scholarly journals 951 A phase 1 first in human study of adenovirally transduced anti-HER2 CAR macrophages in subjects with HER2 overexpressing solid tumors: preliminary safety, pharmacokinetics, and TME reprogramming data

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A1000-A1000
Author(s):  
Kim Reiss ◽  
Yuan Yuan ◽  
Debora Barton ◽  
Amy Ronczka ◽  
Daniel Cushing ◽  
...  
Keyword(s):  
T Cell ◽  
Solid Tumors ◽  
Phase 1 ◽  
Human Study ◽  
Comprehensive Cancer Center ◽  
Cancer Center ◽  
List Type ◽  
Extrahepatic Cholangiocarcinoma ◽  
Cell Product ◽  
The University

BackgroundCT-0508 is an autologous monocyte-derived pro-inflammatory macrophage cell product engineered with Ad5f35 to express an anti-HER2 CAR. In pre-clinical studies CT-0508 was safe and effective. This abstract contains preliminary results from the first-in-human experience with CAR macrophages (CAR-M).MethodsThis First-In-Human Phase 1, multi-center, open-label study is evaluating the safety, tolerability, manufacturing feasibility, pharmacokinetics and mechanism of action of CT-0508 in 18 subjects with advanced solid tumors overexpressing HER2 who have progressed on prior therapies, including HER2 targeted therapies if indicated.Patients receive four doses of filgrastim for monocyte mobilization prior to apheresis. CT-0508 CAR-M is manufactured from autologous apheresis products and delivered as a cryopreserved cell product. Group 1 subjects enter an intra-patient fractionated dose escalation regimen, receiving CT-0508 on D1, D3 and D5, followed by Group 2 subjects who receive CT-0508 on D1. There is no preparative chemotherapy prior to CT-0508 infusion.Pre and post treatment biopsies and blood samples are collected to investigate correlates of safety, serum cytokines and chemokines, pharmacokinetics, TME modulation, and induction of an adaptive anti-tumor immune response.ResultsTo date, two subjects have been treated with CT-0508 (esophageal adenocarcinoma and extrahepatic cholangiocarcinoma). Patient product was successfully manufactured, CT-0508 treatment was well tolerated, with no dose limiting and no major organ toxicities observed.One subject experienced Grade 2 CRS on Day 3 which resolved on the same day.Grade 3 AEs included anemia (present at baseline for both subjects) and lymphopenia (present at baseline in one subject). One subject experienced one SAE of Grade 4 tumor bleeding which was unrelated to CT-0508, 88 days after the last infusion.CAR-M were transiently detected in the peripheral blood following each infusion, demonstrating rapid egress from the periphery into tissues within hours. Transient cytokine/chemokine elevations were observed (peak: 2 hours, back to baseline at 48 hours). Single cell RNAseq analysis of dissociated tumor tissue samples (pre-treatment, day 8 and week 4) demonstrated dynamic TME reprogramming, with recruitment of inflammatory innate immune cells and naïve T cells at day 8, and significant CD8+ T cell infiltration, activation, and proliferation at week 4.ConclusionsCT-0508 has been administered to two subjects thus far, exhibiting safety, good tolerability, T cell repertoire modulation, and reprogramming of the TME consistent with the induction of anti-tumor immunity. The study continues to recruit patients and updated data will be presented.Trial RegistrationNCT04660929ReferenceKlichinsky M, Ruella M, Shestova O, et al. Human chimeric antigen receptor macrophages for cancer immunotherapy. Nat Biotechnol 2020;38(8):947–953.Ethics ApprovalEthics approvals have been obtained from the clinical sites enrolling patients: the University of Pennsylvania (844106/IORG0000029), the University of North Carolina and City of Hope Comprehensive Cancer Center (20201732/IORG0000432).

388 Preliminary results from KEYNOTE-A36, a study of GB1275, a first-in-class oral CD11b modulator, alone and with pembrolizumab or chemotherapy in specified advanced solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A413-A413
Author(s):  
Johanna Bendell ◽  
Wells Messersmith ◽  
Drew Rasco ◽  
Andrea Wang-Gillam ◽  
Wungki Park ◽  
...  
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Tumor Tissue ◽  
Phase 1 ◽  
Cancer Center ◽  
List Type ◽  
Advanced Solid Tumors ◽  
Serial Blood ◽  
Biomarker Analysis

