La Jolla Pharmaceutical

Disclaimer In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. Purpose Traditional treatments for obstructive hypertrophic cardiomyopathy (oHCM) include β-blockers, calcium channel blockers, and disopyramide. Mavacamten, a novel cardiac myosin inhibitor, is a promising oHCM therapy but has practical challenges limiting its use. This descriptive study aimed to describe a clinic workflow for mavacamten management in a real-world setting, addressing challenges such as cost, drug interactions, and monitoring requirements. The focus was on reducing patient-level costs while ensuring feasibility and efficiency. Summary A retrospective analysis was conducted on 34 patients with oHCM for whom mavacamten was considered between May 2022 and May 2023. The clinic workflow involved cardiologist assessment, pharmacist evaluation of drug interactions, enrollment in the mavacamten risk evaluation and mitigation strategy program, cost reduction measures, and initiation of monitoring through scheduled echocardiograms. Of the 34 patients, 21 (62%) were initiated on mavacamten and followed for up to 1 year on therapy. The median time from referral to prior authorization approval and first fill was 5 and 22 days, respectively. Patients demonstrated high adherence (99.1%) as measured by the proportion of days covered. Echocardiogram follow-up showed improvements in left ventricular outflow tract parameters with no patients having a decrease in left ventricular ejection fraction to less than 50%. Conclusion The described workflow effectively addressed challenges associated with mavacamten management, emphasizing roles for clinic personnel, cost reduction strategies, and structured patient monitoring. While the workflow’s specifics may need adaptation in different settings, this report provides valuable insights for clinics implementing structured mavacamten management approaches.

While the need to measure burnout, stress and mental health among pharmacy students has been emphasized in the literature, there is limited information on which validated scales should be used. The objective of this scoping review was to identify published studies that used validated scales for burnout, stress and mental health among pharmacy students to provide recommendations for implementation at schools/colleges of pharmacy. Thirty-two out of 153 articles published in the United States from 1 January 2000 to 30 September 2022 were included and categorized into studies measuring stress (20), burnout (4) and depression/anxiety (8). The most common validated scales used to assess stress and burnout among pharmacy students were the Perceived Stress Scale (PSS) and the Maslach Burnout Inventory and the Oldenburg Burnout Inventory, respectively. For mental health, anxiety was most commonly investigated using a variety of scales such as the Generalized Anxiety Disorder-7; the Patient Health Questionnaire, 9-item was used to measure depression in two studies. Validity, ease of use, cost and generalizability are important considerations for selecting a scale. The PSS has been studied extensively in pharmacy students and has been correlated with other well-being domains. Studies that measured burnout and mental health (specifically, depression and anxiety) have less published evidence among pharmacy students.

255 Background: Liposarcomas (LPS) are rare tumors that are among the most common soft tissue sarcomas (STS) worldwide. In the US, the incidence rate of LPS is increasing. The variable clinical presentation, prognosis, and response to treatment for the LPS subtypes coupled with the lack of substantial changes to systemic therapy for STS since the 1970s highlight the challenges for patients (pts) in seeking accurate diagnosis and treatment. Data on the impact of LPS on the quality of life (QoL) of pts and their caregivers are limited. Here we present interim results of a survey conducted to help understand the burden of LPS on pts in the US, their diagnostic journey, and the impact on their QoL. Methods: Pts with LPS aged ≥18 years and residing in the US completed an online survey on their experiences with the diagnostic journey, burden of disease and treatment, QoL, and sources of support. Survey enrollment is ongoing. A descriptive statistical analysis was performed. Results: Of 40 pts who completed the survey between 4 Aug 2023 and 1 Mar 2024, 83% were white and 58% lived in a suburban area. Most pts (60%) had employer-provided insurance, and 13% had an individual insurance plan. Collectively, the pts consulted at least 7 types of specialists for initial symptoms and concerns. Most (n=16) consulted with an internal medicine practitioner first and 10 with an oncologist first; many consulted with oncologists second (n=14) or third (n=10). Most pts (60%) were diagnosed by a surgeon or an oncologist. Nearly one third (n=12) of pts were unsure of their LPS stage at diagnosis; 8 noted that it was not discussed. At the time of completing the survey, 53% of pts were in remission and 18% were unsure of their stage. Approximately 25% of pts needed to travel more than 1.5 hours for treatment. In addition, 25% of pts noted that treatment did not improve their QoL. Patients’ greatest concerns about the impact of LPS were physical condition (73%) and financial aspects (53%). Over half of the pts (55%) reported that there were activities they could no longer perform because of LPS. Pts were most comfortable asking their physicians questions related to LPS, followed by physician assistants. Most pts found support resources through Facebook groups and specialists, reporting peer-to-peer support (48%), financial assistance (30%), and mental health resources (28%) as the most useful types of support. Conclusions: The interim findings of this survey underscore the challenges that pts with LPS face while navigating the healthcare system. Consultation of numerous specialists and travel time to receive treatment impact access to timely diagnosis and quality care. The impacts of LPS on QoL and finances were also key unmet needs experienced by pts, which supports an increase in QoL and financial support resources for pts. There is also a need for increased awareness among physicians about LPS and the impact on pts’ QoL as well as for effective treatments that improve QoL.

