bluuebunny/crossref_metadata_2025 huggingface dataset:
Multidisciplinary consensus recommendations for the management of non-spine bone metastases: Results of a modified Delphi process in a community-academic partnership.
Authors: Mathis Noah J , Yang Jonathan T. , Vaynrub Maksim , Santos Martin Ernesto , Kotecha Rupesh , Panoff Joseph , Salner Andrew L. , McIntosh Alyson F , Gupta Ranju , Gulati Amitabh , Yerramilli Divya , Xu Amy , Bartelstein Meredith , Guttmann David , Yamada Yoshiya , Pfister David G. , Lin Diana , Lapen Kaitlyn , Lipitz-Snyderman Allison , Gillespie Erin F.
Published: June 2021

e24092

Background: Local therapy for bone metastases is becoming increasingly complex, but national guidelines remain limited. We leveraged a community-academic partnership to develop consensus recommendations for multidisciplinary treatment of non-spine bone metastases which are generalizable to diverse practice settings. Methods: We convened a group of 15 physicians (9 radiation oncologists, 2 orthopaedic surgeons, 2 medical oncologists, 1 interventional radiologist, 1 interventional pain specialist) treating bone metastases across 4 institutions from Apr 2020-Feb 2021. We distributed a survey to identify questions warranting consensus development in the treatment of non-spine bone metastases. A literature review was conducted to inform answer statements, and evidence was rated using the Strength of Recommendation Taxonomy. A modified Delphi process was employed to reach consensus defined (a priori) as ³75% of respondents indicating “agree” or “strongly agree”. Results: A total of 16 questions were identified, including indications for multidisciplinary discussion or referral (n=4), appropriate use and duration of RT (n=4), and handling of systemic therapies during RT (n=5). After 2 rounds of modified Delphi process, consensus has been reached on 9 questions (see Table). Strength of Recommendation was rated A (1/9, 11%), B (5/9, 56%), or C (3/9, 33%). Conclusions: Our consensus process provides guidance for management of non-spine bone metastases that expands upon current guidelines. We also highlight areas where prospective trials are needed, including the role of RT prior to stabilization surgery and the selection of patients for ablative treatment. [Table: see text]
Breaking bad news in the oncologic population: Residents' perspective.
Authors: Thota Vihitha , Paravathaneni Mahati , Konduru Sudheer , Baralo Bohdan , Mulla Sana , Thirumaran Rajesh
Published: June 2021

e24113

Background: Delivering bad news to patients is a delicate but required skill for doctors as part of patient care. There has been evidence that good communication from health care providers can improve patients' compliance to treatment as well as be beneficial emotionally. While many studies have been done in regards to patients' perceptions of receiving bad news, there are limited studies looking at a physicians' perspective, and even more so concerning residents' perceptions. In community hospitals, many patients are diagnosed with cancer, and resident physicians are often responsible for informing the patients and their families regarding the diagnosis. The manner in which the news is delivered is important, however it is unclear how much training is provided to residents before they are required to break bad news to patients. The lack of training can often result in improper delivery and poor patient care. Methods: We surveyed Internal Medicine and General Surgery residents at Mercy Catholic Medical Center, a conglomeration of two community teaching hospitals in Philadelphia, about prior training, confidence level, attitudes, and need for further education on delivering bad news to oncologic patients using a survey created after extensive research. The factors associated with confidence level were analyzed using paired T-test and ANOVA methods. Results: A total of 65 residents (72%) participated. No statistical significance was seen between American versus foreign medical graduates, MD vs. DO residents, or among those in different specialties when assessing their confidence in delivering bad news. Though only 62% of participants reported having had prior training in delivering bad news, residents with previous training (p1) or who have had to deliver bad news previously (p2) reported higher confidence when it came to delivering a new diagnosis of cancer (p1 0.03, p2 0.001), delivering news regarding the progression of cancer (p1 0.03, p2 0.02), delivering news regarding the recurrence of cancer (p1 0.04, p2 0.002), and delivering news regarding end-stage cancer with little to no treatment options left (p1 0.04, p2 0.003). 100% of participants thought communicating bad news is an important skill for a physician, and 92% of participants thought further education would help prepare them for similar scenarios in the future. Simulated patient scenarios (64%), grand rounds lectures/presentations (59%), and feedback from faculty after actual patient scenarios (57%) were the most requested whereas pamphlets/brochures (17%) and online training courses (20%) were less popular. Conclusions: Our study highlights the importance of prior training or exposure among residents in being able to deliver bad news to patients effectively. We propose that implementing further training in the form of simulated scenarios and lectures can improve residents' confidence at delivering bad news and result in a better physician-patient relationship.
Evaluating the dyadic management of sexuality-related parameters in women with early breast cancer (EBC): The emergence of “partner reported outcome measurements” (pROMs).
Authors: Sapir Eli , Corn Benjamin W. , Hasid Lior , Deutsch Irad , Vorobiof Daniel A.
Published: June 2021

