Preliminary Antitumor Activity Research Articles

Safety and clinical activity of JNJ-78306358, a human leukocyte antigen-G (HLA-G) x CD3 bispecific antibody, for the treatment of advanced stage solid tumors

BackgroundJNJ-78306358 is a bispecific antibody that redirects T cells to kill human leukocyte antigen-G (HLA-G)-expressing tumor cells. This dose escalation study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of JNJ-78306358 in patients with advanced solid tumors.MethodsAdult patients with metastatic/unresectable solid tumors with high prevalence of HLA-G expression were enrolled. Dose escalation was initiated with once-weekly subcutaneous administration with step-up dosing to mitigate cytokine release syndrome (CRS).ResultsOverall, 39 heavily pretreated patients (colorectal cancer: n = 23, ovarian cancer: n = 10, and renal cell carcinoma: n = 6) were dosed in 7 cohorts. Most patients (94.9%) experienced ≥ 1 treatment-emergent adverse events (TEAEs); 87.2% had ≥ 1 related TEAEs. About half of the patients (48.7%) experienced CRS, which were grade 1/2. Nine patients (23.1%) received tocilizumab for CRS. No grade 3 CRS was observed. Dose-limiting toxicities (DLTs) of increased transaminases, pneumonitis and recurrent CRS requiring a dose reduction were reported in 4 patients, coinciding with CRS. No treatment-related deaths reported. No objective responses were noted, but 2 patients had stable disease > 40 weeks. JNJ-78306358 stimulated peripheral T cell activation and cytokine release. Anti-drug antibodies were observed in 45% of evaluable patients with impact on exposure. Approximately half of archival tumor samples (48%) had expression of HLA-G by immunohistochemistry.ConclusionJNJ-78306358 showed pharmacodynamic effects with induction of cytokines and T cell activation. JNJ-78306358 was associated with CRS-related toxicities including increased transaminases and pneumonitis which limited its dose escalation to potentially efficacious levels.Trial registration number ClinicalTrials.gov (No. NCT04991740).

Phase I/II safety and preliminary efficacy of PM1022, a bispecific antibody targeting PD-L1 and TIGIT, in patients with advanced solid tumors.

e14694 Background: PM1022 is an anti-PD-L1 × TIGIT bispecific antibody that is engineered with a fully human IgG targeting TIGIT in an IgG1 wild type Fc backbone, fused to a VHH at the c-terminus targeting PD-L1. The potential MOA includes releasing T cell inhibition by blocking both the PD-L1/PD-1 and CD155/CD112/TIGIT pathways, as well as depleting Treg cells in the tumor microenvironment and engaging FcγRs to activate myeloid cells. PM1022 showed robust in vitro and in vivo efficacy in preclinical studies, and this is the first in human study. Methods: This phase Ⅰ/Ⅱ study consists of a standard 3+3 dose escalation and dose expansion part. PM1022 was administered intravenously as monotherapy on Day 1 of 21-day cycle. The primary objectives were to assess safety, tolerability and pharmacokinetics in patients with advanced solid tumors. Results: As of January 28, 2024, a total of 15 patients in dose escalation part have received at least 1 dose of PM1022, with 3 patients in each of the 100, 200, 400, 800 and 1200 mg dose levels respectively. No DLT was observed up to 1200 mg. Of the 15 patients, TRAEs occurred in 8 patients (53.3%), ≥ Grade 3 TRAEs occurred in 1 patient with platelet count decreased. No patients were discontinued from PM1022 due to TRAE. The most common TRAEs were rash (20%) and aspartate transaminase increased (20%). 14 patients completed at least one tumor evaluation. The median duration of PM1022 exposure was 6.1 weeks (range, 5.0-48.0 weeks). The ORR per RECIST 1.1 was 7.1% with a DCR of 35.7%. Preliminary antitumor activity has been observed in 1 patient with NSCLC (1200 mg, still on treatment) with previous PD-L1 TPS 100% who was enrolled after previous 3 lines therapy, including chemotherapy and anti-PD-1 treatment, and had a partial response in target lesion with 56.8% reduction. Another patient with esophageal cancer had been on PM1022 for total of 48 weeks until initiation of new anti-cancer therapy. Pharmacokinetics were dose-proportional with a terminal half-life of 7-13 days across the dose range of 100-1200 mg. Conclusions: PM1022 was safe and well-tolerated up to 1200 mg Q3W with preliminary anti-tumor activity. These findings could support further exploration of PM1022 in advanced solid tumors. Clinical trial information: NCT05867771 .

Preliminary antitumor activity of COM701 in combination with COM902 and pembrolizumab in patients with MSS-CRC and liver metastases.

3597 Background: There is a high unmet need for the treatment of patients [pts] with metastatic microsatellite stable colorectal cancer [MSS-CRC]. We reported encouraging preliminary antitumor activity with the combination of COM701 + nivolumab in patients with MSS-CRC and liver metastases [12/22(77%)], [ORR 2/17 (12%); disease control rate [DCR] 5/17 (29%)]1. COM701 is a novel, 1st-in-class immune checkpoint inhibitor [ICI] that binds to PVRIG, a DNAM-1 axis member, leading to activation of T and NK-cells; COM902 is an ICI of TIGIT. Pembrolizumab is an ICI of PD-1. We hypothesized that in pts with metastatic MSS-CRC, the triple combination by inhibiting the DNAM-1 axis would demonstrate antitumor activity with a favorable safety and tolerability profile. We present encouraging preliminary results. Methods: We enrolled 20 pts with metastatic MSS-CRC who all received COM701 15 mg/kg + COM902 3 mg/kg + pembrolizumab 200 mg all IV Q3W. Primary objectives were safety/tolerability, with secondary objective of antitumor activity of the combination. Key inclusion criteria: Age ≥ 18 yrs, measurable disease, MSS by IHC or genomic testing, ≤3 prior lines including fluroropyrimidines, irinotecan, and oxaliplatin. Key exclusion criteria: prior receipt of ICI including anti-PVRIG, anti-TIGIT. Investigator assessed responses were per RECIST v1.1, safety per CTCAE v5.0. Results: Median age 57.5yrs, 11/20 [F], 15/20 [75%] pts with liver metastases. Median of 3 prior lines of therapy. Objective response rate [ORR] 1/20 [5%] pts; 7 pts with SD. Disease control rate [CR + PR + SD] 8/20 [40%]. In pts with liver mets ORR 1/15 [7%], DCR 6/15 (40%); 6/8 [75%] pts with best response ≥SD had liver mets. Treatment related AEs were reported in 11/20 [55%] pts, the majority were ≤G2 7/20 [35%] with the most frequent TRAE of 4 pts each with ≤G2 fatigue, myalgia, 4/20 pts with G3 TRAE, there were no ≥G4 TRAEs. Strong peripheral IFNɣ induction was observed after treatment. Three pts [1 PR, 2 SD] are ongoing at the time of data cut. Conclusions: The data further supports the antitumor activity of the combination of COM701 + COM902 + pembrolizumab in pts with MSS-CRC and specifically in patients with liver metastases. Of note the data further reinforces the data previously disclosed in a similar pt population of 22 pts that received COM701 + nivolumab1. No new safety signals are reported. Additional clinical and translational data will be presented at the conference. Data cut 01/09/2024. Reference: 1. Rasco D, Dumbrava E, Sharma M, et al659 COM701 plus nivolumab demonstrates preliminary antitumor activity and immune modulation of tumor microenvironment in patients with metastatic MSS-CRC and liver metastases. Journal for ImmunoTherapy of Cancer 2022;10:doi: 10.1136/jitc-2022-SITC2022.0659. Clinical trial information: NCT04354246 .