188 Background: It is well established in the literature that cancer treatment administered at the end of life (EOL) does not improve either quality of life or survival rates. Patients undergoing systemic cancer treatments at near the EOL often have reduced access to hospice services and an increased likelihood of acute medical interventions, including emergency department visits, intensive care unit admissions, and in-hospital deaths. The development of immune checkpoint inhibitors (ICIs) has revolutionized cancer care over the past decade, demonstrating the ability to extend progression-free survival and overall survival in patients with various cancers. Furthermore, ICIs may represent a promising therapeutic option for adults with impaired performance status (PS) due to their relatively favorable side-effect profile when compared to conventional chemotherapy. While numerous studies have examined chemotherapy at the end of life, research specifically focusing on the administration of immunotherapy during this period is scarce. Methods: We conducted a retrospective chart review using the electronic medical record database at Scripps clinic focusing on cancer patients undergoing immunotherapy who passed away between June 1, 2017, and August 30, 2023, comprising a cohort of 641 individuals. Our investigation was designed to provide a retrospective overview of patient characteristics and outcomes, with a specific emphasis on factors at EOL. Results: The most prevalent tumor types were lung (34%), GI (21%), skin (13%), GU (12.6%) and others (19.4%). On average, no patients received immunotherapy in the last 30 days of their lives. Among the different cancer types, breast cancer patients had the longest interval between last treatment and death, averaging 259 days. This was followed by patients with head and neck cancer (207 days), skin cancer (199 days), genitourinary (GU) cancers (177 days), lung cancer (140 days), gynecological (GYN) cancers (135 days), and gastrointestinal (GI) cancers (134 days). 19 patients died from immune-related adverse events (IrAEs). These patients had the shortest interval between their last treatment and death, with a mean of 34 days. This was followed by those who died due to cancer progression, with an average interval of 148 days. Conclusions: The decision to administer anticancer therapies near the EOL is increasingly complex. Oncologists must carefully discuss immunotherapy with patients, monitor for IrAEs, and consider discontinuing treatment if there is disease progression, worsening PS or after two years of treatment.

Topological insulators (TI) and magnetic topological insulators (MTI) can apply highly efficient spin‐orbit torque (SOT) and manipulate the magnetization with their unique topological surface states (TSS) with ultrahigh efficiency. Here, efficient SOT switching of a hard MTI, V‐doped (Bi,Sb)2Te3 (VBST), with a large coercive field that can prevent the influence of an external magnetic field, is demonstrated. A giant switched anomalous Hall resistance of 9.2 kΩ is realized, among the largest of all SOT systems, which makes the Hall channel a good readout and eliminates the need to fabricate complicated magnetic tunnel junction (MTJ) structures. The SOT switching current density can be reduced to 2.8 × 105 A cm⁻², indicating its high efficiency. Moreover, as the Fermi level is moved away from the Dirac point by both gate and composition tuning, VBST exhibits a transition from edge‐state‐mediated to surface‐state‐mediated transport, thus enhancing the SOT effective field to (1.56 ± 0.12) × 10−6 T A−1 cm² and the interfacial charge‐to‐spin conversion efficiency to 3.9 ± 0.3 nm⁻¹. The findings establish VBST as an extraordinary candidate for energy‐efficient magnetic memory devices.

