CTCAE V4 Research Articles

NURS-01. NOVEL TREATMENTS FOR ACNEIFORM ERUPTIONS CAUSED BY TARGETED THERAPIES IN THE PEDIATRIC POPULATION

Abstract BACKGROUND Drugs that target the mitogen-activated protein kinase pathway can cause frequent and severe cutaneous toxicities with acneiform eruptions being one of the most common and challenging to manage. The literature is limited regarding treatment recommendations especially when this rash is refractory to first-line therapies. METHODS A single-institution case series regarding the treatment of acneiform eruptions with oral isotretinoin after failure of first-line therapies was performed. RESULTS Two female, adolescent patients who developed refractory acneiform eruptions while on trametinib were included. Their acneiform eruption emerged within the first cycle of trametinib requiring treatment with oral doxycycline plus a variety of topical medications. They remained on doxycycline for 6 and 7 months. Both patients then switched to oral isotretinoin after minimal rash response and rebound of the rash when attempting to discontinue doxycycline. The initial isotretinoin doses were 0.2-0.3 mg/kg/day rounded per pill size. Both patients required a dose reduction due to worsening xerosis. Once decreased, isotretinoin was well tolerated. No changes in baseline lipid panels or ALT were seen. No associated neurologic symptoms or pseudotumor cerebri. While on oral isotretinoin, no additional topical therapies were required to treat the acneiform eruption. The first patient’s acneiform rash improved from a CTCAE v5 grade 3 to grade 1 after only 3 weeks of isotretinoin. All locations of the rash responded to therapy. The second patient developed a grade 2 acneiform rash after starting trametinib and became ungradable with only residual pink papules to cheeks after receiving isotretinoin. CONCLUSIONS Both patients were successfully treated with isotretinoin after multiple prior therapies including 6 or more months of treatment with oral antibiotics. We recommend further research of treatment therapies in addition to oral antibiotics given concerns on their impact of the microbiome.

NFS-05. INCIDENCE OF BEVACIZUMAB ASSOCIATED TOXICITY IN CHILDREN WITH LOW GRADE GLIOMA WITH AND WITHOUT NF1

Abstract BACKGROUND Low grade gliomas (LGG), both sporadic & Neurofibromatosis1 (NF1) associated, are the commonest pediatric brain tumors. When surgically unresectable, they may become progressive/ symptomatic and require chronic oncological treatment. Bevacizumab (BVZ; Avastin), a recombinant humanized monoclonal antibody to VEGF, has shown efficacy both as a single agent or combined with chemotherapy as second/ third line treatment of progressive LGG especially in the optic pathway. BVZ can be associated with adverse effects including hypertension (HTN) and proteinuria. Children with NF1 have known increased tendency to hypertension however there is no data comparing the frequency of side effects from BVZ in patients with or without NF1. METHODS Retrospective study of all LGG cases treated with BVZ diagnosed 2010-2023 in a tertiary oncology center. We graded hypertension, proteinuria, cardiac function, retinopathy & bleeding according to the CTCAE v5.0 in NF1 and non-NF1 patients. RESULTS 16 children with LGG were treated with BVZ; 7 had NF1. 75% optic glioma, 25% other. All received BVZ as second or third line treatment in combination with chemotherapy. In the non NF1 group, 77% patients developed grade 2 HTN on BVZ treatment; none required medical intervention. 6 had grade 1 elevation of protein-creatinine ratio (median 0.38). In the NF1 group, 71% developed grade 2 or 3 HTN on BVZ treatment including a patient with aortic coarctation (CoA) who had worsening of previous HTN, 2 required antihypertensive therapy (p non-significant HTN non NF1 vs. NF1). Only 1 NF1 patient developed proteinuria. No patients in either group stopped BVZ prematurely for toxicity. Hypertension was reversible after cessation of BVZ in all except the patient with CoA. CONCLUSIONS Hypertension is more common than previously reported in both NF1 and non-NF1 patients treated with BVZ for LGG. Blood pressure should be monitored and treated appropriately. BVZ is safe in young patients with NF1.

NFS-07. RESPONSE OF A CENTRAL NERVOUS SYSTEM (CNS) HEMANGIOBLASTOMA TO BELZUTIFAN IN A PEDIATRIC PATIENT WITH VON HIPPEL-LINDAU DISEASE (VHL)

Abstract BACKGROUND VHL is a rare cancer predisposition syndrome which affects many organ systems, leading to renal clear cell carcinoma (RCC), pheochromocytoma, retinal angiomas and CNS hemangioblastomas. Surgical resection has traditionally been the mainstay of treatment of VHL-associated tumors. In 2021, belzutifan, a Hypoxia Inducible Factor 2-alpha inhibitor was approved by the Food and Drug Administration for the treatment of VHL-associated RCC based on efficacy in adults. There is a paucity of data in pediatric VHL patients with hemangioblastoma treated with this novel agent. Herein we present such a case. CASE A 15-year-old male, diagnosed with VHL caused by a de novo germline mutation at the age of 12, was found to have a left craniocervical junction lesion consistent with a hemangioblastoma on surveillance MRI. The lesion demonstrated growth upon serial imaging but remained asymptomatic. Due to location, the patient was started on medical treatment using once daily oral belzutifan (120mg) continuously, sperm banking was performed prior to initiation of therapy. Hematologic and metabolic laboratory values were monitored, in addition to regular physical examinations including blood oxygen saturation recordings. The first MRI on therapy (3 months after treatment started) demonstrated a major radiologic response using RANO criteria. Treatment has been overall very well tolerated with few treatment-related toxicities limited to CTCAE v5 grade 1 fatigue and grade 2 anemia. No dose reductions or interruptions were required. The patient remains on therapy and has completed 11 months of treatment with further reduction in the size of this target lesion. CONCLUSION Hemangioblastomas are preponderantly characterized by their highly vascular nature making surgical resection in some cases arduous depending on location. This unique pediatric case adds to the growing evidence that therapy with belzutifan may be a safe and efficacious option for VHL-associated CNS Hemangioblastomas. Prospective studies in children are needed.

Perioperative sacituzumab govitecan (SG) alone or in combination with pembrolizumab (Pembro) for patients with muscle-invasive urothelial bladder cancer (MIBC): SURE-01/02 interim results.

