Cavalcante, Ludimila

Background/Objectives: Standard treatment of multiply relapsed Ewing sarcoma remains to be established. Recent studies evaluating tyrosine kinase inhibitors (TKIs) with anti-angiogenic properties have shown encouraging results. Therefore, we conducted a systematic review and meta-analysis to explore the efficacy and safety of TKIs in patients with Ewing sarcoma. Methods: We comprehensively searched PubMed, Embase, and Cochrane databases for clinical trials (CTs) and cohort studies assessing TKIs in the treatment of advanced Ewing sarcoma patients who received at least one prior line of therapy. The main outcome was objective response rate (ORR). All analyses were conducted using R software (v.4.2.2), employing random effects models with 95% confidence intervals (CIs). Results: We included 14 studies (seven phase II CT and seven retrospective cohorts), comprising 257 patients. The following TKIs were evaluated: cabozantinib, regorafenib, apatinib, anlotinib, sorafenib, lenvatinib, sunitinib, fruquintinib, and imatinib. In a pooled analysis of all Ewing sarcoma patients treated with TKIs, the ORR was 23% (95% CI, 11.2–37.1%) and the DCR was 61.1% (95% CI, 47.3–74.2%). Responses were numerically higher but statistically nonsignificant between clinical trials and real-world studies. The analysis including only single-agent TKIs showed better responses for anlotinib and apatinib, yet these drugs are not available in Western countries. Among the FDA-approved TKIs, superior outcomes were noted with single-agent cabozantinib. (ORR: 21.6%) and regorafenib (ORR: 11.3%). Several studies did not report toxicity data exclusively for Ewing sarcoma patients; thus, conclusions about toxicity are mostly based on the general population of studies and may not be fully representative of Ewing sarcoma patients. Conclusions: Anti-angiogenic TKIs have shown important anti-tumoral activity in patients with Ewing sarcoma. Efficacy was consistently seen in both clinical trials and real-world studies. Nonetheless, there are important differences in study design and population that may limit our interpretation of efficacy and toxicity findings.

TPS11585 Background: Soft tissue sarcomas (STS) with genomic complexity are often aggressive but may be sensitive to further genotoxic stress. Leiomyosarcoma (LMS), a common STS, frequently harbors genomic complexity and DNA damage response (DDR) dysregulation. Preclinical data showed hyper-dependency on DNA-PK-mediated non-homologous end joining (NHEJ) DDR, and low-dose liposomal doxorubicin (LD-LPD) synergized with the DNA-PK inhibitor peposertib to inhibit tumor growth in LMS models. We hypothesize that a low, sensitizing dose of LPD enhances DNA damage and safely synergizes with peposertib in LMS and other genomically complex STS. Methods: This phase 1, open label, multicenter dose escalation and dose expansion study (NCT05711615) evaluates LD-LPD given intravenously (IV) on day 1 of 28-day cycles with peposertib given orally (PO) twice daily (BID) continuously (Table). Up to 18 patients (pts) over 18 years-old with advanced or unresectable LMS, undifferentiated pleomorphic sarcoma, myxofibrosarcoma, dedifferentiated liposarcoma, and synovial sarcoma, ECOG performance status ≤2, who received ≥1 prior line of systemic therapy (including anthracycline ≤300 mg/m 2 ) are eligible for dose escalation. Dose expansion will include 12 pts with LMS. The primary objective is to determine the recommended phase 2 dose of LPD+peposertib based on the dose limiting toxicity rate. The Bayesian Optimal Interval (BOIN) design will inform dose escalation decisions. Secondary endpoints for the expansion cohort include adverse event rate, progression-free survival, and objective response rate per RECIST v1.1. Potential predictive biomarkers and changes in DDR biomarkers will be evaluated on biopsies during screening and at cycle 1 day 7. Circulating tumor DNA (ctDNA) collected at baseline (dose escalation and dose expansion), on treatment and at progression (dose expansion) will be correlated with disease activity and response. This trial activated on 8-May-2023 through the Experimental Therapeutics Clinical Trials Network (ETCTN) and is enrolling at select sites in the United States. Dose escalation is ongoing as of January 2025. Clinical trial information: NCT05711615 . Planned dose levels for dose escalation. Dose Escalation Schedule Dose Level Dose Liposomal doxorubicin Peposertib (tablet) -1 10 mg/m 2 IV 50 mg PO BID 0* 10 mg/m 2 IV 100 mg PO BID +1 10 mg/m 2 IV 150 mg PO BID +2 10 mg/m 2 IV 200 mg PO BID +3 15 mg/m 2 IV 200 mg PO BID +4 20 mg/m 2 IV 200 mg PO BID *Starting dose.

