Citations

ABSTRACT The Team Physician Consensus Statement delineates qualifications, duties, and responsibilities of the team physician and provides guidelines to individuals and organizations in selecting team physicians. These delineations and guidelines provide a foundation for best practices in the medical care of athletes and teams. The team physician’s education, training, and experience uniquely qualify them to provide the best medical care for the athlete. This document is not intended as a standard of care and should not be interpreted as such. It is only a guide and, as such, is of a general nature, consistent with the reasonable, objective practice of the healthcare profession. Adequate insurance should be in place to help protect the physician, the athlete, and the sponsoring organization. This document was originally developed as the first in the team physician consensus series, representing an ongoing project-based alliance of the major professional associations concerned about clinical sports medicine issues. The organizations are as follows: American Academy of Family Physicians, American Academy of Orthopedic Surgeons, American College of Sports Medicine, American Medical Society for Sports Medicine, American Orthopedic Society for Sports Medicine, and the American Osteopathic Academy of Sports Medicine.

Objectives: To determine associations between physician sex and use of postoperative healthcare resources among patients undergoing common surgeries in Ontario, Canada. Background: Prior studies have shown that patients of female physicians experience better outcomes and have lower healthcare costs compared with patients of male physicians. Understanding differences in resource utilization may offer insights into the care pathways and practice patterns contributing to these differences. Methods: We conducted a population-based, retrospective cohort study of adults (≥18 years of age) undergoing 1 of 25 common surgeries, between January 1, 2007, and December 31, 2019, in Ontario, Canada. The primary outcome was the utilization of one of the following: intensive care unit admission, other medical interventions (eg, tracheostomy, new dialysis starts, and home oxygen), and discharge care needs (eg inpatient rehab, long-term care, and home care use) within 30 days. The data were summarized using descriptive statistics and adjusted using multivariable generalized estimating equations. Results: This population-based study included 1,100,193 patients (61.8% female). Patients treated by male surgeons had higher use of postoperative resources versus those with female surgeons within 30 days (adjusted rate 33.1; 95% confidence interval [CI]: 28.0–39.2 versus 31.2; 95% CI: 25.8–37.7), 90 days, and 1 year. Consistent with these findings, following adjustment for patient, surgeon, procedural, and hospital characteristics, patients treated by male surgeons were significantly more likely to utilize postoperative resources within 30 days (adjusted odds ratio: 1.14; 95% CI: 1.03–1.27; P = 0.010) and at other time points. This difference was primarily driven by the higher use of home care among patients with a male versus female surgeon at all time points (30 days: adjusted odds ratio, 1.13; 95% CI: 1.05–1.21; P = 0.002). Conclusions: Patients with male surgeons had higher postoperative resource utilization when compared with those treated by female surgeons, which was almost entirely driven by the higher use of home care. Further mixed-methods investigation is needed to better understand other potentially relevant factors including surgical outcomes, individual patient preferences, and surgical team decision-making.

PURPOSE The combination of the Bruton tyrosine kinase inhibitor ibrutinib with bendamustine-rituximab for first-line treatment of mantle cell lymphoma (MCL) prolonged progression-free survival (PFS), but without improvement in overall survival (OS), likely because of toxicity. Acalabrutinib was shown to be efficacious and less toxic than ibrutinib in a head-to-head trial in chronic lymphocytic leukemia and therefore might lead to better outcomes in MCL. METHODS Patients 65 years and older with previously untreated MCL received acalabrutinib (100 mg twice daily) or placebo (until disease progression or unacceptable toxicity), plus six cycles of bendamustine (90 mg/m 2 once daily; days 1 and 2) and rituximab (375 mg/m 2 as a single dose; day 1) followed by rituximab maintenance in responding patients for 2 years. Crossover to acalabrutinib at disease progression was permitted. The primary end point was PFS per the independent review committee; overall response rate and OS were secondary end points. RESULTS In total, 598 patients were randomly assigned, with 299 in each arm. At a median follow-up of 49.8 months using the reverse Kaplan-Meier method, the median PFS was 66.4 months in the acalabrutinib arm and 49.6 months in the placebo arm (hazard ratio [HR], 0.73 [95% CI, 0.57 to 0.94]; P = .0160). Benefit was seen across all subgroups, including those with high-risk features. Overall response/complete response rates were 91.0%/66.6% and 88.0%/53.5% in the acalabrutinib and placebo arms, respectively. OS was not significantly different (HR, 0.86 [95% CI, 0.65 to 1.13]; P = .27). Grade 3 or greater adverse events were reported in 88.9% and 88.2% in the acalabrutinib and placebo arms, respectively. CONCLUSION The combination of acalabrutinib with bendamustine-rituximab significantly improved PFS. Clinical benefit of acalabrutinib with bendamustine-rituximab was achieved with manageable toxicity.