A first-in-human trial of selective CDK7 inhibitor Q901, in patients with advanced solid tumors: Interim results of a phase I study (QRNT-009).

3078 Background: Q901 is a potent, covalently binding CDK7 inhibitor with excellent specificity for CDK7 against other protein kinases. Transcriptional regulation by CDK7 inhibition in cancer cells leads to DNA damage repair response inhibition and increased genomic instability. Q901 also regulates cell cycle checkpoints by inhibiting T-loop phosphorylation and transcriptionally downregulating CDK1, 2 and 4. In preclinical in vivo models, intravenous (iv) administration of Q901 once a week and once every three-week dosing regimen was well tolerated and showed significant antitumor activity. The safety profile, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy data for 18, 36 and 60 mg/m2 are presented. Methods: QRNT-009 (NCT05394103) is an ongoing Phase 1/2 multicenter, open-label, dose escalation and expansion study. Q901 is administered iv once weekly for four weeks, then once every two weeks thereafter in patients with advanced or metastatic ovarian cancer, castration-resistant prostate cancer (CRPC), breast cancer, endometrial cancer, colorectal cancer, small cell lung cancer (SCLC), or pancreatic cancers. Results: As of data cutoff (12Jan2024), 17 patients received Q901 across 3 dose levels: 5 patients at 18 mg/m2, 4 patients at 36 mg/m2, and 8 patients at 60 mg/m2. The median prior lines of systemic therapy were 4 (range 2 - 17). Of 17 patients who received Q901 across all doses, there were no treatment related SAEs, treatment discontinuations, or dose reductions. Most common TRAEs ≥ 15% were nausea (29.4%), anemia (23.6%) and fatigue (23.5%). As of data cutoff, no DLTs were observed. All plasma PK analyses across dose levels showed dose dependent increase of AUC0-last and Cmax. No major metabolite was observed. POLR2A, which is a CDK7 target engagement marker showed biologically effective change starting from 18 mg/m2. 1 patient with pancreatic cancer who received 18 mg/m2 had a partial response with CA19-9 reduction from 4,632 to 219. 2 patients at 18 mg/m2 and 2 patients at 36 mg/m2 had stable disease. Additional safety and efficacy data will be presented. Conclusions: Preliminary data from QRNT-009 study showed that selective CDK7 inhibitor Q901 is well tolerated. Preliminary antitumor activity and pharmacodynamic observations are encouraging. Dose escalation is ongoing to identify MTD or recommended dose for further studies. Clinical trial information: NCT05394103 .

Safety, tolerability, pharmacokinetics and clinical activity of AST-3424, an AKR1C3-activated bis-alkylating moiety prodrug, in subjects with advanced solid tumors in China: A phase I dose-escalation study.

3121 Background: Aldo-keto reductase family 1 member C3 (AKR1C3) modulates cellular differentiation and proliferation through indirect regulation of ligand access to hormone and nuclear receptor signaling. AKR1C3 is expressed at high levels in various human cancers, including hepatocellular carcinoma (HCC). AST-3424 is an AKR1C3-activated prodrug and releases a toxic bis-alkylating moiety (AST-2660) in the presence of AKR1C3, which forms intra- and inter-strand DNA crosslinks resulting in cell death. Here we report the results of a phase I dose escalation study of AST-3424 in patients with advanced solid tumors (NCT06239155). Methods: Patients with histologically and/or cytologically confirmed advanced solid tumors who failed standard treatment or no standard treatment, or not suitable for standard treatment were enrolled to receive AST-3424 intravenously (i.v.) at doses of 1, 2, 4, 6, 8 mg/m2 on Day 1 and Day 8 every 21 days. A parallel and accelerated titration for 1 and 2 mg/m2, and 3+3 dose escalation design for other cohorts were used to guide dose escalation and maximum tolerable dose (MTD) determination. Results: 21 subjects were enrolled and received at least one treatment (HCC=4, colorectal cancer=6, gastric cancer=4, pancreatic carcinoma=2, breast cancer=2, intrahepatic cholangiocarcinoma=1, prostate cancer=1, salivary gland cancer=1). 4 dose-limiting toxicities (DLTs) were observed (3 grade 4 platelet count decreased; 1 grade 2 gamma-glutamyltransferase increased, DLT reported due to dosing delayed more than 14 days). Safety Review Committee confirmed 6.0 mg/m2 as the MTD and recommended Phase 2 dose (RP2D). Grade≥3 adverse events (AEs) were observed in in 10 patients (47.6%). 8 patients (38.1%) had grade≥3 treatment-related AEs (TRAEs), being anemia (33.3%), platelet count decreased (19.0%), white blood cell count decreased (9.5%) and neutrophil count decreased (9.5%). Most of the grade≥3 AEs were observed in the 8.0 mg/m2 cohort. No patient had a fatal TRAE. 15 subjects with baseline target lesions had at least one post baseline assessment. 9 subjects (42.9%) had stable disease (SD); 1 subject (4.8%) had non-complete remission/non-disease progression (Non-CR/Non-PD); 5 subjects (23.8%) had progressive disease (PD). AST-3424 showed linear pharmacokinetic characteristics in the range of 1.0-8.0 mg/m2 with a half-life of 0.16-0.40 hours. AST-2660 showed linear pharmacokinetic characteristics in the range of 4.0-8.0 mg/m2 with a half-life of 1.59-2.08 hours. Conclusions: AST-3424 showed a tolerable safety profile and preliminary anti-tumor activity in advanced solid tumors. The phase II dose expansion phase of AST-3424 monotherapy is ongoing in subjects diagnosed as advanced HCC and with high AKR1C3 expression. Clinical trial information: NCT06239155 .

Safety and efficacy of JSKN003 in patients with advanced/metastatic solid tumors: A first-in-human, dose-escalation, multicenter, open-label, phase I study.