BackgroundGB1275 is a first-in-class CD11b modulator that reduced myeloid-derived suppressor cells (MDSCs) and tumor associated macrophages (TAMs), repolarized M2 immunosuppressive TAMs to an M1 phenotype, and increased tumor infiltration of activated CD8+ T cells in preclinical models. Preclinical anti-tumor activity was observed with single-agent therapy and in combination with chemotherapy or immuno-oncology therapies.1 We report results from the dose escalation portion of an ongoing, first-in-human study of GB1275 monotherapy and combined with pembrolizumab in patients with specific advanced solid tumors. (NCT04060342)MethodsThis study comprises phase 1 dose escalation followed by phase 2 expansion in specific tumor types. In phase 1, cohorts of 3 to 6 patients with histologically confirmed, locally advanced/metastatic pancreatic, esophageal, gastric, MSS colorectal, metastatic castrate-resistant prostate cancer, or triple negative breast cancer are sequentially assigned to one of the ascending dose levels of GB1275 orally twice daily (BID) in 1 of 3 regimens: A (GB1275 monotherapy); B (GB1275 + pembrolizumab) commenced after completion of two cohorts of A; and C (GB1275 + nab-paclitaxel + gemcitabine) will be initiated after A. Patients in Regimens A and B had previously exhausted standard of care treatment options. Dose escalation was based on safety, including dose-limiting toxicity (DLT). Serial blood samples were collected for pharmacokinetic (PK) and biomarker analyses; tumor tissue was also collected for biomarker analysis.ResultsAs of July 28, 2020, 36 patients were treated, 23 in Regimen A (GB1275 100 mg to 1200 mg BID) and 13 in Regimen B (GB1275 100 mg to 800 mg BID + pembrolizumab). No DLTs or adverse events requiring steroid treatment were reported. GB1275-related adverse events were reported in 19 (52.8%) patients; most were Grade 1 and most frequent events (≥10%) were dysesthesia (13.9%) and photosensitivity reaction (11.1%). Stable disease was reported in 4 (17%) patients in Regimen A and 6 (46%) in Regimen B with a median (range) exposure of 84 days (35–172). A dose-dependent increase in GB1275 exposure was observed. An increase in tumor infiltrating lymphocyte (TIL) counts was noted in both Regimens A and B. Other biomarker analyses in serial blood and tumor tissue are ongoing.ConclusionsDose escalation of GB1275, up to 1200 mg and 800 mg BID in Regimens A and B, respectively, demonstrated tolerability as monotherapy and combined with pembrolizumab. The maximum tolerated dose has not been reached. Preliminary observation of an increase in TILs after treatment is encouraging.Ethics ApprovalThis ongoing study is being conducted in accordance with the Declaration of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines. The study was approved by the Ethics Boards of the University of Colorado Hospital, Washington University School of Medicine - Siteman Cancer Center, Memorial Sloan Kettering Cancer Center, The Sarah Cannon Research Institute/Tennessee Oncology, South Texas Accelerated Research Therapeutics, and The Royal Marsden NHS Foundation Trust.ReferencePanni RZ, Herndon JM, Zuo C, et al. Agonism of CD11b reprograms innate immunity to sensitize pancreatic cancer to immunotherapies. Sci Transl Med 2019 Jul 3;11(499).

scholarly journals 501 Survival and immune response data from intratumoral INT230–6 alone (IT-01) and with pembrolizumab [KEYNOTE-A10] in subjects with locally advanced, unresectable and metastatic solid tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A533-A533
Author(s):  
Jacob Thomas ◽  
Anthony El-Khoueiry ◽  
Anthony Olszanski ◽  
Nilofer Azad ◽  
Giles Whalen ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Prognostic Factors ◽  
Solid Tumors ◽  
Cd8 T Cells ◽  
Phase 1 ◽  
Prognostic Score ◽  
Locally Advanced ◽  
Cancer Center ◽  
List Type

