The clinical usefulness of tumor-infiltrating lymphocyte (TIL) has been limited due to an intensive lymphodepletion regimen and high-dose intravenous interleukin-2 (IL-2) administration. We explore the low dose regimens of lymphodepletion and infusion without IL-2 administration in TIL therapy, which showed encouraging outcome in a case report. Thus, a phase I study to evaluate the safety and efficacy of optimized TIL-therapy regimen for the treatment of advanced solid tumors was conducted. The phase 1a part used a conventional 3+3 dose-escalation design. The primary endpoint in the phase 1a part was the frequency of dose-limiting toxicities (DLTs). Patients received three consecutive daily infusions of cyclophosphamide (25 mg/kg/day) from day -5 to day -3, and oral administration of hydroxychloroquine (600 mg once) on day -5. On day 0, patients received a single intravenous adoptive transfer of TILs following the administration of anti-PD-1 antibody (100mg per patient, sintilimab). Adverse events (AEs) were assessed based on Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Clinical responses were assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Three patients were planned for DLT analysis at each dose level of TILs infusion: level 1 (5.0×109± 20% cells), level 2 (1.5×1010± 20% cells), level 3 (3.0×1010± 20% cells), and level 4 (4.5×1010± 20% cells). As of September 15, 2023, ten participants (9/10 with PD-1 antibody resistance) have been enrolled and underwent TIL infusion. None DLT was observed and the clinical responses were observed across different dose levels, suggesting the modified regimen is safe and the recommended dose (RD) of TILs can be defined within a broad range. The phase 1b part would be started in soon future. NCT05417750. Shanghai Juncell Therapeutics Co., Ltd. Shanghai Juncell Therapeutics Co., Ltd.

LX-039 is an oral SERD that blocks ER signaling pathway through receptor antagonism and degradation. LX-039 demonstrated robust antitumor efficacy and good PK profile in preclinical studies. This was a multi-center, open-label, first in human, dose escalation and expansion phase I study to evaluate the safety, efficacy and PK/PD profiles of LX-039 monotherapy in postmenopausal patients(pts) with histologically confirmed ER+, HER2- ABC, who had failed ≥1 line endocrine therapy and ≤2 line chemotherapy. The initial dose was 50 mg, sequentially escalated from 100 mg to 1200 mg via traditional "3+3” design. LX-039 was administrated once daily in 28-day cycles until unacceptable toxicity, progression, or withdrawal of consent. 18FES PET/CT scan was undergone on baseline and day 28 after treatment. Primary endpoint was MTD, secondary endpoints included safety, efficacy, and PK/PD. 44 pts (median age 56.5, ECOG = 1: 88.6%, visceral metastasis: 77.3%) were enrolled. All pts received prior endocrine therapy (range: 1-7 lines, 56.8% fulvestrant) and/or CDK4.6i(40.9%), chemotherapy(54.5%) in the advanced setting. Two pts experienced DLTs: G3 hepatic function abnormal in 1000 mg cohort (1/6) and G4 ALT increased in 1200 mg cohort (1/1), so MTD was not reached. TRAEs were mostly grade 1-2 and experienced by ≥20% of pts were diarrhea (81.8%, G3 15.9%), ALT increased (56.8%, ≥G3 15.9%); AST increased (47.7%, G3 4.5%), fatigue (38.6%), decreased appetite (29.5%), vomiting (29.5%), nausea (27.3%), weight decreased (22.7%). Dose-dependent plasma exposure was seen with an estimated half-life of approximately 7 h. In 29 pts with measurable lesions who received 600 mg or higher doses, 4 pts (13.8%) achieved partial response, with median DOR of 7.4 months. Median PFS in the ITT population was 5.5months (95% CI: 3.5, 5.9). CBR at 24 weeks was 40.0% and DCR was 70.3%. 18FES-PET scan (n = 13) showed that all patients experienced SUVmax decrease from baseline with a median reduction of > 70 %. LX-039 was well tolerated with preliminary anti-tumor activity in ER+, HER2- ABC. RP2D was determined at 600 mg QD and a phase II trial is being planned.