e24118

Background: Patient-centered healthcare has focused on incorporating the values of patients (Pts) during clinical decision-making. Accordingly, assessments are often executed with patient reported outcome measurements (PROMs). In the context of tumors located in a sexual organ, life quality may be predicated on the perception of the patient’s partner when such a relational dyad exists. Therefore, we created a “partner” reported outcome measurements (pROMs). Accordingly, we sought to query the interconnection of PROMs and pROMs in the setting of early breast cancer (EBC) by using a digital health technology application. Methods: In this ongoing study, 93 EBC Pts and 18 partners, active members of Belong.life, a social engagement platform for cancer Pts and caregivers, replied anonymously and voluntarily to a targeted survey related to sexuality and intimacy parameters in the Pts and their partners. 72% of the partners were 50-69 years of age (yoa), 61% were Caucasian. 70% of the Pts were 50-69 yoa and 72% Caucasian. 72% of the Pts and 78% of the partners had college and university degrees. At diagnosis 78% of the Pts had Stages 1-2, 44% had breast conserving surgery, and most (78%) received chemotherapy. Results: We report the interim results of the first 14 patients-partner dyads. At the time of diagnosis, 86% of partners and 50% of Pts were very or extremely concerned about the patient’s health. Of note, 43% of Pts were not concerned at all or slightly concerned about their own health. With the passage of time, the concern about the patient’s health had decreased to 50% among the partners and 28% among the Pts. Regarding intimacy and sexuality issues prior to the EBC diagnosis, 64% of the Pts didn’t have any complaints but it changed dramatically after diagnosis with 50% mentioning less sex drive and 40% less intimacy. In the partners group 67% didn’t have complaints before the diagnosis but 28% voiced complaints after the diagnosis. Only half of Pts and partners felt they could speak freely about their mutual feelings. Only 23% of Pts and 11% of partners indicated they would agree to seek professional help for issues related to sexuality and intimacy. Ultimately, 71% of Pts and 79% of partners felt happy with each other. Conclusions: Partners were very concerned about the health of Pts; however, the dyad was not always synchronized. Notwithstanding it, the dyad adjusted their concerns during the course of treatment. Body changes had modest effect on the relationship. While dissatisfaction of sexual activity was evident it did not significantly affect the feelings of patients and partners towards each other. The development of pROMs could re-synchronize the dyad thereby creating a more meaningful cancer journey.
Adaptive and maladaptive coping strategies among patients with advanced cancer.
Authors: Dev Rony , Reddy Akhila Sunkepally , Arthur Joseph Anthony , Haider Ali , Subbiah Ishwaria Mohan , Delgado-Guay Marvin Omar , Carmack Cindy L. , Bruera Eduardo , Hui David
Published: June 2021

e24129

Background: Few studies have examined the coping mechanisms among patients with advanced cancer seen by palliative care. The objective of the study was to evaluate coping strategies in advanced cancer patients and identity risk factors for maladaptive coping. Methods: The authors conducted a secondary analysis of a cross-sectional survey on chemical coping. We prospectively enrolled patients with advanced cancer from a Supportive Care Clinic and documented the patient demographics, symptom expression (Edmonton Symptom Assessment System), Zubrod performance status, substance use history including tobacco, and coping strategies (the Brief COPE Questionnaire). Univariate and multivariate analyses were performed to identify risk factors for the use of maladaptive coping strategies. Results: Among 399 patients, the most common malignancies were gastrointestinal (21%) and breast (19%). Cancer patients frequently incorporated adaptive coping strategies including acceptance (86.7%), emotional support (79.9%), religion (69.4%), active coping (62.4%), instrumental support (48.4%), positive reframing (48.6%), planning (49.6%), and infrequently, humor (18.5%). Common maladaptive strategies included self-distraction (36.6%) and venting (14.5%), while self-blame (6.3%), denial (4.5%), behavioral disengagement (1.8%), and substance use (1.0%) were infrequently reported. On univariate analysis, venting was significantly associated with anxiety and depression, female gender, and tobacco use; and self-distraction was significantly associated with younger age, gender, depression, dyspnea, and a post-secondary education (P<0.05 for all). On multivariate analysis, male gender (OR -1.22, p<0.0001) and smoking (non-smoker vs everyday OR -1.9, P=0.008 ) remained significant for maladaptive venting; and age (HR -0.026, p=0.005), male gender (OR -0.65, p=0.004), dyspnea (OR -0.12, p=0.01) and post-secondary education (OR 0.596, p=0.022) remained significant for self-distraction. Conclusions: The vast majority of patients with advanced cancer seen by palliative care reported using adaptive coping strategies. We identified subgroup of patients who may be more likely to use maladapative coping strategies and may benefit from further psychological support.
Saci-IO TNBC: Randomized phase II trial of sacituzumab govitecan (SG) +/- pembrolizumab in PD-L1– metastatic triple-negative breast cancer (mTNBC).
Authors: Garrido-Castro Ana Christina , Keenan Tanya Elizabeth , Li Tianyu , Lange Paulina , Callahan Catherine , Guerriero Jennifer , Tayob Nabihah , Anderson Leilani , Yam Clinton , Daniel Brooke R. , Carey Lisa A. , Nanda Rita , Winer Eric P. , Mittendorf Elizabeth A. , Tolaney Sara M.
Published: June 2021