BackgroundBackground: Study IT-01 (KEYNOTE-A10) evaluates INT230-6, a novel formulation of cisplatin (CIS) and vinblastine (VIN) with an amphiphilic cell penetration enhancer designed for intratumoral (IT) administration, as monotherapy and in combination with pembrolizumab (PEM). In preclinical studies, INT230-6 increases drug dispersion throughout the tumor, allows drug diffusion into cancer cells and recruits dendritic, CD4 and CD8 T cells. The addition of PEM improves these responses in mouse models.MethodsIT-01 is an open-label phase 1/2 study, currently enrolling adult subjects with solid tumors in phase 2. The study assesses the safety and efficacy of INT230-6 IT Q2W up to 5 doses as monotherapy or with PEM 200mg Q3W. Biopsies from injected tumor are taken pretreatment and Day 28 for immunohistochemistry (IHC) analysis.ResultsFifty-seven INT230-6, two INT230-6 then PEM combination, and thirteen INT230-6 + PEM combination subjects were enrolled having a median of 4 prior therapies (0, 10). Median age was 62. 20+ cancer types were accrued; breast cancer and sarcoma were the most frequent. Over 500 image guided INT230-6 IT injections were given (253 to deep tumors) at doses of 0.3 to 172mL (86 mg CIS, 17.2 mg VIN) in a single session (contains higher amounts than typical IV chemo doses). PK shows that 95% of INT230-6 active agents remain in the tumor.1 The most common (>25%) related adverse events (AEs) for INT230-6 alone were localized pain (59%), nausea (37%), and fatigue (29%). Safety profile of the PEM combination was similar. There were no related grade 4 or 5 AEs in either arm. The median overall survival (mOS) estimated with removal of <2cm3 and >700cm3 tumor burdens was 433 days for monotherapy (n=51) and 513 days for PEM combination (n=12), which compares favorably to results seen in basket studies of patients having similar prognostic factors (ECOG, LDH, # of metastatic sites).2 IHC results indicate influx of CD4 and CD8 T-cells in injected lesions. No meaningful changes were observed in circulating inflammatory cytokines. Abscopal effects in the monotherapy arm were observed in 15 visceral/deep lesions in 11 patients, primarily who received an INT230-6 dose >50% of their total tumor burden (TTB).ConclusionsINT230-6 is well tolerated when administered IT as monotherapy and combined with PEM. Data suggests that INT230-6 prolongs survival compared to published basket studies in patients with similar prognostic factors. IHC and abscopal results indicate dosing INT230-6 may also activate a T-cell mediated immune response.AcknowledgementsN/ATrial RegistrationNCT# 03058289ReferencesOwelien. Historical PK data from IV administration. J Cancer Res 1977; 8.Abstract. Wagner M, et al. Validation of the Royal Marsden Hospital (RMH) prognostic score in 100 patients with advanced sarcoma enrolled in early phase clinical trials at a major cancer center. JCO 2015. https://ascopubs.org/doi/abs/10.1200/jco.2015.33.15_suppl.10558Ethics ApprovalThe protocol was approved by an institutional review board, independent ethics committee, or research ethics board at each institution. All subjects or their legally acceptable representative provided written informed consent before screening. The study was designed, undertaken, and reported in accordance with the Declaration of Helsinki, and is registered with clinicaltrial.gov with registration no NCT03058289.

scholarly journals 373 Phase 1/2 study of subcutaneously administered ALKS 4230, a novel engineered cytokine, as monotherapy and in combination with pembrolizumab, in patients with advanced solid tumors: ARTISTRY-2

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A398-A398
Author(s):  
John Powderly ◽  
Bradley Carthon ◽  
Marc Ernstoff ◽  
Anthony Olszanski ◽  
John Wrangle ◽  
...  
Keyword(s):  
T Cells ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Colonic Obstruction ◽  
Systemic Exposure ◽  
Comprehensive Cancer Center ◽  
Cancer Center ◽  
Advanced Solid Tumors ◽  
Link Type

