Early Phase Clinical Trials Research Articles

Preclinical studies of an innovative 5T4-ADC ACR246 with the potential to better treat 5T4-positive solid tumors.

e15005 Background: 5T4 oncofetal antigen shows limited expression in normal adult tissues but highly expressed by many different cancers. It drives spread of cancer cells through epithelial mesenchymal transition (EMT), potentiation of CXCL12/CXCR4 chemotaxis and favoring non-canonical Wnt pathway, leading to poor prognosis of cancer patients. Besides, 5T4 has a highly efficient endocytosis ability which enables it to be an ideal target for the development of ADC drugs. A handful of 5T4-targeted ADCs have been evaluated in early phase clinical trials for several years showing only preliminary anti-tumor activity. However, uncertainty of their safety profiles has also raised concerns due to high toxic payloads, MMAF and duocarmycin, being used. Thus, additional approaches to this target with the potential of improved efficacy and reduced toxicity are needed urgently. ACR246, an innovative 5T4-targeted ADC consisting of specific humanized monoclonal antibody site-specifically conjugated with a cell penetrating and moderate toxic payload (DNA topoisomerase I inhibitor, D2102) that has a robust bystander effect through a stable and cleavable linker, with a drug-to-antibody ratio (DAR) of 8, was designed to improve the safety and efficacy in treating tumor patients. Methods: The pharmacologic profiles of ACR246 were assessed in vitro and in vivo including efficacy, pharmacokinetics-pharmacodynamics (PK-PD), safety, and tissue distribution, in 5T4-positive cell lines, cell-derived xenograft (CDX) models and cynomolgus monkeys. Results: ACR246 bound specifically to 5T4 and was internalized into tumor cells followed by D2102 release, which induced DNA damage, cell cycle arrest and apoptosis in 5T4 positive tumor cells in vitro. In vivo low systemic exposure and tumor-specific accumulation of D2102 rendered ACR246 superior efficacy and safety property. Accordingly, ACR246 exhibited robust in vivo anti-tumor activity across various types of 5T4 positive CDX models in a dose-dependent manner, with DNA damage induced by the accumulated D2102 in tumor tissue. GLP toxicity studies indicated that ACR246 was well tolerated in cynomolgus monkeys. The estimated therapeutic index was 24. Conclusions: The overall preclinical profile marks ACR246 has the potential to become the best in class (BIC) 5T4-ADC, showing more favorable benefit-risk ratio in clinic.

Pilot study to evaluate automated laboratory data transfer into Medidata Rave for NCI-supported pediatric cooperative group trials in the Pediatric Early Phase Clinical Trials Network (PEP-CTN) and Pediatric Brain Tumor Consortium (PBTC).

e23017 Background: Electronic data capture (EDC) has the potential to improve data accuracy and efficiency. As an initial step toward improvement in the accuracy and completeness of data acquisition for clinical trials, PEP-CTN and PBTC conducted a pilot project to assess the feasibility of automated transfer of laboratory data from participating institutions’ electronic health records to the NCI Medidata Rave EDC that is housed within each consortium’s Uniform Resource Locator (URL). The pilot aimed to assess feasibility of automated laboratory data extraction and transfer and to evaluate discrepancies between laboratory data obtained retrospectively through automated extraction and data manually ascertained during the original conduct of the study. Methods: Data from patients treated on 7 completed PEP-CTN or PBTC trials at 7 sites were included. Each consortium created a Rave EDC study to receive data. Sites used the ExtractEHR R package or local methods to map and extract laboratory data for designated patients. Post-extraction data were uploaded via a file transfer protocol (FTP) periodically polled by the Rave Batch Uploader (BU) that uploaded data into Rave EDC. After successful upload, extracted data (EHR) were compared to laboratory data that had been manually reported when patients were enrolled on the trials (MANUAL) and discrepancies were identified. Discrepancy types were categorized and 2 sites reviewed discrepancies at their sites to identify reasons. Results: Preparation and support for automated extraction and upload required significant central operations and local site effort. All sites successfully extracted specified laboratory data and had at least one complete upload via BU to Rave EDC. There were more laboratory data in the EHR datasets than MANUAL datasets across most sites. These results were due to multiple EHR results on a given day or from additional days in the study window than specified in MANUAL. Sites verified that laboratory data in MANUAL and not EHR were stored in un-extractable formats (e.g. PDFs) or outside laboratories. Most discrepant results in both EHR and MANUAL were mismatched values or units. Conclusions: This pilot demonstrated the feasibility of implementing automated laboratory data extraction and transfer in the cooperative group setting. Automated data transfer requires significant central operational support as well as detailed protocols, data specifications, and case report forms and engagement of site technical teams to be successful, but also permits collection of more comprehensive data with reduced manual data entry. Clinical trial information: NCT05020951 .

Vincristine (VCR) pharmacokinetics (PK) in infants dosed using a body surface area (BSA) banded dosing table and in older children dosed based on BSA: A pediatric early phase clinical trial network study (PEPN22P1).