TPS1106

Background: Immune checkpoint inhibitors (ICIs) have not yet benefited most patients with breast cancer. In mTNBC, ICIs combined with chemotherapy have improved survival only in PD-L1+ mTNBC. The optimal ICI combination agent to overcome primary resistance in PD-L1– mTNBC is unknown. One promising agent is the anti-Trop-2-SN-38 antibody drug conjugate (ADC) SG, which led to median progression-free survival (PFS) of 5.6 months in mTNBC with ≥2 prior lines of chemotherapy.1 This ADC may boost anticancer immunity by binding immune cell receptors to promote antibody-dependent cellular cytotoxicity.2 In addition, the SN-38 payload of SG is the active metabolite of irinotecan, which depletes regulatory T cells, upregulates MHC class I and PD-L1 expression, and augments the antitumor activity of anti-PD-1/L1 antibodies in murine tumor models.3 The irinotecan analogue camptothecin also enhances CD8+ cytotoxic T cell effector functions and antitumor immune responses by inhibiting NR4A transcription factors,4 which have recently been shown to play a central role in inducing the T cell dysfunction associated with chronic antigen stimulation in solid tumors. Methods: This is a multi-center 1:1 randomized phase II trial to investigate whether the addition of pembrolizumab (200 mg IV every 3 weeks) to SG (10 mg/kg IV days 1+8 every 21 days) improves PFS compared to SG alone in mTNBC that is PD-L1– by standard of care testing with 22C3 CPS < 10 or SP142 immune cells < 1% (NCT04468061). Key eligibility criteria include no prior systemic therapy for mTNBC and evaluable disease. Previously treated brain metastases are permitted. Exclusion criteria include prior treatment with SG, irinotecan, and PD-1/L1 inhibitors. Based on a sample size of 110 patients per arm, the trial has 80% power to detect a 3-month difference in median PFS from 5.5 months in the SG-alone cohort to 8.5 months in the SG + pembrolizumab cohort with a one-sided alpha of 0.1. Participants undergo mandatory baseline and on-treatment research biopsies if their disease is safely accessible. Tumor biopsies will be evaluated for Trop-2, immune cells, inhibitory checkpoints, transcriptomic signatures, and genomic alterations. Stool specimens will be submitted for microbiome analyses, and health-related quality of life will be assessed. The trial is currently open and enrolling patients. References: 1) Bardia A et al. Ann Oncol 31, S1142-S1215 (2020). 2) Cardillo TM et al. Bioconjug Chem 26, 919-931 (2015). 3) Iwai T et al. Oncotarget 9, 31411-31421 (2018). 4) Hibino S et al. Cancer Res 78, 3027-3040 (2018). Clinical trial information: NCT04468061 .
A phase III multicenter randomized controlled trial of postsurgical stereotactic radiotherapy versus surgically targeted radiation therapy (STaRT) for the treatment of large (>2.5cm) newly diagnosed brain metastases: Trial in progress.
Authors: Weinberg Jeffrey , McAleer Mary Frances , Johnson Jason Michael , Kudchadker Rajat , Wefel Jeffrey Scott , Yuan Ying , Lin Heather Y.
Published: June 2021

TPS2067

Background: Resection (R) followed by single or multi-fraction stereotactic radiosurgery (SRT) of brain metastases lowers resection bed recurrence compared to R alone. Nevertheless, for larger (>2.5cm) brain metastasis, 12-month recurrence rates after R+SRT can exceed 20–30%. Aiming to improve outcomes, a permanently implanted collagen tile brachytherapy device (GammaTile or GT, GT Medical Technologies, Tempe, AZ) utilizing Cs-131 seeds embedded within a bioresorbable collagen tile was developed and is described as Surgically Targeted Radiation Therapy (STaRT) to distinguish it from external beam radiation therapy. It is hypothesized that immediate adjuvant radiotherapy (RT) and/or RT dose intensification could improve outcomes. The device is FDA-cleared for this indication and early commercial use is demonstrating favorable safety and efficacy outcomes. STaRT allows rapid dose delivery of radiation therapy directly to the tumor bed with predictable dosimetry immediately at the time of resection, and an intense but localized radiation treatment, which may confer a reduced risk for radiation necrosis compared to other therapies. The device is easily placed with minimal additional operative time and limited staff radiation exposure. It is hypothesized that R+ STaRT will increase the surgical bed recurrence-free survival, while reducing the impact on functional and neurocognitive status compared to R+SRT. Methods: Multicenter, randomized, comparison trial of patients with resectable, previously untreated “index” brain metastases measuring ≥2.5–5 cm, and 0–3 other tumors, will be preoperatively randomized 1:1 to undergo either R+ SRT or R+STaRT to the index lesion; unresected tumors in both groups will receive SRT. Planned sample size is 180 from 13 sites. Enrollment will open in Q1. Primary endpoint is surgical bed-recurrence free survival. Secondary endpoints include overall survival, quality of life (Functional Assessment of Cancer Therapy-Brain, Linear Analog Self-Assessment), neurocognition (Hopkins Verbal Learning Test, Trail Making Tests, Controlled Oral Word Association), functional status (Karnofsky Performance Scale, Barthel-ADL), and adverse events. Follow-up will be at 1,3,6,9, and 12 months, then every 6 months through 24 months. This will be the first randomized trial comparing R+SRT versus R+STaRT delivered by Cs-131 sources in permanently implanted resorbable collagen tile carriers. Primary and secondary outcome measures will be captured to elucidate the potential risks and benefits of these two differing post-operative RT delivery methods in the setting of newly diagnosed metastatic brain tumors. Clinical trial information: NCT04365374.
A multicenter observational study of cs-131 seeds embedded in a collagen carrier tile in intracranial brain neoplasms: Trial in progress.
Authors: Lee K. Stuart , Peach Matthew , Chen Clark C , Dusenbery Kathryn , Ferreira Clara , Shen Colette , Jaikumar Sivakumar , McDermott Michael W , Kotecha Rupesh , McCracken David J , Nowlan Adam W , Dunbar Erin M. , Trusheim John E , Monyak David James , Wanebo John , Choi Mehee , Brachman David , Misell Lisa
Published: June 2021

