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).

Results of two phase I dose escalation studies of the oral heat shock protein 90 (Hsp90) inhibitor SNX-5422.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2617-2617
Author(s):  
Todd Michael Bauer ◽  
Jeffrey R. Infante ◽  
Ramesh K. Ramanathan ◽  
Glen Weiss ◽  
Jasgit C. Sachdev ◽  
...  
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Plasma Concentrations ◽  
Hsp90 Inhibitor ◽  
Low Grade ◽  
Advanced Solid Tumors ◽  
Two Phase ◽  
Blurry Vision

2617 Background: SNX-5422 is a prodrug of SNX-2112, a highly potent, non-geldanamycin analog, HSP90 inhibitor with preclinical anti-tumor activity in multiple tumor models. These phase 1 studies were designed to evaluate safety and tolerability, determine dose limiting toxicities, maximum tolerated doses (MTDs), and describe pharmacokinetics of SNX-2112 and SNX-5422. Methods: Two phase 1, open-label, 3 + 3 dose-escalation studies evaluated SNX-5422 when given daily (QD) or every-other-day (QOD) during the first 30 days of treatment in patients (pts) with advanced solid tumors or lymphoma. Plasma concentrations of SNX-2112 and SNX-5422 were measured after the first and 11th (steady state) doses. Tumor assessments were performed every 8 weeks. Results: In both studies, pts received SNX-5422 QOD, 3 wks on/1 wk off, with doses ranging from 4 to 133 mg/m2 QOD. In one study, pts also received QD doses from 50 to 89 mg/m2, 3 wks on/1 wk off, and 50 mg/m2 QD continuously. Fifty-six pts (34M/22F; mean age 62 years) were enrolled. Treatment-related adverse events were mainly low grade (G), including diarrhea (64%), nausea (39%), vomiting (29%), fatigue (27%), abdominal pain (14%), and anorexia (14%). Reversible G 1 blurry vision, and G 1-2 blurry vision/vision darkening were reported by 1 pt on 100 mg/m2 QOD, and 4 pts treated with 50 to 89 mg/m2 QD. G 3 diarrhea was dose limiting in 2 of 3 pts (89 mg/m2 QD; 133 mg/m2 QOD). MTDs for the QOD and QD schedules were declared at100 mg/m2 and 67 mg/m2, respectively. The QD schedule was associated with higher incidences of treatment related adverse events. 38 pts were evaluable for response including 1 confirmed durable complete response, 1 unconfirmed partial response, and 17 with stable disease. Activity was seen in adrenal, lung, liver, neuroendocrine, GIST, and prostate. All but 2 were seen with the QOD schedule. Conclusions: SNX-5422 mono-therapy was generally well tolerated and showed promising signs of efficacy in pts with advanced solid tumors. Given the superior benefit-risk profile of QOD dosing over QD dosing based on these preliminary clinical findings, 100 mg/m2 QOD has been selected for further clinical testing. Clinical trial information: NCT00506805 and NCT01611623.

Phase 1 dose-escalation study of ACT001 in patients with recurrent glioblastoma and other advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2037-2037
Author(s):  
Jason D. Lickliter ◽  
Ross Jennens ◽  
Charlotte Rose Lemech ◽  
Ganessan Kichenadasse ◽  
Dongpo Cai ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Radiation Treatment ◽  
Phase 1 ◽  
Dose Range ◽  
Malignant Gliomas ◽  
Advanced Solid Tumors ◽  
Biomarker Analysis ◽  
Dose Levels

2037 Background: ACT001, an orally-available parthenolide derivative targeting NF-κB and STAT3 signaling pathways, has immunomodulatory effects and showed promising activity in preclinical models of glioblastoma (GBM). The updated data in this report summarizes clinical findings from this first-in-human clinical trial of ACT001 in patients with advanced solid tumors, including GBM. Methods: Eligible patients were adults with ECOG PS 0-1 and satisfactory hematologic, renal and hepatic function. Additionally, GBM patients had progressive disease despite initial radiation and temozolomide, measurable tumor and no radiation treatment within 3 months prior to enrollment. ACT001 was given orally BID until intolerance or disease progression. Dose escalation followed a standard 3+3 design. Gliomas were imaged with MRI every 8 weeks and responses assessed using RANO criteria. Results: A total of 24 patients were enrolled as of this report: 14 with primary GBM, 2 with secondary GBM, 2 with anaplastic astrocytoma, 2 with colorectal cancer and 1 with each of anaplastic oligioastrocytoma, diffuse intrinsic pontine glioma, non-small cell lung cancer and pleural epithelioid mesothelioma. Median age was 49 years old (range 32-72). ACT001 dose levels were 100 mg BID, 200 mg BID, 400 mg BID, 600 mg BID, 900 mg BID and 1200 mg BID. Study drug treatment was well tolerated with no dose-limiting toxicity or ACT001-related SAE observed. The originally-planned maximum dose of 600 mg BID and the 1200 mg BID dose were expanded to 7 and 5 patients, respectively. The plasma half life of ACT001 was approximately 3-4 hours and no accumulation was observed after multiple dosing. Cmax and AUC0-last were approximately dose linear across the evaluated dose range. Of the 19 patients with recurrent malignant gliomas, a complete remission was observed in 1 patient with GBM (ongoing 27 months from starting ACT001) and stable disease lasting ≥ 6 months was seen in 3 patients. Preliminary biomarker analysis of PBMC samples revealed a post-treatment reduction in CD4+ Treg cells at some dose levels. Conclusions: In this first-in-human phase 1 study, ACT001 was well tolerated and showed satisfactory bioavailability and preliminary evidence of anti-tumor activity in malignant glioma patients dosed at 400 mg BID or lower. A phase 1b trial in recurrent GBM patients of ACT001 at 200-400 mg BID in combination with anti-PD-1 therapy is planned. Clinical trial information: ACTRN12616000228482.

