Advanced Refractory Solid Tumors Research Articles

A novel designed anti-PD-L1/OX40 bispecific antibody augments both peripheral and tumor-associated immune responses for boosting anti-tumor immunity.

Bispecific antibodies (BsAbs) combining simultaneous PD-L1 blockade and conditional co-stimulatory receptor activation have been developed to improve immune checkpoint therapy response. However, several PD-L1-based BsAbs have encountered clinical challenges, including insufficient activity or unexpected toxicity. In this study, we propose OX40 as a more suitable target partner for PD-L1-based BsAb design compared to ongoing clinical partners (CD27 and 4-1BB). We present a novel Fc-silenced tetravalent PD-L1/OX40 BsAb (EMB-09), which efficiently blocks PD-1/PD-L1 interactions and induces PD-L1-dependent OX40 activation, leading to enhanced T cell activation. EMB-09 demonstrated improved anti-tumor activity compared to the anti-PD-L1 monoclonal antibody. Significantly, EMB-09 activated effector memory T cells in peripheral immune system, promoted the influx of stem-like CD8+ T cells into the tumor site, resulting in a more active phenotype of CD8+ tumor-infiltrating lymphocytes. In an ongoing first-in-human study in patients with advanced refractory solid tumors (NCT05263180), EMB-09 demonstrated a consistent pharmacodynamic response and early efficacy signals.

Preclinical evaluation and phase 1 study of the PI3Kα/δ inhibitor TQ-B3525 in Chinese patients with advanced cancers.

Phosphatidylinositol 3-kinase (PI3K) inhibitors transformed management of various malignancies. This study preclinically characterized TQ-B3525 (dual PI3Kα/δ inhibitor) and assessed the recommended phase 2 dose (RP2D), safety, efficacy, and pharmacokinetics in relapsed or refractory (R/R) lymphoma or advanced solid tumors (STs). Oral TQ-B3525 was given at eight dose levels on a 28-day cycle. Primary end points were dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and safety. TQ-B3525 showed high selectivity and suppressed tumor growth. Between June 12, 2018, and November 18, 2020, 80 patients were enrolled (63 in dose-escalation cohort; 17 in dose-expansion cohort). Two DLTs occurred in two (two of 63, 3.2%) DLT-evaluable patients; MTD was not identified. TQ-B3525 at 20 mg once daily was selected as RP2D. Grade 3 or worse treatment-related adverse events mainly included hyperglycemia (16.3%), neutrophil count decreased (15.0%), and diarrhea (10.0%). Two (2.5%) treatment-related deaths were reported. Sixty patients with R/R lymphoma and 11 advanced STs demonstrated objective response rates of 68.3% and 9.1%, disease control rates of 91.7% and 54.6%, median progression-free survivals of 12.1 and 1.1 months; median overall survivals were not reached. TQ-B3525 exhibited rapid absorption and a nearly proportional increase in exposure. Acceptable safety and promising efficacy support further investigation of TQ-B3525 (20 mg once daily) for R/R lymphoma.

Phase I dose escalation trial of the first-in-class TNFR2 agonist monoclonal antibody, HFB200301, in monotherapy and in combination with tislelizumab, an anti-PD-1 monoclonal antibody, in adult patients with advanced solid tumors.

2526 Background: Tumor necrosis factor receptor-2 (TNFR2) is expressed on effector CD8+, CD4+, and regulatory T (Treg) cells, natural killer (NK) cells, and myeloid cells. Activation of TNFR2 is anticipated to yield effective anti-tumor immunity by stimulating T-cell and NK-cell activation and proliferation in the tumor microenvironment. HFB200301 is a first-in-class anti-TNFR2 agonistic monoclonal antibody that triggers both innate and adaptive immune stimulation by binding to a specific epitope on TNFR2. We report initial results of an ongoing Phase I dose escalation, multicenter study (NCT05238883) of HFB200301 in monotherapy and in combination with tislelizumab (TIS) in patients (pts) with advanced refractory solid tumors. Methods: A Phase I trial designed to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and initial efficacy of HFB200301 in monotherapy and in combination with TIS. Eligible pts, ≥18 years with an ECOG PS 0-1 and advanced solid tumors, will be enrolled in dose escalation at 5 different dose cohorts in monotherapy (Q4W), 3 different dose cohorts in combination with TIS (Q4W), or in dose expansion following determination of safety. Radiographic response is assessed every 8 weeks. Results: A total of 39 pts have been enrolled, 27 pts in monotherapy and 12 pts in combination. All pts received prior systemic therapy (median 2, range 1-4); 23 pts (59%) had prior checkpoint inhibitor treatment. No dose limiting toxicities were observed in either the monotherapy or combination arms. Treatment-related adverse events (TRAEs) occurred in 44% of monotherapy and in 50% of combination pts, with pruritis (11%), tremor (7%), fatigue (7%), asthenia (7%) and nausea (7%) being the most common TRAEs. No ≥ Grade 3 TRAEs were reported, and there were no drug discontinuations due to TRAEs. Preliminary HFB200301 PK analysis demonstrated non-linear clearance of HFB200301, with dose-proportional maximum concentration [Cmax], achieving sufficient exposures for peripheral target engagement in all tested doses. Emerging PD data demonstrates evidence of immune activation and expansion of CD8+ T cells, but not Tregs, in the tumor microenvironment and peripheral blood. Single cell RNAseq analysis of peripheral blood mononuclear cells demonstrated PD modulation in TNFR2 positive immune cell types post-HFB200301 treatment. Early response evaluation reveals ongoing durable clinical responses (> 6 months) in a PD-L1+ pleural mesothelioma pt and an EBV+ gastric cancer pt from combination cohorts. Conclusions: HFB200301 demonstrates a favorable safety profile, dose-dependent PK, with PD and preliminary clinical activity in monotherapy and in combination with TIS in pts with heavily pre-treated refractory solid tumors. Clinical trial information: NCT05238883 .