TPS2073

Background: Brachytherapy is an efficacious means for radiation delivery in the treatment of a spectrum of central nervous system tumors. Traditional brachytherapy methods have been limited by uneven dose distribution, complicated workflow, extended procedural times, the cost of dedicated equipment, and frequent adverse events. To address these issues, a permanently implanted device with Cs-131 radiation seeds embedded in a bioresorbable collagen carrier tile (GammaTile [GT], GT Medical Technologies, Tempe, AZ USA) was developed. Described as surgically targeted radiation therapy (STaRT) to distinguish it from external beam radiation therapy, the device is FDA-cleared for use in newly diagnosed malignant intracranial neoplasms and recurrent intracranial tumors, and has demonstrated excellent safety and local control outcomes in early commercial use. Methods: The overarching primary objectives of this multicenter, prospective, observational (phase IV) registry study are to evaluate “real-world” clinical outcomes and patient reported outcomes that measure the safety and efficacy of STaRT using the GT device. The registry is planned for 600 prospectively enrolled subjects at up to 50 enrolling sites. All adult patients undergoing surgical resection of brain tumors of any pathology with intra-operative GT placement are eligible for enrollment, upon consent. Information on patient demographics, tumor pathology, overall survival, adverse events related to radiation or surgery, and quality of life (FACT-Br and LASA) will be collected. Serial MRIs will be collected, and timing of surgical bed recurrence and/or distant recurrence will be collected. Data will be collected at 1-, 3-, 6-, 9-, 12-, 18-, and 24-months, then every 6 months through 5 years. Results will be used to benchmark clinical outcomes of GT therapy, allow for comparisons to other existing treatments, and facilitate the design of future clinical trials. Enrollment opened on November 15, 2020, and seven subjects have been enrolled to date at three centers. This study will be the first observational study of resection plus STaRT, delivered by Cs-131 sources in permanently implanted bioresorbable collagen tile carriers, and will allow for evaluation of this treatment approach in a real world setting, as well as provide an information platform for cross-comparison of results obtained from ongoing GT clinical trials. Clinical trial information: NCT04427384.
GBM AGILE: A global, phase 2/3 adaptive platform trial to evaluate multiple regimens in newly diagnosed and recurrent glioblastoma.
Authors: Wen Patrick Y. , Mellinghoff Ingo K. , Buxton Meredith Becker , Cavenee Webster K. , Colman Howard , De Groot John Frederick , Ellingson Benjamin M. , Gordon Gary B. , Khasraw Mustafa , Lassman Andrew B. , Lim Michael , Perry James R. , Tanner Kirk , Weller Michael , Yung W. K. Alfred Alfred , Cloughesy Timothy Francis ,   GBM AGILE Investigators
Published: June 2021

TPS2074

Background: GBM AGILE, Glioblastoma Adaptive, Global, Innovative Learning Environment, is an international, multi-arm, seamless phase 2/3 response adaptive randomization platform trial designed to evaluate multiple therapies in newly diagnosed (ND) and recurrent glioblastoma (GBM) with the goal of identifying effective therapies matching them accurately to different patient subtypes in an accelerated manner. It is a collaboration between academic investigators, patient organizations and industry to support new drug applications for newly diagnosed and recurrent GBM. Methods: The primary objective of GBM AGILE is to identify therapies that effectively improve overall survival in patients with ND or recurrent GBM. Bayesian response adaptive randomization is used within subtypes of the disease to assign participants to investigational arms based on their performance. Operating under a Master Protocol, GBM AGILE allows multiple drugs from different pharmaceutical companies to be evaluated simultaneously and/or over time against a common standard of care control. Based on performance, a drug may graduate and move to a rapid stage 2 (phase 3) within the trial, and the totality of the data can be used for a new drug application. An active pipeline is critical to the ongoing success of GBM AGILE. With the leadership of the trial’s Arm Selection Committee, uniform processes for including new drugs have been established to ensure a consistent review of drugs/drug combinations over the course of the trial. Factors considered include relevant pre-clinical data, preliminary evidence for antitumor activity. pharmacokinetic data to support proposed drug dosing and administration, and potential biomarkers helpful for the development of a drug. GBM AGILE provides an efficient mechanism to screen and develop robust information regarding the efficacy of proposed novel therapeutics and associated biomarkers for GBM and to quickly move therapies and biomarkers into clinic. GBM AGILE received IND approval from the FDA in April 2019, screening its first patient in June 2019. Site activation is ongoing in the US, with over 35 active sites and over 425 patients screened (as of February 2021). Expansion to Canada, Europe and China are under progress. Clinical trial information: NCT03970447.
A phase 1b, open-label, single-arm study of cofetuzumab pelidotin (a PTK7-targeting antibody-drug conjugate) in patients with PTK7-expressing, recurrent non-small cell lung cancer (NSCLC).
Authors: Schaefer Eric S. , Camidge D. Ross , Yoh Kiyotaka , Zer Alona , Hernandez Guerrero Tatiana , Bar Jair , Okuma Yusuke , Peguero Julio Antonio , De Miguel Maria , Moskovitz Mor Tal , Morgensztern Daniel , Jeffries Shawn , Wang Lan , Lally Satwant , Conn Christopher , Xin Xiaohua , Jeng Edwin E. , Johnson Melissa Lynne
Published: June 2021