10015 Background: The Children’s Oncology Group developed and implemented a unified method of dosing anticancer drugs in infants and small children with a BSA < 0.6 m2. The dosing tables use BSA-based dose banding and account for deliverable doses/volumes of the drugs. We studied the PK of VCR (1.5 mg/m2 dose level) in infants and children to determine whether this new infant dosing method achieves uniform drug exposures across the pediatric age span. Methods: We designed a sampling strategy to limit the blood volume required by focusing on the elimination (β) phase of the VCR concentration-time curve, which accounts for > 80% of the total area-under the curve (AUC). Duplicate samples to detect contamination were drawn at 3 post-infusion time points (2, 6-8 and 18-24 hr) through a central venous catheter (CVC) after a 90 min flush. VCR concentrations were measured at the Children’s Hospital of Philadelphia using a validated high-pressure liquid chromatography/tandem mass spectrometry method with a lower limit of quantitation (LLQ) of 0.25 ng/mL. A one-compartment model was fit to the concentration-time data using population PK methods (Phoenix NLME). The AUCβ was derived from the dose and clearance for each patient. Patients were accrued in 4 age groups (≤6 mo, goal n = 20); > 6 mo to ≤12 mo, goal n = 10; > 12 mo to ≤36 mo, goal n = 10; and > 36 mo to ≤12 yr, goal n = 10) to focus on infants and ensure representation across the pediatric age range. Results: 52 eligible patients have been enrolled and 39 are evaluable for PK analysis, including 9 ≤6 mo, 8 > 6 mo and ≤12 mo, 12 > 12 mo and ≤36 mo, and 10 > 36 mo and ≤12 y,. The median (range) age is 13.5 mo (1.15-112 mo). VCR was quantifiable in all samples, and there was no evidence of contamination in the duplicate samples drawn through the CVC. The mean ± SD AUCβ in the 39 evaluable patients was 54.7 ± 19.8 ng⋅h/mL. As shown in the Table, the AUCβ is similar in patients with a BSA < 0.6 m2 dosed according to the BSA-banded infant dosing table and patients with a BSA ≥0.6 m2 dosed by multiplying their BSA times 1.5 mg/m2 (p = 0.53, Mann Whitney test). Conclusions: The VCR BSA-banded infant dosing table appears to provide uniform VCR exposure for infants and young children compared to conventional BSA-based dosing in older children. The study design and sampling strategy facilitated rapid accrual of a young population and generated more VCR PK data in infants within a year than has been published since the drug was approved in 1963. This study demonstrates the feasibility of systematically studying other anticancer drugs in infants and other special populations to ensure they are receiving safe and effective doses. VCR AUCβ by dosing method. Clinical trial information: NCT05359237 . [Table: see text]

STRIvE-02 Arm C: Phase 1 study of concurrent PD-1 inhibition with B7-H3 CAR T cell immunotherapy for recurrent/refractory pediatric solid tumors.

e14626 Background: B7-H3 expression by a broad range of pediatric solid tumors has led to development of B7-H3-directed chimeric antigen receptor (B7-H3-CAR) T cells. However, early phase clinical trials of B7-H3-CAR T cells in recurrent/refractory solid tumors demonstrated inconsistent CAR T cell expansion and limited anti-tumor activity. We subsequently developed a dual transduced CAR product expressing B7-H3-CAR and CD19-CAR (CARB7H3x19) to enhance CAR T cell expansion with antigenic stimulation by normal B cells (STRIvE-02 Arm B). Augmented expansion was observed but CAR T cell persistence was variable, leading to a hypothesis that concurrent use of pembrolizumab (pembro), a PD1-inhibitor, would help prolong persistence, leading to improved anti-tumor activity. Methods: Patients up to age 26 years with recurrent/refractory solid tumors (excluding primary CNS) enrolled onto Arm C of STRIvE-02 to examine safety and feasibility of CARB7H3x19 at a dose of 0.5 x 106 CD19-CAR T/kg followed by pembro 2 mg/kg (max 200 mg) either 7- (Dose regimen (DR) 1) or 21-days (DR 2) post-CAR T cell using a 3+3 statistical design. All subjects received lymphodepletion with fludarabine and cyclophosphamide prior to CAR T cells. CTCAEv5 was used for toxicity grading. Results: Of six patients (pts) enrolled (age range 11–25 yrs, median 20 yrs, four received CAR T cell+pembro; three received DR1 pembro (day (D)+7), and one received DR2 (D+21). A pt on DR2 with nonseminomatous germ cell tumor developed grade (gr) 5 immune effector cell-associated hyperinflammatory syndrome (IEC-HS) on D+17 prior to pembro, resulting in trial suspension. One pt did not receive CAR T cells and is unevaluable. Adverse effects occurring in pts who received pembro included gr 3 fever in setting of neutropenia (n=1), and gr 2 hyperthyroidism (n=1), with no dose limiting toxicity attributed to CAR T cell+pembro. Maximum circulating CAR T expansion for Arm C was 192.18 cells/uL (range 6.86 – 192.18 cells/uL) with median persistence of 28 days (range 28 - 84), compared to a maximum circulating CAR T expansion of 740.95 cells/uL (range 8.29 – 740.95 cells/uL) and median persistence of 65 days (range 21 - 274) in pts treated on Arm B receiving the same CAR dose level (n=8). D+28 disease restaging in the four Arm C pts who received CAR T cells+pembro demonstrated stable disease (n=1) and disease progression (n=3). Conclusions: Although we observed tolerable toxicity among patients who received CAR T cell+pembro, the small number of patients limit full toxicity assessment. T cell expansion and persistence was observed, but the effects of pembro on CAR T cell fitness are unclear. Phenotypic characterization of circulating CAR T cells is underway to further assess impact of pembro. Of note, this is the first reported death attributed to IEC-HS in a patient after receiving B7-H3-CAR T cells. Investigations into etiology are ongoing. Clinical trial information: NCT04483778 .

Amplifying the Patient's Voice in Oncology Early-Phase Clinical Trials: Solutions to Burdens and Barriers.

