Highest Dose Level Research Articles

Tazemetostat, a Selective EZH2 Inhibitor, in Combination with Pembrolizumab for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: A Phase 1 Trial

Objectives: The primary aim of this phase 1 trial is to establish the recommended phase 2 dose (RP2D) of tazemetostat given with a fixed dose of pembrolizumab in patients with recurrent or metastatic head and neck squamous cell carcinomas (RM-HNSCCs). Methods: A 3 + 3 dose-escalation phase 1 design was used to assess three dose-levels of tazemetostat (400, 600, and 800 mg orally, twice daily) with pembrolizumab (200 mg intravenously). Cycle 1 was 35 days (tazemetostat days 1–35; pembrolizumab day 15). Subsequent cycles were 21 days (tazemetostat days 1–21; pembrolizumab day 1). Dose-limiting toxicity (DLT), assessed during cycle 1, was defined as study-drug-related grade 4 neutropenia or thrombocytopenia, grade 3 febrile neutropenia, or grade 3–4 non-hematologic adverse events (AEs). Patients had to have completed cycle 1 to be evaluable for the DLT assessment; otherwise, an equal number of additional patients were enrolled. The RP2D was defined as the highest dose level in which zero of three or less than or equal to one of six patients experienced a DLT. Results: Twelve patients were enrolled: three on 400 mg, three on 600 mg, and six on the 800 mg dose level of tazemetostat. Three patients on the 800 mg dose level did not complete cycle 1 and were not evaluable for DLT. In the other nine patients, DLTs did not occur during cycle 1. In all 12 patients, the most common AEs included anemia (10 patients), fatigue (eight), and hyponatremia (seven). Conclusions: Among the patients with RM-HNSCCs, the RP2D of tazemetostat was 800 mg and administered twice daily when given with pembrolizumab.

Effect of Amino Acid, Sugar, Ca2+, and Mg2+ on Maillard Reaction-Associated Products in Modified Sparkling Base Wines During Accelerated Aging

The Maillard reaction (MR) between sugars and amino acids, peptides, or proteins is understood to occur gradually during the production and aging of sparkling wines, where it contributes to caramel, roasted, and toasted aromas. Divalent metal ions can accelerate the MR, although this has not been previously reported in wine or wine-like conditions. In this work, the effect of calcium (Ca) and magnesium (Mg) ions on the concentration of 10 Maillard reaction-associated products (MRPs) was measured in modified sparkling base wine during accelerated aging at 50 °C for four weeks. Chardonnay base wine was modified by the addition of fructose (0.02 M) and a single amino acid (lysine, glycine, cysteine; 0.01 M) in combination with Ca2+ or Mg2+ at zero, low (10 mg/L), or high (50 mg/L) dose levels. MRPs were quantified by headspace solid-phase microextraction coupled with gas chromatography–mass spectrometry (HS-SPME-GC/MS), sugar concentration was measured by enzymatic assay, and amino acids and free metal ions were monitored by capillary electrophoresis. Fructose levels did not substantially decrease during aging despite increases in all MRPs, suggesting that trace sugars or α-dicarbonyl species present in the wine matrix likely play a greater role in MRP formation than fructose. Aging duration and amino acid content had a greater effect than metal addition on the composition of the MRPs. Treatments containing cysteine and 50 mg/L Ca2+ had elevated concentrations of benzaldehyde and furfural ethyl ether following 4 weeks of accelerated aging. This work identified key MRPs that increase during base wine accelerated aging and informs future research on the relationship between wine composition and aging markers.

Complement factor H targeting antibody GT103 in refractory non-small cell lung cancer: a phase 1b dose escalation trial

GT103 is a first-in-class, fully human, IgG3 monoclonal antibody targeting complement factor H that kills tumor cells and promotes anti-cancer immunity in preclinical models. We conducted a first-in-human phase 1b study dose escalation trial of GT103 in refractory non-small cell lung cancer to assess the safety of GT103 (NCT04314089). Dose escalation was performed using a “3 + 3” schema with primary objectives of determining safety, tolerability, PK profile and maximum tolerated dose (MTD) of GT103. Secondary objectives included describing objective response rate, progression-free survival and overall survival. Dose escalation cohorts included GT103 given intravenously at 0.3, 1, 3, 10, and 15 mg/kg every 3 weeks, and 10 mg/kg every 2 weeks. Thirty one patients were enrolled across 3 institutions. Two dose-limiting adverse events were reported: grade 3 acute kidney injury (0.3 mg/kg) and grade 2 colitis (1 mg/kg). No dose-limiting toxicities were noted at the highest dose levels and the MTD was not reached. No objective responses were seen. Stable disease occurred in 9 patients (29%) and the median overall survival was 25.7 weeks (95% confidence interval [CI], 19.1–30.6). Pharmacokinetic analysis confirmed an estimated half life of 6.5 days. The recommended phase 2 dose of GT103 was 10 mg/kg every 3 weeks, however further dose optimization is needed given the absence of an MTD. The study achieved its primary objective of demonstrating safety and tolerability of GT103 in refractory NSCLC.

