Jill Fredrickson

First-in-Human Phase I Study of Pictilisib (GDC-0941), a Potent Pan–Class I Phosphatidylinositol-3-Kinase (PI3K) Inhibitor, in Patients with Advanced Solid Tumors

Purpose: This first-in-human dose-escalation trial evaluated the safety, tolerability, maximal-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, pharmacodynamics, and preliminary clinical activity of pictilisib (GDC-0941), an oral, potent, and selective inhibitor of the class I phosphatidylinositol-3-kinases (PI3K). Patients and Methods: Sixty patients with solid tumors received pictilisib at 14 dose levels from 15 to 450 mg once-daily, initially on days 1 to 21 every 28 days and later, using continuous dosing for selected dose levels. Pharmacodynamic studies incorporated 18F-FDG-PET, and assessment of phosphorylated AKT and S6 ribosomal protein in platelet-rich plasma (PRP) and tumor tissue. Results: Pictilisib was well tolerated. The most common toxicities were grade 1–2 nausea, rash, and fatigue, whereas the DLT was grade 3 maculopapular rash (450 mg, 2 of 3 patients; 330 mg, 1 of 7 patients). The pharmacokinetic profile was dose-proportional and supported once-daily dosing. Levels of phosphorylated serine-473 AKT were suppressed >90% in PRP at 3 hours after dose at the MTD and in tumor at pictilisib doses associated with AUC >20 h·μmol/L. Significant increase in plasma insulin and glucose levels, and >25% decrease in 18F-FDG uptake by PET in 7 of 32 evaluable patients confirmed target modulation. A patient with V600E BRAF–mutant melanoma and another with platinum-refractory epithelial ovarian cancer exhibiting PTEN loss and PIK3CA amplification demonstrated partial response by RECIST and GCIG-CA125 criteria, respectively. Conclusion: Pictilisib was safely administered with a dose-proportional pharmacokinetic profile, on-target pharmacodynamic activity at dose levels ≥100 mg and signs of antitumor activity. The recommended phase II dose was continuous dosing at 330 mg once-daily. Clin Cancer Res; 21(1); 77–86. ©2014 AACR.

Phase I Study of Apitolisib (GDC-0980), Dual Phosphatidylinositol-3-Kinase and Mammalian Target of Rapamycin Kinase Inhibitor, in Patients with Advanced Solid Tumors

Purpose: This first-in-human phase I trial assessed the safety, tolerability, and preliminary antitumor activity of apitolisib (GDC-0980), a dual inhibitor of class I PI3K, and mTOR kinases. Experimental Design: Once-daily oral apitolisib was administered to patients with solid tumors for days 1 to 21 or 1 to 28 of 28-day cycles. Pharmacokinetic and pharmacodynamic parameters were assessed. Results: Overall, 120 patients were treated at doses between 2 and 70 mg. The commonest ≥G3 toxicities related to apitolisib at the recommended phase 2 dose (RP2D) at 40 mg once daily included hyperglycemia (18%), rash (14%), liver dysfunction (12%), diarrhea (10%), pneumonitis (8%), mucosal inflammation (6%), and fatigue (4%). Dose-limiting toxicities (1 patient each) were G4 fasting hyperglycemia at 40 mg (21/28 schedule) and G3 maculopapular rash and G3 fasting hyperglycemia at 70 mg (21/28 schedule). The pharmacokinetic profile was dose-proportional. Phosphorylated serine-473 AKT levels were suppressed by ≥90% in platelet-rich plasma within 4 hours at the MTD (50 mg). Pharmacodynamic decreases in fluorodeoxyglucose positron emission tomography uptake of >25% occurred in 66% (21/32) of patients dosed at 40 mg once daily. Evidence of single-agent activity included 10 RECIST partial responses (PR; confirmed for peritoneal mesothelioma, PIK3CA mutant head-and-neck cancer, and three pleural mesotheliomas). Conclusions: Apitolisib exhibited dose-proportional pharmacokinetics with target modulation at doses ≥16 mg. The RP2D was 40 mg once-daily 28/28 schedule; severe on-target toxicities were apparent at ≥40 mg, particularly pneumonitis. Apitolisib was reasonably tolerated at 30 mg, the selected dose for pleural mesothelioma patients given limited respiratory reserve. Modest but durable antitumor activity was demonstrated. Clin Cancer Res; 22(12); 2874–84. ©2016 AACR.