Abstract Background: Given the dramatic rise in incidence of colorectal cancer in young adults, there remain limited treatment options effective in metastatic disease. Although T cell-based therapies have been successful in treating highly antigenic cancers, like melanoma and lung, they have not yet been shown to induce consistent and durable tumor regression in common epithelial malignancies, including metastatic colorectal cancer (mCRC). CISH (Cytokine inducible SH2 containing protein) is a novel intracellular checkpoint target demonstrating PD-L1 ligand independent mechanisms of enhanced anti-cancer activity. Given that CISH is not currently tractable via antibody or small molecule drug modalities, we employed CRISPR for precise inhibition of CISH in tumor infiltrating lymphocytes (TILs). Here, we provide the first clinical report of safety and anti-tumor activity of CISH edited TILs in 12 patients with metastatic gastrointestinal cancers (NCT04426669), including a clinical complete response (CR) in a young-adult patient with immunotherapy-refractory mCRC. Methods: Tumors were surgically resected for TIL harvest, followed by a rapid expansion protocol and CRISPR/Cas9 knockout (KO) CISH. CISH KO, neoantigen-reactive TILs were expanded, then infused following non-myeloablative lymphocyte depleting (LD) chemotherapy (cyclophosphamide & fludarabine) followed by high-dose IL-2. To establish mechanistic attribution of the CR, we used iR-RepSeq+ for serial analysis of the TCR immune repertoire. Results: Our CRISPR engineering led to KO of CISH in T cells with high-efficiency (>90%) without detectable off-target editing. We safely dosed patients at all five dose levels (range: 1.91e8 to 9.93e10 cells). No dose-limiting toxicities attributable to the CISH-KO TIL product were observed. Adverse events were consistent with established risks of LD chemotherapy, IL-2, or disease progression. A durable ongoing complete response (>21 months) was achieved in a patient with microsatellite instability-high (MSI-H) mCRC refractory to anti-PD1/CTLA-4 combination therapy. Conclusions: We provide the first clinical report of CISH checkpoint targeting via genetically modified T cell therapy, with complete response in a patient with mCRC. Persistence and expansion of unique TCR clonotypes detected in neoantigen responsive TIL was temporally consistent with spikes in CISH edited alleles detected by NGS assay; in the patient with CR, four of the clonotypes exhibiting prolonged persistence greater than one-year post-infusion exhibited significantly reduced or undetectable expression of CISH compared to the total infused TIL population. Given these findings, further investigation of CISH checkpoint inhibition, via gene and cell therapy, and next-generation small molecule drugging modalities, is underway. Citation Format: Emil Lou, Modassir S. Choudhry, Timothy K. Starr, Timothy Folsom, Jason Bell, Blaine Rathmann, Anthony P. DeFeo, Ji Hyun Kim, Nicholas Slipek, Zhaohui Jin, Darin Sumstad, Christopher A. Klebanoff, Katherine Ladner, Akshat Sarkari, R Scott McIvor, Thomas A. Murray, Jeffrey Miller, Madhuri Rao, Eric Jensen, Jacob Ankeny, Mahmoud A. Khalifa, Anil Chauhan, Benjamin Spilseth, Ajay Dixit, Paolo P. Provenzano, Wenjing Pan, Daniel Weber, Miranda Byrne-Steele, Tom Henley, David H. McKenna, Matthew J. Johnson, Beau R. Webber, Branden S. Moriarity. First-in-human trial in patients with metastatic colorectal cancer using CRISPR-engineered tumor infiltrating lymphocytes in which the intracellular immune checkpoint CISH is inhibited [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT269.