LBA4517 Background: SG is an antibody-drug conjugate composed of an anti-trophoblast cell surface antigen 2 (Trop-2) antibody coupled to SN-38 (a topoisomerase-I inhibitor) with US FDA-accelerated approval for locally advanced or metastatic urothelial carcinoma (mUC). A multi-cohort, open-label, phase 2 SURE study is evaluating neoadjuvant SG (SURE-01, NCT05226117) or neoadjuvant SG+pembrolizumab followed by adjuvant pembrolizumab (SURE-02, NCT05535218) in MIBC in a flexible design allowing a bladder-sparing approach. We report interim results from SURE-01. Methods: Pts with cT2-4N0M0 MIBC who were ineligible for or refused cisplatin-based neoadjuvant chemotherapy were planned to receive 4 cycles of neoadjuvant SG 10 mg/kg intravenously (IV) on days 1 and 8, Q3W, followed by radical cystectomy (RC). The trial included pre-post MRI imaging of the pelvis and ctDNA analysis. Pts with clinical complete response (cCR, defined with negative MRI, cystoscopy and ctDNA assays) refusing RC were offered redo transurethral resection of the bladder tumor (reTURBT) followed by observation in case no viable high-grade tumor in the bladder was found. The primary endpoint of the study is to assess the proportion of ypT0N0. The assumptions include a ypT0N0≤20% as H0 and ≥45% as H1 in a single-stage A’Hern’s design. Secondary end points include event-free survival (EFS), cCR rate and OS. Treatment-related adverse events (TRAEs) and safety are assessed using standard criteria (CTCAE v5). Tumor samples underwent comprehensive genomic profiling assay. Results: From 03/22 to 11/23, 21 pts were enrolled. After the initial 8 pts the study was amended with SG at 7.5 mg/Kg dose due to a Grade 5 TRAE. Median age was 71y, 7 pts (33.3%) had a cT3-4N0. Ten pts (47.6%) had a mixed variant histology. All pts received at least 1 cycle of SG: Grade ≥3 TRAE occurred in 9 pts (42.5%), including one Grade 5 event (at 10mg/Kg dose). Toxicity was unrelated to UGT1A1 polymorphism. Ten pts (47.6%) achieved a cCR. Sixteen pts are evaluable for final response at treatment completion: one pt had a disease progression and started palliative therapy, two did not undergo RC due to TRAE. Thirteen pts have undergone surgery (RC: N=10; reTURBT: N=3). ypT0N0-x response was achieved in 6/16 pts (37.5%), 7 (43.7%) an ypT≤1N0-x response. All pts with a residual disease revealed a ctDNA-negative test post-RC. Tumor samples from pts with cCR were enriched in ARID1A and BRCA1/2 mutations vs nonCR: 40 vs 9%, 30 vs 18%; nonCR were enriched in ERBB2 mutations vs cCR: 44 vs 10%. Conclusions: Observed ypT0N0-x responses after neoadjuvant SG showed promising activity in MIBC who have a high unmet need, with a potential to avoid RC. Reduced dose of SG was feasible and the data support the ongoing SURE studies in MIBC. Clinical trial information: NCT05226117 ; NCT05535218 .

BEAT-meso: A randomized phase III study of bevacizumab (B) and standard chemotherapy (C) with or without atezolizumab (A), as first-line treatment (TX) for advanced pleural mesothelioma (PM)—Results from the ETOP 13-18 trial.

LBA8002 Background: The currently approved frontline TXs for PM are the combination of ipilimumab/nivolumab or platinum plus pemetrexed. The addition of B to C has been shown to improve overall survival in a randomized clinical trial. While combined immunotherapy or single agent immunotherapy with C is superior to C alone, there is potential for a synergistic triple combination of C, B, and immunotherapy. Methods: BEAT-meso (NCT03762018) is an international open-label, 1:1 randomized phase III trial, stratified by histology and stage. The objective is to determine the efficacy and safety of adding A (1200 mg, Q3W until progression) to B (15mg/kg, Q3W until progression) and standard C (4-6 cycles of carboplatin AUC5 with pemetrexed 500 mg/m2, Q3W), as first-line TX for advanced PM. The trial is designed to detect an increase in the median overall survival (OS, primary endpoint) with the addition of A, aiming for a hazard ratio (HR) of 0.708, at 2.5% 1-sided alpha and 82% power (284 deaths, sample size 400 patients (pts)). In the pre-specified interim efficacy analysis (80% of the events, 01/2023), boundary was not crossed, and the trial continued to completion. Secondary endpoints include progression-free survival (PFS), objective response rate (ORR), disease control rate, duration of response (DoR), adverse events (AEs) assessed by CTCAE v5.0 and symptom-specific and global quality of life (QoL). Results: Between 04/2019 and 03/2022, a total of 400 pts was randomized, 200 per arm. The median age was 70 years, 79% were male, 50% were former smokers, 65% had ECOG performance status 1 and 78% had epithelioid histology. At a median follow-up of 35 months (m) (as of 1/09/2023), median OS was 20.5m [95% CI: 17.5-23.3] in the ABC and 18.1m [15.7-20.9] in the BC arm (deaths: 145 & 150; HRABC vs BC=0.84; [0.66 - 1.06], 2-sided stratified p=0.14, ITT final analysis). PFS was significantly longer in ABC with median 9.2m [8.1-10.9] vs 7.6m [6.9-8.3] in BC (HR=0.72; [0.59 - 0.89], 2-sided stratified p=0.0021). Histology shows a significant TX interaction for both PFS and OS. The OS HR is 0.51 [0.32-0.80] for non-epithelioid and 1.01 [0.77-1.32] for epithelioid (interaction p=0.012). In an exploratory analysis, post-progression OS was significantly different between the two arms, adjusted for post-progression TX (HR=0.76; [0.58 - 0.99]). The ORR was 55% in ABC and 49% in BC (p=0.27), while median DoR was 8.2m [6.8-9.7] in ABC and 5.6m [4.8-7.0] in BC (p=0.0041). Global QoL change was not significantly different between the two arms. Grade≥3 TX-related AEs occurred in 55% of pts in ABC and 47% of pts in BC (grade 5: 7 and 1 pt, respectively). Conclusions: The significant increase in median PFS with the addition of A did not translate into a significant increase in median OS. ABC demonstrated superiority over BC in non-epithelioid cases. Clinical trial information: NCT03762018 .

SACI-IO HR+: A randomized phase II trial of sacituzumab govitecan with or without pembrolizumab in patients with metastatic hormone receptor-positive/HER2-negative breast cancer.