A multi-center, open-label phase 1/1b dose finding, safety, and pharmacokinetic study of MBRC-101, an Anth-EphA5 monomethyl auristatin (MMAE) antibody drug conjugate, in advanced refractory solid tumors.

TPS3161 Background: EphA5 receptor is a member of the Ephrin receptor tyrosine kinase family. Several lines of compelling nonclinical evidence indicate EphA5 is a novel and selective target for solid tumor-directed therapy. Expressed only minimally in normal tissues, it is highly expressed in non-small cell lung carcinoma (NSCLC), head and neck squamous cell carcinoma (HNSCC), and breast, colorectal, pancreatic, gastric, and hepatic malignancies. MBRC-101 is a novel antibody drug conjugate (ADC) composed of an anti-EphA5 antibody conjugated to an MMAE payload (drug-to-antibody ratio of 4) through a valine citrulline cleavable linker. In pre-clinical toxicology studies and testing against a variety of cell-derived (CDX) and patient-derived (PDX) xenograft solid tumor models expressing EphA5--including NSCLC, triple negative breast cancer (TNBC), and HNSCC--MBRC-101 demonstrated favorable safety profiles and robust anti-tumor activity. Methods: This first-in-human, Phase 1/1b, multicenter, open-label study is examining the safety and efficacy of MBRC-101 in patients with advanced metastatic solid tumors refractory to standard treatment. Phase 1 will identify potential optimal biologically relevant doses (OBRD) and the maximum tolerated dose (MTD) of MBRC-101 at one or more dosing regimens. Phase 1b will evaluate the safety and preliminary clinical activity of MBRC-101 at potential OBRDs. Phase 1 will enroll patients (n ≈ 30) with advanced or metastatic solid tumors. EphA5 expression will not be required for enrollment into Phase 1 but will be assessed retrospectively. A modified toxicity probability interval (mTPI-2) method will guide dose escalation using a pre-specified decision matrix. The primary endpoints are MTD, dose limiting toxicities (DLTs), treatment emergent adverse events (TEAEs), and clinical laboratory tests. Phase 1b (n ≈ 60 patients) will include 3 expansion cohorts (n ≈ 20 patients per cohort): Cohort A, NSCLC; Cohort B, triple negative or HR+/HER2- breast cancer; and Cohort C, solid tumors irrespective of histologic tissue type (i.e., tumor agnostic) excluding NSCLC and breast cancer. Expression of EphA5 in primary or metastatic tumor tissue will not be required for enrollment into cohorts A and B but will be required for Cohort C. The primary endpoints are TEAEs, clinical laboratory tests, and investigator-assessed objective response rate (ORR) by RECIST v1.1 and clinical evaluation. Secondary endpoints for Ph1 and 1b include PK analytes and EphA5 expression as determined by immunohistochemistry (IHC). A Safety Review Committee will monitor safety at each dose escalation in Phase 1 and at regular intervals throughout Phase 1b. Clinical trial information: NCT06014658 .

Interim analysis of a phase I study using cryopreserved non-genetically modified allogeneic natural killer cells with enhanced cytotoxicity (SNK02) in patients with advanced solid tumors without lymphodepletion.

e14515 Background: Natural killer (NK) cells play a key role as the main effector cells toward cancer in innate immunity. A leading approach to boost NK cell-mediated anti-tumor activity is via the adoptive transfer of ex vivo activated NK cells. Current allogeneic donor-derived products require lymphodepletion to prevent immunologic rejection of donor cells by the recipient and ensure adequate cell delivery of the product cells to the target. However, lymphodepletion can negatively impact combination therapies where a robust T cell response is desired. SNK02 is a first-in-kind, cryopreserved allogeneic non-genetically modified NK cell product with significant anti-tumor cytotoxicity and over 90% expression of CD16, NKG2D, NKp46, and DNAM-1, that can be consistently produced on a large commercial scale. We hypothesized that higher doses of SNK02 (to overcome autodigestion) could be delivered frequently without the need for lymphodepletion and that it might demonstrate activity against solid tumors that have failed multiple prior standard-of-care treatment options. Methods: In this Phase 1 dose escalation study (NCT05990920), SNK02 was administered intravenously (IV) weekly for 8 consecutive weeks in patients with advanced solid tumors. The starting dose was 6 x 109 SNK02 cells. The primary endpoint was safety based on adverse events (AEs), vitals, laboratory tests, and physical exams. Results: As of Feb 1, 2023, 5 patients with advanced refractory solid tumors have been enrolled. Median age was 64 (range 44 – 71) and 3 were male. The subtypes were 1 leiomyosarcoma, 1 angiosarcoma, 1 endometrial adenocarcinoma, 1 undifferentiated pleomorphic sarcoma, and 1 colorectal adenocarcinoma. Four of five patients completed 8 cycles of SNK02. There was 1 death on study, which was deemed unrelated to the investigational product (IP). Out of the 36 doses administered through Cycle 8, there were 17 Grade 1, 3 Grade 2, and 1 Grade 3 adverse AEs related to IP. The Grade 3 AE of increased fatigue resolved after 1 day with no intervention required. Antibodies appeared to develop around cycle 5 and appeared to correlate with AEs. The best objective response of SD was demonstrated in 100% of patients that completed the 8 cycles. Conclusions: SNK02 was well tolerated as a monotherapy and appears to have some clinical activity against pretreated solid tumors despite the lack of lymphodepletion. SNK02 will continue to be studied as a monotherapy and in potential combination treatment regimens with monoclonal antibodies and immune checkpoint inhibitors. Clinical trial information: NCT05990920 .

