Metastatic Solid Tumors Research Articles

Performance of Tumor Surveillance for Children With Cancer Predisposition

Pediatric oncology patients are increasingly recognized as having an underlying cancer predisposition syndrome (CPS). Surveillance is often recommended to detect new tumors at their earliest and most curable stages. Data on the effectiveness and outcomes of surveillance for children with CPS are limited. To evaluate the performance of surveillance across a wide spectrum of CPSs. This cohort study reviewed surveillance outcomes for children and young adults from birth to age 23 years with a clinical and/or molecular CPS diagnosis from January 1, 2009, through September 31, 2021. Patients were monitored using standard surveillance regimens for their corresponding CPS at a specialty pediatric oncology center. Patients with hereditary retinoblastoma and bone marrow failure syndromes were excluded. Data were analyzed between August 1, 2021, and December 6, 2023. Cancer predisposition syndrome. Outcomes of surveillance were reviewed to evaluate the incidence, spectrum, and clinical course of newly detected tumors. Surveillance modalities were classified for accuracy and assessed for common strengths and weaknesses. A total of 274 children and young adults (mean age, 8 years [range, birth to 23 years]; 144 female [52.6%]) with 35 different CPSs were included, with a median follow-up of 3 years (range, 1 month to 12 years). During the study period, 35 asymptomatic tumors were detected in 27 patients through surveillance (9.9% of the cohort), while 5 symptomatic tumors were detected in 5 patients (1.8% of the cohort) outside of surveillance, 2 of whom also had tumors detected through surveillance. Ten of the 35 tumors (28.6%) were identified on first surveillance imaging. Malignant solid and brain tumors identified through surveillance were more often localized (20 of 24 [83.3%]) than similar tumors detected before CPS diagnosis (71 of 125 [56.8%]; P < .001). Of the 24 tumors identified through surveillance and surgically resected, 17 (70.8%) had completely negative margins. When analyzed across all imaging modalities, the sensitivity (96.4%), specificity (99.6%), positive predictive value (94.3%), and negative predictive value (99.6%) of surveillance were high, with few false-positive (6 [0.4%]) or false-negative (5 [0.3%]) findings. These findings suggest that standardized surveillance enables early detection of new tumors across a wide spectrum of CPSs, allowing for complete surgical resection and successful treatment in the majority of patients.

QOL-21. FUNCTION-BASED OUTCOME MEASURES AND HOW THEY CAN BE APPLIED IN PATIENTS WITH PEDIATRIC BRAIN TUMOR FOR TRACKING RECOVERY AND RESEARCH

Abstract BACKGROUND Currently an estimated 15,000 children are diagnosed with cancer annually in the United States. Among pediatric patients, central nerve system tumors make up the highest percentage of solid tumor malignancies. Tumors of the peripheral nervous system also occur, most commonly in syndromes such as neurofibromatosis. Tumor growth and tumor treatments can result in developmental and functional impacts on patients. As survival rates continue to improve through the years with advancement of pediatric cancer treatment, an increasing focus is being placed on improving function and quality of life both during and after treatment. This presentation aims to introduce a variety of validated outcome measures that assess a patient’s strength and function, to discuss how they can be applied to patient monitoring, and to propose future studies in the pediatric neuro-oncology population. METHODS This presentation will review the currently validated and commonly used outcome measures used by physicians and therapists for assessing a patient’s strength, endurance, and function. Emphasis will be placed on how these tools can be used in assessing and monitoring patients with conditions such as chemotherapy induced peripheral neuropathy, posterior fossa syndrome, and cachexia. RESULTS AND CONCLUSIONS This presentation aims to educate attendees on the current tools and outcome measures available to track a patient’s function and progress during and after treatment of neuro-oncologic conditions. It aims to highlight how these tools can be used in clinic for patient monitoring, and for future possible prospective research.

An open-label phase 1 study to investigate SGNCEACAM5C/SAR445953 in adults with advanced solid tumors (SGNCEA5C-001).

TPS3160 Background: Patients (pts) with recurrent or metastatic solid tumors, including non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), colorectal cancer (CRC), gastric adenocarcinoma (GC), and pancreatic ductal adenocarcinoma (PDAC), have limited treatment options with short PFS and OS despite recent advances (1-3). Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is highly expressed across multiple solid tumors, such as CRC, GC, PDAC, and NSCLC. Restricted normal tissue expression and efficient lysosomal trafficking of CEACAM5 highlight its potential as an anticancer target. SGN-CEACAM5C is a novel investigational antibody-drug conjugate (ADC) directed to CEACAM5 composed of the humanized immunoglobulin G (IgG1) anti-CEACAM5 monoclonal antibody tusamitamab chemically conjugated to 8 molecules of the topoisomerase 1 inhibitor 7-aminomethyl-10,11-methylenedioxycamptothecin (AMDCPT). SGN-CEACAM5C selectively binds to CEACAM5 present on the cell surface and is internalized via the endo-lysosomal pathway, with subsequent release of the payload through enzymatic cleavage. Release of the cytotoxic payload induces DNA damage, cell cycle arrest in S phase, and apoptosis in tumor cells. In vitro bystander activity was observed against tumor cells without CEACAM5 surface expression. SGN-CEACAM5C is highly active in multiple patient-derived xenograft models, including CRC, GC, and NSCLC, across various levels of CEACAM5 expression (4,5). These preclinical findings justify evaluation of SGN-CEACAM5C in a clinical trial setting. Methods: SGNCEA5C-001 (NCT06131840) is a phase 1, open-label, multicenter study designed to characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity of SGN-CEACAM5C in adults with select advanced solid tumors. This study consists of dose escalation (Part A), dose and schedule optimization (Part B), and dose expansion (Part C). Eligible pts are adults ≥18 years of age with confirmed metastatic or unresectable solid tumor malignancy, measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, an ECOG PS of 0-1, and 1 of the following tumor types: CRC, GC/gastroesophageal junction adenocarcinoma (GEJ), PDAC, NSCLC (squamous/non-squamous), or SCLC. Primary endpoints include incidence of AEs, laboratory abnormalities, dose modifications due to AEs, dose-limiting toxicities, and cumulative safety. Secondary endpoints include estimates of PK parameters, incidence of antidrug antibodies, objective response rate and best response per RECIST v1.1 by investigator, duration of response, PFS, and OS. Safety and antitumor activity endpoints will be summarized using descriptive statistics. Recruitment is ongoing for Part A in North America. 1. Bordry 2021. 2. Chakrabarti 2022. 3. Merle 2022. 4. Baudat 2023. 5. Baudat 2024. Clinical trial information: NCT06131840 .

