tbuckley/cabot-search huggingface dataset:
A phase 2 study of ipatasertib in combination with pembrolizumab for first-line treatment of recurrent or metastatic squamous cell cancer of the head and neck.
Authors: Jacob Stephen Thomas, Justine Yang Bruce, Zujun Li, Jochen H. Lorch, Tanyanika Phillips, Victoria Villaflor, Christopher Ruel, Joycelynne Palmer, J. Silvio Gutkind, Miguel Angel Villalona-Calero, Alexander Dimitrios Colevas
Journal: Journal of Clinical Oncology (2024)

TPS6117 Background: Single agent pembrolizumab in relapsed / metastatic head and neck squamous cell carcinoma (R/M HNSCC) has an estimated ORR of 19% and median OS of 13.6 months. There are several factors which may influence which patients respond to antibodies targeting the PD-1 axis. Regulatory T cells (Tregs) play a significant role in an immunosuppressive tumor microenvironment. Anti-PD-1 antibodies induce Treg activation in part through AKT pathway activation, which may contribute to low response rates to checkpoint inhibitor therapy. AKT blockade selectively inhibits the proliferation of human Tregs. Additionally, inhibition of the PI3K-AKT-mTOR pathway limits myeloid-derived suppressor cells (MDSC) infiltration and differentiation, and boosts CD8+ T cell memory and effector function. Ipatasertib is an oral highly selective small-molecule inhibitor of all three isoforms of AKT. This phase 2 trial is designed to compare progression-free survival (PFS) in first line R/M, HNSCC patients treated with the combination ipatasertib and pembrolizumab versus pembrolizumab monotherapy treatment. Methods: In this open-label randomized phase 2 multicenter trial, patients with R/M HNSCC are treated with pembrolizumab 200mg on day 1 +/- ipatasertib 400mg QD days 1-14 of 21-day cycles. Patients must have PD-L1 CPS score ³ 1, have measurable disease per RECIST 1.1, and consent to on-treatment biopsy. Patients will be excluded if they have received prior systemic therapy for R/M HNSCC, cannot swallow a pill, or require insulin for diabetes. The primary objective is to compare the PFS between the two arms. We will estimate the relative hazard ratio associated with ipatasertib plus pembrolizumab compared to pembrolizumab alone using the Cox Model where randomized treatment assignment is the only variable in the model. Secondary objectives include ORR, safety and tolerability of the combination, and changes in tumor immune cell infiltration, AKT signaling, and changes in peripheral blood immune cells. Ultimately, a total of 48 patients will be enrolled, with 24 patients in each cohort. To date, a total of 22 patients have been enrolled from 15 sites. Accrual is ongoing (NCT05172258). Clinical trial information: NCT05172258 .
Charlson’s comorbidity and remission outcomes in women diagnosed with epithelial ovarian cancer.
