ratio of hyperhidrosis reported as a side effect in adults treated with second-generation antidepressants compared to placebo. We used stratified subgroup analysis and metaregression to examine the effects of medication type, class, dosage, indication, and receptor affinity profile on the measured risk of hyperhidrosis. We identified 76 trials involving 28,544 subjects. There was no significant difference in the risk of hyperhidrosis between serotonin-norepinephrine reuptake inhibitors (SNRI) [risk ratio (RR)=3.17, 95% CI: 2.63-3.82] and selective serotonin reuptake inhibitors (SSRI) (RR=2.93, 95% CI: 2.46-3.47) medications compared to placebo. All antidepressant medications were associated with a significantly increased risk of hyperhidrosis except fluvoxamine (RR=0.56, 95% CI: 0.12-2.53), bupropion (RR=1.23, 95% CI: 0.57-2.67), and vortioxetine (RR=1.35, 95% CI: 0.79-2.33). The dose of SSRI/SNRI medications was not significantly associated with the risk of hyperhidrosis. Increased risk of hyperhidrosis was associated with increased affinity of SSRI/SNRI medications to the dopamine transporter. Risk of hyperhidrosis was significantly increased with most antidepressant medications but was associated with dopamine transporter affinity.

Wie soll die Arzneitherapie auf Grundlage pharmakogenetischer Testergebnisse individuell angepasst werden?

Background | Differences (polymorphisms) in genes encoding drug targets, drug transport proteins, or drug metabolizing enzymes may be responsible, among other factors, for the observed variation in patients' responses to medications. The field of pharmacogenetics aims to identify patients at higher genetically-determined risk of adverse effects or poor response to medication. This information would allow for modification of dosage or substitution with alternative therapy. However, there is a lack of awareness of pharmacogenetic clinical practise guidelines. Methods | A systematic literature review was conducted, using the Medline and PharmGKB databases, which focused on published guidelines for dosage modification or selection of drugs based on germline mutations in genes with pharmacokinetic or pharmacodynamic impact. Prescribing information from the European Medicines Agency, the German Federal Institute for Drugs and Medical Devices, and the US Food and Drug Administration was also screened for pharmacogenetic guidance. Results | The literature review revealed 20 guideline publications elucidating 43 drugs with recommendations for genotype-guided prescribing. Moreover, drug labels for 37 drugs also contained genotype-guided prescribing recommendations, some of which were linked to optional or obligatory pre-therapeutic pharmacogenetic testing. Conclusions | Existing guidelines for genotype-based drug prescribing are rarely derived from prospective, controlled trials; thus, their level of evidence is usually low. Even with low-quality evidence, strong recommendations can be made in favour of pharmacogenetic modification of prescription, such as for abacavir and the HLA-B genotype, if there is a large and certain difference between the benefits and harms. For other drug-gene pairs, such as vitamin K antagonists and CYP2C9/VKORC1, the net benefit from the pharmacogenetic-based dosing strategy is small and matter of debate. Because pharmacogenetics is playing a growing role in drug development and pre-prescription genotyping will become more widespread, specific pharmacogenetic guidance for treating physicians will become increasingly important.

Pharmacodynamic Impact of Carboxylesterase 1 Gene Variants in Patients with Congestive Heart Failure Treated with Angiotensin-Converting Enzyme Inhibitors.

BackgroundVariation in the carboxylesterase 1 gene (CES1) may contribute to the efficacy of ACEIs. Accordingly, we examined the impact of CES1 variants on plasma angiotensin II (ATII)/angiotensin I (ATI) ratio in patients with congestive heart failure (CHF) that underwent ACEI dose titrations. Five of these variants have previously been associated with drug response or increased CES1 expression, i.e., CES1 copy number variation, the variant of the duplicated CES1 gene with high transcriptional activity, rs71647871, rs2244613, and rs3815583. Additionally, nine variants, representatives of CES1Var, and three other CES1 variants were examined.MethodsPatients with CHF, and clinical indication for ACEIs were categorized according to their CES1 genotype. Differences in mean plasma ATII/ATI ratios between genotype groups after ACEI dose titration, expressed as the least square mean (LSM) with 95% confidence intervals (CIs), were assessed by analysis of variance.ResultsA total of 200 patients were recruited and 127 patients (63.5%) completed the study. The mean duration of the CHF drug dose titration was 6.2 (SD 3.6) months. After ACEI dose titration, there was no difference in mean plasma ATII/ATI ratios between subjects with the investigated CES1 variants, and only one previously unexplored variation (rs2302722) qualified for further assessment. In the fully adjusted analysis of effects of rs2302722 on plasma ATII/ATI ratios, the difference in mean ATII/ATI ratio between the GG genotype and the minor allele carriers (GT and TT) was not significant, with a relative difference in LSMs of 0.67 (95% CI 0.43–1.07; P = 0.10). Results of analyses that only included enalapril-treated patients remained non-significant after Bonferroni correction for multiple parallel comparisons (difference in LSM 0.60 [95% CI 0.37–0.98], P = 0.045).ConclusionThese findings indicate that the included single variants of CES1 do not significantly influence plasma ATII/ATI ratios in CHF patients treated with ACEIs and are unlikely to be primary determinants of ACEI efficacy.