EMITT-1: Proof-of-mechanism immunopeptidome (ImPD) effects at target PK exposure, in a phase 1 study of GRWD5769 (a first-in-class inhibitor of Endoplasmic Reticulum Aminopeptidase 1 [ERAP1]) in patients with solid malignancies.

2589 Background: GRWD5769 is a first-in-class, orally bioavailable ERAP1 inhibitor that significantly modulates the peptide repertoire displayed on MHC-1 on tumor cells, driving novel T cell response and causing tumor cell killing in preclinical studies. This unique approach has potential to overcome central mechanisms of immune resistance by driving de-novo recognition of previously hidden tumor neoantigens and addressing T cell exhaustion. Here we report initial safety, pharmacokinetic (PK) and pharmacodynamic (PD) endpoints from Part A (monotherapy dose escalation) in the ongoing multicentre, modular phase I dose escalation study (ACTRN12623000108617). Methods: Patients with advanced refractory solid tumors are enrolled using a BOIN escalation design. GRWD5769 is administered BID on days 1-14 during 21-day cycles. The first cycle is the dose-limiting toxicity (DLT) observation period. The PK / PD relationship of GRWD5769 is being evaluated using mass spectrometry analysis of the ImPD. Tumor responses are evaluated by RECIST v1.1 / iRECIST. Results: As of 03 January 2024, a total of 12 patients had been treated with GRWD5769 in 3 dose cohorts (25 mg, 50 mg, 100 mg BID). On average patients have remained on treatment for 4 cycles (range 1-10) No Serious Adverse Reactions, DLTs, immune related AEs or deaths were reported. Two Gr 3 serious adverse events have occurred in 2 treated subjects (aspiration pneumonia and Urinary Tract Infection, neither attributable to GRWD5769). Gr 1+2 AEs were infrequent and manageable. PK analyses for the first 3 cohorts show dose proportional plasma levels, with Tmax at ~3 h and a ~8 h Thalf. The minimum biologically active dose (MBAD) is defined as an average steady state plasma concentration above the IC50 for ERAP1, which was achieved at the 100 mg BID dose level. PD data shows dose-dependent target engagement, with marked shifts in the ImPD. This is consistent with the expected mechanistic effects of ERAP1 inhibition seen in preclinical models and is the first demonstration that the human ImPD can be manipulated pharmacologically in cancer patients, potentially allowing T cells to recognise new targets on tumors. Dose escalation with GRWD5769 monotherapy continues to determine the recommended phase 2 dose (RP2D). GWRD5769 in combination with Immune Checkpoint Inhibition will be investigated in Part B now that the MBAD has been reached. Conclusions: GRWD5769 has been well tolerated at doses up to 100 mg BID. PK / PD data support dose-dependent target engagement of ERAP1. Proof of mechanism has been achieved for this first-in-class therapy, and this is the first demonstration that the human ImPD can be manipulated pharmacologically in cancer patients. Further PD analyses will explore shifts in the T cell repertoire and modulation of immune cell phenotypes. Clinical trial information: ACTRN12623000108617.

A phase I/II, open-label, multicenter study to evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of HB0036 in patients with advanced solid tumors.

e14504 Background: HB0036 is a bispecific IgG1 antibody targeting both human programmed death ligand 1 (PD-L1) and the T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT). Here we report the initial results from the first-in human study ofHB0036 in patients with advanced malignancies. Methods: This is a first-in-human, phase I/II, multicenter, dose escalation and dose expansion study of HB0036 administered intravenously to adult pts with resistant/ refractory advanced or metastatic solid tumors who had failed standard therapies. Monotherapy of HB0036 will be conducted in 72 enrolled subjects. In the dose escalation phase (phase I), an accelerated titration followed by a 3+3 design was used to dose escalation by assessing the safety and tolerability of HB0036 monotherapy (dose range 0.04 mg/kg to 30 mg/kg), and determine the maximum tolerated dose (MTD). HB0036 was administered Q3w on a 21-day treatment cycle and dose-limiting toxicity (DLT) was observed in first treatment cycle. Tumor assessments per RECIST v1.1 were performed once every 6 weeks (2 cycles). HB0036 PK and PD analyses were performed. Results: At cutoff date of Jan 2, 2024, 19 pts (11 females and 8 males; ECOG 0/1, 3/16) with advanced refractory solid tumors have been enrolled in phase I (0.04 mg/kg [n = 1], 0.12 mg/kg [n = 1], 0.36 mg/kg [n = 1], 1 mg/kg [n = 3], 3 mg/kg [n = 3], 6 mg/kg [n = 3], 10 mg/kg [n = 4], 20 mg/kg [n = 3]). The median age was 59 (range 29-80) years. The pts were heavily pretreated with a median of 2 (range 1-4) prior lines of therapy. No DLT was observed. 13 (68.4%) pts experienced treatment-related adverse events (TRAEs), with 1 pt (5.3%) experienced grade ≥3 TRAEs. No grade 5 TRAE occurred. The incidence or severity of AE was not associated with the dose. The most common TRAEs (≥10%) were blood bilirubin increased, anemia, infusion-related reaction, AST elevated, ALT elevated, bilirubin conjugated increased, fever, hypertriglyceridemia, hypoalbuminemia, hypothyroidism and pyrexia. No SAEs related to HB0036 have been reported. As of DEC 25,2023, in 13 pts who had undergone at least 1 post-baseline tumor assessment, the investigator-assessed best response included 9 SDs and 4 PDs. The DCR was 69% (9/14, 95% CI, 38.6%-90.9%). Durable clinical benefit (SD for > 36 weeks) was seen in 1 subject (3 mg/kg) with lung sarcomatoid carcinoma. HB0036 has presented safe and well-tolerated profile up to doses of 20 mg/kg. To date, 5 responders are still on treatment. The dose escalation is still in progress. Conclusions: HB0036 showed an acceptable safety profile and promising anti-tumor activity in advanced solid tumors, which supports further studies to explore the safety and efficacy of HB0036 as a monotherapy and combination with other anti-tumor agents. Based on these data, phase II monotherapy and combination studies are in preparation. Clinical trial information: NCT05417321 .

