Occurrence Of Dose-limiting Toxicities Research Articles

Evaluation of Safety and Efficacy of Cell Therapy Based on Osteoblasts Derived from Umbilical Cord Mesenchymal Stem Cells for Osteonecrosis of the Femoral Head: Study Protocol for a Single-Center, Open-Label, Phase I Clinical Trial.

Although mesenchymal stem cells (MSCs) insertion has gained recent attention as a joint-preserving procedure, no study has conducted direct intralesional implantation of human umbilical cord-derived MSCs (hUCMSCs) in patients with ONFH. This is a protocol for a phase 1 clinical trial designed to assess the safety and exploratory efficacy of human umbilical cord-derived osteoblasts (hUC-Os), osteogenic differentiation-induced cells from hUCMSCs, in patients with early-stage ONFH. Nine patients with Association Research Circulation Osseous (ARCO) stage 1 or 2 will be assigned to a low-dose (1 × 107 hUC-O cells, n = 3), medium-dose (2 × 107 cells, n = 3), and high-dose group (4 × 107 cells, n = 3) in the order of their arrival at the facility, and, depending on the occurrence of dose-limiting toxicity, up to 18 patients can be enrolled by applying the 3 + 3 escalation method. We will perform hUC-O (CF-M801) transplantation combined with core decompression and follow-up for 12 weeks according to the study protocol. Safety will be determined through adverse event assessment, laboratory tests including a panel reactive antibody test, vital sign assessment, physical examination, and electrocardiogram. Efficacy will be explored through the change in pain visual analog scale, Harris hip score, Western Ontario and McMaster Universities Osteoarthritis Index, ARCO stage, and also size and location of necrotic lesion according to Japanese Investigation Committee classification before and after the procedure. Joint preservation is important, particularly in younger, active patients with ONFH. Confirmation of the safety and efficacy of hUC-Os will lead to a further strategy to preserve joints for those suffering from ONFH and improve our current knowledge of cell therapy.

A phase 1b study of the ERK inhibitor MK-8353 plus pembrolizumab in patients with advanced solid tumors

SummaryCombining a checkpoint inhibitor with an inhibitor of extracellular signal-regulated kinase (ERK) may result in synergistic antitumor activity. We evaluated MK-8353, an ERK1 and ERK2 inhibitor, plus pembrolizumab in a phase 1b study in patients with advanced solid tumors. This open-label, nonrandomized, dose-escalation study (NCT02972034) enrolled adults with advanced solid tumors previously treated with 1‒5 prior lines of therapy. MK-8353 was administered orally in combination with pembrolizumab 200 mg every 3 weeks as follows: twice daily (arm A; MK-8353 50‒350 mg), once daily (arm B; MK-8353 50‒600 mg), or once daily every other week (arm C; MK-8353 50‒300 mg). The primary objective was evaluation of safety via occurrence of dose-limiting toxicities (DLTs). A secondary objective was objective response by RECIST v1.1 per investigator assessment. Among 110 evaluable patients (arm A, n = 22; arm B, n = 50; arm C, n = 38), median age was 58.0 (range, 35‒79) years and 50% had received 1 or 2 prior lines of therapy. DLTs occurred in 19 patients (n = 6 [27%], n = 8 [16%], and n = 5 [13%], respectively); the most frequent was grade 3 maculopapular rash (n = 15). Grade 3/4 treatment-related AEs occurred in 35% of patients; the most common were maculopapular rash (13%) and increased lipase (5%); none were grade 5. Eight patients (7%) attained an objective response (arm B, n = 7 [complete response, n = 1; partial response, n = 6]; arm C, n = 1 [complete response]). In conclusion, MK-8353 once daily plus pembrolizumab could be administered with a manageable toxicity profile but had modest antitumor activity in patients with advanced solid tumors.

Clinical implications of nintedanib pharmacokinetics in patients with pulmonary fibrosis

BackgroundNintedanib is used to treat both idiopathic and progressive pulmonary fibrosis (IPF/PPF). Evidence of both an exposure-response relationship and an exposure-toxicity relationship has been found, suggesting the potential value of therapeutic drug monitoring (TDM). We aimed to define the therapeutic window of nintedanib in a real-world cohort. MethodsData from two clinical studies were pooled for this analysis. To quantify exposure to nintedanib, a population-pharmacokinetic (PK) model was developed. Associations between PK and decline in forced vital capacity (FVC) and diffusing capacity (DLCO) were performed using linear-mixed-effect models (LMEM). The exposure-toxicity relationship was evaluated using a Cox proportional hazards model. ResultsIn total, 911 PK samples from 99 patients were used to develop the PK model. The LMEM with random slopes and intercepts included 517 pulmonary function tests (PFT) from 81 patients. The average administered nintedanib dose was associated with the rate of FVC decline (p=0.002). Per 50 mg decrease of daily dosage, the rate of FVC decline increased by 53.5 mL/year. Neither nintedanib exposure nor dose significantly affected DLCO decline and they were also not significantly associated with the occurrence of a dose-limiting toxicity (DLT). This may be explained by a large inter- and intrapatient variability in nintedanib PK. ConclusionNintedanib dose was significantly associated with FVC loss. However, no significant relationship between nintedanib exposure and the occurrence of DLTs was found in this real-world population, and no therapeutic window could be established. The findings in this study indicate that nintedanib is an unsuitable candidate for performing TDM.

DAREON-8: A phase I, open-label, dose escalation/expansion trial of the DLL3-targeting T-cell engager, BI 764532, combined with first-line (1L) standard of care (platinum, etoposide, and anti-PD-L1 antibody) in patients (pts) with extensive-stage small cell lung carcinoma (ES-SCLC).

TPS8127 Background: Platinum/etoposide chemotherapy in combination with anti-PD-L1 antibodies is the 1L standard of care (SoC) for pts with ES-SCLC. However, most pts relapse and subsequent treatment (Tx) options are limited. Hence, outcomes are poor with a 5-year survival rate of < 7%. Delta-like ligand 3 (DLL3) is a Notch receptor ligand expressed on tumor cells but not on normal cells. BI 764532 is an IgG-like T-cell engager (TcE) that binds simultaneously to CD3 on T-cells and DLL3 on tumor cells, resulting in selective, T-cell mediated tumor cell lysis. An ongoing Phase I trial of BI 764532 (NCT04429087) in pts with pretreated DLL3-positive tumors demonstrated an overall response rate of 28%, a disease control rate of 54%, and a manageable safety profile. Here, we describe DAREON-8 (NCT06077500), a Phase I open-label dose escalation/expansion trial of BI 764532 plus SoC as a 1L Tx for pts with ES-SCLC. Methods: Pts will be recruited from ~20 sites into this two-part trial. In Part A (dose escalation), ~30 pts will receive escalating doses of intravenous BI 764532 (target dose after step-in dosing) plus carboplatin/etoposide + atezolizumab. Dose escalation will be guided by a Bayesian logistic regression model with overdose control. Tx with BI 764532 will continue for 36 months, withdrawal or progressive disease (PD). The primary objective is to determine the maximum tolerated dose (MTD) of BI 764532 and/or the recommended dose for expansion (RDE)/recommended Phase II dose (RP2D) for BI 764532 plus SoC. Safety, efficacy and/or PK assessments will guide the RDE/RP2D. The primary endpoint focuses on the occurrence of dose-limiting toxicities (DLTs) in the MTD evaluation period. In Part B (dose expansion), ~30 pts will receive BI 764532 at the RDE/RP2D determined in Part A for 36 months, withdrawal or PD and platinum/etoposide + either atezolizumab or durvalumab. The primary objective of Part B is to confirm the safety and tolerability of BI 764532 at the RDE/RP2D plus SoC Tx as measured by the occurrence of DLTs during the on-Tx period. Key inclusion criteria include confirmed ES-SCLC; no prior systemic treatment for ES-SCLC; and eligibility to receive platinum/etoposide chemotherapy + anti-PD-L1 antibodies. Key exclusion criteria include previous Tx with DLL3-targeting TcEs; persistent, unresolved toxicity from previous Txs; immunodeficiency, or systemic steroid or other immunosuppressive therapy ≤7 days prior to first dose of BI 764532; and significant cardio/cerebrovascular disease. Clinical trial information: NCT06077500 .