Abstract CT303: A phase I pharmacokinetic and pharmacodynamic evaluation of the combination of everolimus and buparlisib for concurrent mTOR and PI3K pathway blockade in patients with advanced solid tumors

Abstract Background: Preclinical work showed improved anticancer efficacy with the combination of an mTOR and a PI3K inhibitor over either agent alone. We conducted a phase I study to determine the recommended phase II dose (RP2D) of the combination of everolimus (E), an mTOR inhibitor and buparlisib or BKM120 (B), a pan-PI3K inhibitor. Methods: Patients with advanced solid malignancies who have exhausted standard treatment options were enrolled. Main eligibility criteria include ECOG performance status 0-2, adequate end organ function and absence of glucose intolerance, uncontrolled hepatitis, anxiety or depression. Dose escalation was performed using a Bayesian Escalation with Overdose Control (EWOC) design to evaluate different doses of E (5mg or 10mg) and B (20, 40, 60 and 80 mg,) once daily continuously. Eligible patients were enrolled in cohorts of 3 patients. Pharmacokinetic (PK) assessment was conducted in cycle 1 on day 8 using peripheral blood samples collected at time 0, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours and prior to dosing on cycle 1 D day 15. Pharmacodynamic (PD) impact on mTOR/PI3K pathway modulation was evaluated in skin punch biopsies collected at baseline and at end of cycle 1. Results: We enrolled 35 patients: Median age 63yrs (range:40-79), 21 females (58%); 2 Latinos (6%), 7 Blacks (20%) and 26 Caucasians (74%); with cancers of the lung (8), colorectal (7), sarcomas (3), salivary gland (3), breast (3), thyroid (3), thymic (2), bladder (2), ovarian (2), head and neck (1) and PNET (1). The safety of 6 different dose combinations of E and B (5/20; 10/20; 5/40; 5/60; 10/60; 5/80) was assessed. The most frequent toxicities were: hyperglycemia, diarrhea, nausea, fatigue and AST elevation. The dose limiting toxicities observed in 6 patients were: fatigue (3), hyperglycemia (1), mucositis (1), acute renal failure (1) and urinary tract infection (1). The 5/60 combination was defined as the RP2D. The median number of cycles completed was 2 (range: 0-20). Of the 25 patients evaluable for efficacy, 8 (32%) had disease progression while 17 (68%) achieved stable disease (SD). Median duration of SD was 18 weeks (range: 2-83) and 7 patients had SD lasting ≥6 months. Steady-state PK data for both agents in 24 evaluable patients showed no evidence of drug-drug interaction, with dose-normalized maximum concentrations (Cmax) and area-under-the-curve (AUC0-∞) values for E and B in combination being comparable to single agent data. Preliminary signal of efficacy for the combination was observed in patients with thymic, breast and lung cancer. PD analysis is ongoing and will be presented at the meeting. Conclusion: The safety profile of the combination of everolimus plus buparlisib is well tolerated and the RP2D is 5mg/day and 60mg/day respectively on a continuous daily schedule. The efficacy data are encouraging and warrant further evaluation in phase II studies. Citation Format: Taofeek Kunle Owonikoko, R.Donald Harvey, Colleen Lewis, Zhengjia Chen, John S. Kauh, Meredith Renfroe, Rijalda Deovic, Gabriel L. Sica, Bradley C. Carthon, Wayne Bernard Harris, Bassel F. El-Rayes, Suresh S. Ramalingam, Fadlo R. Khuri. A phase I pharmacokinetic and pharmacodynamic evaluation of the combination of everolimus and buparlisib for concurrent mTOR and PI3K pathway blockade in patients with advanced solid tumors. [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 CT303. doi:10.1158/1538-7445.AM2015-CT303

Abstract CT418: A Phase Ib study of BKM120 combined with abiraterone acetate for castrate-resistant, metastatic prostate cancer