Seneparib (previously known as IMP4297) is a novel oral PARP inhibitor which is 20-fold more potent than olaparib in vivo and showing strong antitumor activity in preclinical studies. This phase I study of senaparib is to evaluate PK, safety/tolerability and preliminary antitumor activity in patients with advanced solid tumours. The primary objective was to evaluate the safety profile of senaparib given orally QD, including the identification of the maximum tolerated dose and the recommended phase II dose (RP2D). Dose escalation was guided by a modified Fibonacci sequence, starting at 2 mg/day, with a traditional 3+3 design. Dose expansion cohort was planned to start from the dose level in which efficacy was observed. As of Feb 29, 2020, 54 patients, including 34 BRCA mutation carriers, had been enrolled at 2-120 mg dose level. No DLT was observed. The most frequent treatment-related adverse events (TRAE) were anemia (48%), followed by leukopenia (41%), thrombocytopenia (26%), neutropenia (22%), nausea (22%) and fatigue (22%). Most of them were grade 1 or 2 in severity. Seven (13%) patients interrupted and 3 (6%) patients discontinued treatment due to AEs. Among 41 pts with at least one follow-up RECIST 1.1 assessment, 6 germline BRCA+ patients, 1 somatic BRCA+ patient and 2 BRCA- patients had PR, including one long-lasting PR over 9 months (BRCA+ ovarian cancer, 60mg). The overall ORR and DCR was 22% and 61% respectively. In 17 BRCA+ ovarian cancer patients, the ORR is 24% and DCR is 82%. An alternative dosing regimen of 50mg bid is ongoing to compare PK characteristic between QD and BID dosing. We further confirmed senaparib is well-tolerated, with mild to moderate haematologic toxicity as the most frequent TRAEs and showed encouraging signs of clinical activity. The 100 mg orally QD was selected as the RP2D based on safety, pharmacokinetics and clinical activity.

Medulloblastoma (MB) is a malignant brain disease in young children. The overall survival of MB patients is disappointing due to absence of effective therapeutics and this could be attributed to the lack of molecular mechanism underlying MB. FHOD3 was an important gene during cardio-genesis and was reported to promote cell migration in cancer. However, its role in MB is not clear to date. RT-qPCR and IHC analysis were used to determine expression of FHOD3. Survival curve was drawn by K–M analysis. FHOD3 was knocked down by RNAi technology. The effects of FHOD3 on medulloblastoma cells were determined by CCK-8 assay, colony formation assay, transwell assay and FACs analysis. FHOD3 expression increased by 1.5 fold in tumor tissues compared to the control and IHC analysis further confirmed strong expression of FHOD3 in medulloblastoma tissues. Then higher FHOD3 expression was associated with shorter survival time in MB patients (13.0 months versus 43.8 months). In medulloblastoma cells such as Daoy and D283med, FHOD3 also displayed abundant expression. When FHOD3 was knocked down, the ability of cell proliferation and colony formation was reduced over greatly. The capability of cell migration and invasion was also inhibited significantly. However, cell apoptotic rate increased significantly reversely. Mechanistically, the phosphorylation level of RhoA, ROCK1, and LIMK1 was decreased when FHOD3 was knocked down but increased reversely when FHOD3 was over-expressed in Daoy cells. FHOD3 was associated with overall survival time in medulloblastoma patients and was essential to cell proliferation, growth and survival in medulloblastoma and might regulates activation of RhoA/ROCK1/LIMK1 signaling pathway.

Advanced NSCLC patients, harboring EGFR T790M, exhibit marked diversity in tumor behavior and response to AZD9291, yet a discriminable molecular profile remains elusive. In addition, although EGFRC797S was involved in 30% of AZD9291 resistance cases in Western patients, mechanisms for the rest patients remain unclear, especially for the East Asian population. We utilized circulating tumor DNA (ctDNA) profiling to conduct dynamic monitoring in patients undergoing AZD9291, thus characterizing mutational heterogeneity and genomic evolution. Longitudinal plasma samples were collected before, during and post of the AZD9291 treatment in Chinese NSCLC patients with acquired T790M mutation. A ctDNA panel, spanning 160KB of human genome, was used to perform capture-based targeted sequencing that comprises critical exons and introns of 168 genes. The EGFR mutation abundance and dynamic changes of allele fraction (AF) were analyzed with progression-free survival (PFS) after AZD9291 treatment. A total of 61 samples were collected longitudinally from 14 patients, of which 9 have experienced progressive disease (PD). Six patients exhibited a rebound of ctDNA prior to radiographic PD, suggesting the potential of ctDNA in early detection of PD. Several acquired mutations were detected with the AZD9291 resistance, including newly identified EGFR G796S, L792H/F/R/V, V802F, V843I mutations, expect for the previously reported RB1 and EGFR C797S, L718Q mutations. Patients with a higher ratio of T790M and EGFRactivating mutation at baseline had a significantly longer PFS (9.6m vs 4.5m, p=0.008). A lower ratio of EGFRactivating mutation AF compared to baseline at first follow-up was significantly correlated with a longer PFS (8.5m vs 5.0m, p=0.027). Furthermore, patients harboring other known driver mutations in addition to T790M at baseline had an inferior PFS (4.9m vs 7.8m, P=0.039). Several novel resistance mechanisms were identified by ctDNA monitoring in the East Asian patients treated with AZD9291. Relative AF of T790M, changes of AF after treatment and the presence of concurrent driver mutations at baseline could predict clinical benefit of AZD9291 treatment.