DUET-01: A first-in-human, phase 1/2 study of BOXR1030 in patients with advanced glypican-3-positive solid tumors.

TPS2681 Background: Glypican-3 (GPC3) is a membrane-bound heparin sulfate proteoglycan involved in cell proliferation that is overexpressed in several tumor types. BOXR1030 is an autologous T-cell therapy that co-expresses a chimeric antigen receptor (CAR) targeting GPC3 on tumor cells and glutamic-oxaloacetic transaminase 2 (GOT2), a mitochondrial enzyme that plays an important role in maintaining mitochondrial function and improving T-cell functionality in the solid tumor microenvironment. In non-clinical studies, BOXR1030 showed GPC3-specific cytotoxicity, proliferation and cytokine release only in the presence of GPC3+ cells. Methods: DUET-01 (NCT05120271) is an open-label, dose escalation and expansion clinical trial to determine a safe dose of BOXR1030 in patients with advanced GPC3-positive solid tumors. Dose escalation will be guided by the occurrence of dose-limiting toxicities (DLTs) within 28 days of dosing. The Bayesian logistic regression model will be used on the accumulated DLT data to estimate the maximum tolerated dose (MTD). The Dose Escalation Committee will select the recommended phase 2 dose (RP2D) to be used in the expansion phase cohort(s) (10-20 subjects each) based on data accumulated in the dose escalation cohorts. Eligible subjects will undergo leukapheresis to obtain T cells for BOXR1030 manufacturing and will receive 3 days of lymphodepleting chemotherapy with fludarabine and cyclophosphamide within 5 days prior to BOXR1030 administration. The starting dose is 0.3 × 106 BOXR1030 T cells/kg body weight. Antitumor activity will be assessed every 6 weeks after cell infusion per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 and RECIST for immune-based therapeutics (iRECIST). Six months after BOXR1030 administration, subjects will enter long-term follow-up for up to 15 years. Long-term follow-up assessments will focus on long-term safety and disease status. Main inclusion criteria are histologically confirmed advanced unresectable or metastatic hepatocellular carcinoma, squamous cell carcinoma of the lung, myxoid/round cell liposarcoma, or Merkel cell carcinoma; GPC3 overexpression by immunohistochemistry assay confirmed centrally on tumor specimen taken within 6 months prior to signing consent and after the initiation of the subject’s most recent systemic anticancer therapy; body weight of ≥ 50 kg (≥ 65 kg for dose level 1); and life expectancy > 16 weeks. The primary endpoints are the incidence of DLTs; determination of the MTD and RP2D; the type, frequency and severity of treatment-emergent adverse events; clinically significant abnormal safety laboratory findings and vital signs. Key secondary endpoints include efficacy parameters such as objective response rate, BOXR1030 T-cell expansion and persistence, and levels of inflammatory markers and cytokines. The first patient was treated with BOXR1030 in December 2022. Clinical trial information: NCT05120271 .

A phase Ia/Ib, non-randomized, open-label, dose escalation and expansion trial of the B7-H6/CD3 T-cell engager BI 765049 with or without ezabenlimab in Asian patients with advanced solid tumors.

TPS2669 Background: Bispecific T-cell engagers represent a promising therapeutic approach for patients with solid tumors; however, these agents require an appropriate target antigen. B7-H6 is an encouraging target as it is expressed on multiple solid tumors but shows only limited expression on normal tissue (1). BI 765049 is a novel immunoglobulin G (IgG)-like T-cell engager designed to simultaneously bind B7-H6-expressing tumor cells and CD3 on T-cells resulting in the formation of a cytolytic synapse that triggers apoptosis of the tumor cells. Methods: NCT06091930 is a Phase I, non-randomized, open-label, multi-center, dose escalation and expansion trial that aims to assess the safety and tolerability of BI 765049 alone or in combination with programmed cell death protein 1 inhibitor ezabenlimab, in patients with advanced or unresectable gastric cancer, colorectal cancer (CRC), pancreatic ductal adenocarcinoma, hepatocellular cancer, head and neck squamous cell carcinoma, or non-small cell lung cancer. Patients must have progressed on, or be ineligible for, standard therapies. Key inclusion criteria include confirmed B7-H6 expression (central pathology review) except in CRC; ≥1 evaluable target lesion outside of the central nervous system (Response Evaluation Criteria in Solid Tumors [RECIST] v1.1); and Eastern Cooperative Oncology Group performance status 0/1. Patients with prior B7-H6-targeted treatment are ineligible. The study is divided into four parts: dose escalation and expansion of BI 765049 monotherapy (Parts I and II, respectively), and in combination with ezabenlimab (Parts III and IV, respectively). BI 765049 dose escalation will be guided by a Bayesian logistic regression model with overdose control. Treatment will continue until progressive disease or discontinuation for other reasons, or for up to 36 months. The primary endpoint for Parts I and III is the occurrence of dose-limiting toxicities; and for Parts II and IV it is objective response (OR; determined by the investigator; RECIST v1.1). The secondary endpoints for Parts I and III are pharmacokinetic (PK) parameters and OR (RECIST v1.1); and for Parts II and IV secondary endpoints are progression-free survival, duration of response, disease control, PK measurements, and OR (immunotherapy RECIST [iRECIST]). 1. Zhang W, et al. Clin Cancer Res 2022;28(23):5190–5201. Clinical trial information: NCT06091930 .

Phase I, open-label, dose-escalation trial investigating the safety and efficacy of oncolytic virus BI 1821736 in patients with advanced solid tumors.

