INCB099280, an oral, programmed death ligand 1 (PD-L1) inhibitor, has shown preliminary efficacy and acceptable safety in an ongoing Phase 1, open-label, multicenter study in patients (pts) with advanced solid tumors (Prenen, et al. SITC 2022). Here we present updated results. Eligible pts were ≥18 years with ECOG PS ≤1, and disease progression after available treatment (tx) or were ineligible for/without access to standard tx. In part 1, INCB099280 dose was escalated from 100 mg QD with a Bayesian optimal interval design. In part 2, 3 expansion cohorts with select tumor types were studied: 1) IO-naive pts, 2) IO-naive pts with MSI-H/dMMR tumors, 3) pts who progressed on anti-PD-1 mAb. Primary endpoints are INCB099280 safety, tolerability, and pharmacologically active/MTD determination. INCB099280 pharmacokinetics, objective response rate per RECIST v1.1, and biomarkers of pharmacologic activity were also analyzed. As of June 22, 2023, 172 pts had received INCB099280 at doses from 100 mg QD to 800 mg BID (median age, 63 years [range, 21–86]; ≥2 prior lines of tx, 64.0%; prior IO, 14.5%; most common tumor types: anal [14.5%], cervical [8.7%], and colorectal [7.6%]). Dose was escalated to 800 mg BID; MTD was not reached. 5 dose levels were expanded in part 2 up to 800 mg BID. Overall, 137 pts (79.7%) discontinued treatment, 119 (69.2%) due to disease progression; 95.3% of pts had ≥1 tx-emergent adverse event (TEAE) (Table). Several responses have been observed, and updated results will be presented. In pts with complete response (n=2), baseline tumor mutational burden scores were high (34–49 mut/Mb) and ctDNA levels at cycle 4 day 1/end of tx had decreased by 92.3% from baseline.Table 155P:SafetyTEAEs, n (%)Total Pts (N=172)Any gradeGrade ≥3All cause TEAEs164 (95.3)61 (35.5)Occurring in >20% of ptsAsthenia52 (30.2)4 (2.3)Decreased appetite47 (27.3)4 (2.3)Nausea43 (25.0)2 (1.2)Vomiting39 (22.7)2 (1.2)Fatigue35 (20.3)3 (1.7)Immune-related TEAEs37 (21.5)10 (5.8)Serious TEAEs45 (26.2)Occurring in >1 ptPyrexia4 (2.3)Pneumonia3 (1.7)Sepsis3 (1.7)Anemia2 (1.2)Dyspnea2 (1.2)Hypercalcemia2 (1.2)Large intestinal obstruction2 (1.2)Pneumothorax2 (1.2)Urinary tract infection2 (1.2)Grade ≥3 tx-related TEAEs21 (12.2)Occurring in >1 ptIncreased ALT4 (2.3)Increased AST3 (1.7)Increased lipase3 (1.7)Anemia2 (1.2)Lymphopenia2 (1.2) Open table in a new tab INCB099280 was generally well tolerated at all doses tested. Updated results indicate promising antitumor activity and support future development of INCB099280 as monotherapy and in combination regimens for advanced solid tumors.
<div>AbstractPurpose:<p>Patients with advanced gastric/gastroesophageal junction cancer (GC/GEJC) have limited treatment options after first-line therapy. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGFβRII receptor (a TGFβ “trap”) fused to a human IgG1 antibody against programmed death ligand 1 (PD-L1), potentially offering a new treatment approach for these patients. We report results for bintrafusp alfa in GC/GEJC.</p>Patients and Methods:<p>Asian patients with recurrent GC/GEJC for whom standard therapy does not exist or for whom standard therapy has failed enrolled in this expansion cohort of an ongoing phase I trial and received bintrafusp alfa 1,200 mg once every 2 weeks until disease progression, unacceptable toxicity, or withdrawal. The primary objective was to assess safety/tolerability.</p>Results:<p>By July 23, 2018, 31 heavily pretreated patients received bintrafusp alfa for a median of 10.1 weeks; 3 patients remained on treatment. Six patients (19%) experienced grade 3 treatment-related adverse events (AE); no grade 4 events occurred. One on-treatment death occurred (sudden death); rupture of a preexisting thoracic aortic aneurysm was the suspected cause. Ten patients (32%) had immune-related AEs. The confirmed objective response rate per independent review committee was 16%; disease control rate was 26%. Median duration of response was 8.7 months (range, 2.4–12.4+). Responses occurred irrespective of PD-L1 expression or microsatellite instability status and appeared to correlate with high tumor <i>TGFB1</i> levels.</p>Conclusions:<p>In this first evaluation in Asian patients with heavily pretreated advanced GC/GEJC, bintrafusp alfa demonstrated a manageable safety profile and clinical activity.</p></div>