A first-in-human phase dose-escalation study of YH002, a recombinant humanized agonistic anti-OX40 IgG1 monoclonal antibody, in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14501-e14501
Author(s):  
Vinod Ganju ◽  
Adam Cooper ◽  
Kate Wilkinson ◽  
John J. Park
Keyword(s):  
Prostate Cancer ◽  
Adverse Events ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Cancer Breast ◽  
Dose Levels

e14501 Background: YH002 is a recombinant humanized IgG1 antibody that targets the human OX40 receptor. Preclinical studies have demonstrated the specificity, potency, and anti-cancer efficacy of YH002 in a comprehensive panel. The totality of nonclinical data supports progression of YH002 into clinical studies in adult patients (pts) with advanced solid tumors. Methods: This is an ongoing phase 1 dose-escalation study. Patients with advanced or metastatic refractory solid tumors received YH002 as single agent by IV administration at 0.01 to12.0 mg/kg dose levels every 21 days (Q3W), to evaluate the safety, tolerability and preliminary efficacy. An accelerated titration dose escalation design followed by a traditional 3+3 dose algorithm were utilized to assess dose-limiting toxicity (DLT) and identify MTD and/or RP2D. Tumor assessments were performed per RECIST v1.1 every 9 weeks. Results: By December 31 2020, six patients were enrolled and treated at escalating dose levels of 0.01 (n=1), 0.03 (n=1), 0.1 (n=1) and 0.3mg/kg (n=3), with tumor types including colon cancer, thymic cancer, prostate cancer, colorectal cancer, breast cancer and bladder cancer. Median treatment duration was 10.2 weeks (range 2 – 18). The median age of patients was 67 years old (range 47-78). These patients had progressed after a median of 2 prior lines of available standard therapy. As of data cutoff, no dose limiting toxicities (DLTs), no Grade (G) 3 or above adverse events (AE) or AEs leading to treatment discontinuation were reported. Drug-related adverse events (AEs) were all G1/2 events and occurred in 4 patients, including 8 G1 AEs (pneumonitis, rash, pruritus, arthralgia, myalgia, fatigue, lethargy, rash pruritic) and 3 G2 AEs (1 pneumonitis and 2 fatigue). Out of 5 patients having tumor assessment by RECIST, one pt with Thymic SCC at 0.3 mg/kg had best response of stable disease at week 9, one pt with prostate cancer at 0.1 mg/kg experienced Non-CR/Non-PD, and rest of 3 pts experienced progressive disease. Conclusions: These preliminary results demonstrate that YH002 was safe and tolerable up to 0.3mg/kg. Updated safety and antitumor activity will be presented. Clinical trial information: NCT04353102.

401 Phase 1/2 study of novel HER2-targeting, TLR7/8 immune-stimulating antibody conjugate (ISAC) BDC-1001 with or without immune checkpoint inhibitor in patients with advanced HER2-expressing solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A426-A426
Author(s):  
Manish Sharma ◽  
Ecaterina Ileana Dumbrava ◽  
Richard Carvajal ◽  
Daniel Catenacci ◽  
Leisha Emens ◽  
...  
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Phase 1 ◽  
List Type ◽  
Dependent Manner ◽  
Antibody Conjugates