Added Value of Biological Effective Dose in Dosiomics-Based Modelling of Late Rectal Bleeding in Prostate Cancer.

Extracting spatial features (texture analysis) from dose distributions (dosiomics) for outcome prediction is a rapidly evolving field in radiotherapy. To account for fraction size differences, the biological effective dose (BED) is often calculated. We evaluated the impact and added value of the BED in the dosiomics prediction modelling of grade ≥ 2 late rectal bleeding (LRB) probability within 5 years after treatment in three parts. For N = 656 prostate cancer patients previously treated in a randomized trial with conventional (CF) or hypofractionated (HF) radiotherapy, 42 dosiomic features were extracted from the dose distributions of the delineated rectum in physical doses and from dose distributions converted to the BED. Part 1: To assess whether an HF BED dosiomics model is generalizable to CF and vice versa, multivariate logistic regression BED models were constructed for HF and CF separately and tested on the other fractionation scheme. Part 2: The BED models were fitted to combined HF and CF data together to test whether this resulted in better models. Part 3: Separate physical HF and CF models were constructed and compared to the BED models. Part 1: Dosiomics related to large-zone and long-run high-dose levels were predictive for both HF and CF. Deviation from the mean gray level was only predictive for HF. The BED HF model calibrations with CF data and vice versa were generally poor. AUCs ranged from 0.55 to 0.65. Part 2: Compared to the separate models, the models fitted to the combined HF and CF data showed better discriminative ability in CF but not in HF. Part 3: The apparent performances of models for the BED and physical dose were similar. Using the BED in the predictive dosiomic modelling of late rectal bleeding after prostate cancer radiotherapy to account for differences in fraction doses was of limited value.

Comparative Analysis of Bare and Quercetin-Loaded Nonionic Block Copolymer Micelles in an Artificial Gastrointestinal Medium.

Block copolymer micelles have been increasingly used for the solubilization and delivery of hydrophobic drugs. There exists a possibility of dissociation of micelles and formation of other association structures in contact with the gastrointestinal fluid. In this study, we demonstrated the effect of the fed-state intestinal fluid (FeSSIF) upon characteristics of bare and quercetin (QCT)-loaded pluronic 123 (P123) micelles. Characterizations were performed using dynamic light scattering (DLS), 1H NMR, heteronuclear single-quantum coherence (HSQC), two-dimensional 1H-1H nuclear Overhauser effect spectroscopy (2D-NOESY), and diffusion-ordered spectroscopy (DOSY). In the case of bare micelles, we found copolymer-bile salt mixed aggregates without any noticeable change in size. DOSY data revealed that lecithin formed a separate aggregate in the FeSSIF. Complete micellar solubilization of QCT could be verified by the disappearance of its proton signals. At higher dose levels, the diffusion coefficient of micelles increased in the FeSSIF. We speculate that QCT-induced hydrophobicity and availability of FeSSIF components would have driven the formation of small-sized mixed assemblies. On the contrary, the diffusion coefficient of micelles decreased with an increase in the QCT load in the medium devoid of FeSSIF components. We deduce that lack of lecithin and bile salts precluded the formation of mixed assemblies in this case, and therefore, micelles turned heavier at higher QCT loads. Such insights on self-assembled formulations can be valuable in improving their biological performance.

Photon-counting computed tomography versus energy-integrating computed tomography for detection of small liver lesions: comparison using a virtual framework imaging.

Photon-counting computed tomography (PCCT) has the potential to provide superior image quality to energy-integrating CT (EICT). We objectively compare PCCT to EICT for liver lesion detection. Fifty anthropomorphic, computational phantoms with inserted liver lesions were generated. Contrast-enhanced scans of each phantom were simulated at the portal venous phase. The acquisitions were done using DukeSim, a validated CT simulation platform. Scans were simulated at two dose levels ( 1.5 to 6.0mGy) modeling PCCT (NAEOTOM Alpha, Siemens, Erlangen, Germany) and EICT (SOMATOM Flash, Siemens). Images were reconstructed with varying levels of kernel sharpness (soft, medium, sharp). To provide a quantitative estimate of image quality, the modulation transfer function (MTF), frequency at 50% of the MTF ( ), noise magnitude, contrast-to-noise ratio (CNR, per lesion), and detectability index ( , per lesion) were measured. Across all studied conditions, the best detection performance, measured by , was for PCCT images with the highest dose level and softest kernel. With soft kernel reconstruction, PCCT demonstrated improved lesion CNR and compared with EICT, with a mean increase in CNR of 35.0% ( ) and 21% ( ) and a mean increase in of 41.0% ( ) and 23.3% ( ) for the 1.5 and 6.0mGy acquisitions, respectively. The improvements were greatest for larger phantoms, low-contrast lesions, and low-dose scans. PCCT demonstrated objective improvement in liver lesion detection and image quality metrics compared with EICT. These advances may lead to earlier and more accurate liver lesion detection, thus improving patient care.

