bluuebunny/crossref_metadata_2025 huggingface dataset:
Objective assessment of fatigue, sleep and insomnia in breast cancer survivors on estrogen deprivation therapy.
Authors: Fowler Lauren A. , Myers Jamie S. , Re Shelby , Tedrick Maddie , Hudson Matthew F. , Stephenson Joe , O'Rourke Mark Allen
Published: June 2023

TPS12145

Background: Fatigue, insomnia and sleep problems are common among breast cancer survivors (BCS). These symptoms remain underassessed, underreported and undertreated. Validated and objective measures of sleep metrics have yet to be widely incorporated into BCS studies to help examine the role that these play on patient patient reported fatigue and insomnia. While more than 50% of BCS experience fatigue and insomnia, most research on BCS fatigue is limited to short-term, self-report data that does not objectively assess sleep metrics. Estrogen Deprivation Therapy (EDT) has been shown to exacerbate sleep problems and contribute to perceptions of fatigue and insomnia, yet there is a paucity of research examining the specific effects of EDT on sleep metrics over time, especially objective measures. Wrist actigraphy is a non-invasive, objective measure of rest/activity cycles and sleep via a wrist-worn device. This study utilizes a novel instrument, called Readiwatch (Fatigue Sciences). It is widely validated in the military and in industry but has not been used in patient studies. The Readiwatch assesses fatigue and estimates cognitive performance, based on the Sleep Activity and Task Effectiveness (SAFTE) model developed in conjunction with the Department of Defense in 2004. The Readiwatch syncs with the Fatigue Avoidance Scheduling Tool (FAST) app on the participant’s smartphone to provide a score, called Readiscore, based on previous sleep and activity. It has been shown to have greater than 92% accuracy with lab polysomnography results. The Readiscore also serves as a “cognition” measure that represents the person’s cognitive capacity based on sleep metrics. This novel, objective feedback to the BCS could be very accessible and useful in community medical practice. Methods: This single-center, pilot study of BCS, receiving endocrine therapy, possessing a smartphone and Scoring >8 on the Insomnia Severity Index (ISI), has enrolled 25 of 50 planned participants. Participants wear the Readiwatch for two months to objectively assess their sleep metrics. Patient reported levels of fatigue and insomnia will be assessed prior to, midway, and following the two-month period. Participants document their self-reported experiences through surveys and track their own sleep and fatigue metrics using their smartphone app. At the conclusion of the study participants are provided with personalized feedback about their sleep metrics, along with detailed information related to sleep hygiene. Data analysis will model the effect of actigraphy fatigue measures on reported pain, anxiety, depression, and cognitive impairment and will also examine sleep metrics, perceptions of fatigue and insomnia scores in relation to type of EDT the patient is currently undergoing to determine if there are specific types of adjuvant therapy that are associated with fewer fatigue and insomnia problems.
Prospective observational study to evaluate lemborexant utility in insomnia among women with breast cancer (WJOG14921B, LUNAR study).
Authors: Ozaki Yukinori , Hosonaga Mari , Futamura Manabu , Kurozumi Sasagu , Onoe Takuma , Iwasa Tsutomu , Kamio Hidenori , Terata Kaori , Watanuki Rurina , Masuda Hiroko , Saeki Yoshinori , Kitano Shigehisa , Sakamaki Kentaro , Nonogaki Kiyomi , Yoshimura Yuta , Kawai Daisuke , Takano Toshimi
Published: June 2023

TPS12148

Background: Insomnia occurs in approximately 60% of cancer patients. The importance of early intervention to treat insomnia has been advocated because insomnia may be associated with poor prognosis, early discontinuation of treatment and decreased quality of life. It has been reported that breast cancer patients receiving endocrine therapy have the highest rate of insomnia among all cancer patients due to vasomotor symptoms (ie, hot flashes) and comorbid symptoms associated with fatigue and depression. Insomnia has also been found to occur in patients with metastatic/recurrent breast cancer. Lemborexant (LEM) is a dual orexin receptor antagonist, which has been shown to be effective for insomnia patients without malignancies. In clinical practice, while LEM has been administered to cancer patients with insomnia, there are no prospective data. The aim of this study is to evaluate prospectively whether LEM improves insomnia in patients with breast cancer receiving endocrine therapy. Methods: This is an open-label, prospective, multicenter, observational study to evaluate efficacy and safety of LEM to treat insomnia in patients with breast cancer receiving endocrine therapy [UMIN000047718]. The primary endpoint is change from baseline of total Insomnia Severity Index (ISI) score at 1 month. Secondary endpoints include change from baseline of cancer fatigue scale scores, EORTC QLQ C-30 and BR23 score, and Patient Health Questionnaire-9 score after 1 month and 3 months, change from baseline in total sleep time and sleep efficiency using an electronic sleep diary after 2 weeks, 1 month and 3 months, and safety profile. Exploratory endpoints include biomarker analysis including evaluation of cytokines and orexin A levels, and evaluation of sleep parameters using Oura ring, which is a ring-type wearable device. The primary endpoint will be assessed by the Wilcoxon signed-rank test. Total sample size will be 70 patients (adjuvant cohort: 50 patients, recurrent and/or metastatic cohort: 20 patients). Patients ≥20, meeting Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition for Insomnia Disorder and ISI score ≥10 will be eligible. LEM 5mg will be administrated orally every night. Dosage of LEM will follow clinical practice and the Japanese LEM label. Enrollment began in September 2022; 14 patients have been recruited in adjuvant cohort as of January 2023. Clinical trial information: UMIN000047718 .
Korean Precision Medicine Networking Group study of molecular profiling guided therapy based on genomic alterations in advanced solid tumors (KOSMOS) II (KCSG AL 22-09).
Authors: Kim Sun Young , Kim Jee Hyun , Kim Tae-Yong , Park Sook Ryun , Yoon Shinkyo , Lee Soohyeon , Lee Se-Hoon , Kim Tae Min , Han Sae-Won , Yun Hongseok , Lee Sejoon , Kim Jihun , Choi Yoon-La , Choi Kui Son , Chae Heejung , Ryu Hyewon , Lee Gyeong-Won , Zang Dae Young , Ahn Joong
Published: June 2023