Results of a first-in-human, dose-escalation phase 1 study of the ERK1/2 inhibitor ATG-017 in patients with advanced solid tumors.

e15114 Background: This open-label, first-in-human, phase 1 study evaluates the safety, pharmacokinetics, and maximum tolerated dose (MTD) of ATG-017, an oral, potent, and highly selective inhibitor of ERK1/2, in patients with refractory advanced solid tumors. Methods: Twenty-one patients with solid tumors harboring activating alterations in the RAS-MAPK pathway were enrolled in the 3+3 design dose-escalation phase for continuous dosing: 5 mg QD (n=1), 5 mg BID (3), 10 mg BID (3), 20 mg BID (7), 30 mg BID (4), and 40 mg BID (3). Results: Safety: All patients reported at least 1 treatment-emergent adverse event (TEAE). Fourteen patients (66.7%) experienced serious adverse events. At 40mg BID, 2 of 3 patients experienced a dose-limiting toxicity (DLT) (grade 3 diarrhea and grade 3 retinopathy). At 30mg BID, 2 of 4 patients experienced a DLT (grade 3 acneiform dermatitis and grade 2 blurred vision). All DLTs resolved with drug interruption. At 20mg BID, a potentially biologically active dose, 7 patients were treated with no DLTs observed. At all dose levels, the most commonly observed TEAEs were consistent with previously reported toxicities with other ERK pathway inhibitors (gastrointestinal, skin, and ocular adverse events). Pharmacokinetics: Between 5mg BID and 30mg BID, exposure increased proportionally. At doses 20mg BID or higher, the concentration in the whole dosing interval (≥ 328ng/mL, geometric mean) was higher than the target concentration (231 ng/mL) for effective ERK inhibition derived from preclinical PK/PD models. Efficacy: Of the 21 treated patients, one patient (4.8%) with mesonephric-like ovarian adenocarcinoma (KRAS G12V mutation) in the 30 mg BID cohort achieved a best response of partial response (sustained for six cycles of treatment), and 8 (38%) patients were assessed as having stable disease (sustained over an average of five cycles), based on RECIST v1.1. Conclusions: In patients with solid tumors, 20mg BID continuous dosing of ATG-017 was identified as the MTD and delivers exposure that is likely to be active in inhibiting ERK. This dose is currently being explored in a dose expansion phase. A combination regimen with nivolumab is also being investigated. Clinical trial information: NCT04305249 .

A precise thymalfasin-regulated PRaG regimen for advanced refractory solid tumors: An open-label, prospective, multicenter clinical study (PRaG 5.0 study).

e14637 Background: PRaG regimen, which consisted of anti-PD-1 therapy, radiotherapy and GM-CSF, had a positive efficacy and tolerable safety for advanced refractory solid tumors who were heavily treated. However, severe lymphocytopenia was one of the major hurdles for immunotherapy. Thymalfasin has been wildly used as an adjuvant therapy for multiple carcinomas for elevating and sustaining the abundance of T lymphocyte. An exploratory phase II study was conducted to assess the efficacy of a meticulously thymalfasin-controlled PRaG regimen in advanced solid tumors (NCT05790447). Methods: Subjects with advanced solid tumors, having progressed beyond at least first-line chemotherapy, were eligible and treated with thymalfasin at three doses, dependent on the baseline absolute T lymphocyte count. Following seven days of thymalfasin treatment in patients with low baseline lymphocytes, they received at least two cycles of the PRaG regimen until either no suitable lesions remained for irradiation or the normal tissue tolerance dose was reached. When completing PRaG cycles, patients were maintained PD-1 inhibitor and thymalfasin until disease progression or intolerable adverse events. The primary endpoint was the overall response rate (ORR) according to RECIST 1.1. Peripheral blood samples were collected for subsequent translational research. Results: As of January 31, 2024, six patients were enrolled in the study and completed at least one tumor assessment. The ORR was 33.3%, and the disease control rate was 50.0% (2 patients with partial response (PR), one patient with stable disease (SD), and three patients with progressive disease). Four patients underwent single-cell RNA sequencing (scRNA-seq) analyses of frozen peripheral blood mononuclear cells (PBMCs) derived from before and after two cycles of therapy. Early-activated CD8+T cells, the intermediate state between the naïve-like and the effector-memory subsets, increased post-treatment, especially in three responders with PR and SD after two cycles of PRaG and thymalfasin, while a CD8+ terminally exhausted (Tex) cluster showed a decreasing trend in these responders. Seventy-six differential genes were identified in early-activated CD8+T cells, mainly enriched in activation of immune response, myeloid leukocyte activation, and T cell receptor signaling pathways (gene ontology). CCL3, PTPRC, NFKBIA, FOSB, RELB, and TGFB1 were vital genes in the gene network analysis. Conclusions: The preliminary results of the PRaG 5.0 regimen revealed a manageable safety profile and encouraging efficacy. A loading dose of thymalfasin modulation appeared to increase in early-activated CD8+T cell proportions, which might correlate with favorable responses. These results should be validated in a larger cohort of patients, and the underlying mechanisms warrant further exploration. Clinical trial information: NCT05790447 .