A phase 1/1b first-in-human (FIH) study of JZP898 as monotherapy and in combination with pembrolizumab in adult patients with advanced or metastatic solid tumors.

TPS3190 Background: JZP898 is a conditionally activated prodrug of interferon alpha (IFNα) that can preferentially deliver IFNα to the tumor microenvironment while potentially minimizing systemic IFNα therapy-associated toxicity. Antitumor activity of IFNα is well-established, but concerns regarding systemic toxicity restrict its use in clinical practice. JZP898, in combination with a checkpoint inhibitor such as pembrolizumab, may provide lasting and potent antitumor activity with minimal additive toxicity attributed to conventional or pegylated IFNα. This phase 1 FIH study will determine a maximum tolerated dose (MTD)/recommended dose (RD) and investigate safety, tolerability, pharmacokinetics (PK), immunogenicity, and preliminary antitumor activity of JZP898 monotherapy and JZP898 combined with pembrolizumab in adult patients with advanced or metastatic solid tumors. Methods: This phase 1, FIH, open-label, multicenter study (NCT06108050) is investigating JZP898 intravenous infusion in adult patients (≥18 years old) with histological or cytological diagnosis of advanced or metastatic solid tumors, European Cooperative Oncology Group performance status ≤1, and measurable disease per RECIST v1.1 criteria. The study consists of a dose finding phase (JZP898 as monotherapy and in combination with pembrolizumab; Part A) and a combination dose expansion phase (JZP898 in combination with pembrolizumab; Part B). In Part A (dose finding), the JZP898 MTD and/or monotherapy RD will be determined using Bayesian optimal interval (BOIN) design based on the incidence of dose-limiting toxicities (DLTs) and all available safety and PK data; the combination recommended phase 2 dose (RP2D) will be determined using BOIN criteria and all available safety, PK/PD, immunogenicity, and preliminary signal of antitumor activity data. Patients will be treated until disease progression, death, unacceptable toxicity, or withdrawal from the study. All patients will be followed for survival until 18 months after the last patient starts study intervention. Primary endpoints include: the incidence and nature of DLTs (Part A); investigator-assessed objective response rate (ORR) per RECIST v1.1 (Part B); the incidence and severity of treatment-emergent adverse events (TEAEs) and serious adverse events; changes in laboratory values or vital signs; and the incidence of dose modifications or discontinuations due to TEAEs. Secondary endpoints include: PK parameters; incidence of antidrug antibodies; investigator-assessed duration of response; progression-free survival; disease control rate; investigator-assessed ORR (Part A); and overall survival (Part B). The study is actively enrolling patients with a planned enrollment of up to 177 patients. Clinical trial information: NCT06108050 .

A phase 1 trial in progress for in situ immunomodulation with CDX-301, radiation therapy, poly-ICLC, and CDX-1140 in patients with unresectable and metastatic solid tumors.

TPS2697 Background: The prognosis for patients with unresectable and metastatic solid tumors that progress on standard of care therapy remains poor due to limited treatment options. Compelling evidence suggests that the induction and activation of tumor-residing conventional type-1 dendritic cells (cDC1) is critical to elicit anti-tumor immunity. Recently, we have demonstrated that a combinatorial regimen comprised of in situ delivery of Fms-like tyrosine kinase 3 ligand (Flt3L), radiation therapy (9Gy), and dual TLR3/CD40 stimulation 1) mobilizes cDC1 to the tumor microenvironment; 2) induces maturation of cDC1; 3) facilitates trafficking of cDC1 carrying tumor antigens to tumor-draining lymph nodes; 4) elicits de novo adaptive T cell immunity; 5) triggers regression of primary tumors, as well as non-irradiated distant tumors; and 6) develops tumor-specific systemic immunological memory using multiple syngeneic orthotopic murine models (1-4). Based on results from preclinical studies, we have initiated a phase 1 study as below. Methods: This is a phase 1 study of in situ immunomodulation with CDX-301 (Flt3L), radiation therapy, CDX-1140 and Poly-ICLC (dual CD40/TLR3 stimulation) in patients with unresectable and metastatic solid tumors. Eligibility for this study includes patients ≥ 18 yrs who have clinically or pathologically confirmed diagnosis of unresectable and metastatic melanoma, cutaneous squamous cell carcinoma, Merkel cell carcinoma, high-grade bone and soft tissue sarcoma or HER2/neu (-) breast cancer with no curative treatment options, and progressed on at least one line of standard systemic therapy. The unresectable disease to be irradiated and injected with medications must be located in breast, dermal, subcutaneous, or soft tissue, or lymph nodes with the longest axis of the tumor 2-7 cm, and should be considered safe for injection by the investigator. The metastatic disease must be measurable per irRECIST criteria. Patients will be treated with daily intratumoral injection of CDX-301 for 5 days (Day 1-5), radiation therapy (9Gy, Day 8) followed by administration of CDX-1140 and Poly-ICLC (Day 9). Up to 4 cycles of this combination therapy can be given every 3 weeks. The primary endpoints are safety/tolerability and to evaluate the MTD of for injection (intratumoral in the cohort A and intratumoral and intravenous in the cohort B) of CDX-1140. A standard 3+3 design, allowing for dose de-escalation, will be used within each cohort. Secondary endpoints are to evaluate immune signatures in blood and the tumor. This phase 1 trial opened to enrollment at the University of Southern California Norris Comprehensive Cancer Center in January 2023 (recruitment is currently 4 on February 6, 2024). 1. Nature Communications 2020. 2. J. Immunology 2021. 3. Cancer Research 2021. 4. Scientific Reports 2022. Clinical trial information: NCT04616248 .

A phase I study to evaluate the safety and tolerability of JCXH-211 (a self-replicating mRNA encoding IL-12) intratumoral injection in patients with malignant solid tumors: Results from the phase Ia dose escalation.