TPS1608

Background: Next-generation sequencing (NGS) has been introduced to many Korean institutions as molecular diagnostics for cancers since 2017, when it was reimbursed by the National Health Insurance Service. However, molecularly-guided treatment (MGT) options based on NGS results have been limited due to the strict regulation for prescribing outside of the approved indication, lack of clinical trial availability, and limited access to molecular tumor boards (MTB) in most institutions. Given our previous KOSMOS study results, which showed MGT was available for 54% (124/198) of patients based on local NGS (ESMO Open 2022;7(6, Suppl 1);100653), KOSMOS-II study was designed to demonstrate MGT would be feasible and effective via a nation-wide precision medicine platform. Methods: This national, prospective, pragmatic, multi-cohort study comprised of a framework to screen pts with metastatic solid tumors for actionable genetic alterations (GA) based on local NGS testing and to recommend MGT by a remote and centralized MTB held weekly or biweekly. MGT can be one of the following options: Tier 1, the therapeutic use of investigational drugs targeting GAs including ALK, EGFR, ERBB2, BRAF, FH, ROS1, RET, or high tumor mutational burden; Tier 2, drugs that are allowed for treatment outside of the approved indications by the National Health Insurance; Tier3, clinical trials matched for GA recommended by MTB. To estimate the proportion of patients receiving MGT to be 50±3.25% with 95% confidence interval, we will enroll 1,000 pts, considering 5% drop-out rate. The clinical benefit rate of MGT beyond 16±2 weeks is the second co-primary endpoint, which is expected to be 30% with type I error of 5% and 90% power. Pts must have progressed ≥ 1 or more lines of therapies; have undergone NGS testing; are able to provide the Variant Call Format (vcf) file of the NGS results. MTB determines clinical actionability of GA and recommends MGT if possible, according to Tier 1,2, or 3. The vcf files and matched clinical information will be deposited to the repository of National Center Center Korea and will be curated in a de-identified clinico-genomic database. As of Feb 2023, 139 of planned 1,000 have been enrolled. Clinical trial information: NCT05525858 .
Screening for high frequency malignant disease (SHIELD).
Authors: NGUYEN HA , Cotton Lindsey , Vento-Gaudens Erika , Raymond Victoria M. , Eagle Craig
Published: June 2023

TPS1610

Background: Insufficient adherence to guideline recommended cancer screening undermines the effectiveness of current modalities to improve cancer related outcomes, resulting in an unmet clinical need. Implementation of a convenient blood-based cancer screening option, utilizing a test with high sensitivity and specificity, has the potential to address this unmet need. We aim to evaluate the performance of a blood-based multi-cancer screening test in a population of screen eligible individuals across multiple cancer types, encompassing a diverse representation of racial and ethnic groups. Methods: SHIELD (Screening for High Frequency Malignant Disease; NCT#05117840) is a prospective, observational, multi-center basket study in the United States and Europe designed to recruit individuals undergoing screening across multiple cancer types. The study’s primary objective is to evaluate the performance of a blood-based multi-cancer screening test (GuardantLUNAR-2, Guardant Health, US) to detect cancer in screen-relevant individuals compared to the reference standard cancer screening modality. Each study cohort represents a unique cancer type(s). Eligible individuals consent to whole blood collection within 90 days of the standard of care screening for the respective cancer type. Clinical diagnoses, e.g., cancer, are made per standard of care. Primary outcomes: sensitivity, specificity, negative and positive predictive value of the blood-based multi-cancer screening test. Secondary outcomes: number of screen-detected cancers, early and late-stage screen-detected cancers per 1000 screened individuals. One- and two- year clinical outcomes are collected by implementing HIPAA compliant, patient-level linkage of trial data with real-world data sources (Medidata, USA) to which patients consent subsequent to main study consent. Cohort A: Lung cancer screening. Eligibility is aligned with USPSTF screening recommendations; age 50-80 years with > 20 pack-year smoking history who are current smokers or quit within the past 15 years, without any history of cancer or preinvasive lung lesions, and without recent surgery or trauma. This cohort will enroll 9,000 subjects over 24 months at up to 120 global sites. This cohort was initiated in January 2022. As of January 2023, 94 study sites have been activated with 4,977 individuals consented and 4,866 individuals enrolled (defined as study blood sample collected). To date, 4679/4977 (94%) individuals consented to the linkage process. Cohort A is on track to meet enrollment targets by the end of 2023 and on track for final primary outcome data collection by December 2024. Clinical trial information: NCT05117840 .
The PLATON Network: An interactive platform for precision oncology.
Authors: Al-Batran Salah-Eddin , Goetze Thorsten Oliver , Saborowski Anna Lena , Agaoglu Nihat Bugra , Broeckling Sebastian , Dreyling Clara , Lorenzen Sylvie , Modest Dominik Paul , Schuler Markus K , Westphalen Benedikt , Wild Peter , Zäpf Bianca , Vogel Arndt
Published: June 2023