Authors: Kimberly L. Cannavale, Amrita Mukherjee, Lanfang Xu, Alec Gilfillan, Elizabeth A. Szamreta, Matthew Monberg, Melissa Hodeib, Chun Chao
Journal: Journal of Clinical Oncology (2024)

e17562 Background: Several prior studies have examined the role of comorbidity on overall survival in ovarian cancer (OC) patients and reported an association between comorbidity and inferior overall survival. However, it is unclear if the inferior survival was solely due to the excess mortality from the comorbidities, or that the comorbidities can impact OC treatment outcomes. Our objective was to determine whether pre-existing Charlson comorbidity index (CCI) was associated with lower likelihood of achieving complete remission. Methods: This retrospective cohort study included patients diagnosed with OC of epithelial subtype between 01/01/2017-06/30/2021 at a large integrated healthcare delivery system in the United States. OC patients were identified from the healthcare system’s cancer registry or via chart review of those with the ICD-10 diagnosis code. Patient’s CCI was determined based on data from the 12-month window prior to OC diagnosis. Patients’ remission outcomes, including complete remission and clinical remission (complete + partial remission) were ascertained via chart review, considering physician’s assessment, CA125 value and imaging evidence. Data on potential confounders (pandemic period, age, race/ethnicity, FIGO stage, prior length of membership, and time to treatment) were obtained from the healthcare system’s electronic medical records. Bivariate and multivariable modified Poisson regressions adjusting for potential confounders were used to evaluate the associations between CCI and achieving complete remission or clinical remission by end of therapy. Results: A total of 799 patients diagnosed with OC were included in our study. Overall, the cohort was racially/ethnically diverse with 46.2% White, 33.8% Hispanic, 12.4% Asian, and 7.6% Black patients. In the crude analysis, those with CCI score=1 and CCI≥2 had lower likelihood of achieving complete remission, compared with those with CCI=0 (no Charlson comorbidity) [RR= 0.84 (0.76-0.93) and RR=0.72 (0.64-0.81), respectively]. In the multivariable analysis, those with CCI=1 and CCI≥2 continued to have lower likelihood of achieving complete remission, compared with those with CCI= 0 [RR= 0.84 (0.77-0.92) and RR=0.81 (0.72-0.91), respectively]. Similar findings were observed for clinical remission, although the associations were attenuated: RR= 0.95 (0.89-1.01) for CCI=1 and RR=0.92 (0.86-1.00) for CCI≥2 vs. CCI=0. Conclusions: Having Charlson comorbidity was associated with lower likelihood of achieving complete remission in OC patients. This finding suggest that pre-existing comorbidities may contribute to inferior survival via, at least in part, adversely affecting the likelihood of achieving complete remission. The potential mechanisms underlying this association should be further studied to inform patient management.
Docetaxel plus cis-platinum chemotherapy for the posterior line treatment of metastatic castrate-resistant prostate cancer with elevated neuron specific enolase.
Authors: Tingshuai Zhai, Jinliang Ma, Huanrong Jiang, Jun Tian
Journal: Journal of Clinical Oncology (2024)

e17042 Background: This Study is to figure out the efficacy of docetaxel plus cis-platinum (DC) chemotherapy as the posterior line treatment for metastatic castrate-resistant prostate cancer (mCRPC) with elevated neuron specific enolase (NSE). Methods: We performed a retrospective study of men suffered mCRPC with elevated NSE from December 2019 to August 2022. All men were treated with DC after resistance to previous therapy. Biochemical progression-free survival (BPFS) were depicted using Kaplan-Meier curves. Results: 10 mCRPC patients aged 65.8 ± 7.0 (Median: 66.5, Range: 52-77) received DC for 1 to 10 cycles (Median: 7). Of the 10 patients, 2, 1 and 7 patients underwent DC as the 2nd, 3rd and 4th line therapy, respectively. 3 patients received previous chemotherapy and 9 patients underwent new endocrine therapy. All patients suffered bone metastases, 6 patients suffered distal lymph node metastases and 3 patients suffered visceral metastases. 6.1 ± 2.8 cycles (Median: 7, Range: 1-10) of DC were finished. Median follow-up time was 6.5 (Range: 2-11) months. After DC, Prostate specific antigen (PSA) response rate (&gt;50%) was 90% and NSE response rate (&gt;50%) was 60%. Median BPFS was 10 (Range: 4-18) months. Pain score declined from 6.6 ± 3.1 to 3.9 ± 2.4 evidently (P &lt; 0.05) and Karnofsky (KPS) score increased from 80 ± 14.9 to 91 ± 16.0 significantly (P &lt; 0.05). Of the 6 patients assessed by radiological examinations, 5 patients experienced partial response and 1patient achieved stable disease. Conclusions: Our pilot study showed docetaxel plus cis-platinum chemotherapy was effective for the mCRPC patients with elevated NSE resistant to multi-line therapies, indicating the potential value of DC for mCRPC with neuroendocrine differentiation.
Development and validation of an efficacy assessment platform utilizing patient-derived xenograft (PDX) models in ovarian cancer research.