LBA1004 Background: Sacituzumab govitecan (SG) is a TROP2 antibody drug conjugate (ADC) with a topoisomerase I inhibitor payload (SN-38) approved for previously treated triple negative and hormone receptor-positive/HER2-negative (HR+/HER2-) metastatic breast cancer (MBC). Double-strand DNA breaks induced by SN-38 activate cGAS-STING, stimulating type I IFN production and T cell recruitment. SN-38 can upregulate MHC class-I and PD-L1 expression, enhance cytotoxic T cell effector functions and deplete regulatory T cells. To evaluate if SG synergizes with pembrolizumab (PD-1 inhibitor) we conducted a randomized, open-label phase 2 study comparing SG with or without pembrolizumab in HR+/HER2- MBC (NCT04448886). Methods: Eligible patients (pts) had unresectable locally advanced or metastatic HR+ (ER≥1% and/or PR≥1%), HER2- breast cancer treated with ≥1 prior endocrine therapy and 0-1 chemotherapy (CT) for MBC. Pts with brain metastases were eligible if locoregional therapy was completed and steroids discontinued ≥7 days before study therapy. Pts who received prior topoisomerase I inhibitor ADC, irinotecan or PD-1/L1 inhibitors were excluded. Pts were randomized 1:1 to Arm A [SG 10 mg/kg IV (D1, D8) + pembrolizumab 200 mg IV (D1), 21-day cycle] or Arm B (SG alone). The primary endpoint was progression-free survival (PFS); secondary endpoints included PFS in PD-L1+ pts (22C3 CPS ≥1), overall survival (OS), objective response rate (ORR) and toxicity (NCI CTCAE v5.0). Baseline and on-treatment biopsies were performed for correlative analyses. For this preliminary analysis, data were locked 1/12/24. Results: Between 03/2021-01/2024, 110 pts enrolled; 104 pts (52 Arm A; 52 Arm B) started study therapy and were included in the analysis. Median age was 57 yrs (range: 27-81); 102 pts (98.1%) were female. 80 pts (76.9%) received prior CDK4/6 inhibitor for MBC; 58 (55.8%) had no prior CT, 46 (44.2%) had 1 prior line of CT for MBC. At a median follow-up of 9.2 months (mo), median PFS was 8.4 mo in Arm A vs 6.2 mo in Arm B (HR 0.76, 95% CI 0.47-1.23, log-rank p=0.26); ORR 21.2% and 17.3%, respectively. OS data are immature with only 26 events to date; OS was 16.9 mo vs 17.1 mo (HR 0.65, 95% CI 0.30-1.41, log-rank p=0.28), respectively. The most frequent treatment-related toxicities (≥G2) in Arm A were neutropenia (67.3%), fatigue (36.5%), alopecia (36.5%), anemia (32.7%), leukopenia (26.9%), diarrhea (21.2%) and nausea (21.2%); in Arm B, neutropenia (59.6%), alopecia (38.5%), diarrhea (34.6%), nausea (32.7%), fatigue (32.7%) and anemia (21.2%). Conclusions: Addition of pembrolizumab to SG showed a non-significant trend toward improved PFS in unselected HR+/HER2- MBC at this preliminary time point. Final PFS and updated OS with further follow-up will be presented at the meeting. Exploratory outcome analyses by TROP2 and PD-L1 expression will be reported. Clinical trial information: NCT04448886 .

Radiation pneumonitis prediction with dual-radiomics for esophageal cancer underwent radiotherapy

BackgroundTo integrate radiomics and dosiomics features from multiple regions in the radiation pneumonia (RP grade ≥ 2) prediction for esophageal cancer (EC) patients underwent radiotherapy (RT).MethodsTotal of 143 EC patients in the authors’ hospital (training and internal validation: 70%:30%) and 32 EC patients from another hospital (external validation) underwent RT from 2015 to 2022 were retrospectively reviewed and analyzed. Patients were dichotomized as positive (RP+) or negative (RP-) according to CTCAE V5.0. Models with radiomics and dosiomics features extracted from single region of interest (ROI), multiple ROIs and combined models were constructed and evaluated. A nomogram integrating radiomics score (Rad_score), dosiomics score (Dos_score), clinical factors, dose-volume histogram (DVH) factors, and mean lung dose (MLD) was also constructed and validated.ResultsModels with Rad_score_Lung&Overlap and Dos_score_Lung&Overlap achieved a better area under curve (AUC) of 0.818 and 0.844 in the external validation in comparison with radiomics and dosiomics models with features extracted from single ROI. Combining four radiomics and dosiomics models using support vector machine (SVM) improved the AUC to 0.854 in the external validation. Nomogram integrating Rad_score, and Dos_score with clinical factors, DVH factors, and MLD further improved the RP prediction AUC to 0.937 and 0.912 in the internal and external validation, respectively.ConclusionCT-based RP prediction model integrating radiomics and dosiomics features from multiple ROIs outperformed those with features from a single ROI with increased reliability for EC patients who underwent RT.

Efficacy and safety of dendrimer-enhanced (DEP) cabazitaxel (DEP CTX) in patients with advanced solid cancers in a phase 1/2 trial (P1/2).

3004 Background: DEP CTX is a highly optimized dendrimer nanoparticle formulation of cabazitaxel that achieves sustained cytotoxic drug delivery to tumors via enhanced permeability & retention effects. Unlike standard cabazitaxel (s-CTX), DEP CTX is highly water soluble, does not contain toxic excipients associated with anaphylaxis & does not require steroid/antihistamine premedication. We report the final P2 efficacy and safety results in patients (pts) with advanced/metastatic solid tumors. Methods: Pts were treated with DEP CTX at 20 mg/m2 cabazitaxel, IV 3-weekly. Efficacy was assessed by RECIST v1.1, Prostate Cancer Working Group 3 (PCWG3) guidelines or serum tumor markers; evaluable pts had relevant criteria at baseline and a follow-up assessment per protocol window. Safety was assessed by CTCAE v4.03. (EudraCT 2017-003424-76). Results: In P2, 75 pts were enrolled, prioritizing metastatic castration-resistant prostate cancer (mCRPC, s-CTX’s only approved indication), esophagogastric (EG) & ovarian (OV) cancers. For all pts, median progression free survival (mPFS) and overall survival (mOS) were 3.8 and 9.0 mths, respectively. Objective response rate (ORR) was 20% in 45 evaluable pts. All 25mCRPC pts were heavily pre-treated with a median of 4 prior lines of anticancer treatment. mPFS was 4.4 mths (radiographic or prostate specific antigen [PSA]); mOS was 14.7 mths. The disease control rate (DCR) was 70.6%; ORR was 16.7%. PSA reduced in 90% pts (by > 50% in 52.4%); 87% with bone metastases had no progression or improved. Of 15 EG pts, 9 were adenocarcinoma (ADENO) (3 gastric, 2 esophageal & 4 EG junction) & 6 were esophageal squamous cell carcinoma (SCC). For all EG pts, mPFS was 4.0 mths, mOS was 8.6 mths. mPFS was 4.0/1.9 mths for ADENO/SCC, respectively. Overall, DCR was 80%; ORR 30%. DCR was 100%/50% and the ORR was 33%/25% for ADENO/SCC, respectively. Of 22 OV pts, 96% were platinum resistant (Pt-R), with a median of 4 prior lines of anticancer treatment, including 59% with ≥ 3 platinum lines. mPFS/mOS were 3.1 mths & not reached, respectively. DCR was 66.7%; ORR 17.6%. Treatment related adverse events (TRAEs) were mostly mild/moderate (grade (G) 1/2; 64%/25%). Only 21% of pts had G 3/4 non-hematological TRAEs, while G3/4 lab detected neutropenia was seen in only 23% of pts despite no routine G-CSF. TRAEs observed in ≥10% of pts included fatigue, neutropenia, anemia, thrombocytopenia, diarrhea, nausea, vomiting, peripheral neuropathy and decreased appetite. Conclusions: DEP CTX exhibited clinically meaningful, durable antitumor activity in multiple advanced solid cancers, including mCRPC, Pt-R OV and EG cancers without the need for steroid premedication. The antitumor activity & safety results compare favorably to s-CTX, or standard of care chemotherapy in non-prostate cancers, and highlight the promising potential of dendrimer-enhanced delivery of cabazitaxel. Clinical trial information: 2017-003424-76 .