Treatment with a human recombinant monoclonal IgG antibody against oxidized LDL in atherosclerosis-prone pigs reduces cathepsin S in coronary lesions.

BACKGROUND Immunization with oxidized LDL (oxLDL) reduces atherosclerosis in rodents. We tested the hypothesis that treatment with a human recombinant monoclonal antibody against oxLDL will reduce the burden or composition of atherosclerotic lesions in hypercholesterolemic minipigs. METHODS AND RESULTS Thirty-eight hypercholesterolemic minipigs with defective LDL receptors were injected with an oxLDL antibody or placebo weekly for 12weeks. An 18F-fluorodeoxyglucose positron emission tomography (FDG PET) scan (n=9) was performed before inclusion and after 3months of treatment. Blood samples were obtained prior to each injection. Following the last injection all animals were sacrificed, and the heart, aorta, and iliac arteries were removed. The left anterior descending coronary artery was sectioned at 5mm intervals for quantitative and qualitative assessments of atherosclerosis, including immunohistochemical phenotyping of macrophages using a pan-macrophage marker (CD68) and markers for putative pro-atherogenic (cathepsin S) and atheroprotective (CD163) macrophages. Aorta, right coronary artery, and left iliac artery were stained en face with Sudan IV and the amount of atherosclerosis quantified. There was no effect of treatment on plasma lipid profile, vascular FDG-PET signal or the amount of atherosclerosis in any of the examined arteries. However, immunostaining of coronary lesions revealed reduced cathepsin S positivity in the treated group compared with placebo (4.8% versus 8.2% of intima area, p=0.03) with no difference in CD68 or CD163 positivity. CONCLUSIONS In hypercholesterolemic minipigs, treatment with a human recombinant monoclonal antibody against oxLDL reduced cathepsin S in coronary lesions without any effect on the burden of atherosclerosis or aortic FDG-PET signal.

18F-fluoroestradiol PET/CT Measurement of Estrogen Receptor Suppression During a Phase I Trial of the Novel Estrogen Receptor-targeted Therapeutic GDC-0810.

Purpose: Evaluate 18F-fluoroestradiol (FES) PET/CT as a biomarker of estrogen receptor (ER) occupancy and/or downregulation during phase I dose escalation of the novel ER targeting therapeutic GDC-0810 and help select drug dosage for subsequent clinical trials. Experimental Design: In a phase I clinical trial of GDC-0810, patients with ER-positive metastatic breast cancer underwent FES PET/CT before beginning therapy and at cycle 2, day 3 of GDC-0810 therapy. Up to five target lesions were selected per patient, and FES standardized uptake value (SUV) corrected for background was recorded for each lesion pretherapy and on-therapy. Complete ER downregulation was defined as ≥90% decrease in FES SUV. The effect of prior tamoxifen and fulvestrant therapy on FES SUV was assessed. Results: Of 30 patients who underwent paired FES-PET scans, 24 (80%) achieved ≥90% decrease in FES avidity, including 1 of 3 patients receiving 200 mg/day, 2 of 4 patients receiving 400 mg/day, 14 of 16 patients receiving 600 mg/day, and 7 of 7 patients receiving 800 mg/day. Withdrawal of tamoxifen 2 months prior to FES PET/CT and withdrawal of fulvestrant 6 months prior to FES PET/CT both appeared sufficient to prevent effects on FES SUV. A dosage of 600 mg GDC-0810 per day was selected for phase II in part due to decreases in FES SUV achieved in phase I. Conclusions: FES PET/CT was a useful biomarker of ER occupancy and/or downregulation in a phase I dose escalation trial of GDC-0810 and helped select the dosage of the ER antagonist/degrader for phase II trials. Clin Cancer Res; 23(12); 3053–60. ©2016 AACR.