2539 Background: Although interleukin (IL)-12 demonstrated strong preclinical antitumor activity and potent immune-stimulating potentials clinically, systemic administration of IL-12 protein was associated with poor clinical safety profiles. IL-12 functions locally through paracrine and autocrine mechanisms, thus maximizing local concentration of IL-12 in the tumors is important. JCXH-211 is a self-replicating ribonucleic acid (srRNA) encoding human IL-12 encapsulated in lipid nanoparticles. Intratumoral (IT) administration of JCXH-211 is expected to produce the desired spatiotemporal distribution of IL-12 in the cancer lesions. srRNA features enhanced translatability in immunosuppressed tumor microenvironment (TME) than in normal tissues further limiting off-target toxicity. Additionally, the self-replicating nature of JCXH-211 engages multiple immune effector mechanisms and helps inflame TME. We present interim results of the dose escalation part of JCXH-211 IT injection as monotherapy in patients (pts) with malignant solid tumors. Enrollment for the 100 μg cohort is ongoing and updated data will be presented at the meeting. Methods: Pts with advanced solid tumors suitable for IT injection are enrolled. JCXH-211 at 5, 25, 50, and 100 μg are given every 4 weeks (Q4W). Dose Limiting Toxicities (DLT) are monitored for 28 days after 1st dose. Dose escalation follows “3+3” principle. Tumor assessment is performed Q6W using RECIST v1.1. Results: Ten pts with advanced cancers have been enrolled in 5 μg, 25 μg, and 50 μg cohorts: 3 melanoma (MEL), 3 breast cancer (BC), 2 head and neck cancer (HNSC), 1 nasopharyngeal cancer and 1 sarcoma. Nine pts completed DLT observation without DLT; 1 pt withdrew early. No drug-related SAE was reported. Most drug-related AEs were Grade 1/2 and recovered quickly. Only 1 pt in the 25 μg cohort reported 3 Grade 3 AEs possibly related to drug: lymphocytopenia (2 events) and anemia. Seven pts completed at least one post-dose tumor assessment. Three pts experienced shrinkages of the treated lesions by 13.0%, 33.3% and 43.0%, corresponding to BC, HNSC and MEL in the 5 μg, 25 μg, and 50 μg cohorts, respectively. Tumor shrinkage of 31% was also observed in a non-injected lesion of an HNSC pt receiving 25μg JCXH-211 suggesting abscopal effects. Histopathological analysis of the treated lesions demonstrated increased T and NK cell infiltration (as high as 138 folds) post study drug administration. Conclusions: JCXH-211 IT administration with doses of 5μg, 25μg, 50μg Q4W demonstrated good safety profile. Antitumor activities were observed in the heavily pretreated late-stage pts. Significant increases of T and NK cell infiltration were observed. These data support continued evaluation of JCXH-211 IT. Clinical trial information: NCT05727839 .

Results of a phase 1/2 study of MHB088C: A novel B7H3 antibody-drug conjugate (ADC) incorporating a potent DNA topoisomerase I inhibitor in recurrent or metastatic solid tumors.

3012 Background: MHB088C is an investigational B7H3-directed ADC, created by coupling a humanized anti-B7H3 monoclonal antibody with a highly potent DNA topoisomerase I inhibitor (5~10 times more potent than DXd). Preclinical studies demonstrated robust binding affinity, superior internalization rates, powerful tumor killing activities (3~10 times more potent than the DS-7300a analog in CDX models) and a favorable safety profile with no unique toxicities observed in the GLP study as compared to other B7H3 ADCs and no occurrences of interstitial lung disease (ILD). We here present the safety and efficacy results from a first-in-human phase 1/2 study of MHB088C. Methods: The study enrolled patients (pts) with recurrent or metastatic solid tumor across two segments: dose-escalation (D-esc) and dose-expansion (D-exp). In the D-esc phase, MHB088C was administrated intravenously at doses of 0.8, 1.6, 3.0mg/kg Q2W; 3.0, 4.0 mg/kg Q3W. Results: As of the data cutoff on Dec 31, 2023, 60 pts were enrolled and received at least one dose of MHB088C (D-esc, n=14; D-exp, n=46). 55 pts remain on the treatment and 12 pts had at least one tumor assessment according to RECIST 1.1. Dose-limiting toxicities (DLTs) were platelet count decreased and febrile neutropenia at 4.0 mg/kg Q3W. The MTD was determined to be 3.0 mg/kg Q3W. The most common TRAEs overall in ≥25% of pts were neutrophil count decreased, lymphocyte count decreased, and white blood cell (WBC) count decreased. The most common Grade ≥3 TRAEs (≥5% of pts) were neutrophil count decreased (33.3%), lymphocyte count decreased (30.0%), WBC count decreased (26.7%), platelet count decreased (23.3%), and anemia (15.0%). No ILD was reported. Of12 response-evaluable pts, 5 partial responses (PRs) were observed (ORR: 41.7%). The disease control rate was 91.7% (11/12). In the subset of 3 SCLC pts, all 3 showed PRs (ORR: 100.0%), with one case demonstrating complete response of the target lesion and another with close to 80% tumor volume reduction. The efficacy of 2 SCLC pts was achieved in 1.6 mg/kg Q2W group without major hematologic side effects. All responses among SCLC pts occurred at the first tumor assessment. Conclusions: MHB088C exhibited a manageable safety profile, with striking efficacy in SCLC pts. The dose optimization and expansion study is continuing to establish the RP2D for MHB088C. Clinical trial information: CTR20231298.

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 open-label study of a novel IL-2Rβ/γ cytokine agonist, LTC004, in patients with advanced or metastatic solid tumors.