3038 Background: JSKN003 is a biparatopic HER2-directed ADC conjugated to a topoisomerase I inhibitor with an average DAR 4. Preclinical studies showed that JSKN003 had a good serum stability and strong anti-tumor activity. Hence JSKN003 could be effective in HER2 expressing tumors with a potentially broader therapeutic window. Methods: JSKN003-101 is a first-in-human, dose-escalation and -expansion study in Australian pts with advanced solid tumors. Pts (ECOG 0-1) with histologically documented HER2-expressing (HER2-positive defined as IHC 2+ or 2+/ISH+, HER2 low defined as IHC 1+ pr 2+/ISH-) or HER2-mutation by local testing who failed prior systemic therapies were recruited and received JSKN003 monotherapy intravenously Q3W. The objectives were safety, tolerability, MTD or RP2D, PK, and preliminary antitumor activity. Here the results from dose-escalation part were reported. Results: As of 15 Dec 2023, 32 pts were enrolled and received JSKN003 across 7 dose levels (1.0-8.4 mg/kg, Q3W). Among the 32 pts, 9 were IHC 1+, 16 were IHC 2+, and 7 were IHC 3+. Most pts (22/32, 68.8%) received ≥ 3 prior lines of therapy. The median duration of treatment was 15.8 (range, 6-54) weeks, and 19 pts (59.4%) remain on treatment. TRAEs occurred in 27 pts (84.4%) and 2 pts (6.3%) in 4.2mg/kg and 7.3mg/kg experienced grade 3 TRAE (anemia and fatigue); the most common TRAEs were diarrhea (62.5%) and nausea (50.0%), which were all grade 1-2. Only 1 pt experienced ILD/pneumonia (7.3mg/kg, grade 2). To date, no DLT events were found yet, and no TRAE led to death or treatment discontinuation. MTD has not been reached in 8.4 mg/kg. Following a single dose, exposures (Cmax and AUC) of JSKN003 and released TOP1i increased proportionally over a dose range of 4.2 mg/kg to 8.4 mg/kg. T1/2 of JSKN003 is approximately 5-6 days for 6.3 mg/kg and higher doses and increases with dose escalation. Accumulation of JSKN003 was minimal within the range of 1.1-1.5. The exposure of released payload was significantly lower than JSKN003 ADC, demonstrating the stability of the JSKN003 in circulation. All pts had at least one post-baseline tumor assessment. 16 pts achieved PR per RECIST 1.1 by investigator. Thus, ORR and DCR was 50.0% (95%CI: 31.9%, 68.1%) and 90.6% (95%CI: 75.0%, 98.0%), respectively. The ORR in pts with IHC 1+, 2+ and 3+ was 55.6% (5/9), 37.5% (6/16), and 71.4% (5/7), respectively. As for the efficacy of the HER2-positive and HER2-low breast cancer, the ORR was 80% (4/5) and 40.0% (4/10), respectively. Conclusions: JSKN003 was well tolerated with encouraging preliminary antitumor activity in heavily pretreated pts with advanced/metastatic solid tumors, especially in pts with HER2 expressed tumors. As of the cut-off date, no DLT was observed, MTD has not been reached yet. Clinical trial information: NCT05494918 .

Phase I/II trial of LAVA-1207, a novel bispecific gamma-delta T-cell engager alone, or with low dose IL-2 or pembrolizumab, in metastatic castration resistant prostate cancer (mCRPC).

TPS2672 Background: LAVA-1207 is a humanized bispecific antibody that binds with high affinity to the Vδ2 chain of Vγ9Vδ2-T cells and to prostate-specific membrane antigen (PSMA). It comprises a heterodimer of two fusion proteins, each consisting of a VHH linked to a human IgG1 Fc domain. Preclinical evidence demonstrates that, upon binding both targets, LAVA-1207 leads to potent Vγ9Vδ2-T cell degranulation and cytolytic activity against PSMA-expressing prostate cancer cells. IL-2 is an immune modulator which has been shown to support expansion of activated Vγ9Vδ2-T cells. PD-1 is an inhibitory immune checkpoint receptor that can dampen (Vγ9Vδ2-) T cell reactivity, suggesting that pembrolizumab could potentiate the effect of LAVA-1207. Methods: This trial is a phase 1/2a open label study with a 3+3 design in patients with refractory mCRPC to assess the safety of LAVA-1207 alone or with low dose IL-2 or with pembrolizumab, and to determine the recommended Phase 2a dose (RP2D). Secondary objectives include evaluation of pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary antitumor activity. Exploratory endpoints include evaluation of the effect of study treatment on circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA). LAVA-1207 is administered IV every two weeks. Two parallel cohorts assessing LAVA-1207 with low dose subcutaneous IL-2 have been implemented: (1) single IL-2 administration and (2) three IL-2 administrations on consecutive days per cycle for up to four cycles. An additional dose escalation arm evaluates LAVA-1207 in combination with pembrolizumab, 400mg Q6W, IV. Patients with mCRPC that have failed at least one prior AR therapy and taxane-based chemotherapy (unless deemed medically unsuitable to receive a taxane) will be enrolled on the study. Patients should have progressive disease either by PSA or by RECIST 1.1 or appearance of 2 or more bone metastases. Patients must have ECOG performance status of 0-1. PSMA-PET is performed at baseline. Paired biopsies are requested to further assess LAVA-1207 activity. Dose escalation is ongoing. Expansion arm(s) will be included based on available data from part 1 of the study and may include one or more of LAVA-1207, LAVA-1207 with low dose IL-2, or LAVA-1207 in combination with pembrolizumab. Clinical trial information: NCT05369000 .

Open-label, phase 1, multicenter study to evaluate the safety and preliminary anti-tumor activity of NT-175 in human leukocyte antigen-a*02:01-positive adult subjects with unresectable, advanced and/or metastatic solid tumors that are positive for the TP53 R175H mutation.

e14514 Background: The TP53 tumor suppressor gene is the most commonly mutated gene across all cancer types, and TP53 R175H is the most common recurrent mutation across indications, identified in 6.7% of patients with breast cancer, 6% of patients withs colorectal cancer, and 4.2% of patients with pancreatic cancer. No therapy is approved for treatment directly targeting TP53 R175H. NT-175 is an armored autologous T-cell product expressing an HLA-A*02:01-restricted TCR recognizing TP53 R175H with disruption of the endogenous TCR and the transforming growth factor beta receptor type 2 (TGFBR2) genes. Methods: This first-in-human phase I, open label study will assess the safety and preliminary anti-tumor activity, identify the maximum tolerated dose (MTD), and evaluate the persistence, and functional capacity of NT-175 in subjects with advanced, recurrent unresectable/metastatic solid tumors refractory to treatment options. The study will enroll approximately 24 subjects harboring TP53 R175H and HLA-A*02:01. Enrolled patients will undergo leukapheresis from which CD4 and CD8 T cells will be enriched and activated ex vivo. The endogenous TCR α and β chain gene are knocked out utilizing clustered Regularly Interspaced Short Palindromic repeats (CRISPR-Cas9) and the TCR encoding an HLA-A*02:01-restricted TCR specific to the TP53 R175H mutation is inserted in the TCR α locus. Additionally, the T cells are edited to disrupt the gene encoding the TGFBR2 to reduce the immunosuppressive effect of TGF-β in the tumor microenvironment. Subjects will undergo lymphodepletion chemotherapy with fludarabine and cyclophosphamide followed by a single infusion of NT-175 and subcutaneous recombinant IL-2 administration for up to 8 days. Dose escalation will occur across 3 ascending dose levels following the BOIN design. Subjects will be monitored for dose-limiting toxicities for 28 days after NT-175 infusion. Tumor response will be assessed by RECISTv1.1 criteria. All subjects will be followed for up to 15 years. Primary endpoints include safety, dose limited toxicities, MTD determination, and recommended Phase II dose. Secondary endpoints include preliminary efficacy measures. Translational analysis will evaluate potential biomarkers for insights into mechanism of action, response prediction, or resistance mechanisms. The study was activated in March 2023 and is open to accrual; 5 patients have been enrolled as of 4 Jan 2024.