Durvalumab and consolidation SBRT following chemoradiation for stage III non-small cell lung cancer: A single institution pilot study.

e20085 Background: Definitive chemoradiation (CRT) followed by consolidative immunotherapy with durvalumab (IO) demonstrated survival benefit and is now standard of care for Stage III Non-small Cell Lung Cancer (NSCLC). However, local-regional control (LRC) remains a concern with intrathoracic progression representing the most common site of failure. Adding stereotactic body radiotherapy (SBRT) boost may enhance the immunogenicity and antigenicity of tumor cells by regulating cell surface receptors and augmenting T-lymphocyte infiltration into tumor. SBRT boost also allows escalated dose to the primary tumor while minimizing dose to critical structures. Methods: Patients with Stage III NSCLC planned for definitive concurrent CRT with 1 year of consolidative IO were prospectively enrolled on a single institutional pilot trial. IO started 6-8 weeks after completion of CRT. SBRT was delivered between cycle 1 and 2 of IO to the residual, primary tumor (20 Gy in 2 fractions for peripheral, 19.5 Gy in 3 fractions for central tumors). Residual tumors needed to be < 120 cc. Lymph nodes were not boosted. Primary endpoints were grade (gr) ≥3 toxicities (CTCAE V4.03) and progression free survival (PFS). Secondary endpoints were Overall Survival (OS), LRC, and distant metastasis (DM). A sample size of 25 patients was proposed to determine safety and efficacy. Results: Accrual was slower than anticipated, and the study closed with 11 patients enrolled over 54 months. Slow accrual was due to a low rate of eligibility based on post CRT clinical status and SBRT target limitations. 1 patient withdrew consent before receiving treatment leaving 10 evaluable patients. Median age was 73 years and median CRT dose was 60 Gy (range 60-66 Gy). 6/10 of patient were adenocarcinoma. 5/10 pts had central tumor location. Median follow-up for evaluable patients is 2.2 years. OS was 90%, 70%, and 70% at 1-year, 2-years, and 3 years, respectively. PFS was 90%, 47%, and 47% at 1 year, 2 years, and 3 years, respectively. LRC was 100%, 83%, and 63% at 1 year, 2 years, and 3 years, respectively. Rates of DM were 0%, 12%, and 34% at 1 year, 2 years, and 3 years, respectively. 1 patient developed gr 3 pneumonitis requiring discontinuation of IO. 1 additional patient developed gr 2 pneumonitis requiring a brief pause in IO therapy and resumed IO without any further complications. One patient developed gr 5 myocarditis 29 days after the first dose of IO and 18 days after SBRT, on investigation deemed to be myocarditis secondary to IO. There was no other gr 3 toxicity attributable to IO or SBRT. Conclusions: The addition of SBRT to consolidative IO in stage III NSCLC patients treated with CRT was feasible. The single gr 5 toxicity was attributed to IO. SBRT boost demonstrated encouraging efficacy and manageable toxicity and merits further study. Our data adds to the growing evidence of harnessing tumor immunogenicity in enhancing IO responses. Clinical trial information: NCT03589547 .

Naxitamab chemo-immunotherapy regimens other than with irinotecan/temozolomide for patients with relapsed/refractory high-risk neuroblastoma.

10037 Background: Patients with relapsed/refractory (R/R) high-risk neuroblastoma (HR-NB) have dismal prognosis with chemotherapy-only salvage regimens. Naxitamab, a humanized anti-GD2 monoclonal antibody (mAb), when combined with Irinotecan and Temozolomide (I/T), has demonstrated clinically meaningful efficacy in R/R HR-NB patients (NCT03189706). We aimed to investigate the potential synergy of naxitamab with other cytotoxics. Methods: In this retrospective analysis, we examined patients treated at SJD with chemo-refractory disease, who received naxitamab in combination with chemotherapeutics other than I/T. Each cycle comprised naxitamab 2.25 mg/kg/day IV over 30 minutes, days 2, 4, 9 and 11 (total 9 mg/kg or 270 mg/m2 per cycle), and GM-CSF 250 mg/m2/day subcutaneously, days 6-10 combined with either a) cyclophosphamide (250mg/m2) and topotecan (0.75mg/m2) D1 to D5 (C/T), b) ifosfamide (1500mg/m2), etoposide (100mg/m2) D1-D3 and carboplatin (400mg/m2) D1 (ICE) or c) doxorubicin 37.5mg/m2 D1-D2 and cyclophosphamide (250mg/m2) D1-D3 (C/D). Toxicity was measured by CTCAE v4.0 and responses by INRC. Results: Twenty-nine patients received naxitamab plus GM-CSF with C/T (n=23), ICE (n=6) and C/D (n=1). One patient received both ICE and C/T. Seventeen patients had a variable number of prior relapses (1 n=14, 2 n=1, and 3 n=2). Twelve patients had refractory disease, most having received additional therapy post-induction. All but 4 patients had received naxitamab and I/T (n=20), and/or ICE (n=3/n=1), and dinutuximab-beta and I/T (n=1). Toxicities of the new regimens included myelosuppression expected with chemotherapy, and pain and hypertension expected with naxitamab. Hemorrhagic cystitis occurred in 2 patients treated with C/T, BK infection documented in one. A total of 113 cycles (median 2; 1-8) were administered, outpatient. Out of the 30 treatments, 5 achieved complete response (CR), 2 partial response (PR), and 2 mixed response (MR), providing an objective response (OR) of 30%. Eight patients achieved stable disease (SD) and 13 progressed on treatment. Disease control rate (DCR) (OR or SD) after 2 cycles was 56.6%. Patients who never responded with prior chemo-immunotherapy progressed through the new combinations. Contrary, patients who showed initial stabilization with I/T or ICE but ultimately progressed, switching drugs resulted in 60% DCR and 30% OR. Most favourable OR (75%) was seen in patients who achieved CR with prior chemoimmunotherapy and relapsed (3 out of 4). Conclusions: Naxitamab-based chemo-immunotherapy with regimens other than I/T exhibited similar and manageable toxicity profiles. Switching chemotherapeutics provided objective responses only to patients who had previously shown efficacy with I/T chemo-immunotherapy.

Naxitamab-related adverse events within and across treatment cycles in patients with relapsed/refractory (R/R) high-risk neuroblastoma.