TPS2688 Background: Despite some advances, the need for novel anti-cancer therapies remains high in patients with advanced solid tumors. Although immunotherapy with checkpoint inhibitors is the preferred treatment for several cancer types, a proportion of patients will have non-responsive tumors or develop resistance. Oncolytic viruses have potential as novel immunotherapies, due to their tumor-selectivity and ability to stimulate a systemic anti-tumor immune response. BI 1821736 is a genetically engineered pseudotype variant of VSV-GP encoding an immune-stimulatory cargo. The VSV-GP backbone is a recombinant chimeric vesicular stomatitis virus modified to replace the innate neurotropic G glycoprotein with the non-neurotropic GP glycoprotein from the lymphocytic choriomeningitis virus. BI 1821736 selectively replicates and lyses cells with defective interferon signaling, which is seen particularly in cancer cells. The immune-stimulating cargo leads to T-cell priming and reactivation within the immunosuppressed tumor microenvironment. Preclinical efficacy, toxicology, and environmental safety results support BI 1821736 administration in humans. Methods: 1467-0001 (NCT05839600) is a Phase I, open-label, dose-escalation study evaluating the safety and early efficacy of BI 1821736 in patients with advanced solid tumors. The study is enrolling adult patients who have exhausted available treatment options, with an Eastern Cooperative Oncology Group Performance Status of 0 or 1, ≥1 lesion amenable to biopsy, and adequate organ function. Patients with brain metastases are excluded unless they have completed brain radiotherapy and are asymptomatic. Patients will receive escalating doses of intravenous BI 1821736 for up to 3 months. Dose escalation will be guided by a Bayesian 2-parameter logistic regression model with overdose control (BLRM-EWOC). The primary objective is to determine the maximum tolerated dose (MTD) and/or recommended Phase II dose based on occurrence of dose-limiting toxicities (DLTs) during the MTD evaluation period of the first treatment cycle (Cycle 1; 21 days). Other safety endpoints include the occurrence of DLTs and adverse events during the treatment period. Further objectives include the assessment of BI 1821736 preliminary efficacy, pharmacokinetics, immunogenicity, shedding, and biomarkers. Patients are being recruited from approximately 10 sites across North America and Europe. Enrollment began in May 2023. A total of six patients have received BI 1821736 as of January 29, 2024. Patients are currently being enrolled to dose level 2. Clinical trial information: NCT05839600 .

Abstract CT090: DAREON™-7: A phase 1, open-label, dose escalation and expansion cohort trial of the delta-like ligand (DLL3)-targeting T-cell engager BI 764532, plus first-line platinum-based chemotherapy in patients with DLL3-positive (+) neuroendocrine carcinomas

Abstract Background Neuroendocrine carcinomas (NECs) have limited treatment options. DLL3 is highly expressed in NECs and is a promising treatment target. In an ongoing phase 1 trial (NCT04429087), BI 764532, a DLL3/CD3 IgG-like T-cell engager, was tolerable with clinical activity in patients with DLL3-positive (+) tumors, including those with small cell lung cancer and other NECs. Purpose DAREON™-7 (NCT06132113), a phase 1, open-label, dose-escalation (Part A) and dose-expansion (Part B) trial, aims to determine the maximum tolerated dose (MTD), recommended dose for expansion (RDE)/recommended phase 2 dose (RP2D), and the safety and efficacy of BI 764532 + platinum and etoposide in patients with DLL3+ NEC. Experimental design Part A: ~25 patients will receive intravenous BI 764532 (target dose after step-in dosing) plus carboplatin/etoposide (CE) until intolerable toxicity, or progression per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, or for a maximum of 36 months. BI 764532 dose escalation will be guided by a Bayesian logistic regression model with overdose control. Part B: 2 cohorts (~15 patients each) will receive BI 764532 at the RDE/RP2D + CE or cisplatin/etoposide (carboplatin/etoposide or cisplatin/etoposide are the most-used standard of care [SOC] regimens). Key inclusion criteria: patients must have no prior systemic treatment for DLL3+ locally advanced or metastatic NEC (extrapulmonary or unknown primary) or large cell NEC of the lung except for 1 cycle of standard platinum/etoposide regimen as first-line treatment prior to entering the treatment period of the trial; patients with localized NEC or resectable disease who received prior adjuvant therapy can participate in the trial if they experienced a treatment-free interval of >6 months prior to the diagnosis of metastatic disease; and patients must have at least 1 measurable lesion as defined per RECIST v1.1. Patients must be adequate candidates to receive platinum/etoposide as the SOC treatment. Primary endpoints: occurrence of dose-limiting toxicities (DLTs) in the MTD evaluation (Part A) and on-treatment (Part B) periods. Secondary endpoints: occurrence of DLTs and adverse events during the on-treatment period (Part B), and efficacy measured by objective response and duration of response (Part B). Enrollment is ongoing. Citation Format: Jaume Capdevila, Timon Vandamme, Patricia Niccoli, Saori Mishima, Ken Kato, Yiyuan Ma, Ping Sun, Lijiang Geng, Ulrich M. Lauer. DAREON™-7: A phase 1, open-label, dose escalation and expansion cohort trial of the delta-like ligand (DLL3)-targeting T-cell engager BI 764532, plus first-line platinum-based chemotherapy in patients with DLL3-positive (+) neuroendocrine carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT090.

Abstract B046: A first-in-human Phase 1a/b of PEP-010, a proapoptotic bifunctional peptide, administered as single agent and in combination with paclitaxel in patients with recurrent and/or metastatic solid cancer: results from the dose escalation study

Abstract Background: PEP-010 is a first-in-class bifunctional peptide that penetrates cells and specifically disrupts the interaction between Caspase9 and PP2A, two proteins involved in the apoptotic cascade, leading to Caspase9-dependent apoptosis in cancer cells. Safety, PK, and preliminary anti-tumor activity from the dose escalation part of a Phase 1a/b study of PEP-010 as a monotherapy and in combination with paclitaxel (P) in recurrent and/or metastatic solid cancer are presented. Methods: PEP-010 was administered as a 3-hour intravenous weekly infusion on 3 consecutive days in patients (pts) with advanced cancer ineligible for standard therapy, in monotherapy (Arm A) or in combination with weekly P (Arm B) for pts eligible for P. In Arm A, pts were enrolled into 8 dose cohorts starting at 0.15 mg/kg up to 15 mg/kg, using an accelerated titration design (first 4 dose levels (DLs)), followed by a 3+3 design. In Arm B, 5 DLs of PEP-010 combined with weekly P (80mg/m²) were explored. The primary objective was the determination of the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) of PEP-010 in both arms, based on occurrence of dose-limiting toxicities (DLTs). Secondary objectives were the safety and tolerability profile, PK and preliminary antitumor activity assessed by RECIST1.1. Results: At data cutoff (March 7, 2023), 19 (Arm A) and 15 (Arm B) pts received PEP-010 across 8 and 3 DLs, respectively. Median age was 57 [32-78] years and 56% were female. Median number of prior therapies was 6 [2-13]. A DLT (Grade 2 infusion-related reaction (IRR)) was observed in 1 pt in Arm A at DL 8 (15 mg/kg). In Arm B, 3 pts experienced a DLT at DL 5 mg/kg: 1 Grade 4 neutropenia and 2 IRR (inacceptable Grade 2 and 4). All DLTs led to permanent treatment discontinuation. MTD was defined as 15 mg/kg in Arm A and 2.5 mg/kg in Arm B. Most common adverse events (AE) related to PEP-010 included asthenia (26.5%) and IRR (14.7%) whereas most common AEs related to P included anemia (66.7%), peripheral neuropathy (33.3%), neutropenia (20%), onychopathy (20%), and diarrhea (20%). Median time on treatment was 5.1 weeks [2.1-25.3] in Arm A and 5.3 [3-18] in Arm B. In Arm A, for 7 pts (36.8%) a stable disease (SD) was observed for a median of 2.8 months [0.6-4.5]. In Arm B, 4 (26.7%) confirmed partial responses were observed in pts with ovarian, pancreatic and thyroid adenocarcinomas, and squamous cell lung carcinoma, and 2 pts (13.3%) had SD for a median of 4 months [2.7-9.6]. PK data indicated a proportionally dose-related increase of systemic exposure to PEP-010. No significant accumulation of PEP-010 over time or impact of P combination was observed. Conclusions: Data from the Escalation Part of the Phase 1a/b clinical trial showed an acceptable safety profile of PEP-010 in monotherapy. In combination, the dose of PEP-010 could not be escalated to the same level because of IRR. Preliminary antitumoral activity was observed with PEP-010 in combination with P including in pts who had previously received taxanes. Further clinical development is warranted. Citation Format: Pauline Du Rusquec, Elodie Coquan, Frederique Berger, Keyvan Rezai, Pierre-Emmanuel Brachet, Sophie Postel-Vinay, Zahra Castel-Ajgal, Gregoire Marret, Marie-Paule Sablin, Segolene Hescot, Raphael Sanchez, Anne-Claire Coyne, Claire Bertrand, Clementine Bouchez, Elsa Lafitte, Lucas Frezouls, Carole Mardesson, Abdelkrim Taamma, Chantal Krezel, Laura Dadon, Christophe Le Tourneau. A first-in-human Phase 1a/b of PEP-010, a proapoptotic bifunctional peptide, administered as single agent and in combination with paclitaxel in patients with recurrent and/or metastatic solid cancer: results from the dose escalation study [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B046.