Clinical translation of ferumoxytol-based vessel size imaging (VSI): Feasibility in a phase I oncology clinical trial population.

To assess the feasibility of acquiring vessel size imaging (VSI) metrics using ferumoxytol injections and stock pulse sequences in a multicenter Phase I trial of a novel therapy in patients with advanced metastatic disease.

Updated results and correlative FDG-PET analysis of a phase IB study of vemurafenib and cobimetinib (MEK inhibitor [GDC-0973]), in advanced BRAFV600- mutated melanoma (BRIM7).

reported fewer AEs compared to BRAFi-naive pts. Most common AEs in BRAFi-naive pts (n=63) were non-acneiform rash (89%), diarrhea (81%), photosensitivity/sunburn (70%), fatigue (67%) and liver test abnormality (59%). Most frequent grade ≥3 AEs in BRAFi-naive pts were liver test abnormality (19%), non-acneiform rash (13%), arthral

FIR: Efficacy, Safety, and Biomarker Analysis of a Phase II Open-Label Study of Atezolizumab in PD-L1–Selected Patients With NSCLC

Introduction: The FIR phase II study (NCT01846416) evaluated the efficacy and safety of anti–programmed death‐ligand 1 (PD‐L1) atezolizumab in advanced NSCLC selected by tumor cell (TC) or tumor‐infiltrating immune cell (IC) PD‐L1 expression. Methods: Patients with PD‐L1 TC2/3 (PD‐L1 staining on ≥5% of TC) or IC2/3 tumors (PD‐L1 staining on ≥5% of IC; determined by SP142 PD‐L1 immunohistochemistry assay) with paired fresh and archival histology samples were recruited into cohort 1 (chemotherapy‐naive/>6 months between adjuvant chemotherapy and recurrence), cohort 2 (≥ second‐line without brain metastases), or cohort 3 (≥ second‐line with treated brain metastases). Patients received 1200 mg atezolizumab on day 1 (21‐day cycles). Primary endpoint was investigator‐assessed modified Response Evaluation Criteria in Solid Tumors, objective response rate (Response Evaluation Criteria in Solid Tumors v1.1). Secondary endpoints were overall survival, progression‐free survival, duration of response, and safety. Results: Patients (N = 138) were enrolled (137 evaluable for response: cohort 1, n = 31; cohort 2, n = 93; and cohort 3, n = 13). Investigator‐assessed objective response rate was 32%, 21%, and 23% for cohorts 1, 2, and 3, respectively. Treatment‐related adverse events were reported in 81%, 67%, and 69% of patients, respectively, including grade 3–4 treatment‐related adverse events in 16%, 19%, and 15%, respectively. Moreover, 88.6% (86 of 97) paired baseline tumor samples had <5% change in TC/IC PD‐L1 expression over time. Conclusions: Atezolizumab monotherapy showed clinical activity in patients with NSCLC, including those with brain metastases; safety was consistent with previous trials. Atezolizumab has completed phase III monotherapy studies in second‐line. Front‐line trials are ongoing, confirming these favorable results.

Abstract B03: Pharmacodynamic biomarker evaluation in phase I clinical trials of selective PI3K and PI3K/mTOR inhibitors