Abstract Background: Endocrine therapy (ET) with aromatase inhibitors (AI) plus ovarian function suppression (OFS) is standard for premenopausal women with ER+/HER2- breast cancer. However, many premenopausal women are intolerant of AI + OFS, leaving tamoxifen (with or without OFS) as their only option. Extensive studies have demonstrated that premenopausal women treated with neoadjuvant ET whose tumors exhibit Ki-67 ≤ 10% following 4 weeks of therapy (defined as endocrine sensitive disease (ESD)) achieve 5-year distant disease-free survival > 96%. Problematically, only 41% of patients reach this ESD threshold with tamoxifen compared to 78% with AI+OFS (Nitz JCO 2022). (Z)-endoxifen (ENDX) is a potent selective estrogen receptor modulator (SERM) that inhibits ERα at plasma concentrations of 3-5 ng/ml and dually targets PKCβ1, a suspected oncogene in breast tumors, at concentrations ≥ 500 ng/ml. We therefore developed the EVANGELINE study (NCT05607004) is an open label, randomized neoadjuvant phase II study that includes a pharmacokinetic (PK) Run-in, aiming to evaluate whether ENDX +/- goserelin is non-inferior to exemestane plus goserelin with respect to ESD rate. Following the completed PK run-in portion of the study, where 40mg/day or 80mg/day ENDX were assessed, the 40 mg/day dose was selected for further evaluation in the second part of the trial. The second part is comprised of a randomized treatment cohort, for patients with a Ki-67% >10% at preregistration randomized to either 40mg (Z)-endoxifen + goserelin or exemestane + goserelin neoadjuvant treatment and a Single Arm Treatment Cohort for patients who have a Ki-67 ≤ 10% at pre-registration assigned to 40mg/day (Z)-endoxifen monotherapy neoadjuvant treatment. Methods: To investigate ENDX further in premenopausal women, a multicenter study in the United States, was designed(EVANGELINE; NCT05607004). This phase 2, open-label, randomized, neoadjuvant trial includes a PK run-in phase designed to assess whether the 4-week ESD rate with (Z)-endoxifen + goserelin is non-inferior to that of exemestane + goserelin in premenopausal women with Stage IIA or IIB ER+/HER2- breast cancer with diagnostic Ki67 > 10%. Additionally, a single arm Phase 2, open-label neoadjuvant Cohort was designed to assess the 4-week ESD rate with ENDX monotherapy in premenopausal women with Stage IIA or IIB ER+/HER2- BC with diagnostic Ki67 ≤10%. Subjects will undergo neoadjuvant treatment for six months before receiving surgical treatment in the involved breast. This study will additionally assess safety, tolerability, response rates, surgical outcomes, and monitor disease progression. Comprehensive biomarker evaluations will be conducted using paired tumor biopsies and blood samples collected at baseline and week four, as well as 6 month surgical specimens. Enrollment in the PK run-in phase (n-22) was completed in Fall 2024 with the second portion of the trial slated to begin early in 2025. Citation Format: Matthew P. Goetz, Vera J. Suman, Claudia Lopez, Hayley Erickson, Lonnissa Nguyen, Sandra S. Hammer, Lida Mina, Pooja Advani, Roberto Leon-Ferre, Karthik Giridhar, Felipe Batalini, Daniel Flora, Jason M. Jones, Nusayba A. Bagegni, Katie N. Hunt, Mara Piltin, Amy Degnim, James N. Ingle, Judy C. Boughey, Sarah A. Buhrow, Joel M. Reid, Matthew Schellenberg, John R. Hawse, Steven C. Quay. A randomized phase 2 non-inferiority trial of (Z)-endoxifen + goserelin and exemestane + goserelin as neoadjuvant treatment for premenopausal women with ER+/HER2- breast cancer (EVANGELINE) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT237.