TPS1613

Background: To increase the access of patients to precision oncology and personalized medicine, we need not only to undertake molecular profiling but rather we need to interlink patients, physicians and researchers using modern technological opportunities, increasing the likelihood of providing new therapies to patients with suitable targets. The PLATON Network (NCT05489250, IKF-T008) addresses these important issues. Methods: The PLATON Network (PLATON) is an interactive structure aiming at improving personalized medicine for all tumor entities (starting with upper GI tumors). The goal of the PLATON Network is to provide a platform for connecting medical practitioners, researchers and patients to personalized cancer treatments. The platform combines comprehensive molecular profiling, data on active clinical trials, remote data access with networking solutions, implemented substudies and associated educational and discussion forums. The main elements of PLATON are: a Platform-study design, an interactive Cloud-based WebApp, Networking, a Molecular Pathology Case Discussion Board, an educational forum, and a BioDataBank. The network will be composed of a global network of cancer centers and cancer specialists who can submit genomic data of their patients to PLATON. The WebApp allows members and associated scientists to view each other's current patients' clinical and molecular data and get into contact with the treating physicians or identify patients for ongoing biomarker-driven clinical trials using advanced algorithms. The PLATON Network also offers molecular testing via Foundation CDx and CDx Liquid for standardized NGS testing and functions as an umbrella for substudies within the platform design. PLATON enrolls patients during first line treatment and collects information on routine clinical data (baseline data, medical history, histopathology reports, treatment decisions, etc.). During follow up, all anti tumor therapy lines, tumor response and survival data are recorded. Importantly, quality of life data is captured monthly under therapy (with EORTC QLQ-30,-BIL21, -HCC18, -PAN26, -STO22 and EQ-5D-5L) and at further follow up (with EQ-5D-5L). So far, 110 cancer centers have joined the PLATON network. Over 200 patients with upper GI tumors received comprehensive molecular profiling and 162 cases were reviewed and discussed in the Molecular Pathology Case Discussion Board. Five sub-projects/-studies have been initiated under the umbrella of PLATON. The educational forum is in the planning stage. PLATON is conducted by the Institute of Clinical Cancer Research (IKF) in Frankfurt with the supervision of an independent scientific steering committee.
A first-in-human pharmacodynamic evaluation of dual polyamine depletion for patients with high-grade gliomas.
Authors: Riviere-Cazaux Cecile , Neth Bryan , Kizilbash Sani Haider , Burns Terry C
Published: June 2023

TPS2082

Background: No drug has improved survival for patients with high-grade gliomas (HGGs) since temozolomide in 2005. Relatively little is known about the live response of in situ gliomas to therapeutic intervention. Phase 0 studies that leverage access to the live human glioma in situ, including via microdialysis to sample the live glioma microenvironment, provide an attractive and feasible solution to this problem. We performed intraoperative microdialysis to evaluate the extracellular metabolome of divergent regions in 15 HGG resections. Our data revealed a conserved metabolic signature of HGGs and a novel glioma-associated metabolite, guanidinoacetate (GAA). Pathways enriched in this tumor signature included methionine and polyamine metabolism. Although GAA is typically converted to creatine, we hypothesize that the high flux of ornithine through ornithine decarboxylase (ODC) results in excess GAA accumulation. As such, in a Phase 0 trial, we will evaluate in situ glioma responses to polyamine depletion via ODC inhibition (Difluoromethylornithine, DFMO), with or without blockade of polyamine uptake (AMXT 1501), to identify candidate extracellular biomarkers of target engagement and cytotoxicity. Methods: Patients will be recruited who are undergoing a clinically indicated subtotal resection for a known or suspected high-grade glioma (NCT05717153). At the end of the surgery, two microdialysis catheters will be implanted for post-operative microdialysis, one in residual tumor and one in brain adjacent to tumor for an internal control. Beginning on post-operative day (POD) 1, patients will be randomized to one of the following three groups, including administration of vehicle, DFMO (500 mg, PO, BID) and AMXT 1501 (600 mg, PO, BID): 1) DFMO + AMXT 1501 (POD1-5); 2) Vehicle (POD1–POD2), followed by DFMO + AMXT 1501 (POD3-POD5); 3) DFMO alone (POD1–POD2), followed by DFMO + AMXT 1501 (POD3- POD5). Throughout this time, extracellular metabolite levels of polyamines, guanidinoacetate, and glutamate will be quantified from microdialysate collected every two hours from intraoperatively implanted 100 kDA microdialysis catheters. The primary outcome of this study is to determine how polyamine depletion impacts extracellular intratumoral guanidinoacetate abundance. The secondary outcomes of this study are to (1) determine the impact of polyamine depletion on polyamine abundance and the global extracellular metabolome within live human gliomas, in situ, and (2) assess the feasibility of longitudinal microdialysis for pharmacodynamic analysis within live human gliomas in situ in the post-operative setting. Clinical trial information: NCT05717153 .
Low-intensity focused ultrasound with systemic microbubble oscillators for blood-brain barrier disruption for liquid biopsy in glioblastoma (LIBERATE).
Authors: Ahluwalia Manmeet Singh , McDermott Michael W , Burns Terry C , de Groot John Frederick , Lee John Y.K. , Mogilner Alon , Schwartz Theodore , Shah Bhavya , Bettegowda Chetan , Ozair Ahmad , Khosla Atulya Aman , Sahgal Arjun , Mishra Mark V. , Achrol Achal , Lipsman Nir , Woodworth Graeme
Published: June 2023