Background: The PI3K/Akt pathway is frequently altered in cancer by multiple mechanisms including PI3K activating mutations, PTEN loss, RTK activation, and other oncogenic mutations. GDC-0941 and GDC-0980 are selective PI3K and dual PI3K/mTOR inhibitors, respectively, which are currently in clinical development. Pharmacodynamic changes in biomarkers in response to dose and exposures were analyzed from sequential biopsies from phase I studies of GDC-0941 and GDC-0980. The purpose was to evaluate pathway inhibition at tolerable doses, as well as look for associations between modulation of phosphorylation and gene expression of downstream PI3K factors and interactions with cancer immune cell infiltration. Methods: Pre- and post-treatment biopsies were collected from a subset of patients who were treated with escalating doses of GDC-0941 (NCT00876122, NCT00876109) or GDC-0980 (NCT00854126). In addition to previously described phospho-S6, phospho-AKT, and phospho-PRAS40 analysis by immunohistochemistry (IHC), CyclinD1, phospho-ERK, Ki-67, and markers of T-cell infiltration (CD8, PD-L1) were also assessed by IHC. Gene expression analysis was also performed with the nCounter® Analysis System (NanoString Technologies) to determine if pathway modulation can be assessed more quantitatively across a broader set of markers, and to determine whether feedback upregulation of pathway components was observed in treated patient samples. Genes analyzed included PI3K pathway, apoptosis/cell cycle, and tumor immunity related genes. Results: Pharmacodynamic biomarker assays were conducted on 23 paired samples from the GDC-0941 study and 22 paired samples from the GDC-0980 study. Post-dose samples were obtained within hours of anticipated Cmax of both drugs. Reduction of phospho-S6, phospho-AKT, and phospho-PRAS40 were observed in a dose and exposure dependent manner. Upregulation of immune-related proteins was not observed after two weeks dosing with GDC-0941 or GDC-0980, which could be impacted by inhibition of T-cell signaling through PI3K. We report here the pharmacodynamic gene expression analysis, as measured by the NanoString nCounter® system, in patients from whom tissue was available, and analysis of the extent to which these the pharmacodynamic biomarkers are associated with each other. Based on PK modeling and PD, the doses achieved in Phase I studies enable future studies to be conducted at doses associated with tumor xenograft shrinkage (J Clin Oncol 29: 2011 [suppl; abstr 3052, 3021], Mol Cancer Ther 2009;8[12 Suppl]:B137). Conclusions: Pharmacodynamic assays confirmed effective broad pathway knockdown of multiple signaling components at safe and tolerated clinical doses of GDC-0941 and GDC-0980. What remains unclear is duration and magnitude of pathway inhibition required will translate to clinical efficacy and translatability across tumor types that may have different PI3K pathway dependencies and alterations. These data supports further clinical testing to evaluate efficacy in these different patient subsets. Citation Format: Yoshito Nakanishi, Jill M. Spoerke, Mika Derynck, Jennifer O. Lauchle, Hartmut Koeppen, Jill Fredrickson, Joseph Ware, Garret Hampton, Yibing Yan, Mark R. Lackner. Pharmacodynamic biomarker evaluation in phase I clinical trials of selective PI3K and PI3K/mTOR inhibitors. [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 B03.

Abstract 4567: Biomarker evaluation in phase I clinical trials of selective PI3K and PI3K/mTOR inhibitors.

Background: The PI3K/Akt pathway is frequently activated in cancer by multiple mechanisms including PI3K activating mutations, PTEN loss, RTK activation, and other means. GDC-0941 and GDC-0980 are selective PI3K and dual PI3K/mTOR inhibitors, respectively, which are currently in phase II clinical development. Assays for candidate predictive and pharmacodynamic biomarkers were conducted on patient samples collected from phase I studies of GDC-0941 and GDC-0980. The purpose was to confirm pathway inhibition at tolerable doses, as well as look for association between anti-tumor activity and candidate predictive biomarkers. Methods: Archival tumor tissue samples were analyzed using a 6 gene qPCR mutation assay (PIK3CA, EGFR, KRAS, BRAF, NRAS, AKT1), an immunohistochemistry assay for PTEN, and a fluorescence in situ hybridization (FISH) assay for PIK3CA. Select samples were analyzed for an expanded qPCR mutation panel and subjected to targeted next-generation sequencing (Illumina). For pharmacodynamic biomarker assays, pre- and post-treatment biopsies were collected from a subset of patients. In addition to previously described pS6 analysis, samples were analyzed for phospho-AKT, phospho-PRAS40, and CyclinD1 by immunohistochemistry. Results: Predictive biomarker assays were conducted on over 200 samples from the phase I studies. Overall we found a prevalence of 7% PIK3CA mutations and 12% loss of PTEN in these samples. PIK3CA amplification was observed in several samples from ovarian cancer patients. Based on several means of evaluating tumor response (FDG-PET, RECIST, time on study), activity was seen at or below clinically relevant doses in several different tumor types, including breast, ovarian, and mesothelioma. We report here the predictive biomarker status in all patients from whom tissue was available, and analysis of the extent to which these alterations are associated clinical outcome, to the extent such associations can be determined from a phase I dose escalation study designed to look a safety and tolerability. Conclusions: Pharmacodynamic assays confirmed effective pathway knockdown at safe and tolerated clinical doses of GDC-0941 and GDC-0980. Anti-tumor activity was observed in patients with PIK3CA mutations, as well as some patients whose tumors did not harbor pathway alterations. These data support patient stratification in phase II clinical studies to determine whether predictive biomarkers will be useful in identifying responsive patients. Citation Format: Jill Spoerke, Rupal Desai, Rajesh Patel, Jill Fredrickson, Yulei Wang, Gallia Levy, Steve Gendreau, Jennifer Lauchle, Mika Derynck, Rajiv Raja, Hartmut Koeppen, Garret Hampton, Yibing Yan, Mark R. Lackner. Biomarker evaluation in phase I clinical trials of selective PI3K and PI3K/mTOR inhibitors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4567. doi:10.1158/1538-7445.AM2013-4567