Dose-finding oncology trials (DFOTs) provide early access to novel compounds of potential therapeutic benefit in addition to providing critical safety and dosing information. While access to trials for which a patient is eligible remains the largest barrier to enrollment on clinical trials, additional direct and indirect barriers unique to enrollment on DFOTs are often overlooked but worthy of consideration. Direct barriers including financial costs of care, travel and time investments, and logical challenges including correlative study designs are important to bear in mind when developing strategies to facilitate the patient experience on DFOTs. Indirect barriers such as strict eligibility criteria, washout periods, and concomitant medication restrictions should be accounted for during DFOT design to maintain the fidelity of the trial without being overly exclusionary. Involving patients and advocates and incorporating patient-reported outcomes (PROs) throughout the process, from initial DFOT design, through patient recruitment and participation, is critical to informing strategies to minimize identified barriers to offer the benefit of DFOTs to all patients.

Telehealth consultations and recruitment trends in clinical trials: A retrospective analysis at investigational cancer therapeutics, a dedicated phase I department at The University of Texas MD Anderson Cancer Center.

1635 Background: Recruitment to phase I/II clinical trials have been reported to vary between 30% and 55% across centers, primarily relying on in-person visits. However, with the onset of the COVID-19 pandemic, there has been a noticeable surge in telehealth consultations. Consequently, there is currently a dearth of data available regarding this approach within the context of early phase-clinical trials. Methods: Data on patient’s first visits to the Investigational Cancer Therapeutics (ICT), a dedicated Phase I department at The University of Texas MD Anderson Cancer Center (MDACC), were retrieved from the institution's electronic platform. The ICT department offers phase I-II clinical trials for patients with advanced cancer. We included first visits between January 2020 and December 2023. Initial telehealth visits were conducted via video or telephone, with patients from either Texas or other states in the United States. Visits were classified into two groups: internal referrals, originating from other departments within MDACC, and new patient visits, including patients who had not been seen at MDACC prior to the ICT visit. Recruitment was defined as the percentage of patients who consented to participate in a clinical trial. Statistical analysis was performed using Statistical Package for Social Sciences (SPSS). Results: A total of 6,965 patients had a first visit in the Investigational Cancer Therapeutics Department between January 2020 and December 2023. Of these, 4,321 patients (62%) had their initial in-person visit, while 2,644 patients (38%) opted for telehealth consultations. Internal referrals accounted for 6,304 patients (90.5%), while new patient visits comprised 661 patients (9.5%). Among the entire cohort, recruitment rate for phase I-II clinical trials was 53.2% (n= 3,702). Patients with initial telehealth consultations had a recruitment rate of 55.1%, compared to 52.0% among those with in-person consultations (χ2=6.538, p<0.011). Recruitment was higher among internal referrals at 53.7% compared to 47.5% for external referrals (χ2= 9.355, p=0.002). Notably, recruitment was statistically higher in internal consults that underwent telehealth versus in-person visits (55.4% versus 52.6%, p=0.027), while there were no statistical differences in new patient visits (47.4% vs. 47.8%, p=0.939). Conclusions: Telemedicine consultations emerge as a valuable alternative for evaluating and discussing treatment options for patients with advanced solid tumors, thereby enhancing accessibility to early-phase clinical trials. The flexibility of conducting initial visits remotely may mitigate geographical and logistical challenges and allow for a more inclusive and diverse participant pool, fostering broader representation in clinical trial research.

Breaking barriers for cancer clinical trials: A multi-tiered interventional approach to boost racial and ethnic minority participation in early-phase studies.

TPS1639 Background: Racial and ethnic minority populations are underrepresented in cancer clinical trials. The USC Norris Comprehensive Cancer Center (USC NCCC) has multiple clinical trial recruitment sites, including the Los Angeles General Medical Center (LAG), the largest safety-net hospital in the western USA. LAG partners with USC to provide cancer care to the underserved minority population of LAC, including clinical trials. As a result, between 2015-2022 a total of 120 LAG patients were accrued to phase I clinical trials; enrolled subjects were 66% Hispanic, 21% Asian, 4% Black, and 9% other. An interventional study was designed to further enhance the referral and participation of racial and ethnic minority patients from other Los Angeles County (LAC) safety-net facilities. The study is funded by the Stand up to Cancer Diversity in Early Development Clinical Trials Research Grants Program. Methods: This interventional study has 3 specific aims. First, to identify barriers to referral for minority and underserved patients: Qualitative interviews will be conducted with key stakeholders in the LAC safety net system which will uncover barriers to referring minority and underserved patients. A screening tool developed by the NCI to characterize barriers will be used. Second, to implement a multi-component program to enhance the referral of patients to early-phase clinical trials. The intervention addresses system-level, provider-level, and patient-level factors to improve the process, with a demonstration site compared to a non-demonstration site. Key features include a streamlined referral process for healthcare professionals with a singular centrally operated email managed by a specialized facilitator, weekly meetings to assign trials to prospective patients, and facilitation of approval and scheduling for referrals. We will educate providers regarding trials and exchange feedback on the referral process. We will extend resources to patients to assist with financial and transportation limitations. We will compare change in referral and enrollment rates at baseline and after the intervention for both the demonstration site and non-demonstration site. Third, to explore the impact of remotely conducted clinical trials: A clinical trial (NCT05340309) administers study drug subcutaneously and uses telemedicine visits, wearable sensors, and a smartphone app for monitoring. This pilot trial will be analyzed to determine the model’s impact on barriers to enrollment. The above interventions may provide a model that can be adapted in other healthcare delivery settings to optimize referral and enrollment of racial and ethnic minorities.