BackgroundALKS 4230 is a novel engineered cytokine designed to selectively bind and activate the intermediate affinity IL-2 receptor. Intravenous (IV) dosing of ALKS 4230 has shown encouraging efficacy and acceptable tolerability, as monotherapy and in combination with pembrolizumab, in patients with advanced solid tumors (ARTISTRY-1, NCT02799095). Subcutaneous (SC) dosing may be preferable to IV in certain clinical situations.MethodsARTISTRY-2 (NCT03861793) is an ongoing phase 1/2 study of SC ALKS 4230 ± pembrolizumab. In phase 1, cohort-specific doses of SC ALKS 4230 are administered on either an every-7-day (q7d) or every-21-day (q21d) schedule during a 6-week lead-in period, followed by combination with IV pembrolizumab 200 mg q21d. Each patient assigned to a given cohort receives ALKS 4230 at a single dose level and on a schedule of either q7d or q21d. Safety, tolerability, dose-limiting toxicities (DLTs), and pharmacokinetics/pharmacodynamics from dose escalation, as of 7/24/2020 are reported in this abstract.Results38 patients have been treated with ALKS 4230 across 7 assigned cohorts, with SC doses ranging from 0.3 mg to 10 mg (median age, 61.5 [28–82] years; median number of prior therapies 4 [0–17]; 45% were previously treated with immunotherapy). 25 patients completed monotherapy and initiated combination therapy. Median duration of treatment was 64.5 (1–506) days. Systemic exposure to ALKS 4230 increased with increasing dose, resulting in a dose dependent increase in circulating natural killer and CD8+ T cells, without significant impact on regulatory T cells. Overall, adverse events (AEs), regardless of causality, occurred in 33 (86.8%) patients. Treatment-related AEs (TRAEs; investigator assessed) occurred in 32 (84.2%) patients, and the most common TRAEs are presented in table 1. One patient experienced a serious TRAE, a grade 3 tumor flare manifesting as colonic obstruction. The maximum tolerated dose as well as recommended phase 2 dose for SC administration has not yet been determined.Abstract 373 Table 1Most common (≥20%) TRAEs overall and by dose schedule (by investigator assessment)ConclusionsALKS 4230 is a promising investigational agent for the treatment of advanced solid tumors. The SC safety profile is consistent with the known and anticipated pharmacologic effects of ALKS 4230. Consistent with IV dosing, SC administration of ALKS 4230 q7d or q21d maintained the desired immune responses as demonstrated by pharmacodynamic outcomes. Potentially lower rates of fever and chills observed, relative to IV dosing, are presumed to be consistent with lower peak concentrations achieved so far via the SC route. The study, including dose escalation, is ongoing.AcknowledgementsThe authors would like to thank all the patients who are participating in this study. The study is sponsored by Alkermes, Inc. Medical writing and editorial support was provided by Parexel and funded by Alkermes, Inc.Trial RegistrationClinicalTrials. gov NCT03861793Ethics ApprovalThis study was approved by Ethics and Institutional Review Boards (IRBs) at all study sites; IRB reference numbers 20182543 (Western IRB), 00006731 (Roswell Park Comprehensive Cancer Center), STUDY00000056 (Georgetown University, MedStar Health Research Institute).

scholarly journals 417 Design and rationale of a phase 1 study evaluating AMG 256, a novel, targeted, IL-21 receptor agonist and anti-PD-1 antibody, in patients with advanced solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A443-A443
Author(s):  
Gregory Durm ◽  
Sophia Frentzas ◽  
Erik Rasmussen ◽  
Saltanat Najmi ◽  
Nooshin Sadraei
Keyword(s):  
Solid Tumors ◽  
Tumor Immunity ◽  
Renal Cell ◽  
Phase 1 ◽  
List Type ◽  
Solid Organ ◽  
Advanced Solid Tumors ◽  
Phase 1 Study ◽  
Drug Study ◽  
Interleukin 21