Abstract 1280: Preclinical and Clinical Evidence for MEK Pathway Inhibition by GDC-0973 using FDG-PET

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Inhibitors of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) can cause potent growth arrest leading to tumor stasis or even regression, especially in BRAF mutant tumors. Seeking a pharmacodynamic marker of drug action, the effect of MEK inhibition on FDG PET signals was studied in rodent xenograft models using responsive and non-responsive cell lines. Colo205, HCT116, and A375 tumors showed substantial (30-50 %) signal (FDG flux, Ki, measured by a Patlak analysis) decreases within 72 h of beginning MEK inhibition and a rebound to baseline signal within 72 h of discontinuing treatment. BT474 tumors showed no effect. In MEK responsive tumors immunohistochemistry showed that glucose transporter GLUT1 redistributes away from the plasma membrane during treatment, which may explain the FDG PET findings. Fluorothymidine (FLT) uptake is also modulated by MEK inhibition, but the relative availability of clinical FDG PET centers and the robust preclinical results suggested the use of FDG PET, and not FLT PET, in clinic. FDG PET was implemented at all 4 Phase 1 study sites according to a standardized scanning charter. Scans were acquired at screening, at days 10-14 of cycle 1 (steady state drug concentration) and at days 26-28 of cycle 1 (trough drug concentration). Patients with RAS or RAF mutant tumors were treated at GDC-0973 MTD on the 21/7 and 14/14 dosing schedules. CT scans were acquired just prior to cycle 3 (∼ day 56) for response assessment. PET images were collected and read centrally. Up to 5 hypermetabolic lesions were assessed for mean and maximum standardized uptake value (SUV). A decrease of more than 20% in mean (across lesions) percentage change-from-baseline in SUVmax was considered a partial metabolic response (PMR). Compliance with the scanning guidelines across sites was generally good. Out of a total of 23 patients from both cohorts with PET scans read to date, 7 patients appeared to show a temporal profile of decreased FDG uptake at steady state with a rebound towards baseline at trough, mirroring the preclinical findings. Of 17 patients in the 21/7 MTD cohort whose PET scans were measured, 9 patients (∼53%) demonstrated a PMR at least one timepoint during cycle 1. Two of these patients demonstrated a PR per CT at 2 months (first tumor assessment) and also showed a robust PET response at both timepoints (Patient 1: -55% and -61% respectively; Patient 2: -63% and -53%). In addition, 2 other patients with a PMR at one or both timepoints had stable disease for at least 5 months. Of 6 patients in the 14/14 MTD cohort with PET scans read, 5 patients (83%) demonstrated a PMR at least one timepoint. Taken together, the preclinical PET evidence for a mechanistic effect of MEK inhibition on tumor glucose metabolism combined with the significant proportion of patients demonstrating PMR in this phase 1 study are consistent with hypothesis that GDC-0973 is achieving pathway modulation when given as single agent. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1280. doi:10.1158/1538-7445.AM2011-1280