Efficacy and safety of PARP inhibitors (PARPi) with immune checkpoint inhibitors (ICI) in metastatic castration-resistant prostate cancer (mCRPC): A systematic review and single-arm meta-analysis.

e17053 Background: Recent therapeutic advances in prostate cancer have allowed patients with metastatic disease to live longer and better, especially in the castration sensitive setting. Although improvements have been observed in the castration resistant space, survival in this setting remains suboptimal. Early-phase clinical trials suggest the combination of PARP inhibitors (PARPi) and immune checkpoint inhibitors (ICI) have synergistic effect by modulating the tumor microenvironment. In this systematic review and meta-analysis, we assessed the efficacy and safety of PARPi and ICI in the metastatic castration-resistant prostate cancer (mCRCP) setting. Methods: Pubmed, Cochrane and EMBASE were systematically searched from inception through December 10, 2023. Randomized and non-randomized clinical trials evaluating PARPi + ICI in mCRPC were included. PSA response rate (PSArr), radiographic progression-free survival (rPFS), objective response rate (ORR) and overall survival (OS) were analyzed. Subgroups according to (HRR) were assessed. We also pooled the prevalence of immune-related adverse events (irAE) and their corresponding 95% confidence intervals (95% CI). Statistical analysis was performed using R software version 4.3.2 and heterogeneity was evaluated through I2 statistics. Results: We screened 1070 reports, and six trials met the inclusion criteria (one phase III RCT and 5 phase I/II non-RCT), involving 799 participants. The overall ORR was 8.48% (95% CI 6.48-10.86 I2 0%). About 19% of patients achieved an PSArr (95% CI 9.51-32.50 I2 75%). Median OS was 15.8 months (95% IC 13.9-15.8), and rFPS was 4.5 months (95% IC 4.4-4.9). In patients harboring HRR mutations, PSArr was 17.53% (95% CI 10.43-27.95 I2 75), while in HRR non-mutated it was 10.49% (95% CI 5.89-17.99 I2 0%). The frequency of any-grade irAEs was 21.12% (95% CI 12.34-33.74 I2 85%), with 6.70% of grade 3-4 irAEs (95% CI 3.09-13.91 I2 80%). Hypothyroidism rate was 8.53% (95% CI 5.86-12.27 I2 29%) and adrenal insufficiency was 2.80% (95% CI 1.81-4.30 I2 0%). Conclusions: This meta-analysis results suggest that the combination of PARPi plus ICI in patients with mCRPC is safe and may benefit mainly patients with HRR mutations. Further studies in biomarker selected patients are needed. [Table: see text]

A multicohort platform trial to improve drug access for pediatric cancer patients in Japan: The PARTNER trial (NCCH2220).

TPS10079 Background: In Japan, there are no pediatric regulations that encourage drug development for pediatric cancer, such as Pediatric Investigation Plans (PIPs) which are mandated in Europe, or the RACE Act in the U.S. Therefore, there are fewer early-phase clinical trials and approved drugs for pediatric cancer than in Western countries. In addition, because there is no rapid compassionate use program, there are delays when using an unapproved drug. According to a report from the Japanese cancer genome profiling (CGP) testing data center, C-CAT, 51.3% of pediatric patients with solid tumors had targetable genetic abnormalities. However, only 5.8% of them had access to the recommended molecular targeted therapy (Tanimura K. et al., presented at the Japanese Society of Pediatric Hematology and Oncology annual meeting 2022). Thus, Japanese pediatric patients with relapsed or refractory solid tumors have limited access to novel drugs, even if they have druggable mutations. Therefore, we designed a platform study (NCCH2220, PARTNER trial) to rapidly deliver molecularly targeted drugs based on CGP testing. Methods: This study has two objectives: first, to administer some drugs to pediatric patients that are not approved for pediatric cancer in Japan. These drugs have been shown to be safe in pediatric patients in foreign countries and are expected to be effective. Second, to evaluate the safety and efficacy of the drug in Japanese pediatric patients and, if necessary, its pharmacokinetics. These data will be used for potential future regulatory filings. This is an open-label, multicenter, multicohort study. Eligible patients are aged 0–29 years with diseases having no standard therapy, which are refractory, or when there is intolerance to standard therapy. The study drug must be recommended for the patient by CGP testing or approved for pediatric use for their disease in the U.S. or Europe, or approved in Japan for use in adults only. The drugs are used as monotherapy in the study. The study schedules follow a master protocol. Up to 30 patients can be enrolled in each cohort. The primary endpoint is the incidence of dose-limiting toxicity in each cohort. The secondary endpoints are the incidence of adverse events, the overall response rate, and, if necessary, the pharmacokinetics in each cohort. As of January 2024, the study had five treatment cohorts with the following agents: imatinib, pazopanib, ruxolitinib, trametinib, and atezolizumab. Additional cohorts will be added. We started planning the study in November 2022, and enrollment began on January 18, 2024. This platform trial has enabled us to deliver drugs to patients more quickly and efficiently than by conducting individual early-phase trials for each drug. Clinical trial information: jRCTs031230544 .

Decoding the anti-cancer potential of Pexidartinib (PLX3397), a Fms-like tyrosine kinase 3 inhibitor, using next-generation knowledge discovery methods.

Acute Myeloid Leukemia (AML) is a complex hematologic malignancy characterized by the rapid proliferation of abnormal myeloid precursor cells. The FMS-like tyrosine kinase 3 (FLT3), a receptor tyrosine kinase, plays a pivotal role in regulating cell survival, proliferation, and differentiation within the hematopoietic system. Mutations in FLT3, particularly internal tandem duplications (ITDs) and point mutations within the tyrosine kinase domain (TKD), are prevalent in AML and are associated with poor prognosis and increased risk of relapse. The development of targeted therapies has revolutionized the landscape of cancer treatment by focusing on the inhibition of kinase signalling. Small-molecule inhibitors designed to selectively target receptor tyrosine kinases, such as PLX3397, have shown promising results in preclinical studies and early phase clinical trials. PLX3397 exerts its inhibitory effects by targeting CSF1R and KIT, leading to the disruption of receptor tyrosine kinase signalling cascades, suppression of leukemic cell growth, and induction of apoptosis. This study emphasizes the significance of FLT3 as a receptor tyrosine kinase as a therapeutic target for PLX3397. After evaluating the usefulness of PLX3397 as an enzyme inhibitor using ADMET prediction, PLX3397 was prepared for molecular docking in the FLT3 crystal structure (PDB: 4XUF). A molecular dynamics simulation was performed on PLX3397 to evaluate its binding affinity and protein stability in a simulated physiological environment. In conclusion, targeting FLT3 as a receptor tyrosine kinase with PLX3397 represents a promising therapeutic strategy for improving outcomes in patients with FLT3-mutated AML. Further clinical investigations are warranted to validate the efficacy and safety of PLX3397 and to optimize treatment strategies for AML patients based on the FLT3 mutational status.