TPS3142

Background: Protein tyrosine kinase 7 (PTK7) is a highly conserved receptor tyrosine kinase involved in the Wnt signaling pathway and is overexpressed in multiple cancer types, including non-small cell lung cancer (NSCLC). Cofetuzumab pelidotin (ABBV-647) is an anti-PTK7 antibody-drug conjugate comprising the hu6MO24 monoclonal antibody, a cleavable cysteine-reactive linker, and Aur0101 (an auristatin microtubule inhibitor). It has shown promising preclinical anti-tumor effects (Damelin et al. Sci Transl Med 2017;9[372]:eaag2611) and clinical activity with a manageable safety profile in a Phase 1 study in patients with advanced solid tumors, with promising anti-tumor activity noted in NSCLC (Sachdev et al. DOI: 10.1200/JCO.2018.36.15_suppl.5565). Methods: This open-label, single-arm, multicenter Phase 1b study (NCT04189614) will assess the anti-tumor activity and safety of cofetuzumab pelidotin in approximately 40 patients with PTK7-expressing, recurrent NSCLC. The primary objective is to assess the objective response rate of cofetuzumab pelidotin according to Response Evaluation Criteria in Solid Tumors version 1.1. Secondary objectives include the duration of response, progression-free survival, overall survival, and safety and tolerability. Pharmacokinetic and biomarker samples will also be collected throughout for analysis. Patients must be aged ≥18 years with an Eastern Cooperative Oncology Group performance status of 0–1 and have recurrent histologically confirmed NSCLC with PTK7-expressing tumor (using a validated immunohistochemistry assay). Patients must have progressed after treatment with a platinum-based chemotherapy doublet and an immune checkpoint inhibitor (for tumors without targetable genetic alterations), or a platinum-based chemotherapy doublet and targeted agent(s) (for tumors with targetable genetic alterations). Patients must also have received ≤2 prior lines of systemic therapy (≤3 prior lines for tumors treated with targeted agent[s] for genetic alterations), including no more than 1 line of systemic chemotherapy. Cofetuzumab pelidotin (2.8 mg/kg) is administered intravenously every 3 weeks until the patient experiences disease progression, intolerable toxicity, or other study treatment discontinuation criteria are met. The study commenced on February 13, 2020 and enrollment is ongoing. Clinical trial information: NCT04189614.
Phase 1/2 study of eprenetapopt (APR-246) in combination with pembrolizumab in patients with solid tumor malignancies.
Authors: Dumbrava Ecaterina Elena , Mahipal Amit , Gao Xin , Shapiro Geoffrey , Starr Jason S. , Singh Parminder , Furqan Muhammad , Ahrorov Afzal , Hickman Denice , Gubits Amy , Attar Eyal C. , Awad Mark M. , Das Satya , Park Haeseong
Published: June 2021

TPS3161

Background: The p53 pathway has been implicated in antitumor immunity, including antigen presentation and T-cell proliferation. Loss of p53 function can increase resistance to immunotherapy across many tumor types. Eprenetapopt (eprenet) is a small molecule that stabilizes the folded structure of p53, resulting in activation of mutant p53 and stabilization of wild-type (WT) p53. It also targets the cellular redox homeostasis, resulting in induction of apoptosis in tumor cells. In vivo, mice carrying supernumerary copies of the TP53 gene harbor a pro-inflammatory tumor microenvironment, an effect recapitulated in TP53 normal-copy mice treated with eprenetapopt. Combining eprenetapopt and anti-PD1 or anti-CTLA4 therapy resulted in enhanced tumor growth inhibition and improved survival in TP53 WT mice inoculated with B16 melanoma and MC38 colon adenocarcinoma cells . Based on these results, we hypothesized that eprenet-induced p53 stabilization may augment response to immunotherapy. To test this hypothesis, we are conducting a phase 1b/2 study of eprenet in combination with pembrolizumab (eprenet+pembro) in pts with solid tumors. Methods: The primary objectives are to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) and to assess the safety and tolerability of eprenet+pembro in pts with advanced solid tumors. The secondary objectives are to estimate the anti-tumor activity and to describe the pharmacokinetics of the combination. Exploratory objectives include assessing predictive and pharmacodynamic markers of response. The study includes a safety lead-in with a 3+3 dose de-escalation design for pts with advanced solid tumors with known tumor TP53 mutation status ( TP53 WT is acceptable) (max 18 pts), followed by expansion cohorts in pts with NSCLC, gastric/GEJ and urothelial cancer (max 100 pts). In expansion, pts with urothelial and gastric cancers must be naïve to anti-PD-1/ L1 therapy. Eprenet is given IV once daily on Days 1–4 while pembro is administered on Day 3 of each 21-day cycle. The RP2D of eprenet+pembro is considered the dose at which ≤ 1 of 6 pts in a cohort has a dose-limiting toxicity (DLT). Primary endpoints are occurrence of DLTs, adverse events (AEs) and serious AEs with eprenet+pembro. Key secondary endpoints are best objective response, progression free survival and overall survival. Exploratory endpoints include gene mutations by next generation sequencing (including TP53), mRNA expression, multiplex immunohistochemistry and transcriptomics, multiplex flow cytometry on peripheral blood mononuclear cells and cytokines in serum. Continuous monitoring of toxicity will be conducted. The trial opened in May 2020 and is actively enrolling patients. Clinical trial information: NCT04383938.
A phase 2, multicenter, open-label study evaluating trastuzumab deruxtecan (T-DXd) for the treatment of solid tumors harboring specific HER2-activating mutations (DESTINY-PanTumor01).
Authors: Li Bob T. , Meric-Bernstam Funda , Puvvada Soham D. , Rowbottom Jacqui , Jolliffe Darren , Gustavson Mark , Mendoza-Naranjo Ariadna
Published: June 2021