Preclinical studies of an innovative 5T4-ADC ACR246 with the potential to better treat 5T4-positive solid tumors.

e15005 Background: 5T4 oncofetal antigen shows limited expression in normal adult tissues but highly expressed by many different cancers. It drives spread of cancer cells through epithelial mesenchymal transition (EMT), potentiation of CXCL12/CXCR4 chemotaxis and favoring non-canonical Wnt pathway, leading to poor prognosis of cancer patients. Besides, 5T4 has a highly efficient endocytosis ability which enables it to be an ideal target for the development of ADC drugs. A handful of 5T4-targeted ADCs have been evaluated in early phase clinical trials for several years showing only preliminary anti-tumor activity. However, uncertainty of their safety profiles has also raised concerns due to high toxic payloads, MMAF and duocarmycin, being used. Thus, additional approaches to this target with the potential of improved efficacy and reduced toxicity are needed urgently. ACR246, an innovative 5T4-targeted ADC consisting of specific humanized monoclonal antibody site-specifically conjugated with a cell penetrating and moderate toxic payload (DNA topoisomerase I inhibitor, D2102) that has a robust bystander effect through a stable and cleavable linker, with a drug-to-antibody ratio (DAR) of 8, was designed to improve the safety and efficacy in treating tumor patients. Methods: The pharmacologic profiles of ACR246 were assessed in vitro and in vivo including efficacy, pharmacokinetics-pharmacodynamics (PK-PD), safety, and tissue distribution, in 5T4-positive cell lines, cell-derived xenograft (CDX) models and cynomolgus monkeys. Results: ACR246 bound specifically to 5T4 and was internalized into tumor cells followed by D2102 release, which induced DNA damage, cell cycle arrest and apoptosis in 5T4 positive tumor cells in vitro. In vivo low systemic exposure and tumor-specific accumulation of D2102 rendered ACR246 superior efficacy and safety property. Accordingly, ACR246 exhibited robust in vivo anti-tumor activity across various types of 5T4 positive CDX models in a dose-dependent manner, with DNA damage induced by the accumulated D2102 in tumor tissue. GLP toxicity studies indicated that ACR246 was well tolerated in cynomolgus monkeys. The estimated therapeutic index was 24. Conclusions: The overall preclinical profile marks ACR246 has the potential to become the best in class (BIC) 5T4-ADC, showing more favorable benefit-risk ratio in clinic.

A phase 1/2 study of the TBL1 inhibitor, tegavivint (BC2059), in patients (pts) with advanced hepatocellular carcinoma (aHCC) with β-catenin activating mutations.

TPS4192 Background: β-catenin mutations are present in up to 40% of aHCC pts. Elevated nuclear β-catenin expression levels correlate with poor responses to standard of care and β-catenin regulates both tumor metabolism and the immune microenvironment. Tegavivint is a first-in-class small molecule inhibitor of TBL1, a novel downstream Wnt-signaling pathway target. Tegavivint binds to TBL1 in the β-catenin pocket, disrupting the formation of the activation complex necessary for oncogenic activity, and enabling degradation of free nuclear β-catenin. The safety, clinical activity, and PK/PD of tegavivint was demonstrated through a proof-of-concept study in pts with desmoid tumors and is being studied through multiple Investigator Initiated Trials in AML (NCT04874480), pediatric solid tumors (NCT04851119), NSCLC (NCT04780568), and lymphoma (NCT05755087). Tegavivint was also studied in preclinical mouse models of β-cateninexon3 mutant HCC and the H22 syngeneic HCC model. In these models tegavivint decreased Wnt target gene expression and enhanced CD3+ T-cell infiltration in liver tumors. Tegavivint treatment of established β-cateninexon3 activated tumors resulted in reduced tumor growth and burden. Based on these promising preclinical results, the following phase 1/2 exploratory study was designed. Methods: This is a phase 1/2 study of tegavivint in pts with aHCC to characterize safety, PK/PD, and preliminary antitumor activity (NCT05797805). Eligibility includes aHCC pts ≥18 years old, with AXIN1or CTNNB1 mutation for all pts, except those in the single agent dose escalation; have BCLC Stage C or Stage B disease not amendable to local therapy or curative approaches, have Child-Pugh class A or B7 liver score, and must have received at least one prior line of systemic therapy. This study will be conducted in 2 parts. First, tegavivint will be administered as a single agent in a dose escalation/optimization and subsequent dose expansion cohort. Upon completion of the dose escalation via a 3+3 design, two dose levels will be selected for the dose selection optimization to determine the recommended phase 2 dose (RP2D) for use in the dose expansion. If sufficient clinical benefit is observed, the combination of tegavivint plus pembrolizumab will be explored in the second part of the study in aHCC pts previously treated with a PD-1/PD-L1 inhibitor. Tegavivint will be administered intravenously weekly. Primary objective is safety and secondary objectives are preliminary efficacy and PK/PD. The first patient began treatment in October of 2023 and the first dose escalation cohort was completed in January. Three institutions are open for enrollment; 5 other sites are pending site activation; all sites are in the United States and Canada. Clinical trial information: NCT05797805 .

A first-in-human, phase 1/2 trial of FOG-001, a β-catenin:TCF antagonist, in patients with locally advanced or metastatic solid tumors.