A novel orf virus vector-based COVID-19 booster vaccine shows cross-neutralizing activity in the absence of anti-vector neutralizing immunity

ABSTRACT Next-generation COVID-19 vaccines are being developed to expand the breadth of coverage against existing and future variants and to extend the duration of protection. Prime-2-CoV_Beta is an orf virus (ORFV) based multi-antigen COVID-19 vaccine that co-expresses Spike (S) and Nucleocapsid (N) antigens. The safety and immunogenicity of Prime-2-CoV_Beta is investigated in a phase 1 first-in-human (FIH) dose-finding trial (ORFEUS study, ClinicalTrials.gov: NCT05367843). Participants of two age groups (18–55 and 65–85 years) who previously completed at least two doses of mRNA vaccines were enrolled and sequentially assigned to different dose groups to receive one intramuscular dose of 3 × 105, 3 × 106, 1.5 × 107, or 3 × 107 plaque-forming units (PFU) of Prime-2-CoV_Beta on day 1 and a second dose on day 29. Here, we report safety and immunogenicity data collected up to 6 months after the first study vaccination. Prime-2-CoV_Beta is safe and well tolerated and elicits immune responses at higher dose levels in participants aged 18–55. A single dose of 3 × 107 PFU boosted binding and cross-neutralizing antibody responses that are maintained through 6 months after the first booster vaccination. Polyfunctional S-specific CD4+ and CD8+ T cell responses are observed after vaccination. No pre-existing or vaccine-induced neutralizing anti-vector antibodies are detected. Our findings highlight the potential of the ORFV vector as a safe platform for future vaccine design, which provides the ability to deliver multiple antigens and allows for repeat immunization.

Chimeric Antigen Receptor T Cells Targeting CD19 and GCC in Metastatic Colorectal Cancer

Chimeric antigen receptor (CAR) T-cell therapy (CART) has transformed the treatment landscape of hematologic cancer, but has negligible effects for adult solid cancers. In this trial, an autologous CAR T-cell product demonstrated antitumor activity in heavily pretreated patients with metastatic colorectal cancer (mCRC). To evaluate the safety and efficacy of guanylate cyclase-C (GCC19) CART in participants with metastatic colorectal cancer (mCRC). This single-arm, nonrandomized, phase 1 trial was conducted at the First Hospital of Jilin University from December 3, 2020, to April 13, 2022. Data analysis was conducted from May 2022 to April 2024. Adults with relapsed and refractory mCRC expressing GCC were treated with GCC19CART, a mixture of autologous CAR T cells transduced with lentiviral vectors expressing genes that encode either CD-19 CAR or GCC CAR. Safety and tolerability of CAR T-cell therapy targeting GCC in patients with mCRC without therapeutic options is capable of conferring a reasonable likeliness of clinical benefit. Other outcomes included objective response rate, progression-free survival, overall survival, and immune activation. Of 15 patients 9 (60%) were women, and the median (range) age was 44 (33-61) years. Treatment with GCC19CART was associated with the development of cytokine release syndrome and diarrhea in most patients, all of which were self-limited and manageable. The objective response rate was 40%, with a partial response in 2 of 8 and 4 of 7 patients treated with either 1 × 106 cells/kg or 2 × 106 cells/kg. Median overall survival was 22.8 months (95% CI, 13.4-26.1) at data cutoff; the median progress-free survival was 6.0 months in the high dose level group (95% CI, 3.0 to not available). The results of this nonrandomized clinical trial suggest that GCC19CART was safe and tolerable in heavily pretreated patients with mCRC and is the first CAR T-cell therapy known to produce objective clinical activity in refractory cancer. Given the paucity of effective therapeutics developed for colorectal cancer in recent decades, the observation that CD-19 CART target engagement can robustly induce GCC19CART target engagement sufficient to produce objective activity may serve as a foundation to develop effective cellular therapy in mCRC and other solid cancers. Chinese Clinical Trial Registry: ChiCTR2000040645.

A phase I safety and efficacy clinical trial of plocabulin and gemcitabine in patients with advanced solid tumors

SummaryPlocabulin (Plo) induces depolymerization of tubulin fibers with disorganization and fragmentation of the microtubule network leading to mitosis. Plo combined with gemcitabine (Gem) showed synergistic anti-tumor activity in preclinical studies. This phase I trial evaluated the safety, pharmacokinetics (PK) and efficacy of Plo 10-min infusion plus Gem on Day 1 and 8 every 3-week in patients with advanced solid tumors. Fifty-seven patients were enrolled into 8 dose levels (DLs); 74%: females; 74%: ECOG performance status 1; median age: 62 years; median number of prior lines of therapy:3. Dose-limiting toxicities (DLT) in Cycle 1 were grade (G) 3 intestinal obstruction at the maximum tolerated dose (MTD), G3 peripheral sensory neuropathy (PSN), G3 abdominal pain, and G4 thrombocytopenia (1 patient each). The highest DL (DL8: Plo 10.5 mg/m2/Gem 1000 mg/m2) was the MTD. Accrual into DL7 (Plo 10.0 mg/m2/Gem 1000 mg/m2) was stopped before it was formally defined as the recommended dose (RD). Most common treatment-related adverse events (AEs) were fatigue (56%), nausea (55%), diarrhea (31%); G3/4 hematologic toxicities comprised anemia (35%), neutropenia (27%) and thrombocytopenia (17%). No treatment-related deaths occurred. PK parameters for Gem or dFdU at all DLs were in line with reference values from the literature. Six of 46 evaluable pts were responders (overall response rate:13%). Of note, 2 partial responses (PR) and 2 stable disease (SD) ≥ 4 months occurred among 13 pts with ovarian cancer. The combination of Plo and Gem is well tolerated. The MTD was Plo 10.5 mg/m2/Gem 1000 mg/m2. No PK drug-drug interaction was found. The most encouraging outcome occurred in ovarian cancer patients.