A phase I study of irinotecan combined with BAY1895344 (ATR inhibitor) in advanced solid tumors: Results of ETCTN 10402 dose escalation.

3077 Background: ATR protein kinase is activated by replication stress and recruited to stalled forks or single strand DNA defects in various cancers. The topoisomerase-I (Top1) inhibitor irinotecan induces DNA damage. The ATR inhibitor BAY1895344 (elimusertib) has demonstrated cytotoxic potential in SCLC and GI cancer xenografts when combined with Top1 inhibitors . Methods: This phase Ia trial assessed elimusertib in combination with irinotecan in adult patients with refractory advanced solid tumors for whom irinotecan can be considered standard care. Patients with previous irinotecan exposure were excluded. Two dosing schedules were used: 1) Biweekly - irinotecan IV (starting at 150 mg/m2) D1 + elimusertib (starting dose 20 mg PO BID) D1,D2 (cycle=14 days); 2) Weekly - irinotecan (starting at 50 mg/m2) IV on D1,8,15 with elimusertib (starting at 20 mg PO daily) on D2,D3,D9,D10 and D16,D17 (cycle=21 days). Dose escalation utilized a 3+3 design. Primary objectives were to assess safety and tolerability and estimate the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Secondary objectives included estimating pharmacokinetic (PK) profiles and assessing anti-tumor activity. Results: A total of 21 patients were enrolled in dose escalation (N=9 [Biweekly] and N=12 [Weekly], median age 58 and 2 lines of prior therapy. For the Biweekly cohort: 3/3 patients enrolled at dose level (DL) 1 experienced hematologic dose-limiting toxicity (DLT); 6 patients received DL-1 without any DLTs. The weekly regimen escalation comprised of 12 patients: 6 enrolled in DL1 with 2/6 having hematologic DLT and 5/6 unable to complete ≥75% of cycle 1 dosing; 6 enrolled in DL-1 with no DLTs observed. Notable grade 3+ treatment-related adverse events and summary best response are summarized (Table 1). The majority of evaluable patients in both schedules had initial disease control (56% [biweekly] and 67% [weekly]). One confirmed partial response was seen in the biweekly RP2D. Median progression-free survival was 2.1 mo [biweekly] and 2.5 mo [weekly]. PK results will be presented at time of meeting. Conclusions: Both RP2D and MTD of elimusertib in combination with irinotecan were reached for both dosing schedules: irinotecan 150 mg/m2 IV D1 + elimusertib 10 mg BID PO D1,D2 (biweekly) and irinotecan 25 mg/m2 IV on D1 + elimusertib (20 mg PO daily) on D2,D3 (weekly). Dose escalation was notably limited by myelotoxicity. Due to sponsor decision, the study was halted prior to planned expansion but the concept of ATR + topo I combination remains scientifically relevant. Clinical trial information: NCT04514497 . [Table: see text]

A phase I study of ATR inhibitor BAY1895344 (elimusertib) plus topotecan (ETCTN 10402): Results of dose escalation.

3076 Background: Ataxia telangiectasia and Rad3-related (ATR) protein kinase is activated by replication stress and recruited to stalled forks or single strand DNA abnormalities in various cancers. The topoisomerase-I (Top1) inhibitor topotecan induces DNA damage. The ATR inhibitor BAY 1895344 (elimusertib) has demonstrated cytotoxic potential in small cell lung cancer and gastrointestinal cancer xenografts when combined with Top1 inhibitors . Methods: This is phase Ia study of elimusertib combined with topotecan in adult patients with refractory advanced solid tumors for whom topotecan can be considered as part of standard care. Patients with previous topotecan exposure were excluded. The study combination was assessed starting at Topotecan 1 mg/m2 IV (D1-D5) plus elimusertib 20 mg BID (D2, D5) (Cycle=21 days). Dose escalation utilized a 3+3 design. Primary objectives were to assess safety and tolerability and estimate the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of the combination. Secondary objectives included estimating pharmacokinetic (PK) profiles and assessing anti-tumor activity of the combinations. Results: Eight patients were treated in dose escalation. Participants were a median of 63 years old and had received 2 median lines of previous therapy. The initial two patients enrolled into dose level (DL) 1 had dose-limiting toxicities with one of patient experiencing respiratory failure and cardiac arrest in setting of pancytopenia related to study drug. Six patients were subsequently enrolled in and received DL-1 (elimusertib decreased from 20 mg BID to 20 mg Daily) and no DLTs were observed. Notable grade 3+ treatment-related adverse events and summary best response are summarized in Table. Disease control rate was 43% among evaluation patient including one unconfirmed partial response. Median progression-free survival in the RP2D cohort was 3.45 months. PK studies are in process and results will be presented at time of meeting. Conclusions: RP2D and MTD was established for elimusertib in combination with Topotecan: Topotecan 1 mg/m2 IV [D1-D5] plus elimusertib 20 mg Daily [D2, D5] every 3 weeks. Dose escalation was notably limited by myelotoxicity. Due to sponsor decision, the study was halted prior to planned expansions cohorts but the concept of ATR + topo I inhibition remains relevant. Clinical trial information: NCT04514497 . [Table: see text]