Abstract Purpose: The safety, pharmacokinetics, and efficacy of elraglusib, a glycogen synthase kinase-3β (GSK-3β) small-molecule inhibitor, as monotherapy or combined with chemotherapy, in patients with relapsed or refractory solid tumors or hematologic malignancies was studied. Patients and Methods: Elraglusib (intravenously twice weekly in 3-week cycles) monotherapy dose escalation was followed by dose escalation with eight chemotherapy regimens (gemcitabine, doxorubicin, lomustine, carboplatin, irinotecan, gemcitabine/nab-paclitaxel, paclitaxel/carboplatin, and pemetrexed/carboplatin) in patients previously exposed to the same chemotherapy. Results: Patients received monotherapy (n = 67) or combination therapy (n = 171) elraglusib doses 1 to 15 mg/kg twice weekly. The initial recommended phase II dose (RP2D) of elraglusib was 15 mg/kg twice weekly and was defined, without dose-limiting toxicity observation, due to fluid volumes necessary for drug administration. The RP2D was subsequently reduced to 9.3 mg/kg once weekly to reduce elraglusib-associated central/peripheral vascular access catheter blockages. Other common elraglusib-related adverse events (AE) included transient visual changes and fatigue. Grade ≥3 treatment-emergent AEs occurred in 55.2% and 71.3% of patients on monotherapy and combination therapy, respectively. Part 1 monotherapy (n = 62) and part 2 combination (n = 138) patients were evaluable for response. In part 1, a patient with melanoma had a complete response, and a patient with acute T-cell leukemia/lymphoma had a partial response (PR). In part 2, seven PRs were observed, and the median progression-free survival and overall survival were 2.1 [95% confidence interval (CI), 2–2.6] and 6.9 (95% CI, 5.7–8.4) months, respectively. Conclusions: Elraglusib had a favorable toxicity profile as monotherapy and combined with chemotherapy and was associated with clinical benefit supporting further clinical evaluation in combination with chemotherapy.

SPOP mutations drive opposing molecular and immune landscapes in prostate and endometrial cancers, suggesting tailored therapies

3079 Background: Elraglusib (9-ING-41), a novel inhibitor of GSK-3β, has been evaluated in >230 patients (pts) with advanced malignancies including metastatic melanoma in the 1801 phase 1/2 trial (NCT03678883). Pts with melanoma treated with single agent elraglusib demonstrated clinical benefit including a durable complete response despite multiple prior lines of therapy including checkpoint inhibitors (CPI). Methods: We collected data from numerous -omic modalities in the 1801 trial to characterize markers of elraglusib response with bioinformatics and machine learning (ML). Genomic panels were collected on 105 pts. The most frequent tumor types included colorectal cancer (n=35), pancreas (n=31), lung (n=15) and metastatic melanoma (n=12). Pts were treated with elraglusib as a single agent or in combination with chemotherapy. Pathway based features were generated by quantifying the percent of each Reactome pathway that was mutated. These pathway features were iteratively evaluated for their performance in shallow neural networks predicting patient RECIST with each model using 5-15 randomly selected features at a time. Publicly available genomic data from an anti-PD-1 trial in patients with metastatic melanoma (Hugo et al., 2017) was transformed into pathway-based features and input into the final model to predict elraglusib response in this population. Results: Our final pathway based genomic model for elraglusib response performed with a training accuracy of 93% and a test accuracy of 88% on the 1801 patients. We then tested the model on metastatic melanoma patients who were treated with anti-PD-1 therapy. We found that patients from Hugo et al. were predicted to respond to elraglusib (22/26). In addition, most patients with tumors resistant to anti-PD-1 therapy were also predicted to respond to elraglusib (10/12). Finally, we tested the model on metastatic melanoma patients treated with elraglusib in the 1801 study that had failed CPI and for whom -omic data was available. The model correctly identified 5/5 patients that demonstrated clinical benefit (1 CR, ongoing>1400 days; 4 prolonged OS of 107, 256, 357, and 556 days). Conclusions: We applied robust in-silico modeling developed using 1801 trial data to develop a rationale for the development of elraglusib in the treatment of metastatic melanoma including patients that failed or were refractory to anti-PD-1 treatment. This model correctly identified metastatic melanoma patients in 1801 with good clinical outcomes that had failed prior CPI treatment. Further, we present this in silico approach as a robust way to repurpose prior clinical study genomics and ML modeling for population enrichment during the clinical development of novel drugs. Clinical trial information: NCT03678883 .