2652 Background: LTC004, a novel IL-2Rβ/γ cytokine agonist, designed to minimize toxicity with improved potency. It has selective affinity for the receptor IL-2Rβγ subunits, preferentially stimulates CD8+ effector T cells and natural killer cells which are associated with tumor killing, while minimizing the activation of immunosuppressive regulatory T cells. LTC004 has shown significant in vitro and in vivo anti-tumor activity in multiple cell lines and murine models respectively. Methods: This is a first-in-human, multicenter, open-label, dose-escalation and dose-expansion phase I study of LTC004 in advanced solid tumors. Dose escalation part assessed safety and tolerability of intravenous LTC004 with doses ranging from 3.0 to 360 µg/kg. The dose escalation schedule utilized an accelerated titration and Bayesian Optimal Interval (BOIN) design. Eligible pts with advanced solid tumor were required to have received prior standard therapy. LTC004 is administrated intravenously once every 3 weeks. Results: The study completed dose-escalation part (3.0 to 360 µg/kg) as of cutoff date (Jan 10, 2024). 17 pts of multiple tumor types (including non-small cell lung, cervical, colorectal, sarcoma, melanoma, parotid adenocarcinoma, thymic adenocarcinoma, gastric and ovarian cancers) were enrolled and received ≥1 dose of LTC004. At baseline, 12 pts (70.6%) had received ≥2 prior lines therapy, 11 pts (64.7%) had received prior targeted therapy, 10 pts (58.8%) had received prior immune checkpoint inhibitor (ICI) therapy. LTC004 generally well tolerated and no dose-limiting toxicities (DLTs) up to and including 360 µg/kg was observed. The most common TEAEs overall in ≥30% of pts were fever, white blood cell decreased, anemia, AST/ALT increased, neutrophil count decreased, GGT increased, nausea and hypotension. Most of the reported AEs were G1 and G2, all drug related events reversible and responsive to supportive care therapy. Fever can be resolved with standard anti-pyretic treatment or steroids, transient hypotension can be preventable with prophylactic fluid infusion. Of 17 pts enrolled evaluable for efficacy per RECIST v1.1, the ORR were 5.9% (1/17), DCR were 58.8% (10/17). A confirmed PR was achieved in a pMMR/MSS CRC patient with prior therapies including fluoropyrimidines, irinotecan, oxaliplatin, targeted therapy and TKI. The starting dose was 45µg/kg, titration to 90µg/kg after 4 consecutive doses at 45µg/kg Q3W. As of cutoff date, the patient sustained PR for 4.8 months with follow-up ongoing. Conclusions: LTC004 demonstrated encouraging anti-tumor efficacy including cold tumor, and well tolerated in patients with advanced or metastatic solid tumors. The further dose expansion in selected tumor types is ongoing, and evaluations in combination with other agents are being planned. Clinical trial information: NCT05666635 .

Phase 1 study of ASP1002, a bispecific antibody targeting claudin 4 (CLDN4) and CD137, in patients with locally advanced (LA) or metastatic solid tumors that express CLDN4.

TPS2670 Background: The lack of benefit for many cancers from newer-generation combination chemotherapies has stimulated research into targeted agents. CLDN4, a claudin protein family member that regulates tight junction formation, is highly expressed in multiple tumor types including non-small cell lung cancer (NSCLC), urothelial carcinoma (UC), colorectal cancer (CRC), prostate adenocarcinoma (PA), ovarian cancer (OC), and triple-negative breast cancer (TNBC). Following primary T cell activation, CD137 provides a costimulatory signal that enhances T cell proliferation and cytokine production. Together CLDN4 and CD137 represent promising therapeutic targets for solid tumors. ASP1002 is a bispecific antibody designed to target CLDN4 and CD137, thereby enhancing the antitumor response of T cells against CLDN4-expressing tumor cells. Methods: This phase 1 first-in-human, open-label, multicenter study (NCT05719558) is evaluating the safety and tolerability, maximum tolerated dose (MTD), and/or recommended phase 2 dose (RP2D) of ASP1002 in adult patients with LA or metastatic solid tumors that express CLDN4. The primary endpoint is safety and tolerability, as assessed by dose-limiting toxicities (DLTs), adverse events (AEs), serious AEs, laboratory tests, vital signs, ECGs, PEs, and ECOG performance status. Secondary endpoints are pharmacokinetic characteristics; confirmed objective response rate (ORR), duration of response, and disease control rate per iRECIST and RECIST 1.1; and incidence rate and expression levels of CLDN4 by immunohistochemistry. Dose escalation will include patients with LA or metastatic NSCLC, UC, CRC, PA, OC, or TNBC. ASP1002 will be administered at escalating doses Q1W IV on days 1, 8, 15 in a 21-day cycle until discontinuation to determine MTD and/or candidate RP2D regimens. At doses ≥10 mg, multi-participant cohorts will be included. Safety follow-up visits will occur within 7 days posttreatment, and on 30 and 90 days posttreatment. Next, dose expansion will enroll patients with LA or metastatic NSCLC, UC, CRC, and other tumor types with confirmed complete response (CR) or partial response (PR) in dose escalation. Candidate RP2D regimens based on dose escalation data will be evaluated in ≤40 patients per dose level, per tumor type in dose expansion. ORR (confirmed CR or PR) per iRECIST will be evaluated in tumor-specific expansion cohorts. The minimum number of responders needed to establish activity is 4 (NSCLC), 3 (CRC), and 7 (UC). Study enrollment is currently ongoing in the United States. Clinical trial information: NCT05719558 .

Combination therapy with the oncolytic virus CF33-CD19 and blinatumomab for the treatment of advanced solid tumors.

TPS2687 Background: CF33-CD19 is a novel chimeric vaccinia virus that selectively replicates in tumor cells and can provoke anti-tumor immunity. CF33-CD19 expresses a truncated and non-signaling CD19 protein on the surface of infected tumor cells before virus-mediated tumor lysis, labeling them for CD19-targeted therapies. Preclinical studies with CF33-CD19 have shown that combination therapy with CD19 targeting chimeric antigen receptor T cells is more effective than either monotherapy in murine xenograft and syngeneic models [1]. Likewise, combination therapy with bispecific T-cell engagers (BiTE)s that bind CD3-positive T cells and infected solid tumor cells that express de novo CD19, showed pronounced recruitment of T cells to the tumor microenvironment, resulting in tumor growth inhibition in mouse models. CD19xCD3 targeting BiTEs such as blinatumomab may offer an off-the-shelf alternative to adoptive cell therapies. This phase I study, called OASIS, dose escalates CF33-CD19 administered intravenously (IV) or intratumorally (IT) combined with blinatumomab in adults with advanced or metastatic solid tumors. Methods: The OASIS study (NCT06063317) is enrolling patients with advanced or metastatic solid tumors with ≥ 2 prior lines of therapy. Patients who have received prior treatment with a poxvirus based oncolytic virus or a bispecific CD19-directed CD3 T-cell engager are excluded. A safety run-in will evaluate the safety of CF33-CD19 monotherapy administered IT or IV before initiating the combination therapy regimen. Combination therapy will be administered in 28-day cycles with CF33-CD19 on days 1 and 15. Following viral transduction to promote de novo CD19 expression, blinatumomab is given on days 2-9 and 16-23 via a 7-day continuous infusion. Patients &gt; 45 kg will receive 9 mcg of blinatumomab during the first week of cycle 1, then 28 mcg during the third week of cycle 1 and subsequent cycles. The study consists of two parts. Part 1 follows a 3+3 dose escalation scheme independently of each route of CF33-CD19 administration (IT and IV) with dose levels of CF33-CD19 ranging from 1.0x107 to 3.0x109 PFU. Part 2 is a cohort expansion in select indications at the optimal dose. The co-primary endpoints are safety and identification of the recommended phase 2 dose. Secondary endpoints include objective response rate according to RECIST v1.1 and iRECIST. Enrollment began in October 2023. 1. Park et al. Sci Transl Med. 2020 Sep 2;12(559):eaaz1863. doi: 10.1126/scitranslmed.aaz1863. PMID: 32878978. Clinical trial information: NCT06063317 .