BackgroundIn spite of advances made in the management of patients with HER2-expressing or -driven solid tumors, there remains a significant unmet need for novel approaches to improve patient outcomes. Intratumoral delivery of antitumor antibodies and immunostimulatory adjuvants such as toll-like receptor (TLR)7/8 agonists has been shown to activate tumor resident antigen-presenting cells (APCs), driving uptake, processing, and presentation of tumor neoantigens to T cells that mediate antitumor immunity. BDC-1001 is delivered systemically and has demonstrated superior preclinical biology. This novel ISAC consists of an investigational biosimilar of the humanized monoclonal antibody trastuzumab chemically conjugated to a TLR7/8 agonist with a non-cleavable linker. BDC-1001 activates human myeloid APCs in addition to retaining antibody-mediated effector functions such as antibody-dependent cellular cytotoxicity/phagocytosis (ADCC/ADCP). Studies in trastuzumab-resistant xenograft models and syngeneic tumor models indicate that HER2-targeted ISACs elicit potent and durable immune-mediated antitumor efficacy, leading to complete tumor regression in a TLR- and Fc receptor-dependent manner.1 2 Importantly, BDC-1001 did not induce interstitial lung disease, cytokine release syndrome, or thrombocytopenia in non-human primate studies. A four-part phase 1/2, first-in-human study has been initiated that evaluates BDC-1001 with or without (±) an immune checkpoint inhibitor targeting PD-1 in patients with HER2-expressing or HER2-amplified advanced/metastatic solid tumors.MethodsThis dose-escalation and dose-expansion study is enrolling up to 390 patients with HER2-expressing (IHC2+ or 3+ protein, irrespective of gene amplification) or HER2-amplified (by in situ hybridization or next-generation sequencing) advanced solid tumors. Primary objectives of the dose-escalation phase are to define safety and tolerability and determine the recommended phase 2 dose of BDC-1001 as monotherapy (Part 1) and in combination with an immune checkpoint inhibitor (Part 2). Part 2 is planned to start once BDC-1001 safety data are available. Primary endpoints include incidence of 1) adverse events and serious adverse events; 2) dose-limiting toxicities within a 3+3 design; and 3) potential immune-related toxicities. The dose-expansion portion of the trial will evaluate preliminary antitumor activity of BDC-1001 alone (Part 3) and in combination with an immune checkpoint inhibitor (Part 4). Secondary objectives will evaluate pharmacokinetic parameters and pharmacodynamic biomarkers in tumor tissue and in peripheral blood associated with drug exposure. These exploratory studies will help elucidate the mechanism of action and seek to identify biomarkers associated with BDC-1001 biological activity with or without immune checkpoint inhibitor. This global study is currently recruiting patients.ResultsN/AConclusionsN/ATrial RegistrationClinicalTrials. gov (NCT04278144).Ethics ApprovalThe study and the protocol were or will be approved by the Institutional Review Board or ethics committee at each site.ConsentN/AReferencesAckerman, et al. TLR7/8 immune-stimulating antibody conjugates elicit robust myeloid activation leading to enhanced effector function and anti-tumor immunity in pre-clinical models. Cancer Res. 2019:79 [13 Suppl]:Abstract 1559.Ackerman, et al. HER2-targeting TLR7/8 immune-stimulating antibody conjugates elicit robust myeloid activation and anti-tumor immune responses in a TLR- and FcR- dependent manner. J Immunother Cancer 2019;7:283

A first-in-human phase I dose escalation of YH001, an anti-CTLA-4 monoclonal antibody (mAb) in combination with toripalimab (anti-PD-1 mAb) in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2577-2577
Author(s):  
Vinod Ganju ◽  
Adam Cooper ◽  
Bo Gao ◽  
Kate Wilkinson
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Gastroesophageal Junction ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Gastroesophageal Junction Cancer ◽  
Anti Cancer ◽  
Ongoing Phase