TPS3162

Background: There are substantial data suggesting that a subset of human epidermal growth factor receptor 2 (HER2)–activating mutations induce ligand-independent constitutive HER2 signaling and promote oncogenesis. Direct therapeutic targeting of HER2 has transformed the treatment of patients with HER2-overexpressing breast and gastric cancers. However, currently no targeted treatments are approved for patients with tumors harboring HER2-activating mutations. T-DXd is an antibody-drug conjugate consisting of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a membrane-permeable topoisomerase I inhibitor payload that may be selectively internalized in tumors with HER2 mutations (Li BT, et al. Cancer Discov. 2020;10:674-687). In a phase 1 study (DS8201-A-J101), T-DXd demonstrated preliminary antitumor activity in patients with tumors harboring HER2 mutations, with confirmed responses observed in 9 of 19 patients (47.4%) (Tsurutani J, et al. Cancer Discov. 2020;10:688-701). Here we describe the DESTINY-PanTumor01 trial (NCT04639219). Methods: DESTINY-PanTumor01 is an open-label, multicenter, single-arm, phase 2 study evaluating T-DXd for the treatment of patients with unresectable and/or metastatic solid tumors (excluding non-small cell lung cancer) harboring prespecified HER2-activating mutations. Patients (N≈100) are required to have progressed following prior treatment for advanced or metastatic disease or have no satisfactory alternative treatment options. Prior HER2-targeting therapy is allowed. HER2 mutation status will be determined locally using next-generation sequencing or a validated nucleic acid–based methodology. The primary endpoint is confirmed objective response rate according to independent central review per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary endpoints include duration of response, disease control rate, progression-free survival, investigator-assessed confirmed objective response rate, overall survival, safety, pharmacokinetics, and immunogenicity. Clinical trial information: NCT04639219.
A phase II trial of trastuzumab plus modified-FOLFOX for gemcitabine/cisplatin refractory HER2-positive biliary tract cancer (BTC): Multi-institutional study of the Korean Cancer Study Group (KCSG-HB19-14).
Authors: Lee Choong-kun , Cheon Jaekyung , Chon Hong Jae , Kim Min Hwan , Kim Jin Won , Lee Myung Ah , Park Hyung Soon , Kang Myoung Joo , Jang Joung-Soon , Choi Hye Jin
Published: June 2021

TPS4161

Background: Biliary tract cancer (BTC), one of the most fatal cancers with limited treatment options, is generally rare in most high-income countries, but is relatively prevalent in South Korea. Recent genomic profilings have provided druggable molecular targets including HER2 amplification, which accounts for about 15% of total BTC patients. Trastuzumab is a humanized monoclonal antibody against HER2 with known efficacy in patients with HER2-positive breast and gastric cancer, and has not been tested prospectively in patients with HER2-positive BTC. The modified-FOLFOX regimen is currently being tested as a second-line therapy of BTC in phase III ABC-06 trial. This phase II study is investigating the combination of trastuzumab and modified-FOLFOX as second- or third-line treatment in HER2-postivie BTC. Methods: This study (KCSG-HB19-14; NCT04722133) is a phase II, multi-institutional, single arm trial to evaluate the efficacy and safety of trastuzumab plus modified-FOLFOX in gemcitabine/cisplatin refractory patients with HER2-positive BTC. The main inclusion criteria are HER2-positive (defined as IHC3+, or IHC2+/ISH+; ISH+ defined as HER2/CEP17 ≥2.0, or ERBB2 gene copy number ≥ 6.0 by NGS) BTC (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder cancer and ampulla of vater cancer) patients who progressed on gemcitabine/cisplatin containing chemotherapy (one or two previous cytotoxic chemotherapy lines permitted), ECOG 0 or 1, and adequate organ function. Patients receive trastuzumab-pkrb 4mg/kg (after 6mg/kg load) D1, oxaliplatin 85mg/m2 D1, leucovorin 200mg/m2 D1, 5-FU 400mg/m2 bolus D1, and 5-FU 2400mg/m2 infusion D1-2 every 2 weeks until unacceptable toxicities or disease progression. The study has a Simon's two-stage design, with objective response rate (ORR) per RECIST v1.1 as primary endpoint. Secondary endpoints included progression-free survival, disease control rate, overall survival, safety, quality of life and correlative biomarker exploration. Additional patients were to be recruited if pre-specified thresholds for ORR are met at the first stage. The study will enroll up to 34 patients and is currently recruiting at eight sites in South Korea. As of February 2021, 16 patients have been enrolled. The pre-specified activity goal for the first stage of accrual was met; second stage accrual began in February 2021. Clinical trial information: NCT04722133.
DNA-damage response-umbrella study of the combination of ceralasertib and olaparib, or ceralasertib and durvalumab in advanced biliary tract cancer: A phase 2 trial-in-progress.
Authors: Yoon Jee Sun , Kim Jin Won , Kim Ji-Won , Kim Tae-Yong , Nam Ah-Rong , Bang Ju-Hee , Seo Hye-Rim , Kim Jae-Min , Oh Kyoung Seok , Mortimer Peter G. , Smith Simon , Oh Do-Youn
Published: June 2021