Abstract Background: Pancreatic ductal adenocarcinoma (PDA) is a disease with guarded prognosis with a 5-year overall survival (OS) of 3.1% in patients with metastatic disease. The need for innovative treatments for this lethal disease is paramount. TTFields is a novel treatment modality that employs low intensity, alternating, and intermediate frequency electrical fields that abrogates cancer cell proliferation through different mechanisms. These include inhibition of mitosis, disruption of cancer cell membranes, metabolomic dysregulation of cancer cells, and immunogenic activation of the tumor microenvironment (TME). TTFields are approved in glioblastoma multiforme, non-small cell lung cancer and malignant mesothelioma. The PANOVA trial demonstrated promising efficacy for TTFields plus chemotherapy in patients with PDA. A trial of GCN in patients with PDA demonstrated exceptional efficacy in patients with metastatic disease. Here in, we present our ongoing clinical trial investigating the safety and efficacy of TTFields plus GCN in patients with PDA (NCT04605913). Methods: This a phase I/II trial with an initial safety run-in phase followed by the phase II portion. The primary objective of the trial is to determine the safety (CTCAE v 5.0) of GCN plus TTFields. Secondary objectives include determining the 6-month progression free survival (PFS) rate, overall response rate (ORR, RECIST v1.1), 12-month survival rate, OS, and QOL (EORTC QLQ-C30, version 3.0.2.3). Inclusion criteria include PDA with liver metastasis (patients can have additional sites of metastasis), ECOG 0-1, measurable disease, and ability to operate the Novo TTF-100L (P)/Novo TTF-200T system. Treatment consisted of TTFields (150 kHz 18 hours/day) and GCN (G: 1000 mg/m2, C 30 mg/m2, and N: 150 mg/m2 every 2 weeks, 28 days cycle), followed by a maintenance phase after 6 months (G: 1000 mg/m2 every 2 weeks) plus TTFields until progression. Six patients were to be enrolled in the phase I portion and if ≤1/6 patients experienced a dose limiting toxicity (DLT, treatment emergent adverse event, or skin toxicity of Gr4), the plan would be to move to a phase II trial enrolling 34 more patients. If 2/6 patients experienced a DLT, 6 patients would be enrolled in dose level -1 (GCN plus TTFields for 9 hours/day followed by the maintenance treatment) and if tolerated the phase II portion would start with dose level -1 regimen. The phase I portion was completed without any DLTs and the trial is currently enrolling to the phase II portion. The total number of patients (40) was powered to the 6-months PFS rate and ORR (estimated using the lower bound of exact one-sided 90% confidence intervals). The goal is to "reject" a 6-month PFS rate of 66% and an ORR of 71% (based on previous GCN trial). Time-to-event endpoints will be assessed using the Kaplan-Meier method. Citation Format: Hani M. Babiker, Jason Starr, Jeremy Jones, Conor O’Donnell, Robert Jones, Jacqueline Boni, Lashundra Stewart, Josh Cameron, Oudom Kour, Kabir Mody, Robert R. McWilliams, Daniel H. Ahn, Tanios Bekaii-Saab, Mitesh J. Borad, Umair Majeed. A phase I/II pilot trial, single arm, open label, of gemcitabine, cisplatin, protein-bound paclitaxel (GCN) combined with Tumor Treatment Fields (TTFields) in patient with metastatic pancreatic adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT190.

Abstract BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a rare but aggressive cancer with limited curative options outside of surgical resection. Trans-arterial radioembolization (TARE) with yttrium-90 is a promising treatment with retrospective data showing an overall survival (OS) of up to 30 months. The single arm prospective MISHPEC trial combined TARE with gemcitabine and cisplatin showed an overall response rate (ORR) of 39% at 3 months along with a median OS of 22 months. PDL1 inhibitor (Durvalumab) has shown modest benefit in addition to chemotherapy in unresectable cholangiocarcinoma with three-year OS of 15% based on the TOPAZ-1 trial. ICC is a biologically cold tumor; preclinical data indicates that Yttrium-90 TARE can alter tumor microenvironment making it conducive to effector T cell recruitment and function leading to enhanced efficacy of immunotherapy. This provides the biological rationale of combining yittrium-90 TARE with systemic immunotherapy involving dual PDL1 and CTLA-4 inhibitors. Here in, we present our ongoing clinical trial investigating the safety and efficacy of yttrium-90 TARE combined with Durvalumab and Tremelimumab in patients with ICC (NCT06058663). METHODS: In this phase 1 study, yittrium-90 TARE will be combined with Durvalumab and Tremelimumab in 16 patients with unresectable or oligometastatic ICC. Eligible patients with histologically confirmed measurable disease must not have received any prior local therapies and any immunotherapy with ECOG PS of 0 or 1, adequate liver (Child Class A, ALBI 1 or 2) and renal function. Patients should also have a favorable mapping angiography based on an angiosomal analysis. Ablative radioembolization would be performed at least a dose of greater than 205 Gy MIRD to >75% of tumor. Study treatment with Tremelimumab (x 1 dose of 300mg total) + Durvalumab 1500mg monthly will continue until unacceptable toxicities, or disease progression for up to 24 months. Durvalumab and Tremelimumab will be infused in two alternate schedules after yittrium-90 TARE. In cohort 1 (3 patients) immunotherapy will be delivered within 24 hours of TARE. In cohort 2 (3 patients) immunotherapy will be delivered 2 weeks after TARE. Subsequent patients will be enrolled in either cohort 1 or 2 based on the safety signal from the first 6 patients. Primary goal of the study is to determine safety of this combination. Secondary goals include ORR per RECIST 1.1, progression-free survival, overall survival, infield and out of field response rate and downstaging to resection. Correlative studies include ctDNA at baseline along with evolution through treatment, pre and post treatment biopsies to look at tumor microenvironment and post treatment dose volume histograms. Three patients have been accrued in the study thus far. Citation Format: Umair Majeed, Jason Starr, Conor O'Donnell, Robert Jones, Jacqueline Boni, Josh Cameron, Oudom Kour, Mitesh Borad, Hani Babiker, Kabir Mody, Beau Toskich. Yttrium-90 radioembolization in combination with tremelimumab and durvalumab for treating patients with locally advanced, unresectable or oligo-metastatic intrahepatic cholangiocarcinoma who are not candidates for curative therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT189.