Objectives Serum creatinine (SCr) is the primary biomarker for assessing kidney function; however, it may lag behind true kidney function, especially in instances of acute kidney injury (AKI). The objective of the work is to develop Nephrocast, a deep-learning model to predict next-day SCr in adult patients treated in the intensive care unit (ICU). Materials and Methods Nephrocast was trained and validated, temporally and prospectively, using electronic health record data of adult patients admitted to the ICU in the University of California San Diego Health (UCSDH) between January 1, 2016 and June 22, 2024. The model features consisted of demographics, comorbidities, vital signs and laboratory measurements, and medications. Model performance was evaluated by mean absolute error (MAE) and root-mean-square error (RMSE) and compared against the prediction day’s SCr as a reference. Results A total of 28 191 encounters met the eligibility criteria, corresponding to 105 718 patient-days. The median (interquartile range [IQR]) MAE and RMSE in the internal test set were 0.09 (0.085-0.09) mg/dL and 0.15 (0.146-0.152) mg/dL, respectively. In the prospective validation, the MAE and RMSE were 0.09 mg/dL and 0.14 mg/dL, respectively. The model’s performance was superior to the reference SCr. Discussion and Conclusion Our model demonstrated good performance in predicting next-day SCr by leveraging clinical data routinely collected in the ICU. The model could aid clinicians in in identifying high-risk patients for AKI, predicting AKI trajectory, and informing the dosing of renally eliminated drugs.

This cross-sectional study examines how list prices for indomethacin have changed since 2019 and characterizes variation in hospital charges for the drug, including gross charges and discounted cash prices.

PURPOSE Phase IIa trial results suggested that RRx-001, an nucleotide-binding domain-like receptor protein 3 inhibitor and nuclear factor erythroid 2–related factor 2 activator, attenuated severe oral mucositis (SOM) in patients treated with concomitant chemoradiation (CRT) for oral cancer (OC) and oropharyngeal cancer (OPC). Given the shared pathobiology of CRT injury among other exposed tissues, we initiated a secondary analysis of reported adverse events (AEs) to assess RRx-001's potential benefit on non-SOM regimen-related toxicities. METHODS PREVLAR was an open-label randomized trial that has been completed and published. Patients were treated with CRT for locally advanced OC or OPC. Arms 1-3 received doses of RRx-001 twice a week beginning 2 weeks before the start of CRT. Arm 2 (n = 11) received additional RRx-001 once during weeks 2 and 5. Arm 3 (n = 13) received RRx-001 once a week for the first 6 weeks of CRT. Arm 4 (n = 10) received CRT only. Patients received standard intensity modulated radiation therapy (daily fractions of 2-2.2 Gy/minimum cumulative dose of 55 Gy) plus cisplatin. Comprehensive toxicity assessment was based on reported AEs graded using Common Terminology Criteria for Adverse Events v5.0 and categorized with the Medical Dictionary for Regulatory Activities. A two-sided Fisher's exact test was performed to compare AE incidences between RRx-001 arms and standard of care in a secondary analysis of the data. Overall false-positive rate in Fisher's exact test was controlled via Hochberg's adjustment method. RESULTS Compared with the control cohort, patients receiving RRx-001 demonstrated fewer AEs attributable to their CRT regimen. Statistically significant differences in AE incidences favoring RRx-001 were dependent on the RRx-001 dosing regimen. CONCLUSION This secondary analysis suggests that RRx-001 infusion may reduce multiple, biologically related AEs associated with a standard CRT regimen. More broadly, it suggests that it is possible that agents that effectively target central pathobiology targets may mitigate more than one toxicity.