Trial in Progress: An Open Label Phase I/II, Multicenter Study Evaluating Safety, Pharmacokinetics and Efficacy of S65487, a BCL-2 Inhibitor Combined with Azacitidine in Adults with Previously Untreated Acute Myeloid Leukemia Ineligible for Intensive Treatment

Preclinical and clinical data support combining Bcl-2 inhibitors (Bcl-2i) with hypomethylating agents (HMAs) in the treatment of acute myeloid leukemia (AML). S65487, a potent intravenous Bcl-2i, has shown promising synergistic activity when combined with azacitidine against in vitro AML models. Based on those data, we initiated a Phase I/II multicenter study of S65487 combined with azacitidine for newly diagnosed patients aged 18 years or older with de novo or secondary AML ineligible for intensive chemotherapy in 6 countries in Europe and Asia (NCT04742101). Secondary AML was defined as those related to previous leukemogenic therapies or transformed from a myelodysplastic syndrome. Patients with AML originating from myeloproliferative disorders were excluded. Ineligibility to intensive chemotherapy was defined as age of at least 75 years or the presence of significant co-morbidities. Previous use of HMA was allowed in the first six dose levels tested in the Phase I portion of the study, but was excluded afterwards, including during the Phase II part. Other eligibility criteria were standard for this patient population. Each cycle of therapy lasts for 28 days. Subcutaneous or intravenous azacitidine is administered at a dose of 75mg/m 2 in 7 consecutive administrations per cycle starting on day (D) 1 with a 2-day interval during weekends. Three schedules of S65487 are planned to be tested during the Phase I part to increase its concurrent administration with azacitidine and their synergism. Schedule 1 consists of weekly administrations (doses on D1, 8, 15, and 22). Two more intensified schedules consist of S65487 administration on D1, D3, D5, D8 (schedule 2) or D1 through D5, D8, and D9 (schedule 3) on the same days of azacitidine dosing. S65487 is administered over 30 minutes. When administered on the same day, S65487 is given first followed by azacitidine within 30 to 60 minutes. Treatment should be discontinued due to disease progression, or if other standard withdrawal criteria are met. The Phase I portion of the study follows a standard design guided by an adaptive Bayesian Logistic Regression Model with overdose control to estimate the maximum tolerated dose (MTD) based on the occurrence of dose-limiting toxicities during cycle 1. Patient accrual for the Phase I portion of this study is ongoing. The planned testing of schedule 1 is limited due to the expected low synergism with azacitidine. Once the recommended Phase II dose (RP2D) or MTD are established for schedules 2 and 3, the Phase II part will start and will be comprised of a maximum of two cohorts, each containing up to 27 patients. A Bayesian optimal design based on complete remission rate will guide the Phase II. Interim futility analyses are planned after enrollment of 10 and 20 evaluable patients. Randomization will not be used to allocate patients to one of the two cohorts planned during the Phase II portion of the study. The primary objective during the Phase I is to determine the safety, tolerability, and the RP2D or MTD of S65487 in combination with azacitidine. The primary objective of the Phase II is to assess the efficacy of this therapy. Pharmacokinetic analyses are included as secondary objectives in both parts of the study. Measurable residual disease will be assessed as a secondary objective in the Phase II part using a well validated, standard flow-cytometry panel. Pharmacodynamic analyses are conducted as exploratory objectives in both parts of the study. In particular, the disruption of the BCL2/BIM complex is followed in peripheral-blood mononuclear cells to guide the estimation of the RP2D.

Rationale for and Design of Papilio-1: A Phase 1/2, Multicenter, Open-Label Study to Evaluate the Feasibility, Safety, and Efficacy of Point-of-Care-Manufactured Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor T Cells (GLPG5301) in Relapsed/Refractory Multiple Myeloma