Bladder Tumor-Focused Adaptive Radiation Therapy: Clinical Outcomes of a Phase I Dose Escalation Study

We determine the maximum tolerated tumor-focused dose (MTD) for the radical treatment of muscle invasive bladder cancer enabled by image guided adaptive radiation therapy and long-term clinical outcomes. Fifty-nine patients with T2 to T4aN0M0 unifocal urothelial muscle invasive bladder cancer suitable for daily radical radiation therapy were recruited prospectively to an ethics-approved protocol (NCT01124682). The uninvolved bladder (PTVbladder) was planned to 52 Gy in 32 fractions. The bladder tumor (PTVtumor) was planned to an assigned dose level of 68, 70, 72, or 74 Gy. If organ at risk dose constraints were violated, then PTVtumor was planned to 64 Gy. Dose level allocation was determined by concurrent toxicity assessment of all previous patients recruited. Acute toxicity was evaluated using Common Terminology Criteria for Adverse Events v3.0; late toxicity was evaluated using Radiation Therapy Oncology Group criteria. The MTD was predefined as the highest dose level with an estimated probability of ≤ 15% ≥ G3 late toxicity and an observed rate of <50% acute G3 and <10% acute G4 toxicity. Twenty-six patients were assigned to 68 Gy, of whom 6 were planned to 64 Gy; 29 patients were assigned to 70 Gy of whom 1 was planned to 68 Gy, 2 patients were assigned and planned to 72 Gy; no patients were assigned to 74 Gy. Three patients did not complete the treatment as planned, of whom only 1 patient stopped treatment because dose-limiting toxicity occurred. The MTD was 70 Gy. Acute genito-urinary and gastro-intestinal G3 acute toxicity was seen in 19% and 7% of patients, respectively. No acute G4 genito-urinary or gastro-intestinal toxicity was seen. Late toxicity (any) G3 and G4 was seen in 14% and 2% of patients, respectively. The 5-year overall survival was 58% (95% CI, 44%-71%). The bladder preservation rate was 89% (95% CI, 88%-96%) with 6 patients not retaining native bladder function. Bladder tumor-focused dose escalation to 70 Gy using image guided adaptive radiation therapy is feasible with acceptable toxicity. This dose level has been evaluated in a phase II randomized control trial (RAIDER NCT02447549).

Application of microalgae in cauliflower fertilisation

Application of microalgae in cauliflower fertilisation

Inhibition of microbially mediated total organic carbon decomposition in different types of cadmium contaminated soils with wheat straw addition

Wheat straw returning is a common agronomic measure in the farmland. Understanding organic carbon transformation is of great significance for carbon budget under the premise of widespread distribution of cadmium (Cd) contaminated soils. An incubation experiment was conducted to assess the influence of Cd contamination on the decomposition and accumulation of total organic carbon (TOC) as well as the composition and abundance of bacterial communities in eight soil types with wheat straw addition. The results showed that inhibition of Cd contamination on microbially mediated organic carbon decomposition was affected by soil types. The lower cumulative C mineralization and higher TOC content could be observed in the acidic soils relative to that in the alkaline soils. The content of Cd in soil exhibits different effects on the inhibition in decomposition of TOC. The high dosage level of Cd had stronger inhibitory impact due to its high toxicity. The decomposition of TOC was restricted by a reduction in soil bacterial abundance and weakening of bacterial activities. Redundancy analysis (RDA) indicated that Proteobacteria and Gemmatimonadetes were abundant in alkaline Cd-contaminated soils with wheat straw addition, while Bacteroidetes dominated cumulative C mineralization in acidic Cd-contamination soils. Moreover, the abundance of predicted functional bacteria indicated that high-dose Cd-contamination and acid environment all inhibited the decomposition of TOC. The present study suggested that pH played an important role on carbon dynamics in the Cd-contaminated soils with wheat straw addition.