BackgroundCheckpoint inhibitors are a promising therapy for patients with solid tumors; however, many patients require additional therapies to maximize clinical benefit or overcome resistance.1 The type-1 cytokine interleukin-21 (IL-21) is a promising candidate for combination and has shown clinical activity in melanoma and renal cell cancer.2 IL-21 has also shown improved efficacy when combined with anti-programmed death (PD)-1 antibodies in preclinical models.3 4 AMG 256 is a mutated IL-21 cytokine fused to an anti-PD-1 antibody to combine IL-21 pathway stimulation with checkpoint inhibition—a strategy that is designed to prime and extend the activity of cytotoxic and memory T cells and induce anti-tumor immunity. This first-in-human (FIH) study will assess safety, tolerability, and estimated dosing of AMG 256 monotherapy in patients with advanced solid tumors.MethodsThis is a FIH, multicenter, non-randomized, open-label, phase 1 study (NCT04362748) of AMG 256 in patients with advanced solid tumors. The planned sample size is approximately 100 patients in two parts: part 1 will evaluate safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and determine the maximum tolerated dose (MTD), part 2 will evaluate the MTD determined in part 1 to further characterize the safety profile and preliminary tumor response. AMG 256 will be delivered by intravenous (IV) infusion. Enrollment criteria include adults with life expectancy of > 3 months, ECOG performance status ≤ 2, histologically or cytologically confirmed metastatic or locally advanced solid tumors not amenable to curative treatment with surgery or radiation, and at least one measurable lesion ≥ 10 mm that has not undergone biopsy within 3 months of screening scan. Exclusion criteria include primary brain tumor, untreated or symptomatic brain metastases, currently receiving treatment in another investigational device or drug study, or less than 28 days since ending treatment on another investigational device or drug study, history of solid organ transplantation or major surgery within 28 days of study day 1, live vaccine therapy within 4 weeks prior to study day 1, and active infection requiring oral or IV therapy. The primary endpoints are incidence of dose-limiting toxicities and adverse events, MTD, and recommended phase 2 dose. Secondary objectives will evaluate PK parameters, preliminary antitumor activity (objective response, duration of response, progression-free survival, disease control rate, duration of stable disease, overall survival), and immunogenicity of AMG 256 via incidence of anti-AMG 256 antibodies.ResultsN/AConclusionsN/AAcknowledgements• The authors thank the investigators, patients, and study staff who are contributing to this study.• The study was sponsored and funded by Amgen Inc. • Medical writing support was provided by Christopher Nosala (Amgen Inc.).Trial RegistrationNCT04362748Ethics ApprovalThe study was approved by all institutional ethics boards.ReferencesKluger HM, Tawbi HA, Ascierto ML, et al. Defining tumor resistance to PD-1 pathway blockade: recommendations from the first meeting of the SITC Immunotherapy Resistance Taskforce. J Immunother Cancer 2020;8:e000398.Thompson JA, Curti BD, Redman BG, et al. Phase I study of recombinant interleukin-21 in patients with metastatic melanoma and renal cell carcinoma. J Clin Oncol 2008;26:2034–2039.Lewis KE, Selby MJ, Masters G, et al. Interleukin-21 combined with PD-1 or CTLA-4 blockade enhances antitumor immunity in mouse tumor models. Oncoimmunology. 2017;7:e1377873.Shen S, Sckisel G, Sahoo A, et al. Engineered IL-21 cytokine muteins fused to anti-PD-1 antibodies can improve CD8+ T cell function and anti-tumor immunity. Front Immunol 2020;11:832.

347 Clinical outcomes of ovarian cancer patients treated with ALKS 4230, a novel engineered cytokine, in combination with pembrolizumab: ARTISTRY-1 trial

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A372-A373
Author(s):  
Ira Winer ◽  
Lucy Gilbert ◽  
Ulka Vaishampayan ◽  
Seth Rosen ◽  
Christopher Hoimes ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Tumor Marker ◽  
Solid Tumors ◽  
Cd8 T Cells ◽  
Comprehensive Cancer Center ◽  
List Type ◽  
Link Type ◽  
Heavily Pretreated