Background and Significance Despite improvements in treatment, patients with multiple myeloma (MM) ultimately relapse or become refractory to available regimens. Triple-refractory (refractory to CD38 monoclonal antibodies [mAbs], 1 proteasome inhibitor [PI] and 1 immunomodulatory drug [IMiD]) or penta-refractory (refractory to CD38 mAbs, 2 PIs and 2 IMiDs) patients have a poor prognosis and are in urgent need of novel treatment options. Chimeric antigen receptor (CAR) T-cell therapies have been used to target B-cell maturation antigen (BCMA) and have shown good clinical activity in patients with relapsed/refractory MM (RRMM). Faster manufacturing procedures may improve clinical outcomes by lowering discontinuation rates and reducing the need for bridging therapy. GLPG5301, a BCMA-directed CAR T-cell therapy, is produced using a novel decentralized and automated point-of-care manufacturing model. This allows administration of a fresh product within 7 days of apheresis. The objective of Papilio-1 is to evaluate the feasibility, safety and efficacy of GLPG5301, manufactured at the point-of-care, in adult patients with RRMM. Study Design and Methods Papilio-1 (CTIS: 2022-500782-27-00) is a Phase 1/2, multicenter, open-label study of GLPG5301 in patients with RRMM after ≥2 prior lines of therapy. Key eligibility criteria are presented ( Table). The study will be conducted in centers across Europe. The Phase 1 primary objective is to evaluate the safety of GLPG5301 and determine the recommended Phase 2 dose (RP2D). The Phase 1 primary endpoint is incidence of serious adverse events, including dose-limiting toxicities (DLTs), until 14 days post-infusion. The Phase 2 primary objective is to evaluate GLPG5301 efficacy. The Phase 2 primary endpoint is best objective response until 2 years post-infusion. Secondary endpoints include: type, frequency and severity of adverse events; duration of response; progression-free survival (PFS); overall survival (OS); minimal residual disease; soluble BCMA levels; time to response; time to progression; GLPG5301 levels in blood and bone marrow; serum levels of chemokines and cytokines; and number of successfully manufactured GLPG5301 products. Exploratory assessments include additional GLPG5301 pharmacokinetics (PK) and pharmacodynamics (PD). Patients will undergo leukapheresis of mononuclear cells for point-of-care manufacturing of GLPG5301 after screening ( Figure). Prior to infusion of GLPG5301, patients will receive fludarabine/cyclophosphamide lymphodepleting chemotherapy, followed by a resting period of at least 2 days. GLPG5301 will be administered as a fresh product, followed by in-hospital monitoring for 7 days. Safety, efficacy, PK and PD will be assessed until end of treatment (100 days post-infusion), and monthly until study completion (2 years). Patients will be enrolled in a long-term follow-up for up to 15 years. In Phase 1, dose escalation will be based on the occurrence of DLTs occurring within 14 days of infusion, according to predefined criteria. Three dose levels (DLs) will be assessed (DL1, DL2 and DL3). Six patients will receive the lowest dose level (DL1) and be evaluated for DLTs and efficacy. The appropriate dose for the following cohort will be then determined by the Safety Review Committee. This will be repeated until RP2D is determined. Approximately 30 patients will be treated with the RP2D in Phase 2. Safety and efficacy data will be analyzed using descriptive statistics. Response status will be summarized as best response (number, percentage, 95% confidence interval) and graphically displayed using swimmer plots by dose. Other binary endpoints will be described using a similar method. PFS and OS will be assessed using the Kaplan‒Meier method and calculated from the median survival time. Summary In Papilio-1, the feasibility, safety and efficacy of GLPG5301, a point-of-care-manufactured BCMA-directed CAR T-cell therapy, will be evaluated in adult patients with RRMM.

A phase 0/Ia study of BI 907828 concentrations in brain tissue and a nonrandomized, open-label, dose escalation study of BI 907828 in combination with radiotherapy in patients with newly diagnosed glioblastoma (GBM).

TPS2081 Background: Murine double minute 2 (MDM2) directly regulates the stability of the tumor suppressor p53, and dysregulation of this pathway can critically disrupt cellular response to genomic stress and lead to cell death. BI 907828 is a highly potent inhibitor of the MDM2-p53 interface that triggers accumulation of p53 and subsequent apoptosis in multiple GBM patient-derived xenografts (PDXs) with wild-type p53. Moreover, the combination of BI 907828 and radiotherapy provides significant survival extension in multiple orthotopic GBM PDXs. Methods: An integrated Phase 0/1 trial design is being used to evaluate the potential for BI 907828 to achieve a therapeutic concentration in brain tumor tissue and to test the safety of the combination with radiation. The co-primary endpoints for the Phase 0 study are i) measured total concentration of BI 907828 and ii) calculated unbound concentration of BI 907828 in contrast and non-contrast enhancing regions of tumor. Key inclusion criteria for the Phase 0 study are patients at least 18 years of age, ECOG performance status of 0 or 1, histologic or radiologic new diagnosis of GBM, and planned surgical resection. The first approximately 6 patients enrolled in the Phase 0 will be treated at the starting dose of 30 mg, and the future patients enrolled will be dosed at higher levels (45 mg or 60 mg) provided there are no safety concerns. If dose-limiting toxicities (DLTs) are encountered, then a Bayesian Logistic Regression Model (BLRM) with overdose control will be used to guide the dose level decisions for the additional patients. Multiple, image-registered tumor samples and intra-operative plasma samples will be analyzed for BI 907828 by LC-MS/MS. Intra-tumoral variation in BI 907828 will be correlated with pharmacodynamic effects of MDM2 inhibition (elevation of p53, p21, MDM2, GDF15, PUMA). Those patients completing the Phase 0 study and who meet additional eligibility criteria can enroll on the Phase 1a portion of the study. The pathologic inclusion criteria are TP53 wild-type, IDH1/2 wild-type, MGMT unmethylated GBM. Co-primary endpoints for the Phase 1a trial are i) occurrence of DLTs during and within 21 days after completion of radiation therapy, and ii) occurrence of adverse events throughout the treatment period. Tolerability of inter-patient dose-escalation of BI 907828 (30, 45, 60 mg) combined with radiation therapy (60 Gy in 30 fractions) will be evaluated with dose-escalation guided by a two-parameter BLRM with overdose control. Patients will remain on BI 907828 monotherapy following completion of radiotherapy until progression. To date, two patients have enrolled on the Phase 0 study, and one patient went on to enroll on the Phase 1a portion of the study. Clinical trial information: NCT05376800 .

CYAD-01, an autologous NKG2D-based CAR T-cell therapy, in relapsed or refractory acute myeloid leukaemia and myelodysplastic syndromes or multiple myeloma (THINK): haematological cohorts of the dose escalation segment of a phase 1 trial

CYAD-01 is an autologous chimeric antigen receptor (CAR) T-cell product based on the natural killer (NK) group 2D (NKG2D) receptor, which binds eight ligands that are overexpressed in a wide range of haematological malignancies but are largely absent on non-neoplastic cells. Initial clinical evaluation of a single infusion of CYAD-01 at a low dose in patients with relapsed or refractory acute myeloid leukaemia, myelodysplastic syndromes, and multiple myeloma supported the feasibility of the approach and prompted further evaluation of CYAD-01. The aim of the present study was to determine the safety and recommended phase 2 dosing of CYAD-01 administered without preconditioning or bridging chemotherapy. The multicentre THINK study was an open-label, dose-escalation, phase 1 study for patients with relapsed or refractory acute myeloid leukaemia, myelodysplastic syndromes, or multiple myeloma, after at least one previous line of therapy. Patients were recruited from five hospitals in the USA and Belgium. The dose-escalation segment evaluated three dose levels: 3 × 108 (dose level one), 1 × 109 (dose level two), and 3 × 109 (dose level three) cells per infusion with a 3 + 3 Fibonacci study design using a schedule of three infusions at 2-week intervals followed by potential consolidation treatment consisting of three additional infusions. The occurrence of dose-limiting toxicities post-CYAD-01 infusion was assessed as the primary endpoint in the total treated patient population. The trial was registered with ClinicalTrials.gov, NCT03018405, and EudraCT, 2016-003312-12, and has been completed. Between Feb 6, 2017, and Oct 9, 2018, 25 patients were registered in the haematological dose-escalation segment. Seven patients had manufacturing failure for insufficient yield and two had screening failure. 16 patients were treated with CYAD-01 (three with multiple myeloma and three with acute myeloid leukaemia at dose level one; three with acute myeloid leukaemia at dose level two; and six with acute myeloid leukaemia and one with myelodysplastic syndromes at dose level three). Median follow-up was 118 days (IQR 46-180). Seven patients (44%) had grade 3 or 4 treatment-related adverse events. In total, five patients (31%) had grade 3 or 4 cytokine release syndrome across all dose levels. One dose-limiting toxicity of cytokine release syndrome was reported at dose level three. No treatment-related deaths occurred, and the maximum tolerated dose was not reached. Three (25%) of 12 evaluable patients with relapsed or refractory acute myeloid leukaemia or myelodysplastic syndromes had an objective response. Among responders, two patients with acute myeloid leukaemia proceeded to allogeneic haematopoietic stem-cell transplantation (HSCT) after CYAD-01 treatment, with durable ongoing remissions (5 and 61 months). Treatment with a multiple CYAD-01 infusion schedule without preconditioning is well tolerated and shows anti-leukaemic activity, although without durability outside of patients bridged to allogeneic HSCT. These phase 1 data support the proof-of-concept of targeting NKG2D ligands by CAR T-cell therapy. Further clinical studies with NKG2D-based CAR T-cells are warranted, potentially via combinatorial antigen targeted approaches, to improve anti-tumour activity. Celyad Oncology.