DIPG-84. PHASE 1 DOSE-ESCALATION STUDY OF ACT001 IN PEDIATRIC PATIENTS WITH ADVANCED BRAIN AND SOLID TUMORS SHOWS ACTIVITY IN DIFFUSE MIDLINE GLIOMA (DMG)

Abstract BACKGROUND ACT001, an oral parthenolide derivative targeting STAT3 and NF-κB pathways, has shown activity in preclinical models of DMG. We evaluated safety, toxicity and activity of ACT001 in this recently completed, first-in-child study of DMG and other relapsed/refractory brain and solid tumors. METHODS Eligible patients ≥ 1 and ≤ 21 years old were enrolled with dose escalation following a rolling 6 design and tumor lesions evaluated every 8 weeks per RANO/ RECIST criteria. RESULTS A total of 29 patients were enrolled across 5 cohorts, including 19 with DMG (13 with Diffuse Intrinsic Pontine Glioma (DIPG)). Median age was 11 years for the whole cohort and 7 years (3-17) for DMG patients. Safety was evaluated in escalating doses in 188, 533, 700, 875 and 1100 mg/m2,BID cohorts. No DLT nor grade 3 and above TRAE was identified. One SUSAR was noted for a grade 1 pain in extremity event. Peak ACT001 concentration for each dose cohort were estimated based on limited PK sampling time (cycle 1 day 1 at pre-dose, 2 and 4 hours post dose; cycle 1 day 15 and cycle 2 day 1 both at pre-dose). ACT001 peak concentration plateaued at the highest dose levels, fluctuating in the range of 6360, 5430 and 5980 mg/m2 for 700, 875 and 1100 mg/m2 cohorts respectively. The half-life was approximately 3 hours. 8/14 DMG patients treated at ≥ 700 mg/m2 exhibited objective response or stable disease (SD), including one patient with SD for 14 months, another patient with confirmed Partial Response who remained on study for 11-months before disease progression and five other patients with different degrees of tumor burden reduction. CONCLUSION ACT001 was well tolerated and showed preliminary evidence of anti-tumor activity in DMG/DIPG patients dosed at the highest dose levels. A Phase 2 trial is planned using 875 mg/m2 as the RP2D.

Oral subchronic toxicity study and genetic toxicity evaluation of mitoquinone mesylate.

Mitochondrial dysfunction and excessive reactive oxygen species production contributes to the pathophysiology of aging. Coenzyme Q10 is thought to protect mitochondria from oxidative damage; thus, mitoquinone was developed as mitochondria-targeted analogue with similar antioxidant activity. Mitoquinone is the oxidized form of mitoquinol. Mitoquinone/mitoquinol mesylate has been proposed as a food ingredient. As part of the safety analysis, we performed genotoxicity assays and a 39-week toxicity study to determine overall toxicity potential. Mitoquinone mesylate showed no evidence of genotoxic potential in two in vitro assays, bacterial reverse mutation and human lymphocyte chromosome aberration, nor in the in vivo micronucleus test in rats. In the 39-week study in dogs, there were no findings observed, which were considered to represent adverse systemic toxicity; therefore, the high dose level (40 mg/kg/day) was considered the NOAEL. The principal findings in this study were fecal disturbances and vomiting. These findings were considered to be due to a local, possibly irritant effect of the test substance on the gastrointestinal tract and were not considered adverse as there were no impacts on clinical or histopathology. This highest dose exceeds the expected daily human intake more than 100-fold. Data from well-designed clinical trials actively collecting safety endpoints corroborate that 20 mg/day can be safely consumed and is not likely to result in significant gastrointestinal complaints. These results support the conclusion that the use of mitoquinone/mitoquinol mesylate as a food ingredient is safe.

OriCAR-017, a novel GPRC5D-targeting CAR-T, in patients with relapsed/refractory multiple myeloma: Long term follow-up results of phase 1 study (POLARIS).

7511 Background: OriCAR-017 is a novel GPRC5D-targeting CAR T-cells. Previously we had presented early study results (Lancet Haematol 2023: 10: e107–16) following OriCAR-017 treatment, the results of good durable response and long-term safety profile support OriCAR-017 is highly probable to be developed as a promising therapy for patients with relapsed or refractory multiple myeloma. All patients had completed at least 2-year follow-up per protocol. Methods: Ten median age of 64 years (range 41–71) pretreated RRMM pts with a median of 5.5 prior lines therapies (range 3-17) received OriCAR-017. Seven (70.0%) pts were cytogenetics high risk, 4 (40.0%) pts had EMD, 3 (30.0%) pts had ISS stage(III), 2 (20.0%) pts had received prior anti-CD38 and 2 (20.0%) pts were treated with auto-HSCT and 5 (50.0%) pts were treated with BCMA CAR-T. Patients were administrated in a single dose of intravenous OriCAR-017 at 1×10⁶CAR-T/kg (DL1,n=3), 3×10⁶CAR-T/kg(DL2,n=4), or 6×10⁶CAR-T/kg(DL3,n=3). Results: At data cut-off (Jan 16, 2024), all 10 enrolled pts had been evaluated for response with the last patient completed 24 months follow up. ORR was 100.0%, sCR was 80.0%, VGPR was 20.0%. All patients achieved MRD negativity at day 28. The mDOR was 10.43 months (95%CI, 5.00-17.00); mPFS was 11.37 months (95%CI, 5.93-18.00) while mOS has not reached (7 pts still undergo survival follow-up, 1 pt died from disease progress, 2 from COVID). The mDOR was 17.23 months (95%CI, 7.33-NR) and the mPFS was 19.10 months (95%CI, 8.30-NR) with 67% prior BCMA CAR-T pts at high dose level. Nine (90%) pts had grade 1 CRS, and 1 (10%) pt had grade 2 CRS. No ≥ G3 CRS was observed. Median time to CRS onset was 2 days (range 1–9) and median duration was 6 days (range 3–9). No ICANS, nor DLTs were observed. There were no SAE and no treatment-related deaths. No PK difference across dose levels with Cmax 7354.7 copies/μL and AUC0-28 68587 copies·day/μg. At high doses, CAR-T cells were detectable at 9 months and one responder at 21 months above the LLOQ. The patients with Tlast≧9 months had a longer PFS than those with Tlast &lt;9 months. No correlation of antigen expression and efficacy was observed. All patients had the positive GPRC5D expression in bone marrow CD138+MMPC at baseline, compared with 50% of relapsed pts had a reduced expression measured by flow cytometry. Conclusions: The updated results showed OriCAR-017 continued to provide deep and durable responses, MRD negativity was achieved in all RRMM pts, including in pts refractory to anti-CD38, PIs and IMIDs and failure to BCMA-directed therapy with excellent safety profile. The results of long-term efficacy and safety follow up support that OriCAR-017 is highly probable to be developed as a promising therapy in RRMM. Further clinical development efforts are undertaking to confirm the clinical benefits of OriCAR-017. Clinical trial information: NCT05016778 .