Cerebroprotective Effects of the TLR4-Binding DNA Aptamer ApTOLL in a Rat Model of Ischemic Stroke and Thrombectomy Recanalization.

ApTOLL, a TLR4 modulator aptamer, has demonstrated cerebroprotective effects in a permanent ischemic stroke mouse model, as well as safety and efficacy in early phase clinical trials. We carried out reverse translation research according to STAIR recommendations to further characterize the effects and mechanisms of ApTOLL after transient ischemic stroke in rats and to better inform the design of pivotal clinical trials. Adult male rats subjected to transient middle cerebral artery occlusion were treated either with ApTOLL or the vehicle intravenously at different doses and time-points. ApTOLL was compared with TAK-242 (a TLR4 inhibitor). Female rats were also studied. After neurofunctional evaluation, brains were removed for infarct/edema volume, hemorrhagic transformation, and histologic determinations. Peripheral leukocyte populations were assessed via flow cytometry. ApTOLL showed U-shaped dose-dependent cerebroprotective effects. The maximum effective dose (0.45 mg/kg) was cerebroprotective when given both before reperfusion and up to 12 h after reperfusion and reduced the hemorrhagic risk. Similar effects occurred in female rats. Both research and clinical ApTOLL batches induced slightly superior cerebroprotection when compared with TAK-242. Finally, ApTOLL modulated circulating leukocyte levels, reached the brain ischemic tissue to bind resident and infiltrated cell types, and reduced the neutrophil density. These results show the cerebroprotective effects of ApTOLL in ischemic stroke by reducing the infarct/edema volume, neurofunctional impairment, and hemorrhagic risk, as well as the peripheral and local immune response. They provide information about ApTOLL dose effects and its therapeutic time window and target population, as well as its mode of action, which should be considered in the design of pivotal clinical trials.

Advances in CAR-NK cell therapy for lung cancer: is it a better choice in the future?

Lung cancer remains one of the leading causes of cancer-related mortality worldwide necessitating the development of innovative therapeutic strategies. Chimeric antigen receptor (CAR) natural killer (NK) cell therapy represents a promising advancement in the field of oncology offering a novel approach to target and eliminate tumor cells with high specificity and reduced risk of immune-related adverse effects. This paper reviews the mechanism, potential targets, and recent advances in CAR-NK cell therapy for lung cancer, including the design and engineering of CAR-NK cells, preclinical studies, and the outcomes of early-phase clinical trials. We highlight the unique advantages of using NK cells, such as their innate ability to recognize and kill cancer cells and their reduced potential for inducing graft-versus-host disease (GvHD) and cytokine release syndrome (CRS) compared to CAR T-cell therapies. Results from recent studies demonstrate significant antitumor activity in lung cancer models with improved targeting and persistence of CAR-NK cells observed in vitro and in vivo. Finally, we discuss the challenges in optimizing CAR-NK cell therapies, including the potential resistance mechanisms. The paper concludes with an outlook on the future directions of CAR-NK cell research and its implications for lung cancer treatment emphasizing the importance of continued innovation and collaboration in the field.

Decline in Smartphone-Assessed Physical Activity Level is Associated With Clinical Outcomes in Phase I/II Clinical Cancer Trials.

A decline in physical function may be an early predictor for complications of cancer treatment. This study examined whether repeated objective smartphone measurements of physical activity and exercise capacity in patients with cancer are feasible during early-phase clinical trials (EPCTs) and whether a decline in physical function is associated with clinical outcomes. Physical activity (steps/day) and exercise capacity (6-minute walk test [6MWT]) were measured with a smartphone before EPCT start (T0) and after 4 weeks (T1) and 8 weeks (T2). Univariable logistic regression analyzed associations between a decline in step count (≥20%), 6MWT distance (≥10%), or deterioration of ECOG performance status (PS) and trial discontinuation at 8 weeks and 90 days. Cox proportional hazards models were used to examine associations with progression-free survival (PFS) and overall survival (OS), adjusting for trial phase (I vs II), cancer type (hematologic malignancy vs solid tumor), and PS (0 vs ≥1). Among 117 included patients, valid step count and 6MWT measurements were available for 96.6% and 76.7% of patients at T0, 74.4% and 53.3% at T1, and 89.7% and 54.4% at T2, respectively. Patients experiencing step count decline between T0 and T1 had higher odds of trial discontinuation at 8 weeks (odds ratio, 8.67; 95% CI, 1.94-61.43), and decline between T1 and T2 was associated with discontinuation at 90 days (odds ratio, 5.20; 95% CI, 1.43-21.14). Step count decline was significantly associated with shorter PFS (hazard ratio, 3.54; 95% CI, 2.06-6.08) and OS (hazard ratio, 2.31; 95% CI, 1.26-4.23). Declines in 6MWT distance or deterioration in ECOG PS were not associated with trial discontinuation or survival. Repeated smartphone measurements of physical activity are feasible in patients participating in EPCTs. Additionally, physical activity decline is significantly associated with trial discontinuation, PFS, and OS. Hence, we envision that objective smartphone measurements of physical activity will contribute to optimal treatment development for patients with cancer.