BackgroundALKS 4230 is a novel engineered cytokine that selectively targets the intermediate-affinity interleukin-2 receptor complex to activate CD8+ T cells and natural killer cells.1 The ARTISTRY-1 trial (NCT02799095) has shown encouraging efficacy and acceptable tolerability of ALKS 4230 among patients with advanced solid tumors.2 We report a detailed analysis of ovarian cancer (OC) patients who received combination therapy in ARTISTRY-1.MethodsARTISTRY-1 is an ongoing multicohort phase 1/2 trial exploring intravenous ALKS 4230 as monotherapy and combined with pembrolizumab. OC patients were enrolled into a cohort with mixed anti PD 1/L1 unapproved tumor types who had progressed on prior chemotherapy. OC patients received ALKS 4230 (3 µg/kg) on days 1–5 and pembrolizumab (200 mg) on day 1 of a 21 day cycle. Outcomes presented include antitumor activity (RECIST v1.1) and safety as of 7/24/2020. To evaluate changes in tumor microenvironment (TME), baseline and on-treatment biopsies were collected.ResultsFourteen heavily pretreated patients with OC were enrolled. Patients received a median of 5 (range, 2 11) prior regimens and all were previously treated with platinum based therapy. Among 13 evaluable patients with ≥1 assessment, 9 experienced disease control and 4 experienced disease progression; median treatment duration was approximately 7 weeks. Three patients experienced an objective response, including 1 complete response, 1 partial response (PR), and 1 unconfirmed PR; all were platinum resistant and negative for BRCA mutations. Five patients experienced tumor burden reductions (table 1). Treatment-related adverse events at the doses tested have generally been transient and manageable, with the majority being grade 1 and 2 in severity. Overall, based on preliminary data, the combination with ALKS 4230 did not demonstrate any additive toxicity to that already established with pembrolizumab alone. Additional safety and efficacy data are being collected in ongoing cohorts. In the monotherapy dose escalation portion of the study, ALKS 4230 alone increased markers of lymphocyte infiltration in 1 paired melanoma biopsy (1 of 1; on treatment at cycle 2); CD8+ T cell density and PD-L1 tumor proportion score increased 5.2- and 11 fold, respectively, supporting evidence that ALKS 4230 has immunostimulatory impact on the TME and providing rationale for combining ALKS 4230 with pembrolizumab (figure 1).Abstract 347 Table 1Summary of response observations among patients with ovarian cancerAbstract 347 Figure 1Increased markers of lymphocyte tumor infiltrationAn increase in CD3+CD8+ T cells (A, red = CD3; blue = CD8; purple = CD3+CD8+; teal = tumor marker), GranzymeB (B, red = CD8; green = granzymeB; yellow = granzymeB+CD8+; teal = tumor marker), and PD-L1 (C, red = PD-L1; blue = tumor marker) in the tumor microenvironment of a single patient was observed after the patient received monotherapy ALKS 4230ConclusionsThe combination of ALKS 4230, an investigational agent, and pembrolizumab demonstrates an acceptable safety profile and provides some evidence of tumor shrinkage and disease stabilization in some patients with heavily pretreated OC. This regimen could represent a new therapeutic option for these patients.AcknowledgementsThe authors would like to thank all of the patients who are participating in this trial and their families. The trial is sponsored by Alkermes, Inc. Medical writing and editorial support was provided by Parexel and funded by Alkermes, Inc.Trial RegistrationClinicalTrials. gov NCT02799095Ethics ApprovalThis trial was approved by Ethics and Institutional Review Boards (IRBs) at all trial sites; IRB reference numbers 16–229 (Dana-Farber Cancer Institute), MOD00003422/PH285316 (Roswell Park Comprehensive Cancer Center), 20160175 (Western IRB), i15-01394_MOD23 (New York University School of Medicine), TRIAL20190090 (Cleveland Clinic), and 0000097 (ADVARRA).ReferencesLopes JE, Fisher JL, Flick HL, Wang C, Sun L, Ernstoff MS, et al. ALKS 4230: a novel engineered IL-2 fusion protein with an improved cellular selectivity profile for cancer immunotherapy. J Immunother Cancer 2020;8:e000673. doi: 10.1136/jitc-2020-000673.Vaishampayan UN, Muzaffar J, Velcheti V, Winer I, Hoimes CJ, Rosen SD, et al. ALKS 4230 monotherapy and in combination with pembrolizumab (pembro) in patients (pts) with refractory solid tumors (ARTISTRY-1). Oral presentation at: European Society for Medical Oncology Annual Meeting; September 2020; virtual.

395 A first-in-human study of FS118, a tetravalent bispecific antibody targeting LAG-3 and PD-L1, in patients with advanced cancer and resistance to PD-(L)1 therapy

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A420-A420
Author(s):  
Timothy Yap ◽  
Deborah Wong ◽  
Siwen Hu-Lieskovan ◽  
Kyriakos Papadopoulos ◽  
Michelle Morrow ◽  
...  
Keyword(s):  
T Cell ◽  
Adverse Events ◽  
Advanced Cancer ◽  
Bispecific Antibody ◽  
Acquired Resistance ◽  
Human Study ◽  
Clinical Activity ◽  
List Type ◽  
Link Type ◽  
Antibody Targeting