Authors: Min Kyu Kim, Hayeon Shin, Jae Hoon Kim, Anna Jun, Jue Young Kim, Ji-Won Ryu, Dawn Chung
Journal: Journal of Clinical Oncology (2024)

e17564 Background: Ovarian cancer predominantly undergoes treatment through surgical and chemotherapeutic interventions. However, with an increasing rate of recurrence, there's a need for systemic chemotherapy. A paradigm shift towards personalized treatment is crucial with concerns escalating about chemotherapy resistance post PARP inhibitor treatment. This paper emphasizes the significance of preclinical drug evaluation platforms using Patient-Derived Xenograft (PDX) models, which resonate with the genuine characteristics of ovarian cancer tissues. Methods: The 112 epithelial ovarian patients' tumors sectioned to approximately 3 mm 2 were subcutaneously transplanted into at least two female 5-week-old BALB/c nude mice. The xenograft tumors engrafted into mice from patient-derived tumors were defined as P1. After that, xenograft tumors serially engrafted into the following mice were termed P2 to P3. We collected and banked small pieces of tumor tissue from each passage of PDX tissue for performing Whole Exome Sequencing (WES) sequencing and RNA Sequencing. Results: We established 54 epithelial ovarian cancer PDX models that are stably growing. They show a ratio of 70.37% Serous, 11.11% clear cell, and 3.7% endometriod. The stage is 14.81% I/II, 61.11% III/IV, and 24.07% Recurrent. BRCA status consists of 59.26% wild type, 9.26% BRCA 1 mutation, 5.56% BRCA 2 mutation, and 11.11% BRAC VUS. We have obtained a variety of ovarian cancer PDX models and confirmed retained the histological characteristics of patients by H&amp;E staining. We validated the similarity of genomic information in patients and PDX models via WES and RNA sequencing. Conclusions: We have a stable and growing PDX model that accurately reflects the actual tissue characteristics of ovarian cancer. In the future, we plan to characterize drug response further and build new models resistant to existing anti-cancer drugs. Based on these, we will validate the efficacy of new drugs and suggest strategies to overcome cancer resistance.
eVOLVE-HNSCC: A global phase 3 study of volrustomig as sequential therapy for unresected locally advanced head and neck squamous cell carcinoma (LA-HNSCC) following definitive concurrent chemoradiotherapy (cCRT).
Authors: Robert I. Haddad, Dario Ruscica, Alexandra Visa, Xia Li, Lisa F. Licitra
Journal: Journal of Clinical Oncology (2024)

TPS6120 Background: Currently there are no approved maintenance therapies for patients (pts) with unresected LA-HNSCC following definitive cCRT. The PD-1 inhibitors pembrolizumab and nivolumab are licensed for treatment of pts with recurrent or metastatic HNSCC who have progressed on or after a platinum-based therapy. Dual inhibition of CTLA-4 and PD-L1 is approved in solid tumors including renal cell carcinoma (RCC), NSCLC, and melanoma, and has shown a numerical trend towards improved survival in first-line pts with recurrent/metastatic HNSCC whose tumors express PD-L1. Volrustomig (MEDI5752) is a monovalent, PD-1/CTLA-4 bispecific, humanized IgG1 monoclonal antibody engineered to specifically inhibit PD-1, with increased CTLA-4 blockade on PD-1+ activated T cells compared to PD-1– resting peripheral T cells. In a first-in-human phase 1/2 study (NCT03530397), volrustomig monotherapy showed promising efficacy with acceptable tolerability in advanced clear cell RCC and in combination with chemotherapy in advanced NSCLC. The phase 3, randomized, open-label, multicenter, eVOLVE-HNSCC study will evaluate the efficacy and safety of sequential therapy with volrustomig compared with observation in pts with unresected LA-HNSCC who have not progressed after receiving definitive cCRT (NCT06129864). Methods: Key eligibility criteria include histologically or cytologically confirmed, unresected LA-HNSCC with no evidence of metastatic disease, i.e. AJCC 8 th edition (TNM staging system) stage IVA/B cancers of the hypopharynx, oral cavity, larynx or HPV-negative oropharynx, or stage III HPV-positive oropharynx cancer; age ≥18 years; WHO/ECOG performance score of 0 or 1; and adequate organ and bone marrow function. Key