Magnetic resonance imaging of tumor response to stroma-modifying pegvorhyaluronidase alpha (PEGPH20) therapy in early-phase clinical trials

Pre-clinical and clinical studies have shown that PEGPH20 depletes intratumoral hyaluronic acid (HA), which is linked to high interstitial fluid pressures and poor distribution of chemotherapies. 29 patients with metastatic advanced solid tumors received quantitative magnetic resonance imaging (qMRI) in 3 prospective clinical trials of PEGPH20: HALO-109-101 (NCT00834704), HALO-109-102 (NCT01170897), and HALO-109-201 (NCT01453153). Apparent Diffusion Coefficient of water (ADC), T1, ktrans, vp, ve, and iAUC maps were computed from qMRI acquired at baseline and ≥ 1 time point post-PEGPH20. Tumor ADC and T1 decreased, while iAUC, ktrans, vp, and ve increased, on day 1 post-PEGPH20 relative to baseline values. This is consistent with HA depletion leading to a decrease in tumor extracellular water content and an increase in perfusion, permeability, extracellular matrix space, and vascularity. Baseline parameter values predictive of pharmacodynamic responses were: ADC > 1.46 × 10−3 mm2/s (Balanced Accuracy (BA) = 72%, p < 0.01), T1 > 0.54 s (BA = 82%, p < 0.01), iAUC < 9.2 mM-s (BA = 76%, p < 0.05), ktrans < 0.07 min−1 (BA = 72%, p = 0.2), ve < 0.17 (BA = 68%, p < 0.01), and vp < 0.02 (BA = 60%, p < 0.01). A low ve at baseline was moderately predictive of response in any parameter (BA = 65.6%, p < 0.01 averaged across patients). These qMRI biomarkers are potentially useful for guiding patient pre-selection and post-treatment follow-up in future clinical studies of PEGPH20 and other tumor stroma-modifying anti-cancer therapies.

Qualitative evaluation of motives for acceptance or refusal of early palliative care in patients included in early-phase clinical trials in a French comprehensive cancer center: the PALPHA study.

The integration of palliative care (PC) into oncological management is recommended well before the end of life. It improves quality of life and symptom control and reduces the aggressiveness of end-of-life care. However, its appropriate timing is still debated. Entry into an early-phase clinical trial (ECT) represents hopes for the patient when standard treatments have failed. It is an opportune moment to integrate PC to preserve the patient's general health status. The objective of this study was to evaluate the motives for acceptance or refusal of early PC management in patients included in an ECT. Patients eligible to enter an ECT were identified and concomitant PC was proposed. All patients received exploratory interviews conducted by a researcher. Their contents were analyzed in a double-blind thematic analysis with a self-determination model. Motives for acceptance (PC acceptors: n = 27) were both intrinsic (e.g., pain relief, psychological support, anticipation of the future) and extrinsic (e.g., trust in the medical profession, for a relative, to support the advance of research). Motives for refusal (PC refusers: n = 3) were solely intrinsic (e.g., PC associated with death, negative representation of psychological support, no need for additional care, claim of independence). The motives of acceptors and refusers are not internalized in the same way and call for different autonomy needs. Acceptors and refusers are influenced by opposite representations of PC and a different perception of mixed management.

Beyond BCMA: the next wave of CAR T cell therapy in multiple myeloma.

Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment landscape of relapsed/refractory multiple myeloma. The current Food and Drug Administration approved CAR T cell therapies idecabtagene vicleucel and ciltacabtagene autoleucel both target B cell maturation antigen (BCMA), which is expressed on the surface of malignant plasma cells. Despite deep initial responses in most patients, relapse after anti-BCMA CAR T cell therapy is common. Investigations of acquired resistance to anti-BCMA CAR T cell therapy are underway. Meanwhile, other viable antigenic targets are being pursued, including G protein-coupled receptor class C group 5 member D (GPRC5D), signaling lymphocytic activation molecule family member 7 (SLAMF7), and CD38, among others. CAR T cells targeting these antigens, alone or in combination with anti-BCMA approaches, appear to be highly promising as they move from preclinical studies to early phase clinical trials. This review summarizes the current data with novel CAR T cell targets beyond BCMA that have the potential to enter the treatment landscape in the near future.

Abstract PO2-13-07: SMARCA2 compensation of SMARCA4 loss mediates adaptive resistance to neoadjuvant systemic therapy in triple-negative breast cancer: paired transcriptomic analysis of pre- and post-treatment samples from NeoSTOP and NeoPACT