Results of a phase 1/2 study of MHB036C: A potential best-in-class TROP2 antibody-drug conjugate (ADC) incorporating a potent DNA topoisomerase I inhibitor in locally advanced or metastatic solid tumors.

e15007 Background: MHB036C, an investigational ADC, comprises a humanized anti-TROP2 monoclonal antibody engineered to minimize potential toxicities mediated by non-specific uptake, and a highly potent DNA topoisomerase I inhibitor (5~10 times more potent than DXd) conjugated via a stable cleavable linker. In preclinical studies, MHB036C demonstrated superior tumor killing activities (5~10 times more potent than the DS-1062a analog) and a favorable safety profile with no unique toxicities as compared to other TROP2 ADCs and no occurrences of interstitial lung disease (ILD). We here present the safety and efficacy results from a first-in-human phase 1/2 study of MHB036C. Methods: Patients with locally advanced or metastatic solid tumors were enrolled in dose-escalation (D-Esc) and dose-expansion (D-Exp) segments. The D-esc study, utilizing an accelerated titration followed by the traditional 3+3 design, assessed MHB036C at doses ranging from 0.25-2.25 mg/kg administered intravenously (IV) every 3 weeks. Results: At data cutoff (Dec 31, 2023), 26 pts were enrolled and received at least one dose of MHB036C (D-Esc, n=11, D-Exp, n=15). Two pts experienced dose-limiting toxicities (Grade 3 stomatitis) at 2.25 mg/kg. The MTD was determined to be 1.5 mg/kg. The most common TRAEs overall in ≥25% of pts were stomatitis, anemia, decreased appetite, vomiting, white blood cell (WBC) count decreased, fatigue, nausea, and neutrophil count decreased. The most common Grade ≥3 TRAEs (occurred in ≥5% of pts) were stomatitis (34.6%), WBC count decreased (11.5%), neutrophil count decreased (7.7%), and anemia (7.7%). No ILD was reported. Of 21 response-evaluable pts, 7 experienced partial responses. In the subset of 12 NSCLC pts treated with doses ranging from 1.3 to 2.25 mg/kg, the ORR was 33.3% (4/12) and the DCR was 83.3%. In the subset of 5 HER2-negative breast cancer pts encompassing 4 TNBC pts and 1 HR+/HER2- breast cancer patient, the ORR was 60.0% (3/5). Conclusions: MHB036C demonstrated a manageable safety profile without either major hematologic side effects or ILDs and encouraging efficacy in NSCLC and HER2- breast cancer, representing a potential best-in-class TROP2 ADC. The dose optimization and expansion study is ongoing to establish the RP2D for MHB036C. Clinical trial information: CTR20231246.

A phase 1/2, first-in-human, open-label, dose-escalation study of TAK-280, an investigational B7-H3 x CD3ε conditional bispecific redirected activation (COBRA) T-cell engager, in adult patients with unresectable, locally advanced, or metastatic solid tumors.

TPS2684 Background: TAK-280 is a novel COBRA T-cell engager that targets the B7 homolog 3 protein (B7-H3), an antigen highly expressed in a range of solid tumors including metastatic castration-resistant prostate cancer (mCRPC) and non–small cell lung cancer. In its prodrug form, TAK-280 binds to B7-H3, but not to CD3ε. Once in the protease-rich tumor microenvironment, TAK-280 undergoes protease-mediated activation through formation of CD3ε-binding active dimers, which stimulate CD3 T-cell activation and cytotoxic antitumor response against co-engaged B7-H3–expressing cells. In preclinical studies, TAK-280 demonstrated cleavage-dependent conditionality, engagement of tumor target antigen, and induction of T-cell mediated tumor killing. TAK-280 has the potential to target solid tumors that are not amenable to treatment with conventional first- or second-generation T-cell engagers, while limiting toxicity to normal tissues. Methods: This phase 1/2 study is enrolling adult patients with unresectable, locally advanced, or metastatic solid tumors described in the literature to have enhanced B7-H3 expression, who are ineligible or intolerant to standard therapies. Other eligibility criteria include Eastern Cooperative Oncology Group performance status ≤1 and measurable disease per RECIST v1.1. Key exclusion criteria include history of autoimmune disease, major surgery ≤8 weeks before first dose of TAK-280, and history of clinically significant cardiac or gastrointestinal disorders. During phase 1 dose escalation, TAK-280 is administered as an intravenous infusion, once weekly, in 28-day cycles at a pre-defined dose level range. Patients who do not experience dose-limiting or other unacceptable toxicities may receive up to 14 treatment cycles depending on response; patients are treated until disease progression, unacceptable toxicity, or withdrawal from study. The dose-escalation phase will determine two recommended doses for expansion to be assessed during the cohort-expansion phase. The primary endpoint is incidence of dose-limiting or other toxicities during dose escalation; secondary endpoints include pharmacokinetic parameters, response assessment per RECIST v1.1, overall response rate, duration of response, progression-free survival, overall survival, disease control rate, and prostate-specific antigen response in patients with mCRPC. Cytokine release syndrome is closely managed and reported per American Society for Transplantation and Cellular Therapy consensus grading. Approximately 182 patients are planned to be enrolled (42 in dose escalation and 100–142 in cohort-expansion); as of the data cutoff date of Jan 10, 2024, 18 patients have received the study drug. Clinical trial information: NCT05220098 .

A first-in-human, phase 1/2a study of GI-102 (CD80-IL2v3) in patients with advanced or metastatic solid tumors: Initial results from dose escalation.