BackgroundUpregulation of immune checkpoints, such as LAG-3, plays an important role in promoting resistance to anti-PD-(L)1 therapy. Targeting PD-L1 and LAG-3 using a bispecific antibody may overcome resistance to PD-(L)1 blockade.1 We report initial data from a first-in-human study evaluating FS118 in patients with advanced cancer and resistance to PD-(L)1 therapy.MethodsThe ongoing Phase I FIH study (NCT03440437) is being conducted to evaluate safety, tolerability, immunogenicity, PK/PD and clinical activity of FS118 administered IV weekly to heavily pre-treated patients who had previously received anti-PD-(L)1 therapy for a minimum of 12 weeks. Adverse events were assessed using CTCAEv4.03 and tumor responses assessed using RECISTv1.1 and iRECIST. Single subject dose escalation cohorts were followed by a 3+3 ascending dose design. Three cohorts (3, 10, 20 mg/kg) were expanded to evaluate PK, PD and clinical activity. Pharmacodynamic studies examined soluble LAG-3 production and peripheral T-cell expansion.ResultsForty-three patients (median 6 lines of prior therapy, including ICB) with solid tumors received FS118 at doses from 0.8 mg up to 20 mg/kg across 8 dose levels. Weekly administration of FS118 was well tolerated and did not result in dose- or treatment-limiting toxicities. An MTD was not reached. No safety signals unexpected for the drug class of immune-checkpoint inhibitors were identified in the early study population. The majority (95%) of treatment-emergent adverse events (TEAE) considered by the Safety Review Committee (SRC) to be treatment-related were Grade 1 and 2. Grade 3 TEAEs toxicities (elevated liver enzymes) were observed in 2 patients (5%). No SAEs or deaths were attributed to FS118 treatment. Anti-drug antibodies, observed in half of patients, were typically transient in nature. The pharmacokinetic profile confirmed preclinical predictions and PD parameters included a dose-dependent increase in serum soluble LAG-3 and expansion of peripheral T cells. Long-lasting disease stabilisation (>6 months) was observed in a subset of patients with acquired resistance (defined as a CR, PR or SD ≥3 months on previous PD-(L)1 treatment), but not in patients with primary resistance. Two patients remain on FS118 treatment as of 2 Jul 2020 (duration 10 and 16 months). Retrospective IHC analysis of PD-L1 and LAG-3 co-expression in the tumor was assessed as a potential biomarker associated with clinical outcome.ConclusionsWeekly treatment with FS118 was well tolerated up to 20 mg/kg and was associated with pharmacodynamic markers of FS118 activity. Encouraging signs of clinical activity were observed in highly pre-treated patients who had acquired resistance to prior PD-(L)1 therapy.Trial RegistrationRegistered at www.clinicaltrials.gov, NCT03440437ReferenceKraman M, Faroudi M, Allen N, Kmiecik K, Gliddon D, Seal C, Koers A, Wydro M, Winnewisser J, Young L, Tuna M, Doody J, Morrow M, Brewis N. FS118, a bispecific antibody targeting LAG-3 and PD-L1, Enhances T-Cell activation resulting in potent antitumor activity. Clin Cancer Res 2020; 26:3333–3344.

418 A phase 1, dose escalation and dose expansion study of SQZ PBMC HPV as monotherapy and in combination with atezolizumab in HLA-A*02+ Patients with HPV16+ recurrent, or metastatic solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A444-A444
Author(s):  
Cathy Eng ◽  
Joaquina Baranda ◽  
Matthew Taylor ◽  
Michael Gordon ◽  
Ursula Matulonis ◽  
...  
Keyword(s):  
T Cell ◽  
Solid Tumors ◽  
Cancer Vaccine ◽  
Phase 1 ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Dose Effect ◽  
Statistical Hypothesis ◽  
Mhc I ◽  
Cell Responses

BackgroundSQZ-PBMC-HPV is a therapeutic cancer vaccine created with Cell Squeeze®, a proprietary cell-engineering system. SQZ-PBMC-HPV is a novel cancer vaccine generated from peripheral blood mononuclear cells (PBMC) squeezed with HPV16 E6 and E7 antigens, resulting in delivery into the cytosol. The resulting antigen presenting cells (APCs) provide enhanced antigen presentation on MHC-I to potentially elicit robust, antigen-specific CD8+ T cell responses. Importantly, SQZ-PBMC-HPV are neither genetically modified nor immune effector cells.Studies in MHC-I knockout mice demonstrated that activation of antigen specific CD8+ tumor infiltrating lymphocytes (TILs) was a direct effect of cytosolic antigen delivery to PBMCs. In the murine TC-1 tumor model, tumor regression correlated with an influx of HPV16-specific CD8+ TILs. In vitro studies with human volunteer PBMCs demonstrated that each subset is capable of inducing CD8+ T cell responses. The Phase 1 study includes a significant biomarker program to investigate whether pharmacodynamic effects observed in non-clinical studies correlate with potential clinical benefit. Immunogenic and pharmacodynamic endpoints include Elispot assays to measure frequency of interferon gamma secreting cells, as well as quantification and characterization of TILs and tumor microenvironment. In addition, various cytokine responses and circulating cell-free HPV16 DNA levels in plasma are measured.MethodsSQZ-PBMC-HPV-101 (NCT04084951) is open for enrollment to HLA A*02+ patients with HPV16+ recurrent, locally advanced or metastatic solid tumors and includes escalation cohorts for monotherapy and in combination with atezolizumab. After initial demonstration of safety, the study assesses dose effect by testing different cell dose levels, the effect of prolonged antigen priming in Cycle 1 [APC administration on Day 1 only compared to Days 1 and 2 (double priming)] and the impact of treatment duration to identify the optimal dose regimen. The cycle length is 3 weeks, and patients will receive SQZ-PBMC-HPV for up to 1 year or until available autologous drug product is exhausted. Atezolizumab will be administered for up to 1 year. Eligible patients including but not limited to anal, cervical and head and neck tumors will undergo a single leukapheresis at the study site. The manufacturing process includes a maturation step and takes less than 24 hours. The vein-to-vein time for the 1st administration is approximately one week. Patients must have a lesion that can be biopsied with acceptable clinical risk and agree to have a fresh biopsy at Screening and on study. A Study Safety Committee is in place. No formal statistical hypothesis testing will be performed.ResultsN/AConclusionsN/ATrial RegistrationNCT04084951Ethics ApprovalThe study is registered on clinicaltrials.gov was approved by the Ethics Board of all institution listed as recruiting.