Abstract Objectives/Rationale: Triple-negative breast cancer (TNBC) patients with residual disease (RD) after neoadjuvant systemic therapy (NAST) are at high risk for disease recurrence and death. While multiple prognostic biomarkers associated with response to NAST have been identified, adaptive resistance mechanisms to NAST remain poorly understood. Identifying and characterizing adaptive resistance mechanisms can illuminate novel therapeutic approaches and improve outcomes for TNBC patients with RD. Methods: Total RNA was isolated from pre-treatment and paired surgical specimens (for patients with RD) from TNBC patients treated with chemotherapy on the NeoSTOP (NCT02413320) or chemoimmunotherapy on the NeoPACT (NCT03639948) neoadjuvant trials and was subjected to RNA exome sequencing. Comparative marker selection analysis was performed by computing the two-sided paired samples t-test for each gene followed by pre-ranked gene set enrichment analysis (GSEA) amongst 23,797 annotated gene sets. Gene sets with false-discovery rate (FDR) corrected P values &amp;lt; 0.001 were determined to be significant. Results: Pre-treatment sequencing data were available for N=200 patients and the overall pathologic complete response (pCR) rate was 56.5%. Paired pre- and post-treatment sequencing data were available for N=58 patients with RD (N=27 from NeoSTOP and N=31 from NeoPACT). 165/23,797 gene sets were significantly enriched in post-treatment compared to pre-treatment samples. SHEN_SMARCA2_TARGETS_UP (M29) was among the top five significantly enriched gene set and was selected for further analysis based on the known role of the SWI/SNF complex in cell survival and the availability of clinically viable SMARCA2 degraders. Pre-treatment SMARCA4 expression was associated with pCR, with lower median expression noted in patients with RD compared to patients who achieved pCR (P=0.04). Pre-treatment SMARCA2 expression was not associated with pCR (P=0.48). On paired sample analysis there was pronounced downregulation of SMARCA4 in post-treatment compared to pre-treatment samples in all patients (mean Z=-1.46, P&amp;lt; 0.0001), in patients treated with chemotherapy (mean Z=-1.65, P&amp;lt; 0.0001), and in patients treated with chemoimmunotherapy (mean Z=-1.28, P&amp;lt; 0.0001). Although there was no difference in SMARCA2 expression between paired pre- and post-treatment samples (mean Z=0.03, P=0.83), there was enrichment of SMARCA2 target expression on GSEA analysis (NES=2.63, FDR q&amp;lt; 0.00001) indicating that SMARCA2 activity is compensating for therapy-induced SMARCA4 loss. Conclusions: We identified 165 gene sets that were significantly enriched in paired post-treatment compared to pre-treatment TNBC samples. Altered activity of the SMARCA2 subunit of the SWI/SNF chromatin remodeling complex was identified as one of the top hits. SMARCA2 and SMARCA4 are mutually exclusive subunits of SWI/SNF, and inactivation of both SMARCA2 and SMARCA4 is synthetic lethal. We observed an association of lower pre-treatment SMARCA4 expression with resistance to NAST and pronounced therapy-induced downregulation of SMARCA4 and induction of SMARCA2 target genes in post-treatment compared to pre-treatment samples, suggesting that SMARCA2 compensates for adaptive SMARCA4 loss. SMARCA2 degraders are in early-phase clinical trials and are known to induce synthetic lethality in SMARCA4-deficient cells. Our results identify adaptive loss of SMARCA4 and synthetic lethal targeting of compensatory SMARCA2 as an attractive therapeutic target in TNBC patients with RD after neoadjuvant chemotherapy or chemoimmunotherapy. Citation Format: Shane Stecklein, Rachel Yoder, Joshua Staley, Zachary Schmitt, Anne O'Dea, Lauren Nye, Deepti Satelli, Gregory Crane, Rashna Madan, Maura O'Neil, Andrew Godwin, Harsh Pathak, Qamar Khan, Joyce O'Shaughnessy, Priyanka Sharma. SMARCA2 compensation of SMARCA4 loss mediates adaptive resistance to neoadjuvant systemic therapy in triple-negative breast cancer: paired transcriptomic analysis of pre- and post-treatment samples from NeoSTOP and NeoPACT [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-13-07.

Abstract PO3-13-07: MUC1-C INTEGRATES CHRONIC ACTIVATION OF INTERFERON PATHWAYS WITH CHROMATIN REMODELING IN TREATMENT RESISTANCE OF TRIPLE-NEGATIVE BREAST CANCER

Abstract Chronic inflammation is intimately linked to cancer progression and resistance to treatment. Triple-negative breast cancer (TNBC) is a recalcitrant malignancy largely unresponsive to cytotoxic, targeted and immunotherapeutic agents. The Mucin1 (MUC1) transmembrane heterodimeric protein, which is aberrantly expressed in TNBCs, evolved in mammals to provide protection of epithelia from the external environment. With loss of homeostasis, the (i) MUC1 N-terminal (MUC1-N) subunit is shed and released into serum as detected by the CA15-3 assay, and (ii) MUC1 C-terminal (MUC1-C) subunit is activated and thereby induces inflammatory, proliferative and remodeling signaling pathways associated with wound healing. However, prolonged MUC1-C activation in settings of chronic inflammation promotes cancer progression and treatment resistance. The SWI/SNF PBAF chromatin remodeling complex includes the polybromo-1 (PBRM1) subunit and drives DNA damage resistance and immune evasion in certain cancer cells through mechanisms that remain unclear. Recent studies in TNBCs have demonstrated that MUC1-C drives intrinsic activation of type II interferon (IFN) pathway that is linked to chronic inflammation and immune evasion. In extending this work, we have found that MUC1-C activates the type I IFN pathway, which contributes to genomic instability and DNA damage tolerance in TNBC cells. Importantly, our results further demonstrate that MUC1-C interacts with interferon regulatory factor 1 (IRF1) as a key regulatory node in integrating activation of the type I and II IFN pathways. Here, we report that MUC1-C is necessary for PBRM1 expression and that it forms a nuclear complex with PBRM1 in TNBC cells. Analysis of global transcriptional (RNA-seq) and chromatin accessibility (ATAC-seq) profiles further demonstrated that MUC1-C and PBRM1 drive STAT1 and IRF1 expression by increasing chromatin accessibility of promoter-like signatures (PLS) on their respective genes. We also found that MUC1-C, PBRM1, and IRF1 increase the expression and chromatin accessibility on PLSs of the (i) type II IFN pathway IDO1 and WARS genes and (ii) type I IFN pathway RIG-I, MDA5, cGAS, STING and ISG15 genes that collectively contribute to DNA damage resistance and immune evasion. In support of these results, targeting MUC1-C in wild-type BRCA1/2 TNBC cells enhanced carboplatin-induced DNA damage and loss of self- renewal capacity. In addition, MUC1-C was necessary for DNA damage resistance, self-renewal and tumorigenicity of olaparib-resistant BRCA1-mutant TNBC cells. Analysis of TNBC clinical samples corroborated that (i) MUC1 and PBRM1 are associated with decreased responsiveness to chemotherapy and (ii) MUC1-C expression is associated with the depletion of tumor-infiltrating lymphocytes. These findings demonstrate that MUC1-C activates PBRM1, and thereby chromatin remodeling of IFN-stimulated genes that promote chronic inflammation, DNA damage resistance, and immune evasion. These findings have identified MUC1-C as a potential target for the treatment of TNBC that have limited therapeutic options. To that end, the generation of MAb 3D1 against the MUC1-C extracellular domain provided an opportunity for the development of agents that target MUC1-C on the cancer cell surface. As one example, an allogeneic anti-MUC1-C CAR T cell using MAb 3D1 sequences is undergoing Phase I evaluation for the treatment of MUC1-C-expressing cancers (NCT05239143: P-MUC1C-ALLO1 Allogeneic CAR-T Cells in the Treatment of Subjects with Advanced or Metastatic Solid Tumors). In addition, anti-MUC1-C huMAb3D1-MMAE ADCs are under development by the NCI NExT Program for IND-enabling studies and performing early phase clinical trials in patients with TNBC. Citation Format: Nami Yamashita, Yoshihiro Morimoto, Atsushi Fushimi, Rehan Ahmad, Atrayee Bhattacharya, Yuka Inoue, Henry Withers, Geoffrey Shapiro, Tomoharu Yoshizumi, Takayuki Ueno, Shinji Ohno, Mark Long, Donald Kufe. MUC1-C INTEGRATES CHRONIC ACTIVATION OF INTERFERON PATHWAYS WITH CHROMATIN REMODELING IN TREATMENT RESISTANCE OF TRIPLE-NEGATIVE BREAST CANCER [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-13-07.