The coronavirus disease 2019 (COVID-19) pandemic significantly impacted pharmacy students’ education and well-being. The primary aim of this study was to evaluate the effects of the pandemic on students’ perceived stress by comparing third- and fourth-year students from the pre-pandemic Class of 2019 with mid-pandemic Class of 2021 at two public institutions. Secondary aims were to evaluate the pandemic effects on students’ academic and professional development skills and practice readiness. The Perceived Stress Scale (PSS) and the Brief Coping Orientation to Problems Experienced (COPE) scale were used to measure student well-being. Students’ self-rated problem-solving, time management, and study skills were used to measure their academic and professional development; practice readiness was measured using students’ self-rated confidence levels. PSS scores were significantly higher in mid-pandemic than pre-pandemic students, and the Brief COPE avoidant coping subscale differed between pre-pandemic and mid-pandemic students. No differences were found in any academic and professional development skills between the pre- and mid-pandemic students, and there were significant improvements in student confidence levels for practice readiness among the mid-pandemic students. In conclusion, the pandemic appeared to affect students’ stress and avoidant coping mechanism but had variable effects on academic and professional development and practice readiness.

Background In the neonatal intensive care unit, infants are at risk for late-onset sepsis. When blood cultures are negative, antibiotic stewardship efforts encourage stopping antibiotics, yet the duration of therapeutic exposure after the last dose is unknown. Methods This retrospective cohort study of simulated antibiotic exposures used published population pharmacokinetic models within drug-specific neonatal intensive care unit cohorts of preterm and term infants, postnatal age 7–60 days and exposed to cefepime, piperacillin-tazobactam or tobramycin. Monte Carlo simulations (NONMEM 7.3) were used to predict steady-state exposures after a 72-hour antibiotic course per Neofax dosing. Exposure was assessed relative to drug-specific minimum inhibitory concentration (MIC) targets between 1 and 16 mcg/mL for Pseudomonas and Enterobacteriaceae species. Postdiscontinuation antibiotic exposure (PDAE) was defined as the time from the last dose to when antibiotic concentration decreased below a specific MIC. Results Piperacillin-tazobactam, cefepime and tobramycin cohorts included infants with median gestation age 29, 32 and 32 weeks and postnatal age 17, 19 and 15 days, respectively. The mean PDAE was 19–68 hours, depending on the specific antibiotic/MIC combination. PDAE was longer for infants <28 days old and preterm (vs. term) infants. Cefepime exhibited the longest mean PDAE of 68 hours for Enterobacteriaceae MIC 1. Piperacillin mean PDAE was 25 hours for Enterobacteriaceae MIC 8. Tobramycin had a short mean PDAE of 19 hours. Conclusions Piperacillin and cefepime exposures remained therapeutic long after the expected 8- to 12-hour dosing interval. PDAE is an important consideration for antibiotic stewardship among hospitalized infants, particularly premature infants and those within 1 month postbirth.