TPS3175 Background: The Wnt/β-catenin pathway is a frequently activated oncogenic pathway and a well-described driver of many cancers. FOG-001 is designed to be a first-in-class direct inhibitor of β-catenin that blocks β-catenin’s interaction with the T-cell factor (TCF) family of transcription factors. Preclinical studies have indicated FOG-001 can cause tumor growth inhibition and regression by disrupting β-catenin-dependent signaling. FOG-001 is unique from previously reported Wnt/β-catenin pathway modulators as it is designed to directly inhibit TCF transcription factor and β-catenin interaction, the most downstream node in the Wnt pathway. It is hypothesized FOG-001 will abrogate the hyperactivation of the Wnt pathway that is driven by most known pathway mutations. Methods: This first-in-human, Phase 1/2, multicenter, open-label, dose escalation (Parts 1a and 1b) and dose-expansion (Part 2) study is evaluating the safety/tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of FOG-001 in patients with advanced or metastatic solid tumors. Patients with the following tumor types are eligible: microsatellite stable (MSS) colorectal cancer (CRC) or any solid tumor with documented Wnt pathway activating mutation (WPAM) (Part 1a), MSS CRC only (Part 1b) and MSS CRC, gastric/gastroesophageal (GEJ) cancer, non-small cell lung cancer (NSCLC), and any solid tumors with documented WPAM in Part 2. Patients must have received ≥1 prior systemic anticancer therapy(ies) and be ineligible for curative surgery or curative chemoradiation. In Part 1, FOG-001 is administered at escalating doses via intravenous (IV) infusion on Days 1, 8, 15, and 22 of each 4-week cycle; additional dosing regimens may be explored. After selection of the preliminary recommended Phase 2 dose(s) (pRP2D) and regimen(s) in Part 1, the following cohorts will be enrolled to receive FOG-001 at the pRP2D in Part 2: (2a) MSS CRC; (2b) NSCLC with documented WPAM in adenomatous polyposis coli (APC) or β-catenin; (2c) gastric/GEJ cancer with documented WPAM in APC or β-catenin; and (2d) solid tumors with ≥1 documented WPAM in any predefined Wnt pathway genes. The primary endpoints are safety/tolerability (Parts 1 and 2), and also preliminary antitumor activity (objective response rate) (Part 2). Secondary endpoints are PK, PD, and additional antitumor activity assessments. Enrollment in Part 1 is ongoing. Clinical trial information: NCT05919264 .

A phase I/II study of maplirpacept in combination with pegylated liposomal doxorubicin (PLD) in patients with platinum-resistant ovarian cancer (OC): Phase 1 results.

e17546 Background: CD47, an overexpressed factor correlated with poor clinical characteristics and prognosis in OC, is an innate immune checkpoint that binds signal regulatory protein alpha (SIRPα) and delivers a signal to suppress macrophage phagocytosis. Maplirpacept (PF-07901801) is a fusion protein consisting of the CD47-binding domain of human SIRPα linked to the Fc region of human IgG4, enhancing phagocytosis by blocking CD47. Blockade of CD47, both alone and combined with doxorubicin, has shown anti-tumor activity in vitro and in vivo in xenograft animal models. PLD 40mg/m2 conveyed poor efficacy (PFS 4 months; ORR 8%), as did bevacizumab + PLD (PFS 5 months; ORR 14%) (AURELIA), highlighting the need for new treatments for platinum-resistant OC. C4971002 [NCT05261490] is an open label, multicenter dose-escalation and expansion study evaluating the safety, preliminary anti-tumor activity, pharmacokinetics and -dynamics of maplirpacept in combination with PLD in patients with platinum-resistant recurrent OC. Methods: The study included adults with platinum-resistant recurrent epithelial OC (PD ≤6 months after platinum-based therapy or unable/unwilling to receive platinum-based therapy). PLD while platinum-resistant or directly prior to study was not permitted. Patients received maplirpacept (12mg/kg Dose Level [DL] 1; 24mg/kg DL2; 48mg/kg DL3) weekly in Cycle 1 and every 2 weeks in Cycle 2+, and PLD (40mg/m2) on Day 1 of each 4-week cycle. Assessments of adverse events (AEs) were based on CTCAE v5.0. Response assessments (RECIST v1.1) were performed every 8 weeks. Results of the Phase I portion, aiming to evaluate the DLTs, the MTD and the RP2D, are presented as of 18 December 2023, after all patients completed the 28-day DLT assessment period. Results: 10 patients were treated (DL1 n=3; DL2 n=3; DL3 n=4) with a median (min, max) age of 69 (53, 77) years, 80% ECOG 1, 60% serous adenocarcinoma. Median (min, max) treatment duration was 14 (8, 32) weeks. Most common adverse events are shown in the table. No DLTs occurred in the assessment period. 1 serious AE (gait disturbance & muscle weakness) related to maplirpacept was reported (DL3). 2 deaths occurred >120 days after 1st dose, both due to disease. 5 (50%) patients had a best response of stable disease, 2 of which were treated into at least Cycle 6. Conclusions: Despite immature anti-tumor activity, maplirpacept + PLD was tolerable at all dose levels, not reaching the MTD. The encouragingly tolerable dose of 48mg/kg thus represents the RP2D which could support further development for this population. Clinical trial information: NCT05261490 . [Table: see text]

An open-label, multicenter phase 1 study to characterize safety, tolerability, preliminary antitumor activity, pharmacokinetics, and pharmacodynamics of VIP943 monotherapy in patients with advanced CD123+ hematologic malignancies.

TPS3167 Background: VIP943 is an anti-CD123 antibody-drug conjugate (ADC) with a unique linker cleaved only by legumain and a novel kinesin spindle protein inhibitor payload. The linker-payload was engineered to increase the therapeutic index thereby improving efficacy and reducing severe toxicities compared with current ADCs. In an in vivo MOLM-13 model, VIP943 had statistically significant (p <0.001) improvement in tumor growth inhibition compared with the only ADC approved for the treatment of acute myeloid leukemia (AML), gemtuzumab ozogamicin (GO). In a nonhuman primate (NHP) single dose toxicology study, VIP943 (20 mg/kg) showed no signs of toxicity as measured by hematology, serum chemistry and survival. In contrast, NHP treated with a single dose of GO (3 mg/kg) had significant toxicity including death and mandatory euthanasia. The single-dose toxicity of GO was ameliorated by substituting the VIP943 proprietary linker and payload on an anti-CD33 antibody (3 mg/kg) as measured by hematology, serum chemistry and survival. (1,2). Methods: This trial in progress (NCT06034275) is an open-label, multicenter, Phase 1, first-in-human (FIH), dose-escalation and dose-optimization study of VIP943 in subjects with relapsed or refractory CD123+ hematologic malignancies including AML, myelodysplastic syndrome, and B-cell acute lymphoblastic leukemia. A cycle of VIP943 treatment is 28 days of once weekly intravenous infusions with no pause between cycles. The dose-escalation portion of this study follows a standard 3+3 design. Dose escalation decisions will be made by the safety review committee, and decisions will be based on the incidence of dose-limiting toxicities (DLTs). Based on FDA guidance, a dose-optimization portion of this study will randomize subjects into ≥2 dose cohorts to derive a recommended dose range for Phase 2. The study will also characterize the pharmacokinetics of VIP943 and its components and explore potential biologic activity by assessing pharmacodynamic/exploratory biomarkers, and antitumor activity using standard response criteria. As this is a FIH study, only subjects with CD123+ hematologic malignancies who have exhausted all available therapies or are not fit for standard of care can be enrolled. The results from this study will form the basis for decisions for future studies. Enrollment for cohorts 1 (no DLTs) and 2 (safety review ongoing) has completed. 1. Stelte-Ludwig et al ASH 2022. 2. Stelte-Ludwig et al ASH 2023. Clinical trial information: NCT06034275 .