exclusion criteria include requiring further treatment with curative intent after definitive cCRT, resected LA-HNSCC, recurrent/metastatic disease, and &gt;1 primary tumor. Following initial screening and definitive cCRT (cisplatin or carboplatin + paclitaxel or carboplatin + 5-FU, plus concomitant radiotherapy), approximately 1145 pts whose disease has not progressed within 12 weeks of the last dose of cCRT will be randomized 1:1 to Arm A or B. Arm A will receive volrustomig intravenously every 3 weeks for a maximum of 12 months or 18 cycles, or until RECIST v1.1-defined radiological progressive disease (PD) or unacceptable toxicity. Arm B will undergo observation for a maximum of 12 months or until PD. The primary endpoint is PFS in pts with PD-L1-expressing tumors. Secondary endpoints include PFS in all randomized pts, OS in pts with PD-L1-expressing tumors and in all randomized pts, PFS2, safety, patient-reported outcomes, pharmacokinetics, and immunogenicity. Exploratory biomarker analyses will also be conducted. Enrollment began in December 2023. Clinical trial information: NCT06129864 .
Repurposing atovaquone as a STAT3 inhibitor for the treatment of platinum resistant ovarian cancer.
Authors: Sarah Jeanne Wood, David Frank, Elizabeth Brannan Haas, Weiyuan Wang, Jane Lowe Meisel, Namita Khanna
Journal: Journal of Clinical Oncology (2024)

TPS5631 Background: Despite advances, ovarian cancer (OC) is the most lethal gynecologic cancer with 5-year survival rates for stage III and IV disease 41% and 21%, respectively. After initial treatment with cytoreductive surgery and chemotherapy, 70% of patients (pts) will relapse. Treatment of relapsed OC is dependent on the amount of time between completion of platinum-based therapy and relapse, known as the platinum-free interval (PFI). Pts with PFI of less than six months are deemed platinum-resistant with low response to further chemotherapy and median progression-free survival (PFS) of 3.6 months. Additional treatment options are needed. Oncogenic signal transduction pathways are a critical component of cancer pathogenesis. In a variety of cancer types, including OC, the transcription factor STAT3 (Signal Transducer and Activator of Transcription 3) has emerged as a key promoter of cellular proliferation and resistance to therapeutic drugs. In OC cells, STAT3 is constitutively activated in over 70% of cells, resulting in enhanced cell survival, angiogenesis, and metastasis. STAT3 also controls innate and adaptive immune response by driving myeloid-derived suppressor cells and regulatory T cells, while hampering CD8+ T cell cytotoxicity. Using the Connectivity Map database to identify drugs that induce gene expression changes contrary to the STAT3 signature, the FDA-approved antimicrobial atovaquone (ATO) was identified as the most active. ATO, a well-tolerated, readily available drug inhibits STAT3 tyrosine phosphorylation by downregulating the cell surface expression of glycoprotein 130, which is necessary for signaling of IL-6 and Janus Kinase, and subsequent phosphorylation of STAT3. Given that the STAT3 pathway is constitutively activated in OC, we hypothesize that ATO, a potent inhibitor of STAT3, could be a repurposed therapeutic agent in OC. Methods: A Phase II, single-arm, investigator-initiated clinical trial is in process at our institution where we are evaluating ATO as targeted therapy in pts with platinum resistant OC whose tumors have progressed despite standard therapies. To date, we have currently enrolled 2 of an anticipated 28 pts. The primary endpoint is PFS, with clinical secondary endpoints to include clinical benefit rate and overall survival. In addition, to confirm the STAT inhibitory effect on OC cells, pre and on-treatment tissue sampling is being obtained to assess changes in STAT3 dependent gene expression via RT-PCR and quantitate changes to the immune profile via flow cytometry. We hypothesize targeting inappropriate activation of STAT3 could be a novel and promising treatment approach in OC. This is the first clinical trial evaluating the clinical efficacy of ATO in OC and could have wide implications on treatment options in the future. Clinical trial information: NCT05998135 .