e14555 Background: 9-ING-41 (elraglusib) is a novel inhibitor of GSK-3β that has shown early signs of clinical benefit in a phase 1/2 clinical trial (ACT1801; NCT03678883). Early data support a multi-modal mechanism of action for elraglusib that targets both the tumor and immune system. Thus, the discovery and validation of biomarkers of drug sensitivity to elraglusib is a high priority. Here, we take inspiration from the literature on checkpoint inhibitor therapy and explore the potential of cytokines to predict elraglusib clinical response. Methods: Peripheral plasma samples from 59 patients enrolled in the 1801 phase 1/2 trial of elraglusib were assayed for 40 circulating cytokine levels. Patients advanced solid tumors refractory to standard treatments and received either elraglusib (1.0-15.0 mg/kg) as a single agent or in combination with other chemotherapies. Samples were taken from time points prior to elraglusib administration (pre-dose), after cycle 1, or after cycle 2. Each cytokine time point combination was used to stratify patients into high and low categories using an optimal cut-point determined using maximally selected rank statistics. Kaplan Meier and Cox Proportional Hazards analysis was used to determine the efficacy of each cytokine as a biomarker. The change in cytokine values between pre-dose and cycle 1 or pre-dose and cycle 2 was evaluated in a similar manner. Results: A total of 142 samples spanning eight different tumor histologies were collected and analyzed. A total of 240 cytokine-timepoint combinations were evaluated, and 53 significantly stratified patients by overall survival (p-value < 0.05). Of those, 35 showed that higher levels of the given cytokine correlated with a survival benefit and 18 a survival decrease. Notable among the cytokines demonstrating survival benefits were Granzyme B at Cycle 1 Day 4 (HR: 9.54, p-value:0.015) and TGF β at Cycle 1 Day 4 (HR: 8.48, p-value:0.0063). Strong hazard ratios were also observed for cytokines that correlated with survival decreases including TRAIL-R2 at Cycle 1 Day 2 (HR: 9.56e-02, p-value:0.0001), and IL-10 at Cycle 1 Day 4 (HR: 8.77e-02, p-value:0.007). Delta between timepoints was also able to stratifying patients by overall survival. Conclusions: Plasma cytokine profiling is a promising approach for discovery and validation of biomarkers prognostic for elraglusib clinical benefit. Numerous cytokines measured pre-dose stratified patients into significant survival groups suggesting a potential strategy for patient enrichment in clinical trials of elraglusib. These initial findings are being expanded by 1) increasing the cohort to accommodate histology specific investigations; 2) examining which cytokines are elraglusib response-specific versus drug-agnostic; and 3) combining cytokines in multivariate and machine learning models for optimal predictive capacity. Clinical trial information: NCT03678883 .

Abstract 9-ING-41 (elraglusib) is a potent and selective GSK-3 inhibitor that has shown anti-tumor activity in patient-derived xenograft models and phase1/2 clinical studies in patients (pts) with advanced solid tumors. Preclinical studies have demonstrated that elraglusib downregulates PD-1, TIGIT and LAG-3, upregulates expression of MHC class I proteins in tumor cells from “cold tumors”, and shows synergy when combined with PD-1 blockade in mouse xenografts. Clinical activity has been observed both as a single agent and in combination with standard of care chemotherapies in several advanced cancer histologies. Here we present initial ‘omics data from our phase 1/2 study (NCT03678883; ACT1801) spanning &gt;100 pts with advanced cancer evaluating both single agent and chemotherapy combinations. The patients (pts) included in this study received elraglusib as a ≥3rd line therapy for advanced disease. Most pts with melanoma treated with elraglusib monotherapy (8/9; 89%) stayed on study for &gt;2 cycles. One patient with melanoma refractory to checkpoint inhibitors achieved a confirmed and durable CR. Clinical benefit was also observed among pts with colorectal cancer with 4/12 (33.3%) pts treated with monotherapy and 12/15 (80%) that received elraglusib plus irinotecan rechallenge stayed on study &gt;2 cycles reaching median overall survival of 106 and 211 days, respectively. Based on emerging in vivo and in vitro results demonstrating that elraglusib activates T and NK cells promoting anti-tumor immune responses, we hypothesize immunomodulation by elraglusib may be contributing to anti-tumor immune response in the 1801 trial. We have acquired TCRseq and RNAseq profiles of PBMC samples from seven patients in 1801 during the first two weeks of treatment with elraglusib monotherapy. In these pts, reduced TCR clonality was observed and specific TCR clonotypes expanded after treatment, indicating T cell activation and expansion. These pts also showed changes in PBMC populations during elraglusib therapy as measured by immune deconvolution of PBMC RNAseq. Taken together, these data support a novel, previously unrecognized immunomodulatory mechanism of action for elraglusib and could provide rationale for future clinical development of elraglusib in pts with advanced malignancies. Additional analysis from TCRseq, immune profiling and cytokine analysis from expanded cohort of pts is ongoing. Citation Format: Taylor Weiskittel, Joseph McDermott, Daniel Billadeau, Hu Li, Anwaar Saeed, Devalingam Mahalingam, Solmaz Sahebjam, Pamela Munster, Ludimila Cavalcante, Frank J. Giles, Andrew Mazar, Benedito Carneiro. Multimodal mechanism of action of the GSK-3 inhibitor 9-ING-41 (elraglusib) includes an immunomodulatory component: preliminary results from the 1801 phase 1/2 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT222.