Background Thissingle-armphase1 studywasconductedtodefinethePK ofREG and its metabolites, M-2 and M-5, in Chinese patients with advanced solid tumors. Methods Patients from China mainland with locally advanced/metastatic, refractory solidtumorswereenrollediftheywerenotcandidatesforstandardtherapyorifthey had metastatic CRC or advanced GIST and REG was a treatment option. The primary objective was PK; secondary objectives were safety, tolerability, and efficacy. Single-dose PKwascollectedonCycle0Day1 upto96hoursafteradministrationofREG160mg followedby6daysofftreatment.FromCycle1Day1,REG160mgwasadministered dailyona3weekson/1 weekoffscheduleina28-daycycleuntiltumorprogression, toxicity,orwithdrawalofconsent.Optionalmultiple-doseREGPKwascollectedon Cycle 1 Day 21 up to 96 hours post dose where applicable. Results All 18 patients who received study treatment were valid for single-dose PK, safety, and efficacy analyses; 9 were valid for multiple-dose PK analysis. After singledose REG, the geometric mean AUC(o -t] ast) (mg-h/L) was 43.1 (REG), 17.1 (M-2), and 3.99(M-5),withmoderatetohighinter-individualvariability:Geo-CV63%(REG), 56% (M-2), 74% (M-5). After multiple-dosing, increases in AUC(o_24) and Cmax were observedforthe 3 analytes (accumulation ratios: REG, 1.83 AUC(o_24) and 1.61 Cm ax; M-2, 3.44 AUC(o_24) and3.51 CIliax M-5, 35.8 AUC(o_24) and 21.2 Cmax ). Themost common drug-related grade >3 treatment-emergent adverse events were hypophosphatemia (39%), lipase increase (22%), and hand-foot skin reaction (22%). The best overall response was stable disease in 10/18 (56%) patients with median overall treatment duration of9.4 weeks. Conclusions:Theinter-individualvariabilityofREG,M-2,andM-5wasmoderateto high after single- and multiple-dose REG, with observed accumulation after multiple dosing.Overall,thePKofREG,M-2,andM-5inpatientsfromChinamainlandwas consistent with that previously reported. The safety profile was consistent with the known safety profile of REG. No safety signals were detected to indicate a potential influence ofChinese ethnicity on the safety profile ofREG. Clinical trial indentification NCT02398513 Legal entity responsible for the study Bayer Funding Bayer Disclosure Q. Wang, Y. Liu, D. Lu, F. Huang: Employee ofBayer. I. Sturm: Employee of Bayer and owns stock in Bayer. A. Cleton: Employee ofBayer and has stockin Bayer, Astrazeneca, Pfizer. All other authors have declared no conflicts ofinterest.

Aim/Background: AL3810 (lucitanib) is a potent, oral tyrosine kinase inhibitor of FGFR1-3, VEGFR1-3 and PDGFR&agr;/&bgr;. These well-described signaling pathways are essential for tumor growth, survival, migration, and angiogenesis. This study aims to evaluate the safety of AL3810 in Chinese patients with advanced solid tumors. Methods: This phase I, single-center study evaluated the tolerability of oral AL3810 in terms of Maximum Tolerated Dose (MTD), Dose-Limiting Toxicities (DLTs), and aimed to identify the Recommended Dose (RD). A 3 + 3 dose escalating design was used. Initial dose levels to be tested were 10mg, 15mg and 20mg daily on a continuous basis. Moreover, up to 12 patients were to be included at the RD level to confirm the RD based on safety and efficacy evaluation. PK analysis using a non-compartmental PK population modeling approach will be performed. Results: As of August 2015, 16 patients (pts) were treated with AL3810, 14 were female, median age was 56 yrs (range 28-64) with ECOG 0/1 in 1/15 pts. During the escalation part, 10mg and 15mg dose levels were explored. Two DLTs occurred at 15mg daily dose out of 5 patients (fatigue Gr 3 and direct bilirubin increase Gr 3,). Therefore 15mg dose level was defined as the MTD and 10mg as the RD. Currently, 8 additional pts are enrolled at this dose level to confirm the RD. Common Gr 2-3 adverse events occurring in ≥ 3pts were hypertension (10 pts), hypothyroidism (9 pts), proteinuria (6 pts), fatigue (3 pts), decreased appetite (3 pts), and white blood cell count decreased (3 pts). Two pts with metastatic breast cancer, treated at 10mg daily, had a confirmed Partial Response according to RECIST. Disease stabilization of 4 months was observed in pt with ovarian cancer treated at 10 mg. Conclusions: This phase I trial, testing for first time AL3810 in Chinese patients, identified 15mg daily as the MTD and 10mg as the RD for future studies. Expansion cohorts are planned in different indications. Clinical trial identification: CL1-8088-005 Disclosure: L. Jiang, X. Ma, J. Pang: employee of HaiHe pharmaceutical. A. Kanehisa, F. Legrand, A. Pallis, G. Paux, R. Robert: employee at Institut de Recherches Internationales Servier (IRIS). X. Chen, P. Letecheur, L. Qiang: employee at ICTR China. J. Ding: employee of SIMM. All other authors have declared no conflicts of interest.