Abstract CT167: Trial in progress: Phase 1 dose escalation study of T-1101, a first-in-class oral Hec1/Nek2 inhibitor, in patients with advanced refractory solid tumors

Abstract Background: T-1101, a novel small molecule, is the first-in-class oral agent that specifically disrupts the interaction between two commonly overexpressed, critical mitotic regulators, Hec1 and Nek2, within cancer cells. Such disruption leads to abnormal mitosis followed by apoptosis of cancer cells and provides a potential therapeutic strategy for cancer treatment. T-1101, with growth inhibition concentrations (IC50) ranging from14 to 74 nM across various human cancer cell lines, exhibited potent anti-liver and breastcancer activities in vivo, and highly active (IC50 7-19 nM) in MDR (multiple drugresistance) expressing cell lines. The effective inhibitory dose of T-1101 was determined to be between 10 and 25 mg/kg twice a day in xenograft animal models. Moreover, T-1101 has synergistic activity when combined with other anticancer drugs such as doxorubicin, topotecan and paclitaxel etc. Clinically, oral powder for constitution (OPC) form was first used in the initial study. To improve better patient compliance, the capsule (CAP) form is then deployed in current T-1101’s phase 1 study. Methods: Two T-1101 oral formulations (OPC and CAP) have been designed for the first-in-human, multi-center, open-label, dose-escalation studies to evaluate the safety, tolerability and establish the Recommended Phase 2 Dose (RP2D) in subjects with advanced refractory solid tumors. The secondary objectives are to assess the pharmacokinetics (PK) and therapeutic response after receiving treatment. DLT was determined within the first treatment cycle. Patients showing clinical benefit after first 2cycles of T-1101may enter extension cohort to continue the treatment. In OPC 3+3 escalation study (NCT03195764, NCT03349073), T-1101 was administered orally once daily, days 1 to 14 every 21 days per cycle with 8 planned dose levels at dose of 9, 18, 36, 54, 72, 90, 108 to 126 mg/m2. The OPC study was terminated at 36 mg/m2 before the primary endpoint (determination of maximum tolerated dose; MTD) was reached and subsequent dosing level will be evaluated with the CAP formulation. Based on the 52% of relative oral bioavailability (%F) of CAP versus OPC in preclinical Beagle dogs’ PK study, the starting dose of CAP form of T-1101 was determined at 100 mg daily forconsecutive 28-day per cycle for 2 cycles with dose levels of 100, 200, 225, 250, 300 and 350 mg/day. The accelerated titration and Bayesian Optimal Interval (BOIN) designs are used for the T-1101 capsule dose escalation study (NCT04685473), in which one subject will be enrolled per dose level until one subject have DLT or two subjects experience ≥ Grade 2 drug-related AE during Cycle 1 at any dose level, then the dose escalation will follow the BOIN design. Cohorts 1 (100 mg/day) 2 (200 mg/day) and 3 (225 mg/day) have been completed without DLT. As of November 2023, the trial remains open to enrollment. Citation Format: Wu-Chou Su, Li-Yuan Bai, Hui-Hua Hsiao, Her-Shyong Shiah, Yu-Min Yeh, Shang-Hung Chen, Shang-Yin Wu, Hui-Ching Wang, Hui-Jen Tsai, Kwang-Yu Chang, Jui-Hung Tsai, Chun-Hui Lee, Chieh Hua Lee, Yu-Sheng Chao, Li-Tzong Chen. Trial in progress: Phase 1 dose escalation study of T-1101, a first-in-class oral Hec1/Nek2 inhibitor, in patients with advanced refractory solid tumors [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 CT167.

Abstract 3132: A novel dual drug antibody-drug conjugate targeting hTrop2 has synergetic anti-tumor activity in solid tumor models

Abstract Antibody-drug conjugates (ADCs) are emerging therapeutic agents for targeted cancer treatment with remarkable clinical success. However, tumor heterogeneity and microenvironment complexity are still the major factors contributing to drug resistance, recurrence, and metastasis, which cannot be resolved with a mono therapy strategy. We’ve developed a novel dual drug ADC (BiADC), BR113, by conjugating an anti-hTrop2 antibody with a drug linker of a Topoisomerase I inhibitor payload, and another drug linker of an immune stimulator. Our studies show that the homogeneous ADC containing two distinct payloads is a new promising drug class, with two different anti-tumor MOAs, synergistic antigen-specific cell killing potency, desirable pharmacokinetic profiles, and minimal toxicity at therapeutic doses. In the cancer cells and human PBMC co-culture assay, BR113 exerts significantly more potent killing on cancer cells than two individual single-drug ADCs and the combination of two single-drug ADCs, which suggested a synergy on anti-tumor effects of this dual-drug ADC. In the xenograft mouse model studies, BR113 exhibits greater treatment effect and survival benefit than the combo of two single-drug ADCs at various doses. This robust superior anti-tumor activity is further confirmed in a hTrop2-MC38 syngeneic model with a prolonged anti-tumor protection against the tumor re-challenge. Finally, the novel BiADC, BR113, is well tolerated in hTop2 humanized mice after repeated administration. Our findings highlight the therapeutic potential of the BiADC format for treating refractory advanced solid tumors. The outstanding anti-tumor activity across various CDX tumor models and its favorable safety profile in mice support further evaluation of the innovative BiADC, BR113. Citation Format: Jie Zhu, Xiaobei Zhao, Eileen Li, Hong Xu, Lei Nie, Gang Chen, Haibing Wang. A novel dual drug antibody-drug conjugate targeting hTrop2 has synergetic anti-tumor activity in solid tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3132.