Exposure-Response Analysis of Osimertinib in Patients with Advanced Non-Small-Cell Lung Cancer.

High interindividual variability (IIV) of the clinical response to epidermal growth factor receptor (EGFR) inhibitors such as osimertinib in non-small-cell lung cancer (NSCLC) might be related to the IIV in plasma exposure. The aim of this study was to evaluate the exposure–response relationship for toxicity and efficacy of osimertinib in unselected patients with advanced EGFR-mutant NSCLC. This retrospective analysis included 87 patients treated with osimertinib. Exposure–toxicity analysis was performed in the entire cohort and survival analysis only in second-line patients (n = 45). No significant relationship between occurrence of dose-limiting toxicity and plasma exposure was observed in the entire cohort (p = 0.23, n = 86). The median overall survival (OS) was approximately two-fold shorter in the 4th quartile (Q4) of osimertinib trough plasma concentration (>235 ng/mL) than in the Q1–Q3 group (12.2 months [CI95% = 8.0–not reached (NR)] vs. 22.7 months [CI95% = 17.1–34.1]), but the difference was not statistically significant (p = 0.15). To refine this result, the exposure–survival relationship was explored in a cohort of 41 NSCLC patients treated with erlotinib. The Q4 erlotinib exposure group (>1728 ng/mL) exhibited a six-fold shorter median OS than the Q1–Q3 group (4.8 months [CI95% = 3.3-NR] vs. 22.8 months (CI95% = 10.6–37.4), p = 0.00011). These results suggest that high exposure to EGFR inhibitors might be related to worse survival in NSCLC patients.

Safety and Efficacy of Stereotactic Ablative Radiation Therapy for Renal Cell Cancer: 24-Month Results of the RSR1 Phase 1 Dose Escalation Study

PurposeStereotactic body radiation therapy (SBRT) has become a new therapeutic option for primary renal cell carcinoma. However, treatment doses lack consistency in the literature. The primary objective of this study was to determine the maximum tolerated dose for renal cancer SBRT. Methods and MaterialsThis phase 1 multicentric dose-escalation study assessed 4 dose levels: 8 Gy × 4, 8 Gy × 5, 10 Gy × 4, and 12 Gy × 4. The primary objective of this study was to determine the maximal tolerated dose, defined by the occurrence of dose-limiting toxicity was defined as any acute side effect of grade ≥4 based on the Common Terminology Criteria for Averse Events, version 4.0. ResultsFrom October 2010 to September 2017, 13 patients were enrolled. The median follow-up was 23 months. There was no dose-limiting toxicity in our study, and the highest dose was reached successfully. No acute or late toxic effects above grade 2 were seen. There was no significant alteration of renal function after treatment. At 24 months, 2 patients had partial response and the others had stable disease. ConclusionsAfter 24 months of follow-up, no dose-limiting toxicity was seen at any of the prescribed dose levels in our study. The findings suggest that our last dose level of 48 Gy in 4 12-Gy fractions can be considered safe and can be used in further studies.

P1087: FAVEZELIMAB (ANTI–LAG-3) AND PEMBROLIZUMAB CO-BLOCKADE IN PATIENTS WITH RELAPSED OR REFRACTORY CLASSICAL HODGKIN LYMPHOMA WHO PROGRESSED AFTER ANTI–PD-1 THERAPY: AN OPEN-LABEL PHASE 1/2 STUDY

Background: PD-1 inhibitors are a standard of care for relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL), but optimal therapy is yet to be defined for patients whose disease progresses after anti–PD-1 treatment. Dual blockade of PD-1 and lymphocyte-activation gene 3 (LAG-3) has demonstrated antitumor activity in preclinical models. Aims: This multicohort phase 1/2 study (NCT03598608) evaluated safety and efficacy of favezelimab (MK-4280), a humanized IgG4 LAG-3 inhibitor, plus the PD-1 inhibitor pembrolizumab in patients with R/R hematologic malignancies. Cohort 2 focused on patients with R/R cHL refractory to anti–PD-1 therapy. Methods: This study included a safety lead-in phase (part 1) to determine recommended phase 2 dose (RP2D) followed by a dose-expansion phase (part 2). Eligible patients in cohort 2 had R/R cHL, relapsed after or were ineligible for autologous stem cell transplantation (ASCT), and progressed after ≥2 doses of anti–PD-1 therapy (within 12 weeks of last dose). In part 1, patients from all cohorts received intravenous (IV) pembrolizumab 200 mg every 3 weeks (Q3W) and favezelimab IV 200 mg or 800 mg Q3W. Dose-finding based on occurrence of dose-limiting toxicities (DLT) was determined using a modified toxicity probability interval design. In part 2, patients received pembrolizumab + favezelimab at the established RP2D for up to 2 years (35 cycles), or until documented disease progression, adverse events (AEs), or withdrawal from study. Primary end point was safety, including DLTs and AEs. Secondary end point was objective response rate (ORR). Duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were exploratory end points. Results: Only 1 DLT (autoimmune hepatitis [grade 4]) was observed among the first 6 patients from all cohorts included in part 1 at the favezelimab 200 mg dose; thus, the dose was escalated to 800 mg. No DLTs were observed in the 15 additional patients at the 800 mg dose. Favezelimab RP2D was defined as 800 mg Q3W + pembrolizumab 200 mg Q3W. In cohort 2, 33 patients were enrolled; median age was 37 years, 64% had ECOG PS 0, and 94% had at least 4 prior lines of therapy. At database cutoff (Nov 1, 2021), 20 patients had discontinued treatment due to adverse events (n=7); disease progression or clinical progression (n=11); or withdrawal/physician decision (n=2). After a median follow-up of 16.5 months, ORR for patients receiving favezelimab 800 mg (n=29) was 31% (95% CI, 15-51; complete response, 2 [7%]; partial response, 7 [24%]). 19 of 29 responders (66%) had an anti–PD-1–based regimen as their most recent line of therapy at study entry. 23 of 29 patients (79%) had a reduction from baseline in target lesions. Median DOR for patients who received favezelimab 800 mg was not reached ([NR]; 95% CI, 0+ to 14+ months). For all patients in cohort 2, the median PFS was 9 months (95% CI, 5-15); 12-month PFS rate was 39%. Median OS was 26 months (95% CI, 26-NR); 12-month OS rate was 91%. Treatment-related AEs (TRAE) occurred in 28 patients (85%); most common (>10%) were hypothyroidism (18%), nausea and fatigue (15% each), and arthralgia and diarrhea (12% each). Grade 3 or 4 TRAEs occurred in 6 patients (18%) and 18% of patients discontinued treatment due to TRAEs. No treatment-related deaths occurred. Summary/Conclusion: Favezelimab 800 mg + pembrolizumab 200 mg Q3W showed a tolerable safety profile and effective antitumor activity in heavily pretreated patients with R/R cHL whose disease had progressed after anti–PD-1 therapy, suggesting that the combination may reinduce a response in these patients.