2598 Background: GI-102 (CD80-IL2v3) is a novel immunocytokine designed to direct IL-2v3 to immune cells and tumor cells. IL-2v3 of GI-102 abolished affinity to IL-2Rα minimizing the impact of IL-2 on Treg cells. Preferential targeting of immune cells and further inhibition of CTLA-4 and PD-L1 via CD80 synergize with potent activity of IL-2v3, resulting in robust proliferation and activation of CD8+ T and NK cells. Here we report preliminary safety and efficacy data of GI-102 from a phase 1/2a trial in patients with metastatic solid tumors. Methods: NCT05824975 is an ongoing, dose escalation (3+3 design) and expansion study to evaluate safety, tolerability, PK, PD and anti-tumor activity of GI-102. Each dose level allows to enroll additional 7 patients to fully inform the safety, PK and PD at that dose level. GI-102 was administered intravenously every 3 weeks until disease progression or unacceptable toxicities. Disease was assessed every 6 weeks using RECIST v1.1. Results: As of 12 Jan 2024, 32 patients were treated in dose escalation: 8 at dose level 0.06 mg/kg, 10 at 0.12 mg/kg, 9 at 0.24 mg/kg and 5 at 0.45 mg/kg. Patients had received median of 3 [1-7] prior lines of therapy, including 25.0% (8/32) who had received ≥ 5 lines and 68.8% (22/32) had experienced immune checkpoint blockade (ICB). No dose-limiting toxicities (DLTs) were observed until the highest dose of 0.45 mg/kg Q3W. The most common treatment-related adverse events (TRAEs, ≥ 10%) were pyrexia [43.8%] and chills [34.4%]. 5 patients [15.6%] had ≥ Grade 3 TRAEs and no patient reported TRAEs leading to discontinuation of GI-102. In 23 patients (7 cutaneous melanoma, 4 non-small cell lung cancer, 3 ovarian cancer and others) who had at least 1 post-treatment tumor assessment, objective responses were observed in 17.4% (4/23). In patients with metastatic melanoma who previously experienced ICB, overall response rate (ORR) and disease control rate (DCR) was 42.9% (3/7) and 85.7% (6/7), respectively, including 3 confirmed partial responses (cPR). The median time to response (TTR) was 6 weeks and duration of response (DoR) was 6.0+, 2.4+ and 1.7+ month, respectively. In patients with metastatic ovarian cancer, ORR and DCR were 33.3% (1/3) and 66.7% (2/3), respectively, including 1 cPR [TTR of 6 weeks; DoR 1.9+ month]. Preliminary PK profile showed target-mediated drug disposition with a half-life of ~48 hours. 0.24 mg/kg of GI-102 resulted in a significant expansion of peripheral lymphocytes, CD8+ T cells (effector &amp; memory) and NK cells, by 4.4 [2.1-9.6], 3.9 [2.0–5.7] and 20.4 [9.5–32.6]-fold change from baseline, respectively. There was no meaningful increase in Treg cells. Conclusions: GI-102 was well tolerated up to dose of 0.45 mg/kg Q3W with meaningful monotherapy activity, regardless of previous ICB experience, in patients who failed on standard of care. The dose-escalation is currently ongoing to identify RP2D. Clinical trial information: NCT05824975 .

Geriatric enrollment patterns in clinical trials at a National Cancer Institute.

e13762 Background: Despite the majority of new cancer diagnoses occurring within the geriatric population, there is a disproportionate rate of clinical trial enrollment within this population. Previous data has estimated enrollment rate to be 18.9% in treatment trials among all adult cancer patients at designated National Cancer Institute Cancer Centers. The objective of this study is to assess geriatric cancer patient clinical trial enrollment rates in a single National Cancer Institute and highlight inequities within cancer care delivery. Methods: We performed a retrospective review of the electronic health record and included patients with cancer ≥ 65 years of age who died at our institution between January 2020 and July 2022. We examined the relationship between cancer type, patient race/ethnic identity, and age and analyzed enrollment in clinical trials. Analyses were conducted using descriptive statistics. Results: Of 117 decedent records analyzed, 11 (9%) were enrolled in treatment clinical trials of which 5 (4.3%) identified as White, 4 (3.4%) Other, and 2 (1.7%) Hispanic. Among the 117 geriatric patient records reviewed, there were 21 Black patients (17.9%) of which 0 (0%) Black patients were enrolled in clinical trials. In comparing enrollment by malignancy type, 5 patients had a hematologic malignancy (leukemia, lymphoma, or multiple myeloma), 3 patients had a genitourinary malignancy, 1 patient had a pancreatic malignancy, 1 patient had an endometrial malignancy, and 1 patient had a breast malignancy. Among all patients analyzed, 37 patients (31.6%) had a hematologic malignancy and 80 patients (68.4%) had a solid tumor malignancy. The average age of enrolled patients was 73, consistent with the average age of all patients analyzed (73.78). Conclusions: Geriatric patients with cancer are disproportionately underrepresented in treatment clinical trials. The inequity is exacerbated when analyzing enrollment among minoritized patients. There was a greater proportion of clinical trial enrollment in patients with hematologic malignancies than solid tumor malignancies, however analysis in larger population samples is necessary. Additional research to identify barriers to clinical trials and methods of increasing geriatric enrollment, including the use of geriatric specific performance scales, is necessary to ensure equitable access and representation in clinical trials. While these results may be skewed in the setting of the COVID-19 pandemic and selection of a decedent population, further research into geriatric accessibility in clinical trials is paramount.