TPS2084

Background: Liquid biopsy in glioblastoma (GBM) is hindered by a lack of requisite circulating-free DNA (cfDNA) levels in blood due to the blood-brain barrier (BBB). This results in challenges to the identification of blood-based biomarkers and the development of novel biomarker-driven systemic therapies. Real-time image-guided low intensity focused ultrasound (LIFU) combined with IV microbubble oscillators (DEFINITY), non-invasively causes BBB disruption (BBBD). This clinical trial aims to evaluate the utility of LIFU for increasing cfDNA in blood for liquid biopsy in GBM. Methods: LIBERATE is a prospective, multi-center, self-controlled, ongoing, pivotal trial evaluating safety and technical efficacy of LIFU for BBBD to increase cfDNA in blood for GBM. Patients aged >18-80 years with suspected GBM planned for tumor biopsy or resection at eleven centers in North America are being included. Patients with multifocal tumors or tumors arising from deep midline, thalamus, cerebellum, or brainstem are excluded. Patients are administered IV oscillating microbubbles for enhancing sonication, after which MR-guided BBBD using a 220 kHz LIFU device is performed with real-time acoustic feedback for effective cavitation. Before and after procedure, phlebotomies and MRI brain are performed to evaluate outcomes. The primary study endpoint is defined, per subject, as the ratio between their cfDNA level in blood 1-hour post-LIFU compared to cfDNA level in blood pre-procedure. The primary study hypothesis is that BBBD with LIFU leads to ≥2-fold increase in cfDNA in blood. The secondary hypothesis is that there exists ≥75% agreement between biomarker pattern in cfDNA sample from 1-hour post-LIFU sample and biomarker pattern in tumor tissue obtained later. The trial has been powered to evaluate both primary and secondary hypotheses. Based on an assumed true agreement rate of 91% and a one-sided alpha of 0.025, an exact test for binomial proportions provides a sample of N=50 with 84% power for the secondary hypothesis. Exploratory endpoints include (1) sensitivity of detection of known somatic mutations in cfDNA from blood samples collected before and after LIFU, (2) estimation of cfDNA levels post-LIFU in samples collected at 30 minutes, 1 hour, 2 hour, and 3 hour to determine time of greatest yield, (3) correlation of MRI parameters related to grading of BBBD and biomarkers positive in cfDNA from post-LIFU blood samples. Patient enrollment commenced in 2022 and 7 patients have been recruited by 02/13/2023. Clinical trial information: NCT05383872 .
Phase 1b multicenter study to evaluate CHM 1101 in patients with recurrent or progressive glioblastoma.
Authors: Litten Jason Blair , Ramakrishnan Aravind , Astrow Stephanie H. , Harrison Cassandra , Aliki Alex , Badie Behnam
Published: June 2023

TPS2086

Background: Glioblastoma multiforme (GBM) is the most common and most aggressive primary brain tumor. More than 300,000 new cases are diagnosed globally with over 250,000 deaths each year (Sung H, et al. CA Cancer J Clin. 2021). Patients with recurrent GBM have a poor prognosis, with limited treatment options and a median survival of less than 1 year (Gallego. Curr Oncol, 2015). While prior attempts to treat GBM with chimeric antigen receptor (CAR) T-cells have been limited by tumor heterogeneity, chlorotoxin (CLTX)-directed CAR T-cells in mice demonstrated broad anti-tumor activity and prolonged survival with no off-tumor toxicity or antigen escape (Wang, et al. Sci Transl Med, 2020). CLTX, a 36–amino acid peptide identified in scorpion venom, selectively binds to malignant glioma cells through matrix metalloproteinase-2 (MMP2) and clinical administration of CLTX-based biologics has been well tolerated in patients (Mamelak, et al. J Clin Oncol, 2005, Patil, et al. Neurosurgery, 2019). CHM 1101 is the first CAR T to utilize CLTX as its tumor targeting domain for autologous CAR T-cell therapy. A single-center first-in-human phase 1 study of CHM 1101 in patients with recurrent GBM is ongoing. Methods: Clinical Trial NCT05627323 is a phase 1b, multi-center study of CHM 1101 in adult subjects with MMP2+ recurrent or progressive GBM after standard therapy. After leukapheresis and tumor resection, pts will receive CHM 1101 at Dose Level 1 (240 × 106 CAR T cells) or Dose Level 2 (440 x 106d CAR T-cells), divided across 3 once-weekly intracranial (intracavitary and intraventricular) administrations; after disease assessment at 28 days, additional doses of CHM 1101 can be administered on a weekly schedule. Eligible subjects have a prior histologically confirmed diagnosis of a grade 4 GBM, a grade 2 or 3 malignant glioma with radiographic progression consistent with a grade 4 GBM (IDH wild type), grade 4 diffuse astrocytoma (IDH mutant), or a unifocal relapse of GBM. MMP2+ tumor expression is confirmed by IHC (≥20% moderate/high MMP2 score [2+ or 3+]). The primary endpoint is safety; key secondary endpoints include feasibility, progression-free survival, overall survival, response rate (RANO criteria), and cellular kinetics. Recruitment is ongoing. Clinical trial information: NCT05627323 .
A phase 1, first-in-human (FIH) study of autologous macrophages engineered to express an anti-HER2 chimeric antigen receptor (CAR) in participants (pts) with HER2-overexpressing solid tumors.
Authors: Abdou Yara , Dees Elizabeth Claire , Mortimer Joanne E. , Pohlmann Paula R , Johnson Melissa Lynne , Maziarz Richard T. , Specht Jennifer M. , Yuan Yuan , Ueno Naoto T. , Angelos Mathew , Gill Saar , Ronczka Amy , Condamine Thomas , Cushing Daniel , Barton Debora , Klichinsky Michael , Swaby Ramona F. , Reiss Kim Anna
Published: June 2023