P1086: FAVEZELIMAB (ANTI–LAG-3) AND PEMBROLIZUMAB CO-BLOCKADE IN ANTI–PD-1–NAIVE PATIENTS WITH RELAPSED OR REFRACTORY CLASSICAL HODGKIN LYMPHOMA: AN OPEN-LABEL PHASE 1/2 STUDY

Background: Programmed cell death 1 (PD-1) inhibitors are a standard of care in patients with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL), but clinical interest persists for new approaches to deepen and lengthen responses. Dual blockade of PD-1 and lymphocyte-activation gene 3 (LAG-3) has demonstrated antitumor activity in preclinical models. Aims: The multicohort phase 1/2 MK-4280-003 study (NCT03598608) evaluated the safety and efficacy of favezelimab (MK-4280), a humanized Immunoglobulin G4 LAG-3 inhibitor, plus pembrolizumab (a PD-1 inhibitor) in patients with R/R hematologic malignancies. This analysis focused on anti–PD-1–naïve patients with R/R cHL (cohort 1). Methods: This study included a safety lead-in phase (part 1) to determine the recommended phase 2 dose (RP2D) followed by a dose-expansion phase (part 2). Eligible patients in cohort 1 must have had R/R cHL after autologous stem cell transplantation (ASCT) or been ineligible for ASCT and have had no prior anti–PD-1 therapy. In part 1, patients from all cohorts received intravenous (IV) pembrolizumab 200 mg every 3 weeks (Q3W) and favezelimab IV 200 mg or 800 mg Q3W. Dose-finding based on occurrence of dose-limiting toxicities (DLTs) was determined using a modified toxicity probability interval design. In part 2, patients received pembrolizumab + favezelimab at the established RP2D for up to 2 years (35 cycles), or until documented disease progression, adverse events (AEs), or withdrawal from the study. Primary end point was safety, including DLTs and AEs. Secondary end point was objective response rate (ORR). Duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were exploratory end points. Results: Only 1 DLT (autoimmune hepatitis [grade 4]) was identified among the first 6 patients from all cohorts included in part 1 at the favezelimab 200 mg dose; thus, the dose was escalated to 800 mg. No DLTs were observed in the 15 additional patients treated at the 800 mg dose. The RP2D for the combination was defined as 800 mg Q3W + pembrolizumab 200 mg Q3W. In cohort 1, 30 patients were enrolled; median age was 40 years, 53% had ECOG PS 0, and 80% had no more than 3 prior lines of therapy. As of the database cutoff (Nov 1, 2021), 9 of 30 (30%) patients had discontinued treatment either due to adverse events (n=3) or disease progression (n=6). After a median follow-up of 13.5 months, ORR for cohort 1 was 73% (95% CI, 54-88; complete response, 7 patients [23%]; partial response, 15 patients [50%]). 28 of 30 patients (93%) had a reduction from baseline in target lesions. Median DOR was not reached ([NR]; 95% CI, 0+ to 23+ months) and 6 patients (51%) had response ≥12 months. The median PFS was 19 months (95% CI, 8-NR) and the 12-month PFS rate was 57%. The median OS was NR (95% CI, NR-NR) and the 12-month OS rate was 94%. Treatment-related AEs (TRAE) occurred in 26 patients (87%); most common (≥10%) were hypothyroidism (27%), fatigue (20%), infusion-related reactions (20%), headache (17%), and arthralgia, hyperthyroidism, myalgia, and nausea (10% each). Grade 3 or 4 TRAEs occurred in 6 patients (20%) and 10% of patients discontinued due to TRAEs. No treatment-related deaths occurred. Summary/Conclusion: Favezelimab 800 mg + pembrolizumab 200 mg Q3W demonstrated an acceptable safety profile and effective antitumor activity in anti–PD-1–naïve patients with R/R cHL. Further studies are merited to compare the activity of this combination to that of pembrolizumab alone.

Abstract CT240: A first-in-human study of the dual A2A/A2B adenosine receptor antagonist M1069 in patients with advanced solid tumors

Abstract A2A and A2B adenosine receptors have been shown to mediate immunosuppressive and tumor-promoting signals in the tumor microenvironment and their inhibition may be a promising treatment strategy for patients with advanced solid tumors. Dual A2A/A2B inhibition has shown an acceptable safety profile as monotherapy and early signs of clinical activity in combination with chemotherapy in patients with advanced solid tumors. M1069 is a novel, orally administered, highly selective dual antagonist of the A2A and A2B adenosine receptors that has recently demonstrated significant anti-tumor activity in vivo as monotherapy and in combination with chemotherapeutic agents in adenosine-rich tumor models. The aim of this Phase Ia First in Human noncontrolled, open-label, multicentre, dose escalation clinical study (NCT05198349) is to investigate the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary activity of M1069 in patients with metastatic or locally advanced unresectable solid tumors. Study Design: Patients aged ≥18 years, with an Eastern Cooperative Oncology Group performance status ≤1, adequate baseline hematological, renal and hepatic function, and with locally advanced or metastatic disease refractory to, or who have progressed with, standard therapy are eligible. Patients who have had prior treatment with another agent targeting the adenosine signalling pathway or prior anticancer treatment within 4 weeks or 5 half-lives are excluded. The study includes a 28-day screening period, a study intervention period of 21-day cycles, a 21-day dose-limiting toxicity observation period, an end of study intervention visit and a safety follow-up period of 30±7 days. Patients (approximately 21-30) will receive M1069 monotherapy twice daily in 21-day cycles until disease progression, unacceptable toxicity, withdrawal of consent or any criterion for withdrawal from study intervention. The starting dose is M1069 150 mg twice daily, with dose escalation decisions (300, 450, 600 and 700 mg twice daily) made by the safety monitoring committee and supported by results of a Bayesian Logistic Regression Model (BLRM). The primary objectives of the study are to determine the dose toxicity relationship and maximum tolerated dose (MTD), if reached, of M1069 and to determine the recommended dose for expansion of M1069 for further exploratory clinical development. These will be measured by the occurrence of dose-limiting toxicities, adverse events and treatment-related adverse events, and, through analysis of the safety, tolerability, pharmacokinetics, pharmacodynamics and post-treatment changes in the tumor microenvironment in available paired tumor biopsies, respectively. The target dose-limiting toxicity probability for the MTD is 30% which will be estimated by the BLRM. Pharmacokinetic parameters will be calculated using noncompartmental analysis. The study is open and patients are being treated at the first dose level. Citation Format: Lillian L. Siu, Martin E. Gutierrez, Guelseren Guezel, Katia Ruth, Ping Hu, Thomas Kitzing, Christina Habermehl, Meredith McKean. A first-in-human study of the dual A2A/A2B adenosine receptor antagonist M1069 in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT240.