Predicting PAM50 subtypes from whole slide images of prostate cancer biopsies.
Authors: Ramin Nateghi Sarjezeh, Marina Ayad, Madeline Saft, Eric Victor Li, Sai Kumar, Clayton Neill, Hiten D. Patel, Edward M. Schaeffer, Yang Liu, Elai Davicioni, Ximing J Yang, Lee A.D. Cooper, Ashley Ross
Journal: Journal of Clinical Oncology (2024)

e17001 Background: Computational analysis of digitized pathological images has been shown to have diagnostic and prognostic applications. Recent research suggests that molecular features, previously defined at the genomic level, might be additionally recognized. In prostate cancer, transcriptomic PAM50 molecular subtypes may correlate with patient response to systemic therapy. Here we investigate whether computational analysis of digital prostate biopsy slides can predict PAM50 category. Methods: Our study utilized digitized images of 704 prostate biopsy slides from 336 patients with prostate cancer at Northwestern Memorial Hospital with Decipher testing (Veracyte, Inc San Diego, CA). All slides analyzed contain carcinoma with the majority being primary Gleason pattern 3 (545 out of 704). Hematoxylin and eosin stained slides were scanned on a Leica GT450 scanner at 40x magnification. PAM50 subtypes were derived from the Decipher Genomic Resource Information Database (GRID). Data were split at the subject level using 80% for training, 10% for validation, and 10% for evaluation, facilitating model development and assessment. We devised a model comprising two decoupled parts: a multi-instance learning model that utilizes a multi-class attention mechanism to explore relevant class-specific information from slides, and a pre-trained network to extract high-dimensional semantic features from the tiles of WSIs. The model trained based on the WSIs of the training set to predict PAM50 subtypes (luminal A, luminal B, and basal). This attention-based training approach allowed the model to capture relevant patterns and information present in the WSIs. Following the training phase, the model was subsequently evaluated on the testing set. Results: Model AUC on the evaluation set was 0.78. Among evaluation set misclassifications, no luminal samples were misclassified as basal subtype. Conclusions: Our investigation provides preliminary results on the ability to predict RNA expression-based subtypes from prostate cancer biopsy histology. This approach may help to preserve tissue, minimize costs, and decrease turnaround time associated with molecular testing in prostate cancer while offering patients with prostate cancer opportunities for precision medicine.
Rationale and study design of the KOV-HIPEC-04: A phase III randomized controlled trial in primary stage III and IV ovarian cancer after interval cytoreductive surgery (FOCUS).
Authors: Myong Cheol Lim, Ji Hyun Kim, Boram Park, Jung-Yun Lee, Suk-Joon Chang, Yoo-Young Lee, Chel Hun Choi, Jeong-Yeol Park, Dae-Yeon Kim, Dae Gy Hong, Hyun-Woong Cho, Jae-Yun Song, Yun Hwan Kim, Ki Hyung Kim, Sang-Yoon Park, Benoit You, Seob Jeon
Journal: Journal of Clinical Oncology (2024)

TPS5636 Background: The addition of hyperthermic intraperitoneal chemotherapy (HIPEC) during interval cytoreductive surgery increases progression-free and overall survival for patients with stage III ovarian cancer in two randomized controlled trials (OV-HIPEC-01 and KOV-HIPEC-01) in the era of platinum. The aim of this trial is to identify the survival benefit of HIPEC in stage III &amp; IV ovarian cancer with maintenance therapy of bevacizumab and/or PARP inhibitor. Methods: The KOV-HIPEC-04 trial is the international, multicenter, 1:1 randomized, phase III trial that will enroll 520 patients with stage III &amp; IV ovarian cancer who received neoadjuvant chemotherapy. Patients with residual tumor &lt; 2.5mm after interval cytoreductive surgery will be randomized to the trial arm (HIPEC, 41.0-42.0°C cisplatin 75mg/m 2 , 90 minutes) or control arm. After recovery from surgery, patients will receive postoperative platinum-based adjuvant chemotherapy followed by maintenance therapy with PARP inhibitor or bevacizumab by the institutional guideline based on BRCA/HRD status. The primary endpoint is to evaluate overall survival (OS); secondary objectives are progression-free survival (PFS), cancer-specific survival, time to the first subsequent therapy, safety, and quality of life. Assuming that the enrollment period is 5 years and the follow-up period is 3 years, the total number of events required is 263. Based on the log-rank test, the total number of subjects required to prove HR 0.67 with a two-sided alpha of 0.05 and 90% power is 494. Considering 5% drop-out, 520 patients are finally enrolled. ClinicalTrials.gov (NCT05827523). Clinical trial information: NCT05827523 .