BC3195, a novel ADC targeting CDH3: Preliminary results of a first-in-human phase I study in patients with advanced solid malignancies.

e15008 Background: Cadherin-3 (CDH3), a calcium-dependent cell-cell adhesion glycoprotein, is overexpressed on lung, breast, ovarian, colorectal, pancreatic, head and neck and other malignancies, but with negligible expression on nonmalignant tissues, and associated with cancer aggressiveness, invasiveness, and poor prognosis. BC3195 is known as the only antibody drug conjugate (ADC) in clinical stage, targeting CDH3 with payload of monomethyl auristatin E (MMAE). Methods: A phase I, open-label, first in human study to evaluate the safety, tolerability, PK, and preliminary antitumor activity of BC3195 is being performed in subjects with advanced solid malignancies. Disease assessments are performed every 6 weeks using RECIST v1.1. BC3195 is administered as 1 hour (h) IV infusion every 3 weeks. An evaluation of seven dose levels is planned: 0.3, 0.6, 1.2, 2.4, 3.0 and 3.6 mg/kg with a BOIN design guiding dose escalation. Results: Up to January 1st, 2024, nine patients (median age, 59; male, 56%) have been enrolled and treated with BC3195, with 3 patients each in the 0.3, 0.6 and 1.2 mg/kg dose cohorts. No DLT was observed across all the 3 dose cohorts. Treatment emergent adverse events (TEAEs) occurring in ≥3 patients included: aspartate aminotransferase increased (5/9, 55.6%), conjugated bilirubin increased (5/9, 55.6%), triglycerides increased (4/9, 44%), uric acid increased (3/9, 33.3%), heart rate increased (3/9, 33%), and hypoalbuminemia (5/9, 55.6%), cough (4/9, 44.4%), hyponatraemia (4/9, 44.4%), anemia (4/9, 44.4%), asthenia (3/9, 33.3%), rash (3/9, 33.3%), vomiting (3/9, 33.3%) and back pain (3/9, 33.3%). Two subjects experienced ≥ Grade 3 TEAEs unrelated to study drug. Six subjects were evaluable for tumor assessment, and 3 subjects (3/6, 50%) show stable disease (SD) as the best response (2 subjects with target lesion reduction). PK results demonstrated that exposure for the ADC and total antibody (TA) increased with dose, the relationship between AUC0-last and dose was greater than dose-proportional, while Cmax was linear. Free MMAE was highest at the 1.2 mg/kg dose level. Median Tmax values for ADC and TA were 1 h (end of infusion), and median Tmax for free MMAE was 25-169 h. In addition, elimination t1/2 values averaged 27-48 h, 31-68 h and 63-76 h for the ADC, TA, and MMAE, respectively. Conclusions: BC3195 exhibited favorable safety profile and PK characteristics up to 1.2mg/kg. Given BC31095’s safety and PK behavior, as well as preliminary activity at the 0.6 mg/kg dose level, patient enrollment at higher dose levels is ongoing. Clinical trial information: NCT05957471 .

Interim results from the ELiPSE-1 study: A phase 1, multicenter, open-label study of CNTY-101 in subjects with relapsed or refractory CD19-positive B-cell malignancies.