Safety and preliminary efficacy of different doses of fecal microbiota capsule transplantation combined with anti-PD-1 inhibitor for patients with advanced malignant solid tumors.

e14622 Background: Chemotherapy combined with anti-PD-1 inhibitors has now become the standard first-line(1L) treatment for most malignant solid tumors. However, most Phase III studies have found that overall progression-free survival (PFS) with 1L combined subsequent immuno-maintenance therapy (IMT) is still less than 1 year. Fecal microbiota transplantation (FMT) has been shown to synergize with PD-1 antibodies to enhance efficacy. In this study, we administered oral microbiota capsule transplantation to patients(pts) during 1L IMT to evaluate its safety, preliminary efficacy, optimal dosage, and explore the changes in gut microbiota composition and serum metabolism (ChiCTR2100054928). Methods: This is a dose-escalation, exploratory clinical trial. The donor capsules were derived from the feces of a healthy 10-year-old child from a rural area. Twelve late-stage pan-cancer pts who had received standard 1L chemotherapy + PD-1 antibodies and achieved stable or responsive disease were enrolled. The first 3 patients were in the i group (5 capsules po tid d1-3). If no dose-limiting toxicities (DLTs) were observed, another 3 patients were escalated to the i+1 group (10 capsules po bid d1-3). If no DLTs were observed again, another 3 patients were escalated to the i+2 group (10capsules po tid d1-3), and so forth, until the i+3 dose group (20 capsules po bid d1-3). Simultaneously, patients continued receiving the original PD-1 IMT. Fecal samples were collected at baseline (S0), after 10 days (S1), 25days (S2), and 50days (S3) of FMT. Results: From March 2023 to December 2023, 12 pts were successfully enrolled. As of the data cutoff date (December 31, 2023), the median follow-up time was 9.05 months (6.5-9.5 months), and the median PFS has not been reached, with 3 patients experiencing disease progression. Four patients (33.3%) experienced Grade 1-2 FMT-related toxicities, including diarrhea, bloating, and abdominal pain, with no Grade 3 or higher adverse events observed. Fecal metagenomic sequencing analysis showed that the relative abundance levels of Blautia and Faecalibacterium significantly increased after FMT, peaking at day 25 and remaining higher than pre-transplant levels at day 50. We also found that patients in the i+1 group exhibited the greatest changes in microbial composition before and after transplantation, with high absolute and relative transplantation indices. Further analysis of host serum metabolism revealed an increase in molecules related to fatty acid metabolism, such as L-carnitine, stearic acid, and arachidic acid, especially a more pronounced increase in the i+1 group. Conclusions: This preliminary study demonstrates that the combination of oral microbiota capsule and immunotherapy can open up a more economical, safe, and effective avenue for 1L maintenance immunotherapy in tumors. Clinical trial information: ChiCTR2100054928.

A phase I clinical study to evaluate the safety, tolerability, immunogenicity, pharmacokinetics and preliminary efficacy of SCB-219M in patients with chemotherapy-induced thrombocytopenia (CIT): An interim analysis.

e15015 Background: CIT is a serious, chemotherapy-associated complication observed in a wide range of cancer patients with various types of cancer. Incidence of CIT can occur in about 15-25% of patients undergoing standard chemotherapy regiments with platinum, taxane and/or gemcitabine-based regimen. CIT can lead to chemotherapy dose delay or dose reduction, and potentially bleeding events. Currently, there is no FDA-approved therapy for CIT. SCB-219M, a thrombopoietin receptor agonist (TPO-RA) mimetic bispecific Fc-fusion protein produced from CHO cells can efficiently raise PLT count under normal and pathological conditions in laboratory animals. Methods: This is a single-arm, multi-center, open-label, dose escalation Phase Ia clinical study to evaluate the safety, tolerability, and immunogenicity, PK profile and preliminary efficacy of a single ascending dose of SCB-219M administered one day after a chemotherapy in prior CIT patients with malignant solid tumors and lymphoma. The study design of accelerated titration combined with "3 + 3" is used, and the number of subjects planned to enroll is 12 to be assigned to 4 cohorts with 2, 6, 10 and 15 mg/kg subcu administration of SCB-219M, respectively. Enrollment criteria include episode of CIT experienced (&lt;75 × 109/L in PLT count) in prior cycle of chemotherapies and PLT count has recovered to &gt;75 × 109/L prior to initiation of this study . The chemotherapy regimen allowed include either mono or combination chemotherapy (including targeted therapy and/or immunotherapy). The observation period of dose-limiting toxicities (DLTs) is 21 days. Chemotherapy is planned at each study site. There will be no change in the planned dose or frequency of chemotherapy in the study. Results: As of Dec 20, 2023, 9 prior CIT patients including 3 at 15 mg/kg were enrolled. SCB-219M was well tolerated. There were no SAEs or AESIs (Adverse Event of Special Interest) observed. DLT was not reached. A favorable PK profile, in particular in serum availability (AUC) and half-life (T1/2) was obtained. All 9 prior CIT patients in the study maintained PLT counts &gt;75 x 109/L from 1-week following chemotherapies with a single dose of SCB-219M, and durable responses experienced through at least 3 weeks. Conclusions: In this interim analysis, drug safety, PK profile and durable efficacy are expected to support SCB-219M dosing interval of ≥2-weeks or a single dosing regimen within a chemotherapy cycle. Accordingly, a Phase Ib trial evaluating repeated dosing of SCB-219M is planned to initiate in 2024. Clinical trial information: NCT05426369 .

An open-label, phase 1, multicenter study to evaluate the safety and preliminary anti-tumor activity of NT-112 in human leukocyte antigen-C*08:02–positive adult patients with unresectable, advanced, and/or metastatic solid tumors that are positive for the KRAS G12D mutation.

TPS2677 Background: The landscape of cancer treatment is evolving with the emergence of innovative immunotherapies. Among these, T cell receptor-engineered T cell (TCR-T) therapy has shown promise for patients with solid tumor malignancies. Targeting driver mutations, such as KRAS, may offer novel therapeutic options for patients with limited treatment options. Oncogenic driver mutations in KRAS typically involve single-base mutations at genomic hotspot locations. The KRAS isoform is mutated in 84% of RAS-driven cancers and in nearly 100% of pancreatic ductal adenocarcinoma (PDAC). The KRAS G12D mutation is the most frequent mutation in PDAC (28%), followed by colorectal cancers (12%). Despite its well-established target role in tumorigenesis, there is no FDA-approved therapy targeting the G12D variant. NT-112 is an autologous TCR-T cell therapy targeting the KRAS G12D mutation presented by HLA-C*08:02, armored by disruption of the gene encoding the transforming growth factor beta receptor type 2 (TGFBR2) in order to reduce the immunosuppressive effect of TGF-β in the tumor microenvironment. Methods: This first-in-human, open label, multicenter, Phase 1, dose escalation study aims to assess the safety, identify the MTD and evaluate potential anti-tumor activities of NT-112 in subjects with solid tumors. The study will enroll up to 24 adult subjects harboring the KRAS G12D mutation that are HLA-C*08:02 positive, who exhibit progressive or recurrent disease after at least one line of standard of care treatment. Enrolled patients will undergo leukapheresis, from which, CD4 and CD8 T cells will be enriched and activated ex vivo. The genes encoding the TGFBR2 and the endogenous TCR α and β chains are knocked out from the activated T cells utilizing clustered regularly interspaced short palindromic repeats (CRISPR-Cas9). The HLA-C*08:02-restricted TCR specific to the KRAS G12D mutation is knocked-in in the TCR α locus. Subjects will undergo standard lymphodepletion followed by a single infusion of NT-112 and concurrent, daily, subcutaneous, recombinant IL-2 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 following NT-112 infusion. Disease response will be assessed according to the RECIST v1.1 criteria. Comprehensive translational analysis will be conducted to gain insights into the mechanism of action, biomarkers associated with treatment response, and potential mechanisms of resistance. All subjects will be followed for up to 15 years. Clinical trial information: NCT06218914 .