Biomarker-driven radiation therapy dose reduction after transoral robotic surgery for the treatment of HPV-positive oropharyngeal cancer.
Authors: James Edward Bates, William A. Stokes, Mark William McDonald, Soumon Rudra, Madison Miller Stallings, Natalie A Lockney, Kyle Mannion, Nabil F. Saba, Nicole C. Schmitt, Jennifer H Gross, Conor Ernst Steuer, Azeem Kaka, Michael Topf, Mihir R. Patel
Journal: Journal of Clinical Oncology (2024)

TPS6119 Background: HPV-related oropharyngeal squamous cell carcinoma (OPSCC) is a highly curable cancer with a considerable burden of treatment-related toxicities. Transoral surgery (TOS) is a treatment option for patients with early-stage disease; however, adjuvant radiotherapy (RT) is often recommended and can add to these late toxicities. Circulating tumor HPV DNA (ctHPVDNA) is a sensitive marker of tumor recurrence, and undetectable post-operative ctHPVDNA is associated with improved recurrence-free survival. We hypothesize that patients with undetectable post-TOS ctHPVDNA without high risk pathologic factors can safely undergo de-escalation of adjuvant RT to 36 Gy, and this reduction will improve long-term swallowing function. Methods: We opened a multi-institutional phase II study (NCT05387915) including patients with pT1-2, N0-1, M0 HPV-related OPSCC who had TOS resection of their primary site and at least ipsilateral neck dissection. Pertinent inclusion criteria include a &lt;10 pack-year smoking history, or a &lt;30 pack-year smoking history if &gt;10 years since last tobacco consumption, and pathologic findings of one or more intermediate risk factors: close margin (1 – 4 mm), perineural invasion, 2 – 4 positive lymph nodes or a single lymph node &gt;3 cm. Patients with high risk factors (positive margin, extranodal extension, 5 or more positive lymph nodes) are excluded. Patients must have a detectable pre-operative ctHPVDNA and a post-operative ctHPVDNA drawn 7-14 days after TOS; if negative, patients receive 36 Gy of adjuvant RT in 15 fractions of 2.4 Gy delivered daily; if positive, they receive care per the discretion of the treating radiation oncologist. If the final surgical margins at the site of the primary tumor are &gt;2mm, patients are eligible for omission of the primary tumor post-operative bed from the radiation volume. Our primary endpoint is 1-year swallowing function as measured by the composite MD Anderson Dysphagia Index (MDADI) score. Secondary endpoints include overall/progression-free survival and other quality of life metrics. The study is powered to detect an 8.5-point improvement in MDADI composite score at one year over the historical control from ECOG 3311 Arm B. With an alpha of 0.05 and a power of 0.90 we require 27 evaluable patients. Accounting for dropout and patients lost to follow-up, we aim to enroll 35 total patients. Since accrual began in June 2022, we have enrolled 18 patients as of January 2024. We recently opened the study at a second institution and are in the process of opening at a third institution. Clinical trial information: NCT05387915 .