TPS2666

Background: Macrophages are abundant in the solid tumor microenvironment (sTME) and can promote tumor growth (M2) or enhance anti-tumor immunity (M1). CAR expression can redirect macrophage function to selectively target and phagocytose antigen overexpressing cancer cells. CAR-M can reprogram the sTME and present neoantigens to T cells, leading to epitope spreading and anti-tumor immunity. CT-0508 is comprised of autologous monocyte-derived proinflammatory macrophages expressing an anti-HER2 CAR. Pre-clinical studies showed that CT-0508 induced targeted cancer cell phagocytosis while sparing normal cells, decreased tumor burden, prolonged survival, and was safe. Notably, anti-HER2 CAR-M treatment led to activation of the sTME, with infiltration of CD8+ and CD4+ T cells, NK cells, dendritic cells, and increased activated CD8+ tumor infiltrating lymphocytes. In a pre-clinical anti-PD1 resistant solid tumor model, mice that received anti-HER2 CAR-M and anti-PD1 demonstrated improved tumor control, overall survival, and TME activation compared to single treatment alone, indicating synergy and capacity for CAR-M to sensitize solid tumors to checkpoint blockade. Methods: This Phase 1, First in Human study evaluates the safety, tolerability, cell manufacturing feasibility, trafficking, TME activation, and preliminary evidence of efficacy of investigational product CT-0508 in 18 participants (pts) with locally advanced (unresectable) /metastatic solid tumors overexpressing HER2. Pts previously treated with anti-HER2 therapies are eligible. Filgrastim mobilized autologous CD14+ monocytes are collected by apheresis, followed by manufacturing and cryopreservation. Group 1 pts (n = 9; enrollment complete) received fractionated doses of CT-0508 over Days 1, 3, and 5. Group 2 pts (n = 9) receive CT-0508 as a single infusion on D1. Additional cohorts include: CT-0508 co-administered with pembrolizumab and CT-0508 monotherapy administered intraperitoneally in pts with peritoneal predominant disease. Correlative assessments include pre- and post-treatment biopsies and blood samples for safety (immunogenicity), trafficking (PCR, RNA scope), CT-0508 persistence in blood and tumor, target antigen engagement, TME modulation (single cell RNA sequencing), immune response (TCR sequencing) and others. Clinical trial information: NCT04660929 .
Phase 2, multicenter, open-label basket trial of nab-sirolimus for patients with malignant solid tumors harboring pathogenic inactivating alterations in TSC1 or TSC2 genes (PRECISION I).
Authors: Iyer Gopa , Deming Dustin A. , Demeure Michael J. , Federman Noah , McKean Meredith , Lee Elizabeth Katherine , Spira Alexander I. , Kwiatkowski David J. , Hussein Maen A. , Gordon Erlinda Maria , Crockett David G. , Ganjoo Kristen N. , Schulte Brian , Cranmer Lee D. , Ding Li , Schmid Anita N. , Navarro Willis H. , Rodon Ahnert Jordi
Published: June 2023

TPS3168

Background: nab-Sirolimus is a novel albumin-bound mTOR inhibitor (mTORi) approved in the US for adult patients with malignant PEComa. In an exploratory analysis of the pivotal AMPECT trial of nab-sirolimus in advanced malignant PEComa (NCT02494570), 8/9 (89%) and 1/5 (20%) patients with inactivating alterations in TSC2 and TSC1, respectively, had confirmed response (Wagner, J Clin Oncol, 2021). TSC1 and TSC2 alterations have been observed in patients with a broad variety of cancers. Most treatment-related adverse events in AMPECT were grade 1/2 (none were grade ≥4) and were consistent with mTORi class adverse events. Methods: PRECISION I (NCT05103358) will evaluate efficacy and safety of nab-sirolimus in patients with TSC1 (Arm A) and TSC2 (Arm B) alterations. Eligible patients are ≥12 y old and mTORi-naïve, possess malignant solid tumors with TSC1/TSC2 inactivating alterations (confirmed by central review of sequencing reports), and have received appropriate standard treatments, per investigator. nab-Sirolimus 100 mg/m2 will be given weekly intravenously over 30 min on Days 1 and 8 of each 21-d cycle. The primary endpoint is overall response rate per independent radiographic review (IRR) using RECIST v1.1. Other endpoints include duration of response, time to response, progression-free survival by IRR, overall survival, patient-reported quality of life, and safety. Enrollment began March 2022. Collaboration with leading next-generation sequencing vendors will expedite the identification of patients with qualifying TSC1/TSC2 mutations; study access will be facilitated through a just-in-time approach to trial location activation. Based on the prevalence of TSC1/TSC2 inactivating alterations, the most frequent tumor types expected are bladder, hepatobiliary, endometrial, soft tissue sarcoma, ovarian, and esophagogastric (Table). Clinical trial information: NCT05103358 . [Table: see text]
An open-label clinical trial of RP2 and RP3 oncolytic immunotherapy in combination with atezolizumab and bevacizumab for the treatment of patients with advanced colorectal carcinoma.
Authors: Shepard Dale Randall , Ahmed Muneeb , Bekaii-Saab Tanios S. , Wolff Johannes
Published: June 2023