scholarly journals 411 Novel intratumoral agent, INT230–6 induces cancer cell death, increases tumor infiltrates and results in durable benefit alone or in combination with pembrolizumab in refractory patients

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A436-A436
Author(s):  
Anthony El-Khoueiry ◽  
Jacob Thomas ◽  
Anthony Olszanski ◽  
Nilofer Azad ◽  
Lewis Bender ◽  
...  
Keyword(s):  
Cell Death ◽  
T Cell ◽  
Cancer Cells ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Single Agent ◽  
Systemic Exposure ◽  
Systemic Circulation ◽  
Cancer Center ◽  
Advanced Malignancy

BackgroundINT230-6 is a novel formulation of cisplatin and vinblastine with an amphiphilic cell penetration enhancer that has been shown to enhance dispersion of the drug throughout tumors and allow diffusion into cells when given intratumorally. In preclinical models, INT230-6 has resulted in cell death, dendritic cell influx, antigen presentation and T-cell engagement with strong synergy when combined with checkpoint inhibitorsMethodsThis phase 1/2 study evaluated Q2week injections of INT230-6 x 5 dosed by tumor volume alone or with 200 mg pembrolizumab IV Q3 weeks. Eligble patients had any advanced malignancy refractory to standard therapy with an injectable tumor.ResultsSixty subjects (median 3 prior therapies (range 0–10)) were enrolled (53 monotherapy, 7 combo). Median age was 60 (42–85). 19 different cancer types were accrued with breast cancer and sarcoma being the most frequent. Over 200 deep tumor injections were administered at doses of up to 172 ml of INT230-6 (86 mg of CIS, 17 mg of Vin). PK analysis revealed <5% of the drugs were measured in systemic circulation, indicative of minimal systemic exposure. There was no dose limiting toxicity. The most frequent monotherapy drug related AE’s reported were: injection-site pain 58%, nausea 37%, fatigue 33%, and vomiting 27% with only 18% of subjects experiencing a grade 3 AE (no grade 4 or 5). Rates were comparable for the single agent INT230-6 and the combination with pembrolizumab. In the overall monotherapy cohort, patients completing all 5 doses of INT230-6 over 56 days (n=16), the median overall survival has not yet been reached. after a median followup of 408 days. In the 5 evaluable patients who received the pembrolizumab combination, the median TTP has not been reached with a median follow up of 6 mo. Paired biopsies (pre, 1 month) were available in 10 monotherapy patients and revealed a median of 63% reduction in viable cancer cells on H&E (30% had no viable cancer) that was also associated with qualitative decreases in Ki67, increases of CD4 and CD8 T-cells and reduction in FoxP3 Tregs. Despite receiving only 2 month of monotherapy, short half lives of the active agents, and no subsequent therapies, 8 injected tumors continued to regress past 1 year.ConclusionsINT230-6 is well tolerated when administered intratumorally alone or in combination with pembrolizumab. Pharmacodynamic assessments provides proof of concept that this drug can reduce viable cancer cells and increases CD4/CD8 T-cell infiltrates leading to durable clinical benefit off treatment.Trial RegistrationNCT 03058289Ethics ApprovalThe study was approved by USC, Princess Margaret Cancer Center, Fox Chase, UMass, Columbia, and Johns Hopkins Institution’s Ethics BoardConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal

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