7023 Background: CNTY-101 is an allogeneic, iPSC-derived anti-CD19 Chimeric Antigen Receptor NK (CAR-iNK) cell product with Allo-Evasion edits to avoid host rejection. Potential benefits of CNTY-101 include immediate availability for treatment, repeat dosing without the need for lymphodepletion, and the potential for improved safety over T-cell based therapies. The first-in-human Phase 1 clinical trial of CNTY-101, ELiPSE-1 (NCT05336409), evaluates safety, preliminary efficacy, PK, and translational biomarkers in patients with CD19-positive B-cell malignancies. Methods: Subjects with R/R aggressive and indolent B-cell NHL received lymphodepletion (LDC) followed by assignment to 100e6, 300e6 or 1e9 cells at either Day 1 (Schedule A) or Days 1, 8 and 15 (Schedule B). Eligible subjects (ie, achieved SD or better at Day 28 by PET/CT) can receive additional cycles, with or without one additional regimen of LDC. Subjects also receive daily subcutaneous injections of IL-2 for 8 days (A) or 4 days (B) following each infusion. Results: At time of abstract submission, 10 subjects have been treated (n=4 DL1A; n=3 DL2A; n=2 DL3A; n=1 DL2B). Three subjects (1 at DL1A, 2 at DL2A) received additional cycle(s) of CNTY-101. Three subjects have not yet been evaluated for full safety and efficacy within the DLT window. Seven subjects (n=5 DLBCL; n=1 FL; n=1 MZL) had data available as of the data cut (Nov 30, 2023). All had stage 4 disease, 6/7 were refractory to last line of therapy, with a median of 4 (2-5) prior lines of therapy including CAR T (3/7). No DLTs, GvHD or ICANs were observed. Two subjects had cytokine release syndrome (n=1 Gr 1, n=1 Gr 2), all responding promptly to treatment. ORR/CRR was 25%/25% for 100e6 cells (DL1A) and 67%/33% for 300e6 cells (DL2A). Dose escalation is ongoing. In subjects from all three dose levels, CNTY-101 rapidly traffics out of circulation after infusion and is observed via cell-free DNA on Day 3 and detected up to 28 days. CNTY-101 persistence was not adversely impacted when given without lymphodepletion in two subjects who received additional cycles of CNTY-101. Induction of functional humoral immunogenicity against CNTY-101 was not observed at any of the dose levels, regardless of single or multiple cycles of CNTY-101. Adaptive immune responses were observed in the tumor microenvironment on Day 8. Conclusions: CNTY-101 administered as a single dose in multiple cycles has demonstrated a manageable safety profile and preliminary evidence of efficacy. Allo-Evasion edits may allow for repeat dosing for multiple cycles without allorejection in the absence of lymphodepletion. Preliminary efficacy supports dosing at higher dose levels and with more dose-intense regimens. Updated safety, efficacy, PK, and CNTY-101's impact on tumor for DL3A and DL2B will be provided. Clinical trial information: NCT05336409 .

Neoadjuvant HPV16-specific arenavirus-based immunotherapy HB-200 plus chemotherapy followed by response-stratified de-intensification in HPV16+ oropharyngeal cancer: TARGET-HPV.

6017 Background: The role of immunotherapy in curative viral-mediated oropharyngeal cancer (OPC) remains undefined. Human papillomavirus (HPV) 16 positive (+) OPC constitutively expresses viral epitopes that drive antigen-specific anti-tumor immunity, supporting rationale for evaluating neoadjuvant HPV16 directed therapeutics in non-metastatic OPC. HB-200 is an arenavirus-based vector therapy derived from LCMV (HB-201) and Pichinde virus (HB-202) each expressing a non-oncogenic HPV16 E7E6 fusion protein to induce HPV16 specific CD8+ T-cell responses. Building on our OPTIMA II results demonstrating that neoadjuvant chemotherapy/nivolumab led to deep responses in 71% of patients who went on to receive reduced radiation (RT), we hypothesized that adding HB-200 to chemotherapy to drive HPV16-specific anti-tumor immunity would be safe and effective to further deepen responses and facilitate more de-escalation. Methods: In this Phase 1 dose escalation investigator-initiated study, patients with non-metastatic HPV16+ OPC were treated with escalating doses of HB-201 single vector (Arm A) or HB-202/201 alternating vector (Arm B) x3 with neoadjuvant carboplatin AUC5 on day 1 and paclitaxel 100mg/m2 on days 1/8/15 of a 21-day cycle for 3 cycles. Deep responders (≥50% tumor shrinkage) received transoral robotic surgery (TORS) alone or RT to 50Gy +/- cisplatin, while non-responders (&lt;50% shrinkage) received 50 or 70Gy of RT with cisplatin. Primary objective was safety/tolerability and recommended phase 2 dose of HB-200 with chemotherapy. Additional objectives included deep response rate, circulating tumor (ct) HPV-DNA dynamics, and HPV16-specific T-cell response. Results: Twenty-one patients with HPV16+ OPC were enrolled and treated (Arm A, n=9, 43%; Arm B, n=12, 57%). Median age 57, 91% male, 75% base of tongue, 52% non-smokers, and 33% stage II/III (AJCC 8th edition). ≥Grade 3 treatment-emergent adverse events (AEs) occurred in 13 (62%) of patients overall and 3 (14%) non-hematologic during neoadjuvant. There were no Grade 4 AEs reported. All patients completed neoadjuvant HB-200/chemotherapy and response-stratified locoregional treatment. Deep responses following HB-200/chemotherapy were observed in 17/21 (81%) of patients, and in 14/15 (93%) treated on higher dose levels 1 or 2 ( p=0.05). All three patients who underwent TORS had no viable tumor at time of surgery. Two patients (9%) had persistent disease following CRT and underwent salvage surgery with no evidence of disease at last follow-up. ctHPV-DNA and HPV16-specific T-cell response data will be presented at the meeting. Conclusions: Neoadjuvant HB-200/chemotherapy is safe and feasible with early efficacy signal in this setting warranting further study. Enrollment to the subsequent randomized phase II part is ongoing (NCT05108870). Clinical trial information: NCT05108870 .