TPS3628

Background: Colorectal cancer (CRC) is the third most frequently diagnosed cancer and the second leading cause of cancer-related mortality worldwide. PD-1/PD-L1 inhibition, in combination with other modalities, has demonstrated significant benefit in patients (pts) with microsatellite instability-high or mismatch repair deficient CRC. However, these agents have limited, if any, clinical benefit in pts with microsatellite stable (MSS) or mismatch repair proficient (pMMR) CRC. RP2 is an enhanced potency oncolytic herpes simplex virus type 1 which expresses the fusogenic gibbon ape leukemia virus glycoprotein with the R sequence deleted (GALV-GP-R–), granulocyte-macrophage colony-stimulating factor (GM-CSF), and an anti–CTLA-4 antibody-like molecule; RP3 additionally expresses 4-1BB and CD40 activating ligands, but does not express GM-CSF. Both agents have demonstrated preliminary safety and efficacy in pts with solid tumors. This study will evaluate the safety and efficacy of RP2 and RP3 in combination with atezolizumab (Atezo) and bevacizumab (Bev) in pts with advanced MSS and pMMR CRC. Methods: Pts with a histologic diagnosis of unresectable and/or metastatic CRC, with documented MSS or pMMR status, and previously treated with up to 3 standard-of-care systemic regimens will be enrolled in the RP2 + Atezo + Bev or RP3 + Atezo + Bev treatment groups (30 pts per group). Further key inclusion criteria include Eastern Cooperative Oncology Group performance status 0–1 and adequate hepatic, renal, and hematologic function. RP2/RP3 will be injected into tumors by direct (including via colonoscope) or image-guided injection. Pts will receive 8 total doses of up to 10 mL of RP2 or RP3, with a first dose concentration of 1 × 106 plaque-forming units (PFU)/mL, followed by 3 doses of 1 × 107 PFU/mL every 2 weeks, and then 4 doses of 1 × 107 PFU/mL every 3 weeks. Pts may receive a second course of up to 8 injections of RP2/RP3 if study criteria are met. Bev will be administered starting on day 1 (with first dose of RP2/RP3); Atezo will be administered starting week 7 on the same days as RP2/RP3. The primary endpoint is objective response rate; secondary endpoints are safety, overall survival, progression-free survival, duration of response, and complete response rate. Antitumor activity will be evaluated using Response Evaluation Criteria in Solid Tumors version 1.1 as modified for this study. Safety will be assessed by physical examination, clinical laboratory evaluations, vital signs, and monitoring for adverse events (AEs; including serious AEs). Clinical trial information: NCT05733611 .
A phase 1/2a, multicenter, open-label study of CNA3103 (LGR5-targeted, autologous CAR-T cells) in patients with metastatic colorectal cancer (mCRC).
Authors: Desai Jayesh , Iglesias Jose Luis , Jablonskis Lina T , McColl Shaun , Barry Simon C , Morelli Maria Pia
Published: June 2023

TPS3632

Background: Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) is a cancer stem cell (CSC) marker that is abundant in solid tumors, highly expressed in colorectal cancer and involved in tumor initiation, growth, and metastasis. Its expression is linked to poor survival and poor patient response to therapy in mCRC, and presents an attractive opportunity for selectively targeting a highly specific, functional CSC receptor in this disease. CNA3103 is a first-in-class cell product consisting of autologous T cells transduced to express a CAR to target LGR5. It contains the antigen-biding domain of BNC101, a humanized monoclonal LGR5 antibody previously tested in Phase 1 in mCRC subjects and demonstrated to be safe and well tolerated with no off-target binding activity. Methods: This is a first in human, multicenter, open label, Phase 1/2a dose escalation and expansion study to determine the safety of and overall best response to CNA3103 in subjects with mCRC. Up to 44 subjects (24 in Phase 1 and 20 in Phase 2a) will be enrolled. The trial follows a BOIN design with a minimum of 3 consecutively enrolled subjects per cohort, and a 28-day DLT evaluation period. Four cell dose levels (5 × 107, 1.5 × 108, 4.5 × 108, 1.5 × 109) of CNA3103 will be evaluated. A Safety Monitoring Committee (SMC) will oversee the conduct of the study. The pharmacokinetic (PK) profile of CNA3103 in blood will be assessed. Exploratory objectives include evaluation of LGR5+ cells and CNA3103 in tumor biopsies, immune cellular profile, cytokine levels and circulating tumor DNA in blood, and immunogenicity of CNA3103. Main inclusion criteria: mCRC subjects positive for LGR5 expression and failing prior treatment with 5-FU, oxaliplatin and irinotecan-based regimens for metastatic disease; >1 radiologically measurable lesion per RECISTv1.1; >1 biopsiable lesion at baseline; ECOG 0 or 1; serum albumin >3 g/dL; and normal organ and marrow function. Main exclusion criteria: BRAF-mutated disease, clinical ascites/ pleural effusions; active autoimmune/ connective tissue disease; history of inflammatory bowel disease or active peptic ulcer disease. The trial is sponsored by Carina Biotech. Phase 1 enrolment is limited to Australian sites. Phase 2a enrolment will take place in Australia and the US. For information, contact Lina Jablonskis lina@carinabiotech.com or +61 437 891 563.
PACE: A phase III trial of CAPOX versus anti-PD-1 inhibitor as adjuvant therapy for patients with dMMR/MSI-H stage III colon cancer.
Authors: Hou Zhenlin , Jiang Wu , Tang Jinghua , Xiao Binyi , Li Yuan , Li Dandan , Zhang Xiaoshi , Pan Zhi-Zhong , Ding Peirong
Published: June 2023

TPS3637

Background: Approximately 12% of stage III colon cancer are deficient mismatch repair (dMMR), leading to high levels of microsatellite instability (MSI-H). In the KEYNOTE-177 study, the anti–PD-1 inhibitor Pembrolizumab alone significantly improved progression free survival (PFS) versus chemotherapy as first-line therapy for metastatic colorectal cancer (mCRC) patients with MSI-H/dMMR. We are conducting a phase III randomised trial to determine whether anti-PD-1 inhibitor Sintilimab monotherapy can improve disease free survival (DFS) compared with standard adjuvant chemotherapy in stage III colon cancer patients with dMMR. Methods: This is an open-label, multicentre, randomised phase III study. Patients aged ≥ 18 years with completely resected, stage III colon cancer confirmed to have dMMR/MSI-H and ECOG performance status 0-1 are eligible. Approximately 323 patients will be randomly assigned 1:1 to either Sintilimab monotherapy (200 mg IV every 3 weeks for 8 cycles) or CAPOX regimen (capecitabine, oxaliplatin for 4 or 8 cycles according to current standard practice). Adverse events (AEs) will be assessed throughout treatment and for 30 days thereafter (90 days for serious AEs) and graded per NCI CTCAE v4.0. Primary endpoint is 3-year DFS. The study was estimated to provide approximately 80% power to detect a hazard ratio of 0.56 for DFS at a two-sided alpha of 0.05. Secondary endpoints include OS, safety profile, toxicity, and quality of life. Archived tumor tissue and blood samples will be collected for correlative studies. Study enrollment is ongoing. Clinical trial information: NCT05236972 .
Phase 2 trial of zolbetuximab in combination with mFOLFOX6 and nivolumab in patients with advanced or metastatic claudin 18.2-positive, HER2-negative gastric or gastroesophageal junction adenocarcinomas.
Authors: Shitara Kohei , Yamaguchi Kensei , Shoji Hirokazu , Matsangou Maria , Bhattacharya Pranob P. , Park Jung Wook , Klempner Samuel J
Published: June 2023