Abstract Background GSK3β serine/threonine kinase regulates metabolism and glycogen biosynthesis. GSK3β overexpression promotes progression and resistance through NF-κB and p53 apoptotic pathways. GSK3β inhibits immunomodulation by downregulating PD-L1 and LAG-3 checkpoints and increasing NK and T-cell tumor killing. 9-ING-41, a small-molecule, selective GSK3β inhibitor, showed preclinical activity in chemo-resistant PDX glioblastoma models, including enhanced lomustine antitumor effect. Methods Refractory malignancies (n = 162) were treated with 9-ING-41 monotherapy (n = 65) or combined with 8 cytotoxic regimens after prior exposure (NCT03678883). Recurrent gliomas (n = 18) were treated with 9-ING-41 IV TIW q21day cycles at 3.3, 5, 9.3, 15 mg/kg, as monotherapy or combined with lomustine 30 mg/m² PO weekly q84day cycles. Primary objective was safety. Results RP2D of 15 mg/kg IV TIW was confirmed across all 9 regimens, no accentuated chemotherapy toxicity noted. Glioma subtypes included: 13 glioblastoma, 2 anaplastic astrocytomas, 1 anaplastic oligodendroglioma, 1 astrocytoma. Median age 52 (30–69) years; 6 female, 12 male; median ECOG 1 (0–2); median recurrences 3 (1–6). All received upfront radiation/temozolomide (18/18), plus salvage nitrosoureas (15/18), bevacizumab (8/18), TTFields (6/18), or immunotherapy (4/18). IDH/mutation(3/18); 1p19q/codeletion(1/18); MGMT/methylated(1/18). Four received 9-ING-41 monotherapy, 14 concurrent with lomustine. No severe toxicities were attributed to 9-ING-41, only mild vision changes (9/18, 50%), or infusion reactions (4/18, 22%). Lomustine-related toxicities: G3/4 thrombocytopenia (3/14, 21%), G1/2 fatigue (4/14, 28%). Median days on therapy was 55 (4–305); 1 partial response (&gt;50%) was noted. Median OS was 5.5 (95% CI: 2.8–11.4) months and PFS-6 was 16.7%. Conclusion 9-ING-41 plus/minus lomustine is safe and warrants further study in glioma patients.