Melatonin reduces brain injury following inflammation-amplified hypoxia-ischemia in a translational newborn piglet study of neonatal encephalopathy.

There is a need to develop therapies for neonatal encephalopathy (NE) in low- and middle-income countries (LMICs) where the burden of disease is greatest and therapeutic hypothermia (HT) is not effective. We aimed to assess the efficacy of melatonin following inflammation-amplified hypoxia-ischaemia (IA-HI) in the newborn piglet. The IA-HI model accounts for the contribution of infection/inflammation in this setting and HT is not cytoprotective. We hypothesised that intravenous melatonin (5% ethanol, at 20 mg/kg over 2 h at 1 h after HI + 10 mg/kg/12 h between 24 and 60 h) is safe and associated with: (i) reduction in magnetic resonance spectroscopy lactate/N-acetylaspartate (MRS Lac/sNAA); (ii) preservation of phosphorus MRS phosphocreatine/phosphate exchange pool (PCr/Epp); (iii) improved aEEG/EEG recovery and (iv) cytoprotection on immunohistochemistry. Male and female piglets underwent IA-HI by carotid artery occlusion and reduction in FiO2 to 6% at 4 h into Escherichia coli lipopolysaccharide sensitisation (2 μg/kg bolus + 1 μg/kg/h over 12 h). At 1 h after IA-HI, piglets were randomised to HI-saline (n = 12) or melatonin (n = 11). There were no differences in insult severity between groups. Target melatonin levels (15-30 mg/L) were achieved within 3 h and blood ethanol levels were <0.25 g/L. At 60 h, compared to HI-saline, melatonin was associated with a reduction of 0.197 log10 units (95% CrI [-0.366, -0.028], Pr(sup) 98.8%) in basal-ganglia and thalamic Lac/NAA, and 0.257 (95% CrI [-0.676, 0.164], Pr(sup) 89.3%) in white matter Lac/NAA. PCr/Epp was higher in melatonin versus HI-saline (Pr(sup) 97.6%). Melatonin was associated with earlier aEEG/EEG recovery from 19 to 24 h (Pr(sup) 95.4%). Compared to HI-saline, melatonin was associated with increased NeuN+ cell density (Pr(sup) 99.3%) across five of eight regions and reduction in TUNEL-positive cell death (Pr(sup) 89.7%). This study supports the translation of melatonin to early-phase clinical trials. Melatonin is protective following IA-HI where HT is not effective. These data guide the design of future dose-escalation studies in the next phase of the translational pipeline.

Targeting the Interplay of Proteins through PROTACs for Management Cancer and Associated Disorders

Abstract: Cancer remains a formidable global health challenge, necessitating innovative therapeutic strategies. Traditional small-molecule inhibitors often face limitations in selectively targeting diseaseassociated proteins, leading to side effects and incomplete therapeutic responses. Proteolysistargeting chimeras (PROTACs) turned out to be a promising approach to address these challenges. Unlike traditional inhibitors, PROTACs leverage the cellular ubiquitin-proteasome system to selectively degrade disease-associated proteins. In this review, we addressed PROTACs: Targeted approach for cancer management, key findings, limitations, and future perspectives. For this, the authors have critically reviewed literature obtained from prime sources comprising Google Scholar, Web of Science, PubMed, and Publons. From the selected papers' reference section, a number of pertinent articles were retrieved. Preclinical studies and early-phase clinical trials have demonstrated the efficacy and potential of PROTACs in cancer management. Additionally, the potential of PROTACs in overcoming therapy resistance, tackling tumor heterogeneity, and engaging multiple pathways is explored. As research advances, addressing challenges and refining PROTAC technology will pave the way for their integration into the next generation of cancer therapeutics, marking a transformative era in precision medicine.