TPS4173

Background: Zolbetuximab, a chimeric immunoglobulin G1 monoclonal antibody, binds to claudin 18.2 (CLDN18.2) and mediates tumor cell death through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. In the pivotal phase 3 SPOTLIGHT study, zolbetuximab with modified FOLFOX6 (mFOLFOX6; leucovorin [folinic acid], fluorouracil [5-FU], and oxaliplatin) significantly prolonged progression-free survival (PFS) and overall survival (OS) in patients with CLDN18.2-positive, HER2-negative gastric and gastroesophageal junction (G/GEJ) adenocarcinomas. The phase 2 ILUSTRO trial is investigating the efficacy and safety of zolbetuximab, alone and in multiple combinations, in patients with CLDN18.2-positive, HER2-negative advanced/metastatic G/GEJ adenocarcinomas. Methods: The ILUSTRO trial is enrolling two new cohorts, 4A (safety cohort) and 4B, with approximately 12 and 50 patients planned, respectively, to assess safety and efficacy of the first-line combination of zolbetuximab, mFOLFOX6, and nivolumab in G/GEJ adenocarcinomas. Both cohorts are enrolling patients whose tumors are HER2-negative with high or intermediate CLDN18.2 positivity (moderate to strong immunohistochemistry staining intensity in ≥75% of tumor cells [high] or ≥50% but <75% of tumor cells [intermediate]). In Cohort 4A, patients will receive a loading dose of 800 mg/m2 of zolbetuximab with 240 mg of nivolumab and mFOLFOX6 on cycle 1 day 1, followed by 400 mg/m2 of zolbetuximab with 240 mg of nivolumab and mFOLFOX6 every 2 weeks (on days 15 and 29 of each 42-day cycle). Up to 12 mFOLFOX6 treatments (4 cycles) will be administered; patients may continue to receive folinic acid and 5-FU alongside zolbetuximab and nivolumab. Tolerability and safety of the combination of zolbetuximab, mFOLFOX6, and nivolumab will be evaluated during a 2-week dose-limiting toxicity assessment period. If the 800 mg/m2 loading dose of zolbetuximab was assessed as not tolerable, patients were to be de-escalated to 600 mg/m2 as their loading dose but received the same subsequent 400 mg/m2 doses of zolbetuximab every 2 weeks. Cohort 4B will receive this combination at the dose level determined in Cohort 4A. Efficacy endpoints include objective response rate, disease control rate, duration of response, PFS, and OS. Safety and tolerability, pharmacokinetics, immunogenicity, and health-related quality of life will also be evaluated. Currently, 20+ sites are recruiting in 6 countries (France, Italy, Japan, Korea, Taiwan, United States); more US sites are planned. Clinical trial information: NCT03505320 .
Alliance A022102: Randomized phase III trial of mFOLFIRINOX +/- nivolumab vs. FOLFOX +/- nivolumab for first-line treatment of metastatic HER2-negative gastroesophageal adenocarcinoma (GEA).
Authors: Park Haeseong , Geyer Susan Michelle , Klute Kelsey , Bleeker Jonathan , King Daniel , Strickland Matthew , Goodrich Austin , Carlisle Destin , Shergill Ardaman , O'Reilly Eileen Mary , Meyerhardt Jeffrey A. , Shah Manish A.
Published: June 2023

TPS4175

Background: Platinum/fluoropyrimidine (FP) with PD-1 inhibitor is now established as the standard first-line therapy for most patients with advanced HER2 negative gastric, esophageal, and gastroesophageal junction (GEJ) adenocarcinoma. The FP doublet chemotherapy backbone, most commonly FOLFOX, is recommended based on marginal survival benefits of taxane-containing triplet therapy at the cost of increased toxicity. Although several agents are approved as standard treatment options in later lines, only about 10% of patients in the US receive a third line of therapy, and very few have the opportunity to benefit from all approved agents in this disease. This challenge will only increase as more agents and targeted therapies are approved. FOLFIRINOX is a triplet regimen commonly used in gastrointestinal malignancies with established safety and often with superior efficacy. Two single arm phase II trials of FOLFIRINOX have reported promising activity in GEA with manageable toxicities. Reported median overall survival (OS) from these trials is around 15 months, which is superior to what is expected from FP doublet first-line chemotherapy (about 11 months). We hypothesize that using upfront triplet therapy with a more effective and less toxic triplet combination will result in improved patient outcomes by optimization of available therapies in GEA. Methods: This study is a randomized phase III, open-label, multicenter clinical trial with the primary objective to determine whether modified FOLFIRINOX (FU 2400 mg/m2, leucovorin 400 mg/m2, oxaliplatin 85 mg/m2, irinotecan 150 mg/m2 every 2 weeks) as first-line treatment improves OS compared to mFOLFOX in patients with advanced HER2 negative GEA. Eligible patients will have unresectable or metastatic adenocarcinoma of esophagus, GEJ, or stomach with no prior systemic treatment. Patients must have adequate organ function, and measurable or evaluable disease as defined by RECIST 1.1. Prior neoadjuvant or adjuvant therapy is allowed if completed at least 1 year prior to registration. Patients who will receive nivolumab (mandatory for PD-L1 combined positive score > 5) in addition to chemotherapy must not have any contraindications to immune checkpoint inhibitors. Patients with treated, asymptomatic and stable brain metastases are eligible. The total sample size is 382 evaluable patients for this study (191 patients per arm). The study accrual began January 2023. Clinical trial information: NCT05677490 .
Randomized phase 2 study of maintenance olaparib vs olaparib plus durvalumab for DNA damage repair (DDR) gene mutated unresectable or metastatic biliary tract cancer (BTC) with durable response to first-line platinum-based chemotherapy: OPTIMUM trial.
Authors: Kim YunJung , Ok Boram , Park Inkeun , Ryoo Baek-Yeol , Kim Kyu-Pyo , Yoo Changhoon
Published: June 2023