A first-in-human study of IK-595, an oral MEK/RAF molecular glue, in patients with RAS- or RAF-altered advanced solid tumors.

TPS3185 Background: Alterations in the RAS/RAF/MEK/ERK pathway are the most common drivers of oncogenesis. MEK is a clinically validated cancer target and despite FDA approval of several MEK inhibitors, their clinical utility has been limited to BRAF V600 mutant cancers and NF1 mutant neurofibromas mostly due to early emergence of resistance and low therapeutic indices. IK-595, a potent novel MEK-RAF molecular glue, is being developed to overcome these limitations. IK-595 traps MEK in an inactive complex with all RAF isoforms and blocks RAF-dependent MEK phosphorylation, thereby alleviating CRAF-mediated MEK reactivation that hinders the efficacy of approved MEK inhibitors in RAS/RAF-driven tumors, in addition to kinase independent CRAF activity. IK-595 exhibits potent single agent activity in a wide range of in vivo cancer models harboring various RAS/RAF alterations, including, but not limited to, lung, pancreatic, colorectal cancer (CRC), melanoma, and AML. The preclinical pharmacokinetic profile of IK-595 also enables flexible dosing schedules resulting in a broader therapeutic window. Methods: This is a phase 1, first-in-human, open-label, multicenter study to evaluate IK-595 as monotherapy in patients with RAS- or RAF-altered advanced solid tumors for whom there are no other further treatment options known to confer clinical benefit. Dose escalation uses a Bayesian Optimal Interval Design (BOIN) in patients with advanced and unresectable, or metastatic solid tumors with confirmed RAS/RAF gene alterations. Backfilling of cleared dose levels with key target indications will initiate upon achievement of efficacious plasma exposures. Dose expansion will occur in genetically defined cohorts, for example NRAS-mutant CRC and malignant melanoma, as well as BRAF non-V600 and KRAS mutant tumors using a Simon 2-stage adaptive design. IK-595 will initially be administered on an intermittent dosing schedule in 30-day cycles. Additional dosing schedules may be explored. Primary objectives of the study are to evaluate safety and tolerability of IK-595 and to determine the recommended phase 2 dose (RP2D) and/or maximum tolerated dose (MTD). Secondary objectives include evaluation of preliminary antitumor activity by RECIST 1.1, pharmacokinetic (PK) parameters, and pharmacodynamic effects of IK-595 on pERK in paired tumor biopsies. Key exploratory endpoints include changes in pERK in peripheral blood cells, changes in pERK target genes in tumor biopsies, and assessment of candidate baseline response biomarkers. The study began in December 2023 and enrollment in Cohort 1 was completed with no DLTs; dose escalation continues to enroll. Clinical trial information: NCT.

Exploring the safety and efficacy of GT201 as a first-in-class autologous tumor-infiltrating lymphocyte monotherapy in advanced solid tumors.

2547 Background: GT201, featuring a membrane bound IL-15 stably expressed on tumor-infiltrating lymphocytes (TIL), aims to augment TIL persistence and function as well as ameliorate immune suppression within the tumor microenvironment, offering potential for durable responses in advanced solid tumor patients. We present data from 7 patients enrolled in an open-label, single-arm, multicenter clinical study (NCT05729399), investigating the safety profile and efficiency trend of GT201 therapy. Methods: The GT201 phase 1 trial is designed with the primary endpoint of DLT evaluation and the secondary endpoint of measuring preliminary efficacy parameters including overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of response (DOR, and overall survival (OS) following the RECIST v1.1. Results: As of January 22, 2024, a cohort of 7 pts has been enrolled in the study, with a median age of 48 and a median of 3 prior lines of therapy. Among these patients, 1 pt has a history of bone metastases, 2 pts have a history of liver metastases, and 1 pt has a history of brain metastases. Following the standard FC lymphodepletion, pts underwent infusion with GT201 at doses ≥ 5x109 total viable cells. Five pts subsequently received IL-2 as part of the treatment protocol. Treatment-related AEs were observed in ≥ 50% of pts with no grade≥3 AEs. Grade ≥ 3 AEs related to FC lymphodepleting chemotherapy and IL-2 included decreased lymphocyte count, decreased neutrophil count, and decreased white blood cell count, pyrexia and increased heart rate. Notably, all grade ≥3 AEs were either recovered or downgraded to grade ≤ 2 within 14 days. Among the 7 response-evaluable patients across various indications, including Non-Small-Cell-Lung Cancer (NSCLC), melanoma malignant, cervical cancer, and ovarian cancer, 3 patients (42.9%) achieved a confirmed partial response (PR), and 2 patients (28.6%) demonstrated stable disease (SD) as their best response. Notably, among the NSCLC subgroup, disease control (SD ≥ 24 weeks or any PR) was observed in all 3 pts (3/3, 100 %). GT201 cells can be detected in all patients receiving treatment, indicated by both staining IL15RA protein on peripheral T cells and measuring the transgene copy number in peripheral white blood cells. GT201 cells expanded robustly in patients and persist in peripheral blood beyond at least 6 months post cell infusion. Conclusions: In patients with heavily pretreated advanced or metastatic solid tumor, GT201, when infused after FC lymphodepletion and followed by high dose IL-2, exhibits a manageable safety profile. Notably, GT201 has demonstrated a favorable clinical profile in NSCLC, with an encouraging objective response rate, response durability, and no GT201-treatment related grade≥3 AEs. Clinical trial information: NCT05729399 .