10032 Background: Anti-GD2 monoclonal antibodies, including naxitamab, for the treatment of high-risk neuroblastoma (HRNB) are associated with adverse events (AEs), though few studies have characterized their frequency and patterns of presentation. A practical understanding of AEs can help clinicians expect and manage those requiring intervention. In this post hoc analysis, we report the frequency and severity of naxitamab-related AEs across infusions and treatment cycles, based on data from a prespecified interim analysis of Trial 201. Methods: Trial 201 (phase 2, NCT03363373) is investigating naxitamab plus granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with R/R HRNB with residual disease in bone/bone marrow only. Patients with soft tissue or actively progressing disease were excluded. Naxitamab was infused at 3 mg/kg/dose IV on Days (D) 1/3/5 with GM-CSF administered SC on Days -4 to 5 (monthly cycles [C]). Patients (N=74) were evaluated for safety (CTCAE v4.0), with frequency defined as % of patients reporting >1 events. Frequency of AEs of Grade ≥3 were evaluated for C1-C5. Results: Most (81%) naxitamab-related AEs were Grade 1 or 2. Grade ≥3 AEs reported in ≥10% of patients were hypotension (60% of patients), pain (54%), urticaria (19%), bronchospasm (18%), and abdominal pain (16%). The frequency of related hypotension Grade ≥3 (Grade 4, n=3) decreased across cycles, from C1 (47%) to C5 (33%) and across infusions, from C1D1 (43%) to C1D3 (18%) and C1D5 (11%). Similar decreases were seen during C2 to C5. Among patients with Grade ≥3 hypotension, 73% had their first event C1D1, of whom 34% and 31% had their second event C1D3 or C2D1, respectively. The frequency of related pain Grade 3 AEs (all preferred terms with word “pain”) decreased from C1 (53%) to C2 (37%), generally stabilizing thereafter with frequencies consistent across infusions. Most (77%) had their first event C1D1, of whom 82% had a second event C1D3. The frequency of related bronchospasm Grade 3 (no Grade 4 AEs) was relatively stable around 7% from C1 to C3, decreasing to 4% and 2% in C4 and C5, respectively. Patients generally experienced these events on D1 infusions with few reported D3 or D5. No consistent pattern was seen for Grade 3 urticaria. None of the Grade ≥3 AEs of hypotension, urticaria, pain or bronchospasm resulted in treatment discontinuation. Conclusions: The frequency of naxitamab related Grade ≥3 AEs changed over the course of therapy. Hypotension was most frequent C1D1, decreasing across infusions and cycles. Pain frequency peaked C1 and decreased in subsequent cycles, remaining stable across infusions. Bronchospasm events, though relatively rare, generally occurred D1 and decreased across infusions. The results underline the importance of initial and ongoing monitoring within and across cycles to ensure appropriate and timely management. Clinical trial information: NCT03363373 .

Immune-related adverse event prediction and influential factor identification.

e14650 Background: Immune checkpoint inhibitors (ICIs), have demonstrated efficacy in treating patients with non-small cell lung cancer (NSCLC) and advanced melanoma. However, ICIs can lead to immune-related adverse events (irAE), which will cause discontinuance of the ICI treatment. The objective of this study is to identify factors that predict which patients with NSCLC or melanoma will develop irAE(s) from ICIs. Methods: We curated the patient cohort from the Immune-Oncology data repository developed at the Georgetown-Lombardi Comprehensive Cancer Center. This cohort encompassed 466 patients (245 individuals with NSCLC and 221 with advanced melanoma) who received single-agent anti-PD-(L)1 or combination of anti-PD-1 and anti-CTLA4 therapy. Parameters selected for prediction comprises baseline demographics, laboratory results, treatment information, and cancer-related mutations. The classification of irAE were identified by CTCAE V4.03 guidelines. Overall, 219 patients experienced one or more irAE, while the remaining 247 patients were irAE-free. We employed machine learning models for prediction, which were trained using 80% of the dataset with a five-fold cross-validation, and their performance was evaluated using the area under the receiver-operating curve (AUROC) and F1 score. Furthermore, we identified the key factors that significantly impacted the model by SHAP values. Results: Nine machine learning models were deployed, including logistic regression, support vector machine, gradient boosting (GB), etc. The GB model demonstrated the highest performance, achieving an AUROC score of 75% and an F1 score of 77%. According to the SHAP value obtained from the GB model, NSCLC patients exhibited a higher propensity for irAE development compared to melanoma patients. The top three features associated with a heightened likelihood of irAE development are the treatment of the combination of anti PD-1 and anti CTLA-4, a higher albumin/globulin ratio, and a pre-treatment ECOG Performance Status score of 0. The top three features associated with a lower likelihood of irAE development are an elevated red cell distribution width, the treatment with single agent anti-PD-1, and a higher globulin level. Conclusions: Our research harnesses a comprehensive set of variables to forecast the development of irAEs in NSCLC and melanoma patients undergoing ICI treatment. The results underscore the predictive capabilities of ML models. Investigating the connections between pivotal biomarkers, such as globulin and red cell distribution width, has the potential to offer insights that enable patients to mitigate irAE. These findings emphasize the promising potential of ML techniques not only in predicting the likelihood of irAE but also in the grade of irAE. To mitigate the limitation of a relatively small sample size, we are actively working to expand the data registry by collaborating with additional institutions.

Impact of immune-related adverse events (irAE) onset on disease response and survival in patients (pts) with head-neck cancer treated with immune check point inhibitors (ICI).

6028 Background: ICI or combination chemo-immunotherapy are the mainstay of therapy for metastatic head-neck squamous cell carcinoma (mHNSCC) due to durable responses in certain pts. irAEs have emerged as a new challenge in the management of these pts. Some studies suggest a positive correlation between irAE onset and ICI efficacy in other cancers, however, whether such an association exists in HNSCC remains incompletely explored. Methods: We performed a retrospective, single-center cohort study of pts ≥ 18 years of age, with histologically confirmed mHNSCC who received ≥ 1 dose of ICIs at the University of Virginia Comprehensive Cancer Center, VA, USA between 2013-2022. Demographics, disease and treatment characteristics, and clinical outcomes related to irAEs and ICI re-challenge were analyzed. IrAEs were graded using CTCAE v4.0 criteria by chart review. Independent sample t-tests and chi-square analyses were used for univariate comparisons. Median PFS and OS from ICI therapy initiation were estimated using Kaplan-Meier methodology and censored at date of last follow up. P-values <0.05 were considered statistically significant. Results: Of 1979 pts who received ICI, 110 had mHNSCC (72.7% male; 84.5% White) with a median age of 62.4 years. ICI type included pembrolizumab or nivolumab in 109 pts, and nivolumab/ipilimumab in one pt. 53 (48%) pts experienced any grade irAE and 12 pts (11%) experienced >1 irAE. The most common irAEs were hypothyroidism (30.4%), dermatitis (14.3%), and hepatitis (10.7%). CTCAE ≥G3 irAEs were seen in 22.6% pts (n=12). These included hepatitis (n=3), colitis (n=3), hypothyroidism (n=1), arthritis (n=1), pneumonitis (n=1), adrenal insufficiency (n=1), vasculitis (n=1), and cardiomyopathy (n=1). Men (62% vs 37%, p= 0.015) and pts with prior radiation therapy (83% vs 17%, p=0.047) were more likely to experience irAEs. Treatment interruption/discontinuation occurred in 43% pts with irAEs. Topical/supportive therapy was required in 52.8%, and 35.8% required systemic corticosteroids, with more than half experiencing complete irAE resolution. A statistically significant association was observed between irAE onset and objective response rate (68% vs 39%, p= 0.009). 12 pts underwent ICI re-challenge, resulting in partial response in 3 (25%), stable disease in 4 (33.3%) and progressive disease in 3 (25%) pts. There was no statistically significant difference in PFS (4.9 vs 9.7 months, p = 0.731) or OS (30.5 vs 21 months, p = 0.159) in irAE vs non-irAE groups, respectively. Conclusions: irAEs onset was associated with improved best response to ICI therapy in mHNSCC. Although OS was numerically superior in the irAE group, it did not meet statistical significance. ICI re-challenge is feasible in select pts, however further studies are needed to evaluate long term benefit of ICI re-challenge.