TPS4180

Background: BTC is rare and aggressive disease with heterogeneous genetic profiles. Gemcitabine plus cisplatin (GemCis) with or without durvalumab is the standard first-line therapy but further improvement in survival outcomes is needed. In a prior study (Chae HJ et al, Eur J Cancer 2019), germline or somatic mutations in DDR genes including BRCA are detected more than half of BTC patients and associated with better survival outcomes with platinum-based chemotherapy. As the potential efficacy of Olaparib in DDR-mutated cancers and synergism between PARP inhibitors and immune checkpoint inhibitors, we designed randomized phase 2 trial investigating the efficacy and safety of olaparib monotherapy vs olaparib plus durvalumab in BTC patients as maintenance therapy for BTC patients who showed durable response to first-line platinum-based chemotherapy. Methods: This is a randomized, open-label phase 2 study conducted in a single center (Asan Medical Center, Seoul, Korea). Key eligibility criteria include histologically documented locally advanced unresectable or metastatic BTC, no progression at least 16 weeks with first-line platinum-based chemotherapy, DDR mutations on targeted sequencing of tumor tissues and ctDNA, ECOG performance status 0–1, and adequate organ function. Eligible patients will be randomized 1:1 into olaparib monotherapy arm (300 mg twice daily, every 4 weeks) or olaparib plus durvalumab (1,500 mg intravenous, every 4 weeks) arm. Study treatment is continued until disease progression, unacceptable toxicity, withdrawal of consent, or death. Response evaluation is performed every 8 weeks (fixed). Stratification factors are tumor location (intrahepatic vs extrahepatic/gallbladder) and best response to platinum-based chemotherapy (CR/PR vs SD). The six-month progression-free survival rates are the primary endpoint and overall survival, progression-free survival, response rates, and safety profiles are secondary endpoints. A total of 62 patients (31 for each arm) are planned, and 23 (37%) patients (ATM [n=6], BRCA2 [n=7], CHEK2 [n=2], BRCA1 [n=1], RAD51C [n=1], and PBRM1 [n=1]) are enrolled as of Jan 2023. Clinical trial information: NCT05222971 .
ABC-12: Exploring the microbiome in patients (pts) with advanced biliary tract cancer (BTC) in a first-line study of durvalumab in combination with cisplatin/gemcitabine (cis/gem).
Authors: McNamara Mairead Geraldine , Timmins Hayley , Osborne Ashley , Cox Rebecca , Wasan Harpreet Singh , Corrie Pippa , Gillmore Roopinder , Sivakumar Shivan , Ma Yuk Ting , Faluyi Olusola Olusesan , Arora Arvind , Arif Seema , Canham Jo , Hurt Chris , Hubner Richard , Bridgewater John A , Adams Richard , Valle Juan W.
Published: June 2023

TPS4183

Background: Durvalumab/cis/gem improved overall survival (OS) in pts with advanced BTC versus placebo/cis/gem (Oh et al. NEJM Evid 2022). Disruption of the microbiota may impair tumour response to immunotherapy and chemotherapy and a better understanding of its role in the efficacy of these therapeutics in advanced BTC is required. Methods: This is a multi-centre, single arm trial exploring the microbiome in pts receiving durvalumab 1500 mg intravenously (IV) Q3w, in combination with cis 25 mg/m2, gem 1000 mg/m2 (Days 1 and 8, Q3w) up to 8 cycles, followed by durvalumab 1500 mg as monotherapy Q4w, until progression or intolerable toxicity. Pts with an ECOG performance status of ≤1 and histologically-proven BTC, including cholangiocarcinoma and gallbladder carcinoma, who have had no prior systemic chemotherapy for locally advanced or metastatic disease are eligible. Pts must provide a saliva and stool sample prior to commencement of durvalumab/cis/gem and at 18 weeks, or at progression (if earlier than 18 weeks). Taxonomic profiling via 16S Ribosomal ribonucleic acid gene sequencing will examine the differences in the diversity and composition of the pt gut microbiome. Pts must also have availability of a tumour biopsy. This study plans to recruit 70 pts from 10 UK centres (over 12 months). The primary objective is to determine the difference in baseline alpha diversity between “responders” (partial or complete response) and “non-responders” at 18 weeks (RECIST 1.1) in patients treated with durvalumab/cis/gem. Secondary objectives include investigation of the association between microbiome parameters and objective response rate, tumour control (partial + complete response + stable disease), progression-free and OS, and to investigate the interaction between treatment effect and microbiome parameters on clinical outcomes. The tumour biopsy will be used for research into the tumour microbiome and/or factors that may influence response to chemotherapy/immunotherapy, including, but not limited to tumour mutation burden, programmed cell death 1/programmed death-ligand 1 status, and microsatellite instability status. Clinical trial information: ISRCTN11210442 .