Abstract Introduction: There is significant cross-talk between PI3-kinase (PI3K) and androgen receptor (AR) signaling pathways, respectively, which are both critical for cell survival in castrate-resistant prostate cancer (CRPC). The primary study objective (NCT01741753) is to determine the safety profile and maximum tolerated dose (MTD) of BKM120 (pan-PI3K inhibitor) in combination with abiraterone/prednisone (A/P) in CRPC patients. The secondary study objectives are to assess the impact of PTEN status on duration of response/time to progression in the expansion cohort, and to evaluate the impact of BKM120 on a PI3-kinase activation fingerprint in metastatic bone or lymph node tissue samples. An exploratory objective of the study is to assess the effect of BKM120 on transcription of a set of AR-regulated genes in metastatic bone biopsy samples. Methods: The trial design involves a 14 day lead-in phase with BKM120 alone, to assess single-agent toxicity and perform correlative studies. A/P is combined with BKM120 at the end of 14 days using the standard 3+3 dose-escalation design with 3 dose levels of BKM120 (80 mg, 100 mg, 120 mg, respectively), and participants are assessed for safety and MTD on the combination therapy. To determine pharmacodynamic impact of single agent BKM120 on the PI3K activation signature at a metastatic site, a mandatory CT-guided bone or lymph node biopsy is performed prior to BKM120 initiation and at the end of 2 weeks on BKM120 single-agent therapy. Immunohistochemical (IHC) stains for three markers (p-AKT, p-S6 and PTEN) are used to obtain a semi-quantitative PI3K activation score, based on the quartile levels of continuous staining scores of each marker. Results: The clinical, PSA biochemical responses, immunohistochemical and molecular RT-PCR data for three enrolled patients are summarized here. The first patient had symptomatic bone pain with limited functional mobility at baseline, and was treated with the first BKM120 dose level of 80 mg daily. He had a decline in PSA from 156.5 to 129.6 during the lead-in phase with single-agent BKM120 treatment with partial symptomatic pain relief. Interestingly, comparison of pre- and post-treatment metastatic bone tumor IHC staining on single-agent BKM120 showed inhibition of phospho-S6 staining. Upon adding A/P to BKM120 treatment, he had a striking decline in his PSA to 23.3 within 1 week, which reached a nadir of 9.2 within 4 weeks of combination therapy treatment. This striking biochemical improvement corresponded to a marked decline in narcotic pain requirements, increased mobility and quality-of-life. However, he developed clinical, biochemical and radiographic disease progression after 4 cycles of combination therapy treatment, so had to withdraw from study. The second and third patient had a >90% biochemical improvement within 4 weeks of combination therapy treatment and remain on study to date. To evaluate cross-talk between AR and PI3K signaling in the bone microenvironment, RT-PCR analyses on pre- and BKM120-treated bone biopsy samples were performed. The results showed that the feedback relationship between PI3K and AR signaling are heterogeneous, and dependent on the PTEN status of the tumor. Conclusion: The pan-PI3K inhibitor/abiraterone combination is well-tolerated, and demonstrates promising anti-tumor activity in CRPC patients. Citation Format: Akash Patnaik, Massimo Loda, Justin Kung, Jim Wu, MaryEllen Taplin, Philip Kantoff, Lewis Cantley, Steven Balk, Glenn Bubley. A Phase Ib study of BKM120 combined with abiraterone acetate for castrate-resistant, metastatic prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT418. doi:10.1158/1538-7445.AM2014-CT418

Phase I Safety, Pharmacokinetic, and Pharmacodynamic Study of SAR245409 (XL765), a Novel, Orally Administered PI3K/mTOR Inhibitor in Patients with Advanced Solid Tumors

This phase I, first-in-human study evaluated the safety, maximum-tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary efficacy of SAR245409, an inhibitor of pan-Class I phosphoinositide 3-kinase (PI3K) and mTOR, administered orally once or twice daily in patients with advanced solid tumors. Eighty-three patients received SAR245409. Doses ranged from 15 to 120 mg twice daily, and 70 to 100 mg once daily. A 3+3 dose-escalation design was used to determine the MTD. Patients were evaluated for adverse events and response. Assessments included pharmacokinetic, pharmacodynamic impact of SAR245409 on PI3K pathway signaling in hair sheath cells, skin and tumor, and characterization of tumor molecular alterations. The MTDs were 50 mg twice daily and 90 mg once daily. The most frequent treatment-related adverse events were nausea (36.1%), diarrhea (21.7%), vomiting (19.3%), and decreased appetite (16.9%). The most frequent treatment-related grade 3/4 adverse events were increases in alanine aminotransferase (6.0%) and aspartate aminotransferase (4.8%). SAR245409 had a relatively short plasma half-life (2.96-7.52 hours). At MTDs, once- and twice-daily regimens yielded similar mean steady-state plasma exposure. A reduction in PI3K and mTORC1/mTORC2 pathway signaling was observed in serial hair sheath cells, skin, and tumor samples. Best response was stable disease in 48% of evaluable patients; seven patients had minor tumor regression. Twelve patients with stable disease were treated for ≥16 weeks. No trend was observed correlating tumor molecular alteration with antitumor activity. SAR245409 had a manageable safety profile, demonstrated reduced PI3K and mTORC1/mTORC2 pathway signaling and was associated with clinically relevant stable disease.