TPS4166

Background: Ceralasertib (AZD6738) is a selective ATR inhibitor that causes stalled replication forks to collapse, leading to accumulation of double-strand DNA breaks, which is expected to have synergistic anti-tumor effects with immune checkpoint inhibitors (ICI) or PARP inhibitors. First, accumulation of DNA damage by ceralasertib induces tumor cell death, leads to the release of tumor-specific antigen, changing the tumor microenvironment to promote antigen presentation and enhances the anti-tumor effect of ICI. Second, by simultaneously inhibiting two DNA-damage response (DDR) pathways downstream of PARP and ATR, cancer cells are unable to repair damaged DNA, leading to cell death. Ceralasertib has demonstrated promising anti-tumor activity and manageable toxicity in combination with durvalumab or olaparib in solid tumors in a phase 1 study (NCT02264678). In preclinical studies, ceralasertib has shown potent anti-tumor effects in biliary tract cancer (BTC) as a monotherapy and in combination with chemotherapy (Nam, et al, 2019). Methods: This is an open-label, phase 2 umbrella study assessing the efficacy of ceralasertib in combination with durvalumab or olaparib in patients with advanced BTC. Eligible patients have histologically confirmed BTC (including intrahepatic or extrahepatic cholangiocarcinoma, gallbladder cancer, or ampullary cancer), have failed at least one chemotherapy and have ECOG performance status of 0-1. Patients who have received prior ICI, ATR or PARP inhibitor are excluded. Each cycle consists of 4 weeks. In ceralasertib /durvalumab cohort, 37 patients will receive durvalumab 1.5g on day 1 and ceralasertib 240mg twice daily on days 15-28. In ceralasertib /olaparib cohort, 37 patients receive ceralasertib 160mg once daily on days 1-7 and olaparib 300mg twice daily on days 1-28. The primary endpoint is disease control rate, with key secondary endpoints including overall response rate, progression-free survival, overall survival, and safety. Tissue and blood samples are being collected for translational biomarker studies. Clinical trial information: NCT04298021.
KEYNOTE-B15/EV-304: Randomized phase 3 study of perioperative enfortumab vedotin plus pembrolizumab versus chemotherapy in cisplatin-eligible patients with muscle-invasive bladder cancer (MIBC).
Authors: Hoimes Christopher J. , Bedke Jens , Loriot Yohann , Nishiyama Hiroyuki , Fang Xiao , Kataria Ritesh S. , Homet Moreno Blanca , Galsky Matt D.
Published: June 2021

TPS4587

Background: Standard of care for MIBC is neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy and pelvic lymph node dissection (RC+PLND); however, in time, patients experience disease recurrence or progression. Enfortumab vedotin (EV) is a Nectin-4–directed antibody–drug conjugate comprising a fully human, monoclonal antibody and the microtubule-disrupting agent monomethyl auristatin E. The KEYNOTE-869/EV-103 phase 1/2 study (NCT03288545) showed that the PD-1 inhibitor pembrolizumab + EV had encouraging antitumor activity and acceptable safety as first-line treatment for cisplatin-ineligible patients with metastatic urothelial cancer (Rosenberg JE et al. J Clin Oncol. 2020;38[15 suppl]:5044). Based on these data, investigating EV + pembrolizumab in an earlier setting such as MIBC and in a perioperative fashion is appropriate. KEYNOTE-B15/EV-304 (NCT04700124) is a randomized, open-label, phase 3 study to evaluate the efficacy and safety of perioperative EV + pembrolizumab versus neoadjuvant chemotherapy using gemcitabine/cisplatin in cisplatin-eligible patients with MIBC. Methods: Patients must have histologically confirmed urothelial cancer/MIBC (clinical stage T2-T4aN0M0 or T1-T4aN1M0) with predominant (≥50%) urothelial histology, have nonmetastatic disease (≥N2 disease and/or M1 excluded) confirmed by blinded independent central review (BICR), have ECOG PS 0 or 1, and not have previously received systemic therapy for MIBC. Approximately 784 patients will be randomly assigned 1:1 to receive either 4 cycles of neoadjuvant EV + pembrolizumab followed by 5 cycles of adjuvant EV + 13 cycles of adjuvant pembrolizumab after RC+PLND or 4 cycles of neoadjuvant cisplatin-based chemotherapy followed by observation after RC+PLND. Neoadjuvant and adjuvant pembrolizumab 200 mg + EV 1.25 mg/kg will be administered intravenously every 3 weeks (Q3W), and neoadjuvant chemotherapy will consist of gemcitabine 1000 mg/m2 + cisplatin 70 mg/m2 Q3W. Randomization will be stratified by centrally determined (pathology or imaging) initial T and N stage (T2N0 or T3/T4aN0 or T1-T4aN1), PD-L1 combined positive score (CPS ≥10 or CPS < 10), and geographic region (United States or Europe or most of world). Imaging (CT or MRI) will be performed ≤6 weeks before cystectomy and 6 weeks after cystectomy. After postcystectomy imaging, additional imaging will be performed Q12W up to the end of year 2 (week 96) and at discontinuation. In year 3 and beyond, imaging will be performed Q24W. Primary end points are pathological complete response and event-free survival by BICR. Secondary end points are overall survival, disease-free survival, pathological downstaging, and safety and tolerability. Clinical trial information: NCT04700124.
KEYNOTE-B61: Open-label phase 2 study of pembrolizumab in combination with lenvatinib as first-line treatment for non-clear cell renal cell carcinoma (nccRCC).
Authors: Lee Chung-Han , Li Chenxiang , Perini Rodolfo F. , Hoehn Daniela , Albiges Laurence
Published: June 2021