10613 Background: Li-Fraumeni Syndrome (LFS) is a hereditary cancer predisposition syndrome caused by mutations in the tumor suppressor gene TP53. Since its discovery, a growing list of cancers have been described in association with LFS, predominantly solid tumors. However, hematologic malignancies (HMs) cumulatively account for 4-10% of cancer diagnoses in LFS. In this study, we present the largest series of HMs in families with LFS with detailed clinical courses. Methods: This was a two-center retrospective observational cohort study conducted at the University of Utah and the University of Wisconsin-Madison with IRB approval. Cancer genetics clinic registries were reviewed to identify all families with LFS who also had a confirmed diagnosis of a HM. To meet criteria for LFS, the patient had to have a confirmed germline pathologic or likely pathologic TP53 variant. Patients with a TP53 variant of unknown significance (VUS) were also included if they met classical LFS testing criteria. Data was gathered by manual chart review of both the families’ histories and electronic health records. Results: Among the 121 families identified with LFS, 35 (29%) families had one or more HM. Of these, 17 individuals from 16 families (13%) had confirmed germline TP53 mutations. The most frequent HMs found were acute lymphoblastic leukemia (ALL) (n=6), non-Hodgkin lymphoma (NHL) (n=5), myelodysplastic syndromes (MDS) (n=3), and chronic lymphocytic leukemia (CLL) (n=2). Acute myeloid leukemia (AML), Langerhans cell histiocytosis (LCH), and chronic myeloid leukemia (CML) were each diagnosed once. Most cases were identified in adulthood (n=12, 71%). Of the 19 total HMs, the minority (n=5, 26%) were diagnosed post-cytotoxic therapy and only six (35%) individuals had received a diagnosis of LFS prior to HM diagnosis. The MDS/AML cohort (n=4) all exhibited bi-allelic inactivation of TP53. Two of these four patients achieved long term survival after matched-unrelated donor (MUD) hematopoietic stem cell transplant (HSCT). All three patients who underwent MUD donor HSCT had immune-mediated adverse events. Conclusions: In this study we found a significantly higher incidence of HMs in LFS than previously described, with a predominance of lymphoid over myeloid malignancies. The majority of patients had excellent outcomes after standard of care therapy pointing towards more favorable outcomes for patients with LFS and HMs than previously reported. We also report several unusual immune-mediated adverse events in our patients indicating possible immunogenicity of some TP53 variants. Most patients did not have prior exposure to cytotoxic treatments and were diagnosed with the HM prior to their LFS diagnosis. We also show that 38% of individuals with an HM have multiple family members with an HM, consistent with a familial HM pattern. This underscores the importance of detailed family and personal histories in HM patients found to carry a somatic TP53 variant.

2016 Background: Ibudilast is a selective inhibitor of macrophage inhibitory factor (MIF) activity, which is upregulated in GBM and promotes stem cell growth. It also disrupts the interaction between MIF and CD74. When combined with temozolomide (TMZ) in preclinical studies, it attenuates the immunosuppressive properties of myeloid-derived suppressor cells and enhances tumor regression. This is a phase 1b/2a single-center, open-label, dose escalation study evaluating the safety, tolerability, and efficacy of the combination of Ibudilast and TMZ in newly diagnosed (nGBM) and recurrent (rGBM) GBM was initiated (NCT03782415). Methods: We included patients with nGBM who had completed concurrent chemoradiation, and patients with first GBM relapse who had a measurable enhancing disease. Patients were treated with monthly cycles of temozolomide (5 days of a 28-day cycle) and daily ibudilast, with a starting dose of 30 mg twice daily (BID), and escalated to a maximal dose of 50 mg BID. The primary objectives were to evaluate the safety and tolerability of the combination and determine the phase 2 recommended dose (R2PD) for phase 1b, and to evaluate the efficacy of the combination, determined by the 6-month progression-free survival rate (PFS-6) for phase 2a. A standard 3+3 design was used for phase 1b. For the rGBM cohort, a sample size of 30 provided 80% power to discriminate between historical 15% and 35% PFS-6 rates for rGBM patients. The trial would be considered successful if at least 8 patients were progression free at 6 months. Secondary objectives included overall survival (OS). Immunohistochemistry (IHC) studies were performed on archival tumor samples to evaluate factors of the tumor immune microenvironment. Results: 36 patients with nGBM and 26 patients with rGBM were included; 61% were males, with median age of 59 years. Ibudilast 50 mg BID was deemed to be the R2PD. PFS-6 was 44% (16 patients) in nGBM, and 31% (8 patients) in rGBM. The median OS was 21.0 months (17.7, 23.1) for nGBM and 8.6 months (7.8, 10.5) for rGBM. IHC evaluation on the original tumor tissue for patients with rGBM revealed a significantly higher CD3 positive cells infiltration, and elevated CD74 expression in tumors of patients who progressed at 5 months compared to those who did not. Conclusions: This study met its primary endpoint for rGBM, as the combination of ibudilast and TMZ was associated with a higher PFS-6 rate than historical controls. CD3 expression was a good predictor for tumor progression at 5 months in patients with rGBM. Encouraging preclinical studies suggest enhanced efficacy of ibudilast in GBM when combined to immune checkpoint blockade agents. Clinical trial information: NCT03782415 .