Abstract Background: Kinases from the SRC family of kinases (SFK) are predominantly inactive in non-cancerous cells and have been shown to be highly activated in tumor tissue. The role of SFKs in cell adhesion, invasion, proliferation, survival, and angiogenesis during tumor development has been extensively described. NXP900 is a novel, selective SFK inhibitor with low nanomolar potency against YES1 (0.47nM) and SRC (2.4nM). NXP900 has a unique binding mode of action (MOA), whereby it locks its target into its native “closed” conformation (type 1.5 inhibitor), resulting in inhibition of both the kinase and the scaffolding functions of the target kinase. This MOA differentiates NXP900 from other multi-kinase inhibitors, that, among other kinases, also inhibit the kinase activity of SFK targets. These multi-kinase inhibitors lock their targets in the active “open” conformation (type 1 inhibitors), and in the case of SFK targets, while this results in inhibition of the kinase activity, it also promotes the association of SFK with pro-cancer signaling partners. In addition, NXP900 is very selective, with minimal inhibitory activity against kinases outside the SFK. Methods: Study NXP900-101 (NCT05873686) is a first-in-human, Phase 1, dose escalation and expansion clinical trial of NXP900 in patients with advanced solid tumors. The primary objective of the study is to identify a dosing regimen with an acceptable safety profile and clinically relevant pharmacokinetics and pharmacodynamics (PK/PD) for additional clinical investigations. The key safety endpoints are estimation of the incidence and intensity of adverse events and identification of the highest tolerable dose. To characterize the PK/PD profile of NXP900, serial blood samples were collected after single and multiple doses of NXP900. Results: In 26 patients with advanced solid tumors treated with 20-200 mg/day NXP900, the median age was 61 years (range: 35-88), 65% were male and the median number of prior lines of anti-cancer therapy, including surgery, was 5. The most common treatment emergent adverse events (total incidence >20%) were largely reported as Grade 1-2 and included fatigue (42%, Grade 1-2: 91%), diarrhea (35%, Grade 1-2: 89%), nausea (31%, Grade 1-2: 100%), and dyspnea (23%, Grade 1-2: 67%). NXP900 exposure was dose proportional across the evaluated range (20-200 mg); following a single 200 mg oral dose, NXP900 demonstrated rapid absorption with median peak plasma concentration and terminal half-life of approximately 3 and 12 hours, respectively. Multiple dosing (20-200 mg daily) resulted in moderate drug accumulation. PD analysis showed that NXP900 potently inhibited the phosphorylation of SRC across a range of clinically relevant doses in peripheral blood mononuclear cells. Conclusions: In its first-in-human clinical trial in patients with advanced solid tumors NXP900 was biologically active with an acceptable safety profile, supporting its continued clinical development. Citation Format: Gerald Falchook, Jordi Rodon Ahnert, Shivaani Kummar, Hani M. Babikar, Stefan Symeonides, Mitesh J. Borad, Jason Henry, J. Mark Sloan, Justin L. Hay, Megan Sardone, Udai Banerji. First in human phase 1 trial of the SRC family kinase inhibitor NXP900 in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT153.