Intravenous infusion (IV) or intracavitary perfusion (IP) of T3011, an oncolytic HSV expressing IL-12 and PD-1 antibody: Analyses of two phase 1 studies.

e14581 Background: T3011 is a recombinant HSV-1 oncolytic virus expressing both IL-12 and anti-human PD-1 antibody. Upon delivery, locally produced IL-12 and PD-1 induces IFN-γ production, enhances the oncolytic activity of NK cells and cytotoxic T lymphocytes, promotes anti-angiogenesis, and inhibits tumor growth. We present the results of T3011 monotherapy administered via IV in advanced solid tumors or IP for malignant pleural effusion/ascites. Methods: In a phase 1, dose-escalation and expansion study using a 3+3 design with 5 cohorts (1×106, 1×107, 1×108, 5×108, 1×109 PFU), T3011 was administered intravenously on Days 1, 4, 8, 11,15,18 of a 28-day cycle in pts with advanced solid tumors. The primary objective was to evaluate the safety and tolerability of IV T3011, characterize dose-limiting toxicities (DLTs), MTD or RP2D, pharmacokinetic and pharmacodynamic profiles. In another pilot study to evaluate the safety and efficacy of T3011 in pts with malignant pleural effusion or ascites, T3011 was infused into the pleural or peritoneal cavity through an indwelling catheter on Days 1, 4, 8, 11 with 2 cohorts (5×108, 2×109 PFU). The response of malignant pleural effusion or ascites was assessed by WHO criteria. Results: As of 15 Dec 2023, 18 pts were enrolled and treated with IV T3011,4 pts received IV T3011 therapy at the highest dose level, 1×109 PFU. T3011 was well tolerated without ≥ Grade 3 TRAEs or DLTs. MTD was not reached. The most common TRAEs (≥ 10%) were nausea and infusion-related reactions, diarrhea, etc. Among 14 evaluable pts with advanced solid tumors, 3 pts had confirmed SD per RECIST1.1 and tumor burden reduced significantly. All the pts had detectable T3011 DNA in blood within 0.5-2 hours after administration, which was cleared subsequently within 3-7 days. As of 5 Jan 2024, 6 pts (pleural effusion 3, ascites 3) were dosed with IP T3011. 2 pts received 5×108 PFU and 4 pts received 2×109 PFU. Most TEAEs were grade 1 or 2. Only 1 pt developed grade 3 leukopenia, which resolved with G-CSF. No SAE occurred. 3 pts with pleural effusion showed 1 CR, 1 PR and 1 SD. 3 pts with malignant ascites secondary to advanced colorectal cancer, 1 was evaluable with PR. Conclusions: IV T3011 monotherapy has a very manageable safety profile and some encouraging activity in advanced solid tumors. IP T3011 monotherapy is also well tolerated and demonstrates promising activity against malignant pleural effusion and ascites. Clinical trial information: NCT04780217 .

A phase I study of TAK-659 and paclitaxel in patients with taxane-refractory advanced solid tumors

Paclitaxel resistance limits durability of response in patients with initial clinical benefit. Overexpression of spleen tyrosine kinase (SYK) has been proposed as a possible resistance mechanism. This phase I trial evaluated the safety and preliminary activity of the SYK inhibitor TAK-659 combined with paclitaxel in patients with advanced taxane-refractory solid tumors. Patients with advanced solid tumors and prior progression on taxane-based therapy received intravenous infusion of paclitaxel on days 1, 8, and 15 plus oral TAK-659 daily in 28-day cycles. The dose-escalation phase included six cohorts treated at different dose levels; the dose-expansion phase included patients with ovarian cancer treated at the highest dose level. Toxicity was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Efficacy was evaluated using Response Evaluation Criteria in Solid Tumors version 1.1. Our study included 49 patients. Maximum tolerated dose was not reached, but higher rates of adverse events were observed at higher dose levels. There were no treatment-related deaths. The most common treatment-related adverse events of any grade were increased aspartate aminotransferase (n= 31; 63%), increased alanine aminotransferase (n= 26; 53%), decreased neutrophil count (n= 26; 53%), and decreased white blood cell count (n= 26; 53%). Most adverse events were either grade 1 or 2. In the 44 patients with evaluable disease, 12 (27%) had stable disease as the best overall response, including three patients with prolonged stable disease, and 4patients (9%) achieved a partial response. The combination of paclitaxel and TAK-659 showed preliminary activity possibly overcoming resistance to taxane-based therapy as well as a tolerable safety profile in patients with advanced solid tumors.