2577 Background: YH001 is a humanized anti -hCTLA-4 IgG1 mAb that relieves CTLA-4-mediated immunosuppression, and thereby enhances the T-cell-mediated antitumor immune response. Pre-clinical data have shown potent anti-cancer activity when combined with anti-PD-1 mAb. Methods: This is an ongoing phase 1 dose-escalation study. Patients (pts) with advanced solid tumors received YH001 by IV administration at 0.05 to 6.0 mg/kg for 1 cycle (21 days) then in combination with Toripalimab (anti-PD-1 mAb) at 240 mg Q3W for 4 cycles. An accelerated titration method followed by the standard “3+3” design was utilized to evaluate safety, tolerability and preliminary efficacy. Results: As of 31-Dec-2020 data cut-off, 10 pts were enrolled and treated at 0.05 mg/kg (n = 2), 0.1 mg/kg (n = 3), 0.3 mg/kg (n = 3) and 1 mg/kg (n = 2). The median age was 62 years (range 46-74). Baseline ECOG scores were 0 (n = 8), 1(n = 2) with all pts progressed after a median of 2 prior lines of available standard therapy (range 1-4) including 1 pt progressed after immunotherapy of pembrolizumab. There were no dose limiting toxicities (DLT) observed. No severe adverse events (SAEs), Grade (G) 3 or above adverse events (AEs) and AEs leading to treatment discontinuation were reported. Twelve drug related AEs were all G1/2 events including 2 G2 AEs (1 rash maculopapular at 0.05mg/kg, 1 hypothyroidism at 0.1mg/kg), 10 G1 AEs (1 hypotension, 1 dry skin, 1 pruritus at 0.05mg/kg; 1 rash, 1 rash macular, 1 hyperthyroidism, 2 rash pruritus at 0.1mg/kg, 2 fatigues at 0.3mg/kg). Among 7 patients having imaging tumor assessment by RECIST v1.1, there were 4 SD, including 1 at 0.05 mg/kg with tongue carcinoma at week 8 assessment, 1 at 0.1 mg/kg with nasopharyngeal carcinoma at week 8 and 15 assessment, 2 at 0.3 mg/kg with gastroesophageal junction cancer and uterus leiomyosarcoma at week 8. Conclusions: YH001 combined with Toripalimab is safe and tolerable up to 1 mg/kg dose level. Updated safety and preliminary efficacy data will be presented. Clinical trial information: NCT04481009.

scholarly journals 470 A phase 1/2, open-label, dose escalation and expansion study of GI-101 as a single agent and in combination with a pembrolizumab, lenvatinib or local RT in advanced solid tumors (KEYNOTE-B59)

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A499-A499
Author(s):  
Byoung Chul Cho ◽  
Sang Joon Shin ◽  
Jae-Lyun Lee ◽  
Byoung Yong Shim ◽  
Hyung Soon Park ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Single Agent ◽  
Interleukin 2 ◽  
List Type ◽  
Advanced Solid Tumors ◽  
Part D ◽  
Anti Tumor Activity

BackgroundGI-101 is a novel bispecific fusion protein containing CD80 and interleukin-2 (IL-2) variant, designed to exhibit high affinity to cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and preferential binding to IL-2Rβ subunit. In various animal models, GI-101 exerted strong anti-tumor efficacy, accompanied by robust stimulation of CD8+ T and NK cell proliferation without a significant increase in regulatory T cells. GI-101 also elicited synergistic anti-tumor efficacy when used in combination with pembrolizumab (anti-PD1 agents), lenvatinib (tyrosine kinase inhibitor) and radiation in in vivo.1 Given the complementary mechanisms of action of GI-101 via blocking CTLA4 with IL-2 activity to enhance the proliferation and activation of effector T and NK cells, it was hypothesized that GI-101 as a single agent or in combination with other immunotherapies, VEGF inhibitors or RT may exert anti-tumor activity in cancers with high unmet needs.MethodsKEYNOTE-B59 (NCT04977453) is an ongoing phase 1/2 study composed of 4 parts. This study is planned to enroll approximately 374 patients across the indications. Patients assigned to Part A and B receive either GI-101 monotherapy (Part A) or GI-101 + 200 mg of pembrolizumab (Part B) via IV infusion on every 3 weeks (q3w). In Part C, patients will receive GI-101 q3w in combination with lenvatinib (oral, once daily). In Part D, patients will be given GI-101 q3w in combination with local tumor irradiation. Each part is initiated with dose-escalation/optimization phases which will enroll patients with advanced solid tumors, except Part D that enrolls advanced melanoma and sarcoma only. This phase utilizes conventional 3+3 design to determine the maximum tolerated dose and recommended phase 2 dose (RP2D) of GI-101 as a monotherapy and in combination. Once RP2D is determined, patients will be enrolled in dose-expansion phases of each part that includes specific tumor types, such as solid cancers failed on standard of care, treatment-naïve unselected or CPI-treated solid tumors. Patients with advanced solid tumors and recovered from prior therapy will be enrolled. This study will assess safety, tolerability, dose-limiting toxicities, MTD, RP2D, preliminary anti-tumor activity, and pharmacokinetics/pharmacodynamics of GI-101 as a single agent and in combination.ResultsThis study is currently enrolling patients with advanced or metastatic solid tumors.AcknowledgementsThe authors would like to thank all the patients who are participating in this study. The study is sponsored by GI Innovation, Inc.Trial RegistrationNCT04977453ReferencePyo KH, Synn CB, Koh YJ, et al. Comprehensive preclinical study on GI-101, a novel CD80-IgG4-IL2 variant protein, as a therapeuticantibody candidate with bispecific immuno-oncology target. Cancer Res 2021;81(13_Suppl).Ethics ApprovalThis study was approved by Severance hospital institutions’ Ethics Review Board (IRB); approval number 4-2021-0185, Asan Medical center‘s IRB; approval number 2021-0669.

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.

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