AIM:The aim of this study was to investigate the potential of sequential positron emission tomography (PET)/CT standardized uptake value (SUV)/metabolic area variation in predicting the pathological response to preoperative chemoradiotherapy (CRT) for rectal cancer. METHOD:Fifty-three patients diagnosed with clinical T3-4 and/or N+ rectal cancer were enrolled. All patients received CRT followed by radical surgery after 6-8 weeks. A PET/CT scan was performed before (PET/CT1) initiation of treatment and a second scan (PET/CT2) was performed within 1 week after the completion of CRT. Thirty-five of 53 patients also underwent a third (PET/CT3) scan within 1 week before surgery. Maximal SUV within the tumour (SUVmax), average SUV within the tumour (SUVmean), metabolic tumour volume (MV), total lesion glycolysis (TLG) and response indices (∆%, i.e. the percentage difference between two different PET/CT scans for SUVmax, SUVmean, MV and TLG) were calculated. The different metabolic parameters were analysed and correlated with the tumour regression grade (TRG) score. RESULTS:When patients were regrouped as responders (TRG 3-4) and nonresponders (TRG 0-2), significant differences were observed in the percentage differences between PET/CT1 and PET/CT3 for MV (∆%MV(1-3); 91.08% vs 75.43%) and for TLG (∆%TLG(1-3); 94.00% vs 82.02%). As demonstrated by receiver-operating characteristics analysis, ∆%MV(1-3) and ∆%TLG(1-3) both had a strong capability to discriminate between responders and nonresponders. Patients classified as having a pathological complete response (pCR) and a non-pCR showed significant differences in the percentage difference between PET/CT1 and PET/CT3 in SUVmax (∆% SUVmax(1-3); 69.17% vs 57.77%), SUVmean (∆% SUVmean(1-3); 44.20% vs 30.19%), ∆%MV(1-3) (90.93% vs 80.30%) and ∆%TLG(1-3) (94.22% vs 85.63%). ∆%TLG (1-3) was a more powerful discriminator than the others. CONCLUSION:Differences in the SUV/metabolic area with 18F-fluorodeoxyglucose (18(F) -FDG) PET/CT have the potential to predict a response to preoperative CRT for rectal cancer.

3702 Background: Colorectal cancer is one of the most common malignancies in China. The oral fluoropyrimidine X is preferentially converted to 5-FU in tumor tissue by thymidine phosphorylase (TP). In addition, radiotherapy upregulates TP in tumor cells but not in normal tissues. We evaluated the synergistic effect and safety of X chemoradiation in Chinese pts with advanced or relapsed rectal carcinoma. Methods: 100 pts were enrolled between Jun 02 and Oct 03. All had measurable advanced or relapsed rectal carcinoma, KPS >60, adequate bone marrow, renal and hepatic functions. Prior radiotherapy to sites other than those evaluated in the trial and adjuvant fluoropyrimidines (>1 months previously) were permitted. Pts received radiotherapy at 1.8Gy/d for approximately 6 weeks (total dose 60Gy) plus X 825mg/m2 bid for the duration of radiotherapy. Results: 73 pts are evaluable. The remainder are not evaluable due to ongoing treatment. Baseline characteristics: 51 men, 22 women; median age 52 years (range 33–74). Measurable lesions: rectum 55%, pelvic 43%, skin 6%, liver 3%, lymph nodes 3%, other 3%. Number of metastatic sites: 1 (86%), 2 (11%), 3 (3%). 92% of pts completed 6 weeks of treatment; the remainder were treated for 5 weeks (1% for 4 weeks and 1% for 3 weeks). Anti-tumor efficacy is shown in the table. Median progression-free and overall survival have not yet been reached. The most common treatment related grade 1/2 adverse events (grade 1/2) were leucopenia 32%, hand-foot syndrome 26%, diarrhea 22%, nausea 11% and thrombocytopenia 10%. Grade 3 adverse events were rare: HFS 3%, diarrhea 3%, nausea 1%. Only 3 pts (4%) had grade 4 events (all thrombocytopenia). Treatment delays/dose adjustments resulted in improvement/cure for all grade 3 events from 2 weeks to 2 months. Conclusions: X chemoradiation is a highly active and well-tolerated regimen in Chinese pts with advanced or relapsed rectal carcinoma. No significant financial relationships to disclose.