H3B-6545 + palbociclib in patients (pts) with locally advanced/metastatic estrogen receptor-positive (ER+), HER2 negative (–) breast cancer (BC).

1051 Background: H3B-6545 — a novel selective ER covalent antagonist (SERCA) that potently inactivates wild-type and mutant ERα — has shown preliminary antitumor activity and tolerable safety in pts with advanced/metastatic, ER+, HER2– BC. Palbociclib (palbo), an oral CDK4/6 inhibitor, has shown activity in metastatic disease when combined with endocrine therapy. The dose escalation part of this open-label, multicenter, phase 1b study of H3B-6545 + palbo in pts with ER+, HER2– BC aimed to identify the recommended phase 2 dose (RP2D) of H3B-6545 + palbo and characterize safety and efficacy. Methods: Females aged ≥18 years with ER+, HER2–, locally advanced/recurrent/metastatic BC, ECOG PS 0–1, and progression on/after standard therapy were eligible. In the dose escalation phase, pts had to have received ≥2 prior hormonal therapies. Palbo was to be escalated no higher than 125 mg orally QD (days 1–21) and H3B-6545 no higher than 450 mg orally QD (days 1–28). The MTD was the highest dose at which ≤1 of 6 pts had a dose-limiting toxicity (DLT). The primary endpoint was determination of the MTD and/or RP2D. Secondary endpoints included safety and efficacy (by investigator per RECIST v1.1). Results: At data cutoff (16 Sept 22), 31 pts were treated: Cohort (C) 1: H3B-6545 300 mg + palbo 100 mg (n=7); C2: H3B-6545 300 mg + palbo 125 mg (n=8); C3: H3B-6545 450 mg + palbo 125 mg (n=8); C3b: H3B-6545 450 mg + palbo 100 mg (n=8). 3 DLTs (grade 3/4 neutrophil count decreased [n=2] and grade (G) 3 QTcF prolongation [n=1]) were observed in C3 (5 DLTs were observed at C3b); C2 dose was deemed the MTD. Of all pts, 90.3% had G ≥3 TEAEs, 32.3% had serious TEAEs, and 6.5% had TEAEs leading to drug withdrawal. Sinus bradycardia (67.7% [G ≥3, 0%]) and anemia (54.8% [G ≥3, 19.4%]) were the most frequent TEAEs. QT prolongation and rash occurred in 19.4% [G ≥3, 12.9%] and 16.1% [G ≥3, 9.7%] of pts, respectively. ORR in response evaluable pts was 23.1% (95% CI 9.0–43.6). The Table shows additional results. Conclusions: H3B-6545 300 mg + palbo (100/125 mg) had manageable safety and encouraging preliminary antitumor activity. Further studies are warranted to identify the RP2D. Clinical trial information: NCT04288089 . [Table: see text]

The FIPO23 trial: First-in-human phase I/II study of XON7 in advanced solids tumors.

TPS2673 Background: XON7 is a first-in-class glyco-humanized polyclonal antibody (GH-pAb) targeting selectively multiple tumor-associated antigens. XON7 induces tumor cell apoptosis and promotes the elimination of tumor cells by immune effector cells through CDC (Complement Dependent Cytotoxicity) and ADCP (Antibody-Dependent Cell Phagocytosis). XON7 demonstrated anti-tumor efficacy in mice xenograft models with human solid tumors such as colon, prostate, lung and triple negative breast cancers. Safety pharmacology and toxicology studies in non-human primates demonstrated an acceptable safety profile for XON7. Taken together, these preclinical data support the initiation of human trials in patients with advanced solid tumors. Methods: First-in-patient, multicenter, open-label, two phases (dose-escalation (ESC) followed by dose expansion (EXP)) study of XON7 single agent, in patients with relapsed refractory, locally advanced or metastatic solid tumors without standard available treatments ( NCT06154291). Key eligibility criteria include disease progression after ≤ 4 lines of therapy; age > 18 years; ECOG performance status ≤2; adequate organ functions; no known CNS involvement. All advanced or metastatic tumor types except glioblastoma, can be included during ESC. Primary endpoints: safety, tolerability and determination of MTD/RP2D. Secondary endpoints: pharmacokinetics (PK), pharmacodynamics, immunogenicity and preliminary anti-tumor activity (RECIST 1.1). AEs graded according to CTCAE 5.0. In the ESC part, XON7 is administered as 60-min intravenous infusion every 2 weeks according to an escalating schedule of doses from 1.5 to 20 mg/kg for up to 12, 28-day cycles. Dose escalation/de-escalation is based on the Bayesian Optimal Interval (BOIN) design, up to 45 pts are planned. At the recommended dose, up to 7 EXP cohorts (30 pts each) defined according to the primary tumor site are planned. Bayesian sequential monitoring will be used. Patient recruitment is planned or ongoing at 25 sites worldwide. Results: As of Feb 3rd, 2024, 3 pts are enrolled in the first dose cohort and have received XON7 at dose 1,5 mg/kg Q2W for the first 28-days cycle. Conclusions Accrual is ongoing in this first-in-human trial of XON7. Clinical trial information: NCT06154291 .

Evaluation of the safety, pharmacokinetics, and efficacy of JSKN003 in patients with advanced solid tumors: A phase I/II clinical study.