A first-in-human, phase 1b study to evaluate the safety, tolerability, pharmacokinetics, and anti-tumor activity of neoadjuvant use of ph-762 administered intratumorally in subjects with advanced melanoma.

TPS9608 Background: Antibodies targeting immune checkpoints such as PD-1 and CTLA-4 has shown significant benefit in late-stage melanoma. But further improvements in therapeutic options are still required. Two approaches for improving the outcome of immunotherapy with checkpoint inhibitors are neoadjuvant treatment and local intratumoral (IT) injection. IT immunotherapy uses the tumor as its own vaccine to activate the immune system, priming an anti-tumor immune response and generating systemic tumor responses, whilst minimizing systemic exposure and off-target toxicities. Neoadjuvant therapy provides the opportunity for preoperative disease shrinkage with the potential to improve surgical morbidity. There is currently no neoadjuvant standard of care for resectable, advanced melanoma patients. PH-762 is a potent RNAi molecule targeting PD-1 with structural and chemical modifications conferring properties suitable for IT administration, including an optimized cell and tissue uptake profile. Pharmacology studies show potent in vitro silencing of PD-1 associated with T cell activation, and robust, dose-dependent in vivo inhibition of tumor growth in syngeneic tumor models. Methods: The purpose of this study is to evaluate the safety of neoadjuvant use of PH-762 administered by IT injection in subjects with resectable stage IIIB/IIIC/IIID or IV melanoma, to determine the recommended Phase 2 dose, PK after IT injection, and potential immunologic and pathologic tumor responses. Study treatment constitutes of once weekly injections with PH-762 into one designated tumor lesion for 4 weeks prior to surgical excision at 5-6 weeks after the initial injection, with up to 5 dose levels tested in a serial fashion in cohorts of 3 or more subjects. Eligible subjects will have at least one resectable melanoma deposit that is large enough to allow IT injection, and that can undergo repeated biopsy. Subjects with active brain metastases, leptomeningeal disease, uveal melanoma, and auto-immune disease are excluded. The dose of PH-762 will be normalized to tumor volume to ensure an equivalent local dose (tumor tissue concentration). Post tumor excision, subjects will be followed-up for 6 weeks. Primary endpoint is to determine a safe dose of PH-762 assessed by incidence of Dose Limiting Toxicities (DLT) prior to tumor resection. Bayesian optimal interval (BOIN) design will be employed to evaluate escalating doses of PH-762 to determine the Maximum Tolerated Dose based on occurrence of DLT. Tumor changes will be evaluated per RECIST criteria (version 1.1 and iRECIST version adapted for use with IT therapy) and pathological response. Immunological response in tumor tissue and blood samples will be assessed as secondary endpoints. Enrollment commenced in February 2022. Clinical trial information: 2021-002859-10.

P-123 A phase Ia/Ib, open-label, dose-escalation study of the TRAILR2 agonist BI 905711 in combination with chemotherapy in patients with advanced gastrointestinal cancers

Activation of the tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAILR2) induces apoptosis via the extrinsic pathway. Targeting TRAILR2 is therefore an attractive therapeutic strategy in oncology, but some early TRAILR2 agonists showed limited clinical success due to low efficacy or severe hepatotoxicity. The tetravalent bispecific antibody BI 905711 represents a novel, liver-sparing, TRAILR2 agonist, which cross-links TRAILR2 with cadherin 17 (CDH17) to induce CDH17-dependent TRAILR2 oligomerisation. CDH17, a membrane protein highly expressed in gastrointestinal (GI) cancers, is not expressed in normal hepatocytes. Thus, using CDH17 as a liver-sparing anchor may avoid hepatotoxicity while increasing selectivity to cancer cells. In preclinical models of GI cancer, including colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC), BI 905711 showed activity both as a single agent and in combination with chemotherapeutic agents (Garcia-Martinez et al., Mol Cancer Ther 2021;20:96–108). Preclinical studies also showed synergism of BI 905711 and SoC chemotherapy, particularly irinotecan. This phase Ia/Ib open-label, multicentre study (NCT05087992) aims to determine the maximum tolerated dose (MTD) and recommended dose for expansion (RDE), pharmacokinetics (PK), and preliminary efficacy of BI 905711 in combination with chemotherapy (FOLFIRI; irinotecan, leucovorin, and fluorouracil) with or without bevacizumab in patients with advanced, refractory GI cancers. Up to 100 patients with histologically or cytologically confirmed, advanced, unresectable or metastatic GI cancers will be enrolled. In phase Ia, approximately 20 patients with CRC will receive intravenous BI 905711 at escalating doses (starting dose 0.6 mg/kg) on day 3 of 14-day cycles, plus FOLFIRI and bevacizumab (5 mg/kg IV infusion over 30 mins) on day 1. BI 905711 dose escalation will be guided by a Bayesian logistic regression model with overdose control based on dose-limiting toxicities (DLTs) during the MTD evaluation period (first two 14-day cycles). BI 905711 will be administered until disease progression, unacceptable toxicities or another reason requiring treatment discontinuation. In phase Ib, patients with CRC or PDAC will be enrolled to one of two dose expansion cohorts. In the CRC cohort, patients who have progressed after prior oxaliplatin-based therapy will be randomised in a 2:1 ratio to receive FOLFIRI and bevazicumab with or without BI 905711. In the PDAC cohort, patients with CDH17-positive PDAC who have progressed after prior platin/gemcitabine-based first-line therapy will receive FOLFIRI plus BI 905711. In both cohorts, BI 905711 will be administered at the RDE determined in phase Ia. A safety run-in will be included in the PDAC cohort to confirm the RDE defined in phase Ia prior to enrolling further patients. Primary endpoints are the MTD based on the occurrence of DLTs (phase Ia), and confirmed objective response (OR) according to RECIST 1.1 (phase Ib). Secondary endpoints include PK assessments (phase Ia), progression-free survival, tumour shrinkage, duration of OR and disease control (phase Ib). Further endpoints include assessment of immunogenic response and pharmacodynamic biomarker modulation (including caspase activation and changes in circulating tumour DNA levels). Patient recruitment is active and the study is ongoing. NCT05087992. Medical writing assistance, supported financially by Boehringer Ingelheim Pharmaceuticals Inc., was provided by Jane Saunders of Ashfield MedComms, an Ashfield Health Company, during the preparation of this abstract. The authors received no direct payment. Boehringer Ingelheim.