Efficacy and safety of regorafenib plus ICIs as second-line treatment in advanced HCC post-frontline treatment failure: A real-world study from a single center.

e16141 Background: Tyrosine kinase inhibitor or bevacizumab (TKI/Bev) combined with immune checkpoint inhibitors (ICIs) currently represent the preferred frontline therapy for patients with Hepatocellular Carcinoma (HCC). Despite this, clinical evidence guiding therapeutic choice for patients unresponsive to this initial immunotherapy regimen remains scarce. This real-world study aimed to assess the efficacy and safety of regorafenib combined with ICIs in patients with HCC who have exhibited disease progress during treatment with TKI/Bev plus ICIs. Methods: This retrospective analysis encompassed a cohort of patients who transitioned to a combined regimen of regorafenib and immune checkpoint inhibitors (ICIs) after the progression of hepatocellular carcinoma (HCC) following treatment with tyrosine kinase inhibitors (TKIs) or a combination of bevacizumab and ICIs, from January 2019 to November 2023. Key efficacy metrics included overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). The adverse events (AEs) were systematically classified in accordance with the Common Terminology Criteria for Adverse Events, version 5.0 (CTCAE v5.0). Results: A total of 37 patients were included; 56.8% were Child-Pugh A and 43.2% were Child-Pugh B. Treatment regimens prior to regorafenib and ICIs were lenvatinib plus ICIs in 83.8% of patients, sorafenib plus ICIs in three patients, apatinib plus ICIs, donafenib plus ICIs, and bevacizumab plus ICIs each in one patient. The ORR was 27.0% (10/37), and the DCR was 92.0% (28/37) according to mRECIST criteria. The median PFS was 7.8 months (95% CI, 6.0-9.6). The 6-month and 12-month PFS rates was 60.6% (95% CI, 46.4-79.2) and 40.0% (95% CI, 26.0%-61.6%). The median OS post-regorafenib and ICIs was 16.3 months, with 12-month and 24-month OS rates of 67.0% and 49.7%, respectively. The median OS since first-line treatment initiation was 35.8 months, with OS rates of 94.4% and 72.3% at 12-month and 24-month since first-line treatment initiation, respectively. Subgroup analysis indicated no statistical significance in median PFS between patients with lung metastasis and those without lung metastasis [3.9 months (95% CI, 3.0-4.8) vs 7.80 months (95% CI, 6.1-9.5); P=0.178], but there was a trend toward survival benefit in patients without lung metastasis. Grade 3-4 adverse events were reported in 16.22% of the patients, with no treatment-related fatalities. Conclusions: Regorafenib with ICIs is a promising and tolerable second-line treatment for advanced HCC after initial therapy failure.

Immunotherapy toxicity prediction in patients with melanoma using machine learning algorithms.

e21567 Background: Immune checkpoint inhibitor (ICI) related toxicity is common in melanoma patients, but identifying who will experience toxicity can be challenging. Precision medicine tools that accurately predict ICI toxicity could improve patient outcomes. This study aimed to use Machine Learning (ML) to predict ICI toxicity in patients with melanoma. Methods: 384 datasets were available for patients started on immunotherapy between 2014-2023 in a single, large regional cancer center in Kent, U.K. Raw data was preprocessed using a standard scaling function and one hot encoding, followed by SMOTE to balance the imbalanced classes. Six ML algorithms were developed using 80% of the training data, tested on 20% of validation data and used the Grid Search Cross-Validation technique for hyperparameter optimization. Shapley Additive Explanations (SHAP) explainable artificial intelligence was used to interpret the toxicity prediction model to improve the interpretation and transparency of the decision boundary. Results: Of the 384 patients, 112 patients (29%) had completely resected disease and then had adjuvant treatment while 272 (71%) were unresectable or had metastatic disease and had palliative treatment intent. In the metastatic setting, the commonest immunotherapy regimen was Pembrolizumab (155, 57%), followed by Ipilimumab/Nivolumab (85, 31%). The commonest regimen in the adjuvant setting was Pembrolizumab (86, 77%). 95 patients (25%) experienced ICI-related toxicity. The number of patients with Grades 1-4 toxicity was 2 ,4, 18 and 4 respectively, the remaining had unspecified toxicity grades. The commonest class of toxicity (CTCAE v5) was gastrointestinal (36, 38%), followed by endocrine (20, 21%) and skin (19, 20%). Linear Regression and Gaussian Naïve Bayes predicted toxicity with the most accuracy, 92% (Table 1). The model showed that increasing age, female gender and not receiving Nivolumab predicted toxicity. Regardless of the regimen or treatment intent, our ML model could also predict immunotherapy response with 90% accuracy. Conclusions: These ML algorithms used clinically available data to predict ICI toxicity accurately. Key predictors of toxicity included increasing age, female gender and not receiving Nivolumab in the setting of both adjuvant and palliative intent. Future work will aim to externally validate these models in other centers. We will also explore if models could be trained for use in patients treated with nivolumab in combination with new anti-LAG-3(relatlimab). [Table: see text]

TRITON: Phase 3b study of tremelimumab (T) + durvalumab (D) vs pembrolizumab (P), in combination with chemotherapy (CT), in non-squamous (NSQ) metastatic NSCLC (mNSCLC) with STK11and/or KEAP1 and/or KRAS mutations.