Evaluation of the efficacy and safety of a precise thymalfasin-regulated PRaG regimen for advanced refractory solid tumours: protocol for the open-label, prospective, multicentre study (PRaG5.0 study)

IntroductionThe PRaG regimen, which consists of hypofractionated radiotherapy combined with a programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitor and granulocyte-macrophage colony stimulating factor (GM-CSF), has been demonstrated to have...

Phase I/II Clinical Study of PRaG Regimen Combined With Intraperitoneal Infusion of PD-1 Inhibitor for Advanced Refractory Solid Tumors With Cancerous Ascites (PRaG4.0P Study).

Objective: The prognosis of malignant tumors with peritoneal metastases and cancerous ascites has generally been poor, with limited treatment options. The PRaG regimen, which comprised of hypofractionated radiotherapy, programmed cell death-1 (PD-1) inhibitor, and granulocyte-macrophage colony-stimulating factor (GM-CSF), showed a survival advantage in patients with advanced solid tumors who failed at least the first line of standard systemic treatment. Intraperitoneal infusion of PD-1 inhibitors may be a novel therapeutic strategy for managing malignant ascites. Integrating the PRaG regimen with intraperitoneal perfusion of a PD-1 inhibitor might control malignant ascites and provide further survival benefits in these patients. This proposed study aims to investigate the safety and efficacy of intraperitoneal infusion of serplulimab in combination with the PRaG regimen in patients with simultaneous advanced solid tumors and cancerous ascites who fail at least the first-line treatment. Methods: This proposed study is a prospective, single-arm, open-label, multicenter clinical trial. All eligible patients will receive 2 cycles of intensive treatment, a combination of PRaG regimen with an intraperitoneal infusion of PD-1 inhibitor. The patients who are beneficially treated with intensive treatment will receive consolidation treatment every 2 weeks until ascites disappear, disease progression occurs, intolerable toxicity occurs, or for up to 1 year. Phase I of this study will be conducted using a modified 3 + 3 design. The dose of intraperitoneal infusion of PD-1 inhibitor for phase II will be determined according to dose-limiting toxicity evaluation in the phase I study. Conclusion: This prospective, open-label, multicenter study will potentially lead to intraperitoneal perfusion of a PD-1 inhibitor being a new strategy for malignant ascites patients and provide a meaningful efficacy and safety of the combination of PRaG regimen with an intraperitoneal infusion of PD-1 inhibitor for these patients.

BETA prime: a first-in-man phase 1 study of AdAPT-001, an armed oncolytic adenovirus for solid tumors

AdAPT-001 is an oncolytic adenovirus (OAV) with a transforming growth factor beta (TGF-ß) trap, which neutralizes the immunosuppressive and profibrotic cytokine, TGF-ß. The aim or purpose of this phase 1 study was to assess the safety and tolerability and, secondarily, the efficacy of AdAPT-001 after single intratumoral injection (IT) (Part 1) and multidose IT injection (Part 2) in patients with superficially accessible, advanced refractory solid tumors. Part 1 enrolled 9 patients with a 3 + 3 single dose-escalation safety run-in involving 2.5 × 1011, 5.0 × 1011, 1.0 × 1012 viral particles (vps). No dose-limiting toxicities or treatment-related serious adverse events (SAEs) were seen. In Part 2, a dose-expansion phase, 19 patients received AdAPT-001 at 1.0 × 1012 vps until disease progression according to Response Evaluation Criteria in Solid Tumors or RECIST 1.1. The overall responses to treatment included confirmed partial responses (3), durable stable disease ≥ 6 months (5), and progressive disease (13). AdAPT-001 is well tolerated. Evidence of an anti-tumor effect was seen in both injected and uninjected lesions. The recommended Phase 2 dose was 1.0 × 1012 vp administered by intratumoral injection once every 2 weeks. Combination of AdAPT-001 with a checkpoint inhibition is enrolling.

1033P First-in-human study of MALT1 inhibitor MPT-0118: Results from monotherapy dose escalation in advanced or metastatic refractory solid tumors

1033P First-in-human study of MALT1 inhibitor MPT-0118: Results from monotherapy dose escalation in advanced or metastatic refractory solid tumors

A Prospective Clinical Trial of Radiotherapy Combined with PD-1 Inhibitors and GM-CSF, Sequentially Followed by IL-2 (PRaG 2.0) Regimen in Advanced Refractory Solid Tumors