e13099 Background: Abemaciclib is a CDK4/6 inhibitor which in combination with endocrine therapy (ET) improves progression-free survival in hormone receptor (HR)-positive, HER2 negative advanced breast cancer, as well as invasive disease free-survival in high-risk early-stage breast cancer. However, abemaciclib is associated with adverse events which may limit treatment adherence. In this single-center study, we describe real-world safety outcomes of early-stage and advanced HR-positive, HER2 negative breast cancer patients prescribed abemaciclib in conjunction with ET. Specifically, we analyze the frequency of adverse events and dose reductions (DR). Methods: We conducted a retrospective study of patients treated at Scripps Clinic between 1/1/2019-1/1/2023 with HR-positive, HER2 negative breast cancer prescribed abemaciclib with ET. Primary analyses were performed to discern clinical characteristic differences between groups. Categorical variables were summarized as frequencies and compared between arms by Chi-Square tests or Fisher’s Exact Tests. All continuous variables were summarized as means and standard deviations and compared between arms by T-Tests if normally distributed or summarized as medians and compared between arms by Mann-Whitney Tests otherwise. Statistical significance was set to 0.05 and all analyses were conducted in R. Results: A total of 77 patients were analyzed including 62% in the adjuvant setting and 38% in the metastatic setting. 51% of patients required DR. Patients requiring DR were older relative to those not requiring DR (59 vs 52 years of age, p=0.019). Those requiring DR remained on abemaciclib longer relative to those without DR (509 vs 350 days, p=0.057). Among those requiring DR, there were higher rates of grades II-IV diarrhea (p<0.001) and Loperamide use (p=0.083). Those requiring DR also had higher rates of neutropenia (54% vs 29%, p=0.027), abdominal cramping (39% vs 8%, p=0.002), nausea (39% vs 13%, p=0.011), and fatigue (51% vs 32%, p=0.079). Among 9 patients who expired on abemaciclib, 7 were in the metastatic setting and 1 was linked to an adverse effect from abemaciclib; none required DR (24% vs 0%, p<0.001). Finally, patients in the adjuvant setting remained on abemaciclib longer relative to those in the metastatic setting (526 vs 281 days, p=0.01). 95% of patients experienced symptom improvement with DR (p<0.001). Conclusions: Our study describes real-world safety outcomes of patients with HR-positive, HER2 negative breast cancer treated with abemaciclib and ET. More than half of patients required DR. Those who reduced their abemaciclib dose had improvement of clinical symptoms and remained on therapy longer. Based on our findings and given the importance of adherence in treatment efficacy, a lower starting dose of abemaciclib may be a more tolerable strategy, especially among older patients who required more DR in our study.

2506 Background: The benefit of immune checkpoint inhibition is limited to 20-40% of patients. Moreover, acquired resistance often arises. Also, certain tumor types like breast are more CI-refractory. Therefore, the focus is on new combination strategies to increase clinical benefit. This multicenter phase 2 trial evaluated AdAPT-001, an oncolytic adenovirus armed with a “TGF-β trap” that neutralizes the immunosuppressive cytokine, TGF-β, +/- a checkpoint inhibitor (CI) in resistant patients some of whom previously failed a CI. Methods: Eligible patients with refractory tumors, many of them sarcomas, received 1 or more intratumoral injections of AdAPT-001 at dose level 1 x 10 ¹² viral particles every 2 weeks +/- a CI at Investigator discretion. The CI was administered every 2 nd -3 rd week. Adverse events were recorded and managed. The primary endpoints of this combination therapy were objective response rate (ORR) and progression free survival (PFS). Results: 36 patients (22 males and 14 females) enrolled with a median age of 60.8 years (range 23-86) from Feb 2023-Dec 2023. 24/36 enrolled patients received AdAPT-001 with a CI and 12 patients received AdAPT-001 single agent. The most common treatment related adverse events (TRAE) were transient flu-like symptoms (fever, chills, vomiting, fatigue) 10/36 (27.7%), and injection related events 10/36 (27.7%). Notably, only 1 patient, 1/24 (4.0%), developed an immune-related AE, hypophysitis. All other related AEs were Grade 1/2. 33/36 patients were evaluable for response analysis; monotherapy produced 2/9 (22.2%) favorable responses (complete response (CR): eccrine carcinoma; confirmed partial response (cPR): acral melanoma); and produced a 4/9 (44.4%) clinical benefit rate defined as CR/PR/SD greater than 12 weeks. The combination of AdAPT-001 plus a CI produced 7/24 (29.1%) favorable responses (1 clinical CR: angiosarcoma; 6 cPRs: 3 sarcoma, 1 triple negative breast cancer, 1 head and neck cancer, 1 squamous cell carcinoma; and a 15/24 (62.5%) clinical benefit rate defined as CR/PR/SD greater than 12 weeks. 21/33 failed a CI before enrollment (16/24 before AdAPT-001 + CI). The PFS was 3.5 months (95% CI: 1.8-NA months). Conclusions: Combination therapy of AdAPT-001 with a CI is well tolerated and demonstrates a high ORR including 1 patient with a CR per RECIST 1.1, 1 patient with a clinical CR and 6 PRs. In several cutaneous sarcomas treated with AdAPT-001 plus a CI, radiologic SD belied how much better they looked visually--not only smaller, but less irregular and more circumscribed. Clinical trial information: NCT04673942 . [Table: see text]