TPS8655 Background: Mutations in STK11 and KEAP1, present in approximately 20% and 15% of patients (pts) respectively with NSQ mNSCLC, lead to an immunosuppressive tumor microenvironment and are associated with inferior clinical outcomes with anti-PD-(L)1 based chemo-immunotherapy, especially when co-mutated with KRAS. Pts with tumors bearing STK11, KEAP1and/or KRAS mutations may benefit from combinations with CTLA-4 inhibitors, aimed at increasing immune responses. In the phase 3 POSEIDON trial (NCT03164616), first-line (1L) T+D+CT significantly improved overall survival (OS; HR 0.77 [95% CI 0.65–0.92]; P=0.0030) vs CT. These results were maintained after a median follow-up of >5 years. Subgroup analyses showed sustained OS improvement with T+D+CT vs CT in pts with mNSCLC with STK11 (NSQ), KEAP1(all histologies, due to small sample size), and KRAS (NSQ) mutations (HR [95% CI] 0.57 [0.32–1.04), 0.43 [0.16–1.25], and 0.55 [0.36–0.83], respectively). The TRITON study will further investigate the signal of efficacy observed in the POSEIDON subgroup analysis. The study will compare T+D+CT vs P+CT (a standard treatment for NSQ mNSCLC) in pts with STK11 and/or KEAP1 and/or KRASmutations. The results will help to inform clinical practice and to establish a biomarker-driven treatment strategy for these difficult-to-treat pts. Methods: TRITON (NCT06008093) is a phase 3b, multicenter, open-label, 2-arm parallel randomized study. Eligible pts, aged ≥18 years, must have NSQ mNSCLC (no EGFR or ALK alterations), with STK11, KEAP1, or KRAS mutations/co-mutations, no prior systemic therapy for mNSCLC, and ECOG performance status of 0/1. Approximately 280 pts will be randomized 1:1 to receive either T+D+CT or P+CT. In the T+D+CT arm, pts will receive T (75 mg) + D (1500 mg) + carboplatin (AUC 5 or 6)/cisplatin (75 mg/m2) + pemetrexed (500 mg/m2) every 3 weeks (Q3W) for 4 cycles (a fifth dose of T [75 mg] will be given in combination with D, post-platinum at week 16), followed by maintenance D (1500 mg) + pemetrexed (500 mg/m2) Q4W until disease progression (PD). In the P+CT arm, pts will receive P (200 mg) + carboplatin (AUC 5 or 6)/cisplatin (75 mg/m2) + pemetrexed (500 mg/m2) Q3W for 4 cycles, followed by maintenance P (200 mg) + pemetrexed (500 mg/m2) Q3W until PD, for up to 24 months. Randomization is stratified by mutation type ( KRAS [without STK11 or KEAP1] mutations are capped at 33% of the total sample) and tumor PD-L1 expression (≥1% vs <1%). Primary endpoints are OS in all pts and in the subset with STK11 or KEAP1 mutations/co-mutations. Key secondary endpoints include OS rates at 12 and 24 months, progression-free survival, objective response rate, duration of response (all RECIST v1.1; investigator-assessed) and safety/tolerability (CTCAE v5.0). Enrollment is ongoing. Clinical trial information: NCT06008093 .

Efficacy, safety, and determination of RP2D of ABBV-383, a BCMA bispecific antibody, in patients with relapsed/refractory multiple myeloma (RRMM).

7531 Background: MM eventually becomes refractory to current treatments, and new therapeutic options with convenient dosing and improved safety are needed to enhance patient (pt) adherence, access, and outcomes. ABBV-383 is a distinctive next-generation BCMA x CD3 bispecific antibody composed of 2 high-affinity BCMA-binding domains, a low-affinity CD3-binding domain designed to reduce cytokine release syndrome (CRS) risk, and a silenced Fc tail for an extended half-life allowing convenient dosing. ABBV-383 monotherapy has shown promising activity in the ongoing first-in-human phase 1 trial in RRMM (Vij et al. Blood 2023;142[suppl 1]:3378). Here, safety and efficacy results are reported that support the RP2D of 60mg Q4W as the optimal therapeutic ABBV-383 monotherapy dose. Methods: This phase 1 open-label, dose-escalation/expansion trial (NCT03933735) enrolled pts with RRMM who received ≥3 prior lines of therapy with exposure to PI, IMiD, and anti-CD38 mAb. ABBV-383 regimens explored in the expansion phase included 60mg Q4W and 40 or 60mg Q3W. A modified dexamethasone premedication schedule and shortened CRS monitoring period were implemented in the 60mg Q4W cohort for cycle 1. IV ABBV-383 was administered as a flat dose with no step-up schedule. Treatment was continued until disease progression/unacceptable toxicity. Primary objectives were to assess safety, tolerability, PK, PD, and determine the RP2D. Efficacy evaluation was a secondary objective. TEAEs were assessed per CTCAE v5.0 and tumor response per IMWG 2016 criteria. Results: As of May 2023, 220 pts received ABBV-383 (median age: 68 yr [35–92]; median prior therapy lines: 5 [3‒23]). Median FU was 4.1 mo (0.8–5.2) at 60mg Q4W (n=21), 12.2 mo (1.3–34.4) at 40mg Q3W (n=55), and 24.2 mo (0.6–33.4) at 60mg Q3W (n=61). At 60mg Q4W, with the modified premedication regimen, CRS was reported in 43% of pts (38% G1, 5% G2), and ICANS in 5% of pts (G2). In Q3W cohorts, CRS was reported in 71% (40mg; 45% G1, 25% G2) and 70% (60mg; 51% G1, 18% G2, 2% G3) of pts. The incidence of G3/4 neutropenia, anemia, and thrombocytopenia was 14/24/10% at 60mg Q4W, 31/31/16% at 40mg Q3W, and 34/13/13% at 60mg Q3W. G3/4 infections occurred in 10/24/34% of pts at 60mg Q4W, 40mg and 60mg Q3W, respectively. ORR and ≥VGPR were 65/50% at 60mg Q4W, 64/53% at 40mg Q3W, and 60/52% at 60mg Q3W. Corresponding exposure-response (ER) analyses and correlative analyses further supported RP2D determination (separate abstract submissions). Conclusions: The optimal therapeutic dose of 60mg Q4W ABBV-383 monotherapy was selected on the basis of safety, efficacy, and ER analyses. The extended interval of Q4W, with a shortened CRS monitoring period in cycle 1 and no step-up dosing, will improve convenience and reduce the treatment burden for pts. ABBV-383 at 60mg Q4W will be investigated in the registrational phase 3 trial (NCT06158841) in RRMM. Clinical trial information: NCT03933735 .