3031 Background: JSKN003 is a bispecific HER2-directed antibody-drug conjugate (ADC) conjugated to a topoisomerase I inhibitor via a dibenzocyclooctyne tetrapeptide linker on the glycan of a humanized bispecific antibody. Pre-clinical studies showed that JSKN003 had a good serum stability, that may lead to a broader therapeutic window. Methods: JSKN003-102 (NCT05744427) is a phase I (dose escalation and dose expansion) and phase II (cohort expansion) study in Chinese patients (pts) with advanced solid tumors. Pts (ECOG PS 0-1) with HER2-expressing (IHC ≥ 1+) or HER2-mutant cancers who failed prior systemic therapies were recruited and received JSKN003 monotherapy intravenously Q3W. The objectives were safety, MTD or RP2D, pharmacokinetics, and preliminary antitumor activity. Here the results from phase I were reported. Results: As of 5th Jan 2024, 46 pts (25 breast cancers, 11 gastric cancers, 8 colorectal cancers, 1 lung cancer, and 1 ovarian cancer) were enrolled and received JSKN003 across 6 dose levels, including 2.1 (n=1), 4.2 (n=10), 5.2 (n=14), 6.3 (n=15), 7.3 (n=3), and 8.4 mg/kg (n=3), Q3W, in phase I period. Among the 46 pts, 18 were IHC 3+, 21 were IHC 2+, and 7 were IHC 1+. Most pts (73.9%) received ≥ 3 prior lines of therapy, including 60.9% and 45.6% of pts received prior anti-HER2 and anti-HER2 ADC therapy, respectively. The median duration of treatment was 13.1 (range, 2.1 - 42.4) weeks, and 37 pts (80.4%) remained on treatment. Treatment-related adverse events (TRAEs) occurred in 44 pts (95.7%), and the common, mostly grade 1 and 2, were diarrhea (37.0%) and nausea (32.6%). Only 6 pts (13.0%) experienced grade ≥3 TRAEs, and the common were lymphopenia (4.3%) and neutropenia(4.3%). 1 pt (2.2%) had treatment related SAE (nausea, grade 3). No pts experienced DLT or interstitial lung disease, and no TRAE led to death or discontinuation. Following a single dose, exposures (Cmax and AUC) of JSKN003 increased proportionally over a dose range of 4.2 mg/kg to 6.3mg/kg. T1/2 of JSKN003 is approximately 3-5 days. No significant accumulation was observed after 4 cycles treatment. The exposure of released payload was very low, demonstrating the stability of the JSKN003 in circulation. 37 pts had at least one post-baseline tumor assessment. The ORR and DCR was 51.4% (95%CI: 34.4, 68.1) and 91.9% (95%CI: 78.1, 98.3), respectively. The ORR in pts with HER2 IHC 1+, 2+ and 3+ was 20.0% (95% CI: 0.5, 71.6), 33.3% (95% CI: 11.8, 61.6), and 76.5% (95% CI: 50.1, 93.2), respectively. For pts who received prior anti-HER2 ADC, the ORR was 57.9% (95% CI: 33.5, 79.7). For HER2 positive breast cancer and gastric cancer, the ORR was 66.7% (95% CI: 38.4, 88.2) in 15 pts and 100% (95% CI: 39.8, 100) in 4 pts, respectively. Conclusions: MTD of JSKN003 was not reached yet. And safety of JSKN003 was extremely excellent with encouraging preliminary antitumor activity in heavily pretreated pts with advanced solid tumors. Clinical trial information: NCT05744427 .

A phase I dose escalation trial of BCD-145 in patients with unresectable or metastatic melanoma.

9526 Background: BCD-145 (nurulimab) is a fully human IgG1 mAb with modified Fc-fragment (the 1st Gln is replaced by Glu in the heavy chain sequence, and there is no terminal dipeptide composed by Gly and Lys residues) that binds to cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and blocks the interaction between CTLA-4 and its ligands. This allows to stimulate T-cell proliferation, cytokine production and induces antitumor immune response. Here we present the results of multicenter open-label single-arm multi-cohort phase I trial of pharmacokinetics (PK), pharmacodynamics (PD), safety, and immunogenicity of BCD-145 in pts with unresectable/metastatic melanoma (unr/mM). Methods: BCD-145 monotherapy in 3+3 dose escalation [0.1, 0.3, 1, 3, 10 mg/kg intravenously Q3W] was given to 15 pts with unr/mM with measurable disease, who had failed prior therapy, ECOG 0-2. Pts with brain mts, previous therapy with aCTLA-4 and/or aPD-1/PD-L1 drugs were not allowed. The main objective of the study was to evaluate PK, PD, tolerability, immunogenicity, safety, dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) identification. Secondary objectives included tumor response rate (irRECIST). Results: BCD-145 proved safety and overall was well tolerated. DLT and MTD were not reached. Any grade (Gr) adverse events (AEs) occurred in 100% (15/15) of pts. 33.3% (5/15) of pts had AE/SAE of Gr 3-4, including hypertension Gr 3 (1 at 1 mg/kg), hypercalcemia Gr 4 (2 at 1 mg/kg), hypokalemia Gr 3 (2 at 1 mg/kg), neutropenia Gr 3 (1 at 0.3 mg/kg), anemia Gr 3 (1 at 1 mg/kg), lung infection Gr 3 with hospitalization (1 at 1 mg/kg). Only 2 pts had a treatment-related AE Gr 3-4. Immuno-related AE were identified in 46.7% (7/15), manifested by symptoms of thyroiditis (mainly Gr 1) and diarrhea Gr 2 (1 at 10 mg/kg). There was 1 death (at 1 mg/kg) due to progression. There is dose-dependent peak study drug serum concentrations and systemic exposure. Two dosage regimens (1 mg/kg, 3 mg/kg Q3W) allowed to achieve the optimal concentration. BCD-145 increased subpopulations of activated HLA-DR+ CD4+ and CD8+ T lymphocytes, CD4+ICOS+ T-lymphocytes, absolute lymphocyte counts in all cohorts without significant differences. Binding and neutralizing Abs against BCD-145 were detected in 2 pts from different dose cohorts (0.3 mg/kg, 1 mg/kg). PR and SD were registered in 2 pts of each response group. 30.8% of pts achieved disease control, which is consistent with published data on other CTLA-4 inhibitors. A dose of 1 mg/kg is determined as recommended phase 2 dose (RP2D). Conclusions: BCD-145 demonstrated a tolerable safety profile and preliminary anti-tumor activity in pts with unr/mM. Anti-tumor effects of BCD-145 were observed in pts who had progressed on prior treatment. Further co-targeting PD-1 and CTLA-4 simultaneously will achieve a better anti-tumor activity due to cooperative binding to exhausted T-cell subsets. Clinical trial information: NCT03472027 .

A phase I/II study of C019199 in combination with sintilimab in advanced malignancy.

e15110 Background: C019199 is an oral CSF-1R/DDRs/VEGFR2 multiple kinase inhibitor and modulates the immune micro-environment of tumor cells. Previous phase I study of C019199 as a mono-therapy for advanced solid tumors has shown promising safety and anti-tumor activity. This phase I/II study is to evaluate the safety and efficacy of the combination of C019199 and Sintilimab in solid tumors. Methods: An open label, multicenter phase I/II study of C019199 combined with Sintilimab is currently enrolling (NCT06220318). Eligible subjects (age of ≥18 years and <76 years) with histologically or cytologically confirmed relapsed, refractory, or progressive metastatic solid tumors will be enrolled in. This trial consists of 2 parts: a phase I dose escalation study using a standard 3+3 design with 3 doses of C019199 (100 mg/qd, 200 mg/qd, 300 mg/qd) combined with a fixed dose of Sintilimab (200 mg, iv, q3w) to determine the maximum tolerated dose (MTD) and recommended phase Ⅱ dose (PR2D); A phase II study is planned to enroll about 20 patients in each tumor type, including but not limited to the following: colorectal cancer, gastric cancer, esophageal squamous cell carcinoma, pancreatic cancer, triple negative breast cancer, head and neck squamous cell carcinoma. Results: A total of 10 patients with advanced solid tumors were enrolled in the phase I study from Jul 20, 2023 to Nov 14, 2023. Median age was 54 (range, 37-71), with 6 males and 4 females. Tumor types were colorectal cancer (7 pts), non-small cell lung cancer (2 pts) and cervical cancer (1 pts), with a median 3 prior systemic therapies (range, 1-7). As of Jan 15, 2024, we have assessed safety in all pts and efficacy in pts with at least one tumor assessment result. No dose-limiting toxicities (DLT) observed in the dose range of 100 mg/qd~300 mg/qd and the MTD has not been reached. The most frequently reported TRAEs were aspartate aminotransferase increased (80%), γ-glutamyltransferase increased (70%), proteinuria (70%), creatine kinase-MB increased (70%), alkaline phosphatase increased (60%). Grade ≥3 TRAEs were hypertension (30%), proteinuria (10%), immune hepatitis (10%), diarrhea (10%). Among 7 colorectal cancer patients, 1 subject had partial responds (PR) and 6 had stable disease (SD) as the best responds with ORR of 14.3%, DCR of 100%. Four subjects were still on treatment. Median PFS was not reached (>3month). Two patients with non-small cell lung cancer and 1 patient with cervical cancer achieved the best response of SD, with a DCR of 100%. Phase II study is ongoing. Recommended dose is 200 mg/qd as the RP2D in selected solid tumors. Conclusions: The combination of C019199 and Sintilimab has shown good overall safety and tolerability. No DLT was observed in the dose range of 100 mg/qd ~ 300 mg/qd. Preliminary anti-tumor activity was observed in patients with advanced solid tumors. Phase II study is ongoing to accumulate more clinical data. Clinical trial information: NCT06220318 .