TPS3161 Background: EphA5 receptor is a member of the Ephrin receptor tyrosine kinase family. Several lines of compelling nonclinical evidence indicate EphA5 is a novel and selective target for solid tumor-directed therapy. Expressed only minimally in normal tissues, it is highly expressed in non-small cell lung carcinoma (NSCLC), head and neck squamous cell carcinoma (HNSCC), and breast, colorectal, pancreatic, gastric, and hepatic malignancies. MBRC-101 is a novel antibody drug conjugate (ADC) composed of an anti-EphA5 antibody conjugated to an MMAE payload (drug-to-antibody ratio of 4) through a valine citrulline cleavable linker. In pre-clinical toxicology studies and testing against a variety of cell-derived (CDX) and patient-derived (PDX) xenograft solid tumor models expressing EphA5--including NSCLC, triple negative breast cancer (TNBC), and HNSCC--MBRC-101 demonstrated favorable safety profiles and robust anti-tumor activity. Methods: This first-in-human, Phase 1/1b, multicenter, open-label study is examining the safety and efficacy of MBRC-101 in patients with advanced metastatic solid tumors refractory to standard treatment. Phase 1 will identify potential optimal biologically relevant doses (OBRD) and the maximum tolerated dose (MTD) of MBRC-101 at one or more dosing regimens. Phase 1b will evaluate the safety and preliminary clinical activity of MBRC-101 at potential OBRDs. Phase 1 will enroll patients (n ≈ 30) with advanced or metastatic solid tumors. EphA5 expression will not be required for enrollment into Phase 1 but will be assessed retrospectively. A modified toxicity probability interval (mTPI-2) method will guide dose escalation using a pre-specified decision matrix. The primary endpoints are MTD, dose limiting toxicities (DLTs), treatment emergent adverse events (TEAEs), and clinical laboratory tests. Phase 1b (n ≈ 60 patients) will include 3 expansion cohorts (n ≈ 20 patients per cohort): Cohort A, NSCLC; Cohort B, triple negative or HR+/HER2- breast cancer; and Cohort C, solid tumors irrespective of histologic tissue type (i.e., tumor agnostic) excluding NSCLC and breast cancer. Expression of EphA5 in primary or metastatic tumor tissue will not be required for enrollment into cohorts A and B but will be required for Cohort C. The primary endpoints are TEAEs, clinical laboratory tests, and investigator-assessed objective response rate (ORR) by RECIST v1.1 and clinical evaluation. Secondary endpoints for Ph1 and 1b include PK analytes and EphA5 expression as determined by immunohistochemistry (IHC). A Safety Review Committee will monitor safety at each dose escalation in Phase 1 and at regular intervals throughout Phase 1b. Clinical trial information: NCT06014658 .