Abstract BACKGROUND GSK3β serine/threonine kinase regulates metabolism and glycogen biosynthesis. GSK3β overexpression promotes tumor progression and resistance through NF-κB and p53 apoptotic pathways. GSK3β inhibits immunomodulation by downregulating checkpoints, e.g. PD-L1 and LAG-3, and increasing NK and T-cell mediated tumor killing. 9-ING-41 is a small-molecule, potent, selective GSK3β inhibitor with preclinical activity. In chemoresistant PDX glioblastoma models, 9-ING-41 enhanced lomustine antitumor effect. METHODS Patients with refractory malignancies were treated with 9-ING-41 monotherapy (n=65) or combined with 8 cytotoxic regimens after prior exposure (n=162) in the first-in-human study (NCT03678883). The recurrent gliomas subset was treated with 9-ING-41 monotherapy IV TIW q21day cycles at 3.3, 5, 9.3, 15mg/kg, or combined with lomustine 30 mg/m² PO weekly q84day cycles. Primary objective was safety and tolerability. RESULTS An RP2D of 15mg/kg IV TIW was confirmed across all 9 regimens, no accentuation of chemotherapy toxicity noted. Of 18 glioma patients enrolled, 13 were glioblastoma, 2 anaplastic astrocytomas, 1 anaplastic oligodendroglioma, and 1 diffuse astrocytoma; 6 female, 12 male; median age 52 (30-69) years; median ECOG was 1 (0-2). All received initial radiation and temozolomide (18/18), prior salvage therapies included nitrosoureas (15/18), bevacizumab (8/18), TTFields (6/18), checkpoint inhibitor (4/18). Median recurrences 3 (1-6). NGS alterations included: IDH/wildtype (11), IDH/mutation(3); 1p19q/codeletion(10); MGMT/unmethylated(11), MGMT/methylated(1); EGFR/amplification(6), EGFR/v3mutation(3), TERT/mutation(6), PTEN/loss(3), NF1/rearrangement(2), ATRX/loss (2), TP53/mutation(4), CDKN2A/deletion(2), RB1/loss(1), PALB2/mutation(10). Four patients received 9-ING-41 monotherapy, 14 concurrently treated with lomustine. No SAEs or grade 3/4 AEs attributed to 9-ING-41 noted, only G1/2 vision changes (9/18, 50%), infusion reactions (4/18, 22%). Lomustine-related toxicities included G3/4 thrombocytopenia (3/14, 21%), and G1/2 fatigue (4/14, 28%). Median therapy duration was 55 (4-305); 1 partial response ( &gt;50%) noted with 9-ING-41/lomustine. Median PFS and OS were 1.9 (0.3-11.1) and 6.0 (1.6-16.6) months, respectively. CONCLUSIONS 9-ING-41 plus/minus lomustine is safe and warrants further study in glioma patients.

2051 Background: GSK-3β, a serine/threonine kinase, is a key regulator of metabolism and glycogen biosynthesis. GSK-3β aberrant overexpression promotes tumor progression and chemotherapy resistance through NF-κB and p53-mediated apoptotic pathways. GSK-3β inhibition impacts immunomodulation through downregulation of checkpoints, such as PD-L1 and LAG-3, and increasing NK and T-cell mediated killing of tumor cells. 9-ING-41 is a small-molecule potent selective GSK-3β inhibitor with preclinical antitumor activity against several tumor types. In chemoresistant PDX models of glioblastoma (GBM), 9-ING-41 enhanced the antitumor effect of CCNU and CPT-11. Methods: In the first-in-human study (NCT03678883), patients (pts) with refractory malignancies received 9-ING-41 monotherapy (n = 65) or in combination with one of 8 cytotoxic regimens after prior treatment with the same chemotherapy (n = 162). We report the subset of pts with recurrent gliomas treated with 9-ING-41 monotherapy IV twice a week in 21-day cycles at different dose levels (3.3, 5, 9.3, 15mg/kg), or in combination with lomustine 30 mg/m² orally once weekly in 84-day cycles. Primary objective was safety and tolerability. Results: An RP2D of 15mg/kg IV was confirmed across all 9 regimens, no accentuation of chemotherapy-related toxicity noted. Of 18 glioma patients enrolled, 13 were GBM, 2 anaplastic astrocytomas, 1 diffuse astrocytoma, and 1 anaplastic oligodendroglioma. Four patients received single agent 9-ING-41, 14 treated concurrently with lomustine. Demographics: 6 female, 12 male; median age 52 (30-69) years; median ECOG was 1 (0-2). All received first-line radiation and temozolomide (18/18), prior therapies for recurrences included nitrosoureas (15/18), bevacizumab (8/18), TTFields (6/18), immune checkpoint inhibitor (4/18). Median recurrences 3 (1-6). Genomic alterations from available NGS reports included: IDH WT (11), IDH mutation (3), MGMT promoter unmethylated (11), MGMT promoter methylated (1), 1p19q co-deletion (10), EGFR amplification (6), EGFR v3 mutation (3), TERT promoter mutation (6), PTEN loss (3), NF1 rearrangement (2), ATRX loss (2), TP53 mutated (4), CDKN2A deletion (2), RB1 loss (1), PALB-2 mutation (10). No SAEs or grade 3/4 AEs attributed to 9-ING-41 were noted; AEs included G1/2 transient vision changes (9/18, 50%), infusion reactions (4/18, 22%). Side effects from lomustine included: G3/4 thrombocytopenia (3/14, 21%), and G1/2 fatigue (4/14, 28%). Best overall response: 1 minimal response (-43%) after 2 cycles of 9-ING-41 and lomustine. Median days on therapy was 55 (4-305), 4/18 (22%) were stable for 20 weeks or longer. Conclusions: These results show 9-ING-41 alone or in combination is safe and warrants further study in glioma patients. Clinical trial information: NCT03678883.