Preliminary safety, antitumor activity, and pharmacodynamics of intratumoral ABO2011 (IL-12 mRNA) in patients with advanced solid tumors.

e14583 Background: Interleukin (IL)-12 is a potent immunomodulatory cytokine demonstrating robust antitumor activity in multiple preclinical studies and potent immune-stimulating potential in humans. However, systemic delivery of IL-12 can result in life-threatening toxicity and therefore has shown limited efficacy at doses that can be safely administered. ABO2011 is a human IL-12 mRNA encapsulated in lipid nanoparticle and has been developed to be more effective and less toxic through the use of novel delivery technology and intratumoral injection. Methods: This phase I trial enrolled adults with advanced solid tumors who failed available standard treatments (NCT05392699). The trial was designed to primarily evaluate the safety of ABO2011 in single-dose cohorts and multiple-dose cohorts using “3+3” dose escalation approach. Patients (pts) would receive intratumoral ABO2011 at either a single dose, QW with 3 doses overall, every 3 weeks (Q3W) or QW followed by Q3W. Results: As of 09 December 2023, a total of 20 pts were enrolled and received at least one dose of ABO2011 at 4 μg single dose, 4 μg QW for 3 times, 12 μg single dose, 12 μg QW for 3 times followed by Q3W, 24 μg Q3W and 48 μg Q3W. Seventeen (85%) pts experienced treatment-related adverse events (TRAEs), and all were grade 1 or 2, including pyrexia (35%), pain (25%), and gamma-glutamyl transferase increased (25%). There were no dose-limiting toxicities or treatment-related SAEs reported and no TRAEs leading to treatment discontinuation. Of the 17 evaluable pts per RECISIT v1.1, 5 maintained stable disease, and the progression free survivals achieved 6.0 months, 5.6 months and 4.1 months for pts with colorectal cancer (6th line), non-small cell lung cancer (5th line) and pancreatic cancer (4th line), respectively. Peripheral blood IL-12 and IFN-γ levels increased and peaked at 24 hours and 48 hours after dosing, respectively, indicating expression of IL-12 and subsequent induction of IFN-γ after ABO2011 administration. Dose-dependent elevation of CXCL9, CXCL10, CXCL11 in peripheral blood was observed, consistent with the activation of downstream pathway of IFN-γ. CD8 T cells infiltration and PD-L1 expression were increased in tumor microenvironment (TME) at day 7, and further RNA sequencing analysis revealed increase of activated CD8 T cell and antigen processing and presentation after study treatment, suggesting the regulation of TME by ABO2011 and supporting the combination with PD-1(L1) inhibitor. Conclusions: Intratumoral ABO2011 was safe and well-tolerated in pts with advanced solid tumors. The pharmacodynamic changes were as expected. Promising preliminary antitumor activities of the single agent and the pharmacodynamic profiles support further investigation of ABO2011 in combination with immune checkpoint inhibitor. Clinical trial information: NCT05392699 .

A phase I/II study of maplirpacept in combination with pegylated liposomal doxorubicin (PLD) in patients with platinum-resistant ovarian cancer (OC): Phase 1 results.

e17546 Background: CD47, an overexpressed factor correlated with poor clinical characteristics and prognosis in OC, is an innate immune checkpoint that binds signal regulatory protein alpha (SIRPα) and delivers a signal to suppress macrophage phagocytosis. Maplirpacept (PF-07901801) is a fusion protein consisting of the CD47-binding domain of human SIRPα linked to the Fc region of human IgG4, enhancing phagocytosis by blocking CD47. Blockade of CD47, both alone and combined with doxorubicin, has shown anti-tumor activity in vitro and in vivo in xenograft animal models. PLD 40mg/m2 conveyed poor efficacy (PFS 4 months; ORR 8%), as did bevacizumab + PLD (PFS 5 months; ORR 14%) (AURELIA), highlighting the need for new treatments for platinum-resistant OC. C4971002 [NCT05261490] is an open label, multicenter dose-escalation and expansion study evaluating the safety, preliminary anti-tumor activity, pharmacokinetics and -dynamics of maplirpacept in combination with PLD in patients with platinum-resistant recurrent OC. Methods: The study included adults with platinum-resistant recurrent epithelial OC (PD ≤6 months after platinum-based therapy or unable/unwilling to receive platinum-based therapy). PLD while platinum-resistant or directly prior to study was not permitted. Patients received maplirpacept (12mg/kg Dose Level [DL] 1; 24mg/kg DL2; 48mg/kg DL3) weekly in Cycle 1 and every 2 weeks in Cycle 2+, and PLD (40mg/m2) on Day 1 of each 4-week cycle. Assessments of adverse events (AEs) were based on CTCAE v5.0. Response assessments (RECIST v1.1) were performed every 8 weeks. Results of the Phase I portion, aiming to evaluate the DLTs, the MTD and the RP2D, are presented as of 18 December 2023, after all patients completed the 28-day DLT assessment period. Results: 10 patients were treated (DL1 n=3; DL2 n=3; DL3 n=4) with a median (min, max) age of 69 (53, 77) years, 80% ECOG 1, 60% serous adenocarcinoma. Median (min, max) treatment duration was 14 (8, 32) weeks. Most common adverse events are shown in the table. No DLTs occurred in the assessment period. 1 serious AE (gait disturbance & muscle weakness) related to maplirpacept was reported (DL3). 2 deaths occurred >120 days after 1st dose, both due to disease. 5 (50%) patients had a best response of stable disease, 2 of which were treated into at least Cycle 6. Conclusions: Despite immature anti-tumor activity, maplirpacept + PLD was tolerable at all dose levels, not reaching the MTD. The encouragingly tolerable dose of 48mg/kg thus represents the RP2D which could support further development for this population. Clinical trial information: NCT05261490 . [Table: see text]