2543 Background: Glypican 3 (GPC3) is a member of the glypican family of heparan sulfate proteoglycans that are attached to the cell surface by a glycosylphosphatidylinositol anchor. High GPC3 expression rates are reported in numerous cancer types with a high unmet medical need, including hepatocellular carcinoma (HCC). TAK-102 is a GPC3-targeted autologous chimeric antigen receptor T cell (CAR-T) immunotherapy armored with IL-7 and CCL19. The addition of IL-7 and CCL19 to the construct was designed to support the expansion of memory subsets and persistence of CAR-T cells. We hypothesized TAK-102 would help overcome the challenges associated with an immunosuppressive tumor microenvironment that limit the activity of nonarmored CAR-T therapies in solid tumors. Methods: The first-in-human, Phase 1 dose escalation study evaluated TAK-102 in patients (pts) with GPC3-expressing solid tumors who were refractory or intolerant to standard treatments. TAK-102 was administered via a single infusion to 3 dose cohorts after lymphodepleting chemotherapy (LDC; consisting of fludarabine and cyclophosphamide): dose level (DL) 1 (starting cohort), 1x10 7 CAR+ cells/body; DL2, 1x10 8 CAR+ cells/body; DL3, 5x10 8 CAR+ cells/body. Objectives included evaluation of safety, dose-limiting toxicity (DLT), recommended phase 2 dose, cellular kinetic (CK) parameters, tumor markers, cytokine/chemokine and antitumor activity based on RECIST 1.1. Results: Eleven pts were enrolled and infused TAK-102 (DL1: 3 pts, DL2: 3 pts, DL3: 5 pts): 1 gastric neuroendocrine carcinoma, 2 liposarcoma, 8 HCC. Five pts achieved stable disease (SD), HCC (GPC3 H-Score: 36) . In patients achieving SD, the greatest reduction in tumor size was 26.4%. No DLTs or neurotoxicity were observed. Six pts experienced cytokine release syndrome (Grade1: 5 pts, Grade2: 1 pt); all cases were manageable. AFP was measured as a tumor marker for HCC. Among 8 pts with HCC, 4 had SD after treatment with TAK-102 and 3 showed a decrease or stabilization of AFP levels corresponding to their clinical status. CK profiles for pts were assessed by flow cytometry and qPCR-based assays. Overall, there was improvement in TAK-102 exposure (Cmax, AUC) when escalating from DL1 to DL2. There was a slight decrease in Tmax from DL2 to DL3. Homeostatic cytokine (IL-7) spiked post-LDC and showed no further increase after TAK-102 infusion across all the DLs. There was dose-dependency observed in peak CCL19, IFN-γ and IL-6 levels. Conclusions: TAK-102, an armored CAR-T, is well tolerated and has a manageable safety profile with some early signs of anti-tumor activity. For CK, TAK-102 exposure (Cmax, AUC) showed improvement from DL1 to DL2, and slight decrease in Tmax from DL2 to DL3. Dose-dependency was observed in peak CCL19, IFN-γ and IL-6 levels, which may point towards increased signal of activity from DL1 to DL3. Clinical trial information: NCT04405778 .
Newly-developed spectrographs with increased resolving powers, particularly those covering the near-IR range, allow the characterization of more and more absorption lines in stellar spectra. This includes the identification and confirmation of absorption lines and the calibration of oscillator strengths. In this study, we provide empirical values of loggf based on abundances of classical Cepheids obtained with optical spectra in Luck (2018), in order to establish the consistency between optical and infrared abundance results. Using time-series spectra of classical Cepheids obtained with WINERED spectrograph (0.97-1.35 $\mu$ m, R ~28000, we demonstrate that we can determine the stellar parameters of the observed Cepheids, including effective temperature (Teff), surface gravity (logg), microturbulence, and metallicity. With the newly calibrated relations of line-depth ratios (LDRs), we can achieve accuracy and precision comparable to optical studies (Luck 2018), with uncertainties of 90K and 0.108 dex for Teff, and log g, respectively. Finally, we created a new atlas of absorption lines, featuring precise abundance measurements of various elements found in the atmosphere of Cepheids (including neutron-capture elements), with loggf values that have been astrophysically calibrated.