Radiotherapy could stimulate the immune response and might synergize with PD-1/PD-L1 inhibitors in the clinical treatment of malignancies. Our previous PRaG trial also demonstrated that SBRT/HFRT in combination with PD-1 inhibitors and granulocyte macrophage-colony stimulating factor (GM-CSF) could improve clinical response in patients with advanced refractory solid tumors (ChiCTR1900026175). To further improve the efficacy of immunotherapy combined with radiotherapy, we conducted the PRaG 2.0 trial (ClinicalTrials.gov: NCT04892498) and optimized the PRaG regimen by adding interleukin-2 (IL-2). Preliminary results of PRaG 2.0 had been reported in the 64th ASTRO. Now we report an updated result. The PRaG 2.0 regimen was administered to patients with advanced refractory solid tumors who lacked or were unable to tolerate standard-of-care treatments. A treatment cycle consisted of SBRT or HFRT (5 or 8 Gy×2-3f) delivered for one metastatic lesion, PD-1 inhibitor dosing within one week after completion of radiotherapy, GM-CSF 200μg subcutaneous (SC) injection once daily for 7 days, and then sequentially followed by IL-2 2million IU SC once daily for 7 days. PRaG 2.0 regimen was repeated every 21 days for at least 2 cycles until no appropriate lesions for irradiation or reached the tolerance dose of normal tissues. Patients who could not continue radiotherapy and had not yet developed progression disease (PD) allowed PD-1 inhibitors to be continued as maintenance therapy until PD or unacceptable toxicity but no more than one year. The primary endpoint was Progression-Free Survival (PFS). As of 31st October 2022, 51 patients were enrolled in the study, and 42 completed at least one tumor assessment. The median Progression-Free Survival (PFS) was 5.8 months, and the median overall survival (OS) was 13.5 months. The objective response rate (ORR) was 21.4%, and the disease control rate (DCR) was 61.9% according to RECIST version 1.1. Lower plasma levels of Interleukin (IL)-6 and IL-17 at baseline were found to be associated with improved PFS. Treatment-related adverse events (TRAE) occurred in 34 of 42 (78.6%) patients, Grade ≥ 3 TRAEs occurred in 4 patients (9.5%). TRAEs leading to discontinuation of all study treatments occurred in three patients (7.1%). The PRaG 2.0 trial demonstrates that PD-1 inhibitors in combination with SBRT/HFRT, GM-CSF, and IL-2 could be a potential treatment regimen for patients with advanced refractory solid tumors, with an acceptable benefit/risk profile.

Phase 1 trial of 4-1BB-based adoptive T-cell therapy targeting human telomerase reverse transcriptase in patients with advanced refractory solid tumors

Background aimsHuman telomerase reverse transcriptase (hTERT) is an attractive target for anti-cancer therapies. We developed an effective method for generating hTERT-specific CD8+ T cells (hTERT-induced natural T cells [TERTiNTs]) using peripheral blood mononuclear cells (PBMCs) from patients with solid cancers and investigated their feasibility and safety. MethodsThis was a single-center phase 1 trial using a 3 + 3 dose escalation design to evaluate six dose levels of TERTiNTs. PBMCs from each patient were screened using an hTERT peptide panel to select those that stimulated CD8+ T cells. The four most stimulatory peptides were used to produce autologous CD8+ T cells from patients refractory or intolerant to standard therapies. Eligible patients received a single intravenous infusion of TERTiNTs at different dose levels (4 × 108 cells/m2, 8 × 108 cells/m2 and 16 × 108 cells/m2). Pre-conditioning chemotherapy, including cyclophosphamide alone or in combination with fludarabine, was administered to induce lymphodepletion. ResultsFrom January 2014 to October 2019, a total of 24 patients with a median of three prior lines of therapy were enrolled. The most common adverse events were lymphopenia (79.2%), nausea (58.3%) and neutropenia (54.2%), mostly caused by pre-conditioning chemotherapy. The TERTiNT infusion was well tolerated, and dose-limiting toxicities were not observed. None of the patients showed objective responses. Seven patients (30.4%) achieved stable disease with a median progression-free survival of 3.9 months (range, 3.2–11.3). At the highest dose level (16 × 108 cells/m2), four of five patients showed disease stabilization. ConclusionsThe generation of TERTiNTs was feasible and safe and provided an interesting disease control rate in heavily pre-treated cancer patients.

A phase Ib/II study of galunisertib in combination with nivolumab in solid tumors and non-small cell lung cancer

BackgroundIn this phase Ib/II open-label study, tumor immune suppression was targeted in patients with advanced refractory solid tumors and patients with recurrent/refractory non-small cell lung cancer (NSCLC) using galunisertib with nivolumab.MethodsEligible patients were ≥ 18 years old, had an Eastern Cooperative Oncology Group performance status ≤ 1, and were treatment-naive for anti-programmed cell death-1, its ligand, or transforming growth factor β receptor 1 kinase inhibitors. Phase Ib was an open-label, dose-escalation assessment of the safety and tolerability of galunisertib with nivolumab in patients with advanced refractory solid tumors. Phase II evaluated the safety of galunisertib with nivolumab in NSCLC patients who had received prior platinum-based treatment but were immuno-oncology agent-naive.ResultsThis trial was conducted between October 2015 and August 2020. No dose-limiting toxicities were observed in phase I. In the phase II NSCLC cohort (n = 25), patients received 150 mg twice daily galunisertib (14 days on/14 days off dosing schedule for all phases) plus nivolumab at 3 mg/kg (intravenously every 2 weeks). In this phase, the most frequent treatment-related adverse events (AEs) were pruritus (n = 9, 36%), fatigue (n = 8, 32%), and decreased appetite (n = 7, 28%). No grade 4 or 5 treatment-related AEs were observed. Six (24%) patients had confirmed partial response (PR) and 4 (16%) had stable disease; 1 additional patient had confirmed PR after initial pseudo-progression. The median duration of response was 7.43 months (95% confidence interval [CI]: 3.75, NR). Among the 7 responders, including the delayed responder, 1 had high PD-L1 expression (≥ 50%). The median progression-free survival was 5.26 months (95% CI: 1.77, 9.20) and the median overall survival was 11.99 months (95% CI: 8.15, NR). Interferon gamma response genes were induced post-treatment and cell adhesion genes were repressed, although the association of these observations with tumor response and clinical outcomes was not statistically powered due to limited samples available.ConclusionsThe study met its primary endpoint as galunisertib combined with nivolumab was well tolerated. Preliminary efficacy was observed in a subset of patients in the Phase 2 NSCLC cohort.Trial registrationTrial registered with ClinicalTrials.gov (NCT02423343; 22.04.2015).