Phase I study of copaiba aqueous mouthwash in patients with head and neck cancer undergoing radiotherapy.

e24103 Background: Due to the contraindication of low-power laser therapy in the tumor region, the use of copaiba for the management of oral mucositis was proposed, given its anti-inflammatory, antimicrobial and healing properties. This study aimed to evaluate the dose-limiting toxicity/maximum tolerated dose of copaiba aqueous mouthwash solution. Methods: This is a phase I study including patients with cavity or oropharynx cancer (CID-10 C00-C06,10), undergoing radiotherapy alone or associated with chemotherapy. Six successive cohorts were proposed, with a minimum of 3 patients each. The copaiba aqueous mouthwash was used daily starting on the first day of radiotherapy and up to 37 days, associated with Low Power Laser applications (100Mw, 660nm, beam area 0.09842 cm²,1J) in non-tumoral areas. In cohorts 1, 2, and 3, a 10% solution was used, and in cohorts 4, 5, and 6, 15%, 2, 3 and 4 times a day, respectively. Daily assessment was carried out evaluating the presence of oral mucositis lesions (World Health Organization and Oral Mucositis Assessment Scale) and complaints of pain (CTCAE v5.0 and Visual Analogue Pain Scale) and xerostomia (presence or absence). Sialometry was carried out through the collection of unstimulated saliva (by Davies (2002) criteria), once a week. Results: Twenty patients were included (cohort 1 = 5, cohort 2 = 3, cohort 3 = 3, cohort 4 = 3, cohort 5 = 3, cohort 6 = 3) - 1 patient was excluded and 1 discontinued from cohort 1 (due to changes in radiotherapy planning and non-adherence to dentistry appointments). A total of 19 participants used the mouthwash. Most of the participants were women (57.9%), with a median age of 63.2 years, and performance status 1 (84.2%). Most tumors were squamous cell carcinomas (84.2%), 47.4% of them in the palate; 57.9% were staged as IVA. Themedian total radiotherapy dose was 68.0 (60.0-70.0) Gy delivered in 33.0 (30.0-34.5) fractions. Pain in the oral cavity (73.7%) and oropharynx (52.6%) were referred, graded respectively as 4.5 (0.75-7) and 1.5 (0-6). Oral mucositis was classified as grade 3 at most; none of the patients developed grade 4 or had to have radiotherapy interrupted due to toxicity. Ulcerated lesions of oral mucositis developed in the tumor area in 68.4% of patients and non-tumor areas in 84.2%. Patients complained of xerostomia in 73.7% of cases and the median unstimulated sialometry was 0.17mL/min. None of the patients experienced dose-limiting toxicity related to the copaiba solution. Conclusions: Copaiba mouthwash did not trigger dose-limiting toxicity in any of the patients throughout the study, leading to amaximum tolerated dose of 15%, 4 times/day. None of the patients complained of pain or burning related to the use of mouthwash in the absence of oral mucositis lesions, suggesting that it is safe and non-toxic for this use. In this sense, considering the obtained results, the development of a phase II study becomes the next logical step in this research area. Clinical trial information: ID - 34635020.5.0000.5274.

Role of celecoxib in reducing cognitive impairment in patients receiving definitive chemoradiation for head and neck carcinoma: A phase II randomized placebo controlled trial (CELCI-HN study).

TPS12150 Background: Head and neck squamous cell carcinoma (HNSCC) is common in the Indian subcontinent and majority (65%) patients present in an advanced stage. Chemotherapy related cognitive impairment (CRCI) is a poorly defined and underestimated phenomenon in the HNSCC population. Through this study, we are attempting to establish evidence of activity of agents targeting neuro-inflammation in reducing or halting cognitive decline associated with definitive chemoradiotherapy for head and neck malignancies without adding to treatment-associated toxicity. This study can potentially aid in developing a cost effective approach with a readily available and cheap agent like celecoxib in improving the quality of life in this cohort of patients. Methods: This is a single center, double blinded placebo controlled phase 2 randomized trial. We intend to randomize 92 non metastatic HNSCC patients registered at a large tertiary cancer center of North India {Department of Medical Oncology (Head and Neck Cancer Clinic, All India Institute of Medical Sciences-National Cancer Institute, India)} planned for definitive chemoradiation (CTRT) with or without induction chemotherapy. Patients in the experimental arm will receive celecoxib 100 mg or matched placebo tablet orally twice a day starting with day 1 of initiation of definitive chemoradiotherapy/induction chemotherapy for a duration of 6 months or until unacceptable toxicity. Our primary objective is to determine the activity of celecoxib versus placebo in reducing cognitive decline in patients undergoing definitive CTRT with or without induction chemotherapy in HNSCC through patient reported outcome tools (FACT cog questionnaire). Secondary objectives include assessment of adverse event profile (measured using CTCAE v5.0), objective assessment of neurocognitive decline using neuropsychological battery of tests, to identify predictors of cognitive decline on the basis of site of malignancy, radiation dose to the base of skull and brainstem, age, comorbidities and educational status. Tertiary objective include evaluation of inflammatory biomarkers e.g serum COX-2, serum Interleukin and tumor necrosis factors-alpha levels at the end of therapy and on follow up. Clinical trial information: CTRI/2022/09/045579.

First-in-human study of 225actinium mti-201 (225Ac-MTI-201) in metastatic uveal melanoma (UM).

TPS9612 Background: Prognosis in metastatic uveal melanoma (UM) has historically been poor approximating 1 year from diagnosis. Tebentafusp is the only approved systemic agent for HLA-A*02:01 positive metastatic UM, and novel therapies are needed. The melanocortin-1 receptor (MC1R) receptor is highly expressed in UM with limited expression in normal tissues. Actinium-225 (225Ac) is an alpha particle emitting radionuclide ideal for targeted ligand binding due to high linear energy transfer and limited free path (<100 µm) in tissue. We developed a novel MC1R targeted radiopharmaceutical 225Ac-MTI-201, and demonstrated high biostability, affinity, MC1R-specific cytotoxicity with defined dosimetry and pharmacokinetics in pre-clinical studies (1). Murine efficacy studies of UM showed significant delay of tumor growth and improved survival compared to controls. Methods: This is a single institution first-in-human phase I study (NCT05496686) of 225Ac-MTI-201 in metastatic UM. The primary objective is to determine the safety of a single intravenous dose of 225Ac-MTI-201 relative to radioactivity dose. Secondary endpoints include 1) pharmacokinetics (PK) and clearance of 225Ac-MTI-201, 2) objective response rate and duration, progression-free survival, and overall survival in metastatic UM. Salient eligibility criteria include: 1) age ≥18 years; 2) histologically confirmed metastatic UM with progression after at least 1 prior line of therapy; 3) measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1; 4) Eastern Cooperative Oncology Group performance status of ≤1; 5) adequate marrow, renal and hepatic function; 6) no more than 25% of bone marrow treated with prior radiotherapy. Patients will receive a single dose of 225Ac-MTI-201 under appropriate guidelines and precautions for administration of radiopharmaceuticals. Pre-injection and post-injection PK sampling at defined intervals are undertaken. There are 12 dose levels for 225Ac-MTI-201 being investigated ranging from 4.7 microcurie (µCi) to 1327 µCi. Dose escalation is done using a modified continual re-assessment method with a cohort size of one based on dose limiting toxicity (DLT) assessment within 28 days of drug administration using CTCAE v5.0. Definitions of DLT include G4 neutropenia or febrile neutropenia, G4 thrombocytopenia or G3 thrombocytopenia with clinically significant bleeding, > G3 non-hematological toxicity with selected exceptions, laboratory abnormalities that satisfy Hy’s law, or any death not related to underlying disease or extraneous cause. Response assessments are undertaken with cross-sectional imaging every 8 weeks in year 1, and every 12 weeks in year 2. This study is currently open for enrollment. Dose levels 1-4 have been completed without DLT. 1. Tafreshi, J Nucl Med 2019. Clinical trial information: NCT05496686 .