The sensitivity of fibroblasts derived from patients with chronic actinic dermatitis (CAD) ultraviolet B (UVB), UVA and superoxide radical was examined. Fibroblasts from the skin of 3 patients with CAD showed abnormal hypersensitivity after exposure to mid-UV (UVB) and near-UV (UVA) radiation in both the dividing and quiescent phases. In their dividing phases, the 3 cell strains (CAD1TO, CAD2TO and CAD3TO) exhibited 78, 55 and 82 J/m2 for the mean lethal dose (Do) values in UVB survival curves. In the quiescent phases their Do values were 262, 226 and 165 J/m2, respectively. Regarding UVA sensitivity, Do value in the dividing phases were 4.9, 3.9 and 3.8 x 10(4) J/m2, and in the quiescent phases, 2.0, 1.9 and 1.7 x 10(5) J/m2. Do values were lower than in the cell strains derived from healthy individuals (Do = 120 +/- 18 and 390 +/- 72 J/m2) for UVB sensitivity in the dividing and quiescent phases and (5.9 +/- 0.6) x 10(4) and (3.2 +/- 1.0) x 10(5) J/m2 for UVA sensitivity in the dividing and quiescent phases. DNA repair synthesis was similar between the cell lines. Furthermore, the 3 CAD cell lines showed a higher sensitivity to superoxide radical generated by hypoxanthine/xanthine oxidase treatment. These results suggest that patients with CAD may suffer from a defect in dealing with damage induced by oxygen radicals.
Abstract Background: Isocitrate dehydrogenase 1/2 (IDH1/2) is mutated in a subset of cholangiocarcinoma (CCA), gliomas, and other solid tumors. LY3410738 is a potent, selective, covalent, dual inhibitor of IDH1/2 mutations (IDH1/2m). LY3410738 binds covalently at a novel binding site, enabling continued potency in preclinical models in the setting of second site IDH resistance mutations. We present initial results from the first-in-human phase 1 study of oral LY3410738 in patients (pts) with IDH1/2m CCA, and IDH1m glioma or other solid tumors. Methods: Dose escalation (3+3 design) evaluated LY3410738 monotherapy in advanced IDHm CCA and other solid tumors (NCT04521686). Key objectives included determining the RP2D, safety, PK, PD (inhibition of plasma D-2-HG), and preliminary antitumor activity. Results: As of 28 July 2022, 80 pts including 42 with CCA (33 IDH1m, 9 IDH2m), 27 with glioma (IDH1m), and 11 other tumor types (IDH1m) received LY3410738 dosed at 25-600 mg QD or 300 mg BID. Pts were median 52 years of age (range, 23-80) with a median of 2 prior therapies (range, 1-7). 19% of CCA pts had received prior IDH1 inhibitor. Median time on treatment was 3.7 months (range, 0.1-19). No DLTs or treatment related deaths were observed; the MTD was not reached. Treatment emergent adverse events (TEAEs) ≥15% included nausea (35%), vomiting (21%), and decreased appetite (19%) and were mostly grade 1-2. Most frequent grade ≥3 TEAEs >2% were anemia (4%), cholangitis (3%), headache (3%), decreased lymphocyte count (3%), and hyponatremia (3%). LY3410738 exposure was dose proportional. In pts with IDH1m cancers, LY3410738 achieved sustained D-2-HG inhibition at all dose levels, including in pts who received prior IDH1 inhibitor. In pts with IDH2m cancers, a higher dose (≥150 mg daily dose) was required for D-2-HG inhibition. Among the 42 pts with R/R CCA, the best response included 1 PR and 22 SD. Of the 22 glioma pts with contrast enhancing tumors, best response included 3 PR and 9 SD. Conclusions: LY3410738 demonstrated a favorable safety profile with potent and sustained D-2-HG inhibition in pts with IDH1/2m advanced solid tumors. Consistent with the expectations for IDH inhibitor monotherapy in this setting, CCA and glioma pts exhibited prolonged stable disease. RP2D evaluation is ongoing. Updated data on LY3410738 monotherapy will be presented at the meeting. Citation Format: Jordi Rodon, Lipika Goyal, Teresa Macarulla Mercade, Masafumi Ikeda, Shunsuke Kondo, Do-Youn Oh, Li-Yuan Bai, Makoto Ueno, Antoine Italiano, Kyriakos Papadopoulos, David Spigel, Sani H. Kizilbash, Rasha Cosman, Joon Oh Park, Li-Tzong Chen, Tomoya Yokota, Anita A. Turk, Chih-Yi Liao, Rachna Shroff, Anthony El-Khoueiry, Taroh Satoh, Antoine Hollebecque, Mitesh J. Borad, Nilofer Azad, Kurt A. Jaeckle, Herbert H. Loong, Jorge Adeva, Wei Peng Yong, Junjie Zhao, Hui Liu, Anna M. Szpurka, Ivelina Gueorguieva, Kamnesh R. Pradhan, Xiaojian Xu, James J. Harding. A first-in-human phase 1 study of LY3410738, a covalent inhibitor of mutant IDH, in advanced IDH-mutant cholangiocarcinoma and other solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT098.