TPS4595

Background: Most RCCs contain clear cell histology; the remainder of cases are summarized as nccRCC. nccRCC is a heterogeneous group of tumors and, with advanced metastases, survival is uniformly worse than with clear cell RCC (ccRCC) because of the aggressiveness of these cancers and a lack of effective systemic treatment options. Because data are limited for patients with nccRCC, the role of various agents in the treatment of nccRCC is poorly defined and there is no standard of care; treatment guidelines recommend clinical trials as preferred strategy. Inhibition of the PD-1/PD-L1 pathway is an effective treatment option for nccRCC, and pembrolizumab monotherapy has shown efficacy with an acceptable safety profile as first-line treatment. The VEGF TKI lenvatinib has also shown efficacy with a tolerable safety profile as combination therapy with everolimus for nccRCC. Also, in the phase 3 KEYNOTE-581 study (NCT02811861), the combination of lenvatinib + pembrolizumab as first-line therapy showed antitumor activity in patients with metastatic ccRCC, suggesting this combination might be an excellent therapeutic option for nccRCC. The phase 2, open-label, single-arm, KEYNOTE-B61 study (NCT04704219) is being conducted to evaluate pembrolizumab in combination with lenvatinib as first-line treatment for nccRCC. Methods: Patients with centrally confirmed nccRCC, locally advanced/metastatic measurable disease per RECIST v1.1 per blinded independent central review (BICR), no prior systemic therapy for nccRCC, and KPS score ≥70 will be enrolled. Approximately 152 patients will receive pembrolizumab 400 mg every 6 weeks and lenvatinib 20 mg once daily. Pembrolizumab treatment will continue for up to approximately 2 years or until a discontinuation criterion is met (disease progression, unacceptable toxicity, or withdrawal of consent); lenvatinib treatment can continue beyond 2 years or until one of the same discontinuation criterion is met. Participants who discontinue one of the treatments can continue to receive the other treatment as monotherapy. A second-course treatment phase is available for patients who meet specific criteria. CT/MRI will be performed at 12 weeks from the start of treatment, every 6 weeks until week 54, and every 12 weeks thereafter. Adverse events will be monitored throughout the study and graded using CTCAE, version 5.0, guidelines. The primary end point is objective response rate based on RECIST v1.1 per BICR. Secondary efficacy end points for this study are clinical benefit rate, disease control rate, duration of response, progression-free survival, overall survival, and safety. Tertiary/exploratory end points are biomarker analysis and association with clinical response/disease etiopathogenesis. Clinical trial information: NCT04704219.
A phase 3, randomized, double-blind, adaptive, placebo/paclitaxel-controlled study of AVB-S6-500 in combination with paclitaxel in patients with platinum-resistant recurrent ovarian cancer (GOG-3059/ENGOT OV-66/AVB500-OC-004).
Authors: Fuh Katherine Cynthia , Herzog Thomas J. , Moore Kathleen N. , Myers Tashanna K. N. , Rimel BJ , Liu Joyce F. , Secord Angeles Alvarez , Hamilton Erika P. , Reid Thomas J. , Lewin Sharyn Nan , Mullen Mary M , Mills Kathryn A. , Anderson Randy , Rangwala Reshma A.
Published: June 2021

TPS5605

Background: The AXL receptor and its activating ligand, GAS6, are important drivers of metastasis and therapeutic resistance in human cancers. This signaling axis represents an attractive target for therapeutic intervention, but the strong picomolar binding affinity between endogenous GAS6 and AXL and the promiscuity of small molecule AXL inhibitors have presented a barrier to specific and potent inhibition of AXL. AVB-S6-500 is a highly sensitive and specific inhibitor of AXL, with ̃200-fold higher affinity than wild-type (WT) AXL. AVB-S6-500 binds GAS6, the sole ligand of AXL, inhibiting its interaction with AXL thereby dramatically reducing AXL signaled invasion and migration of highly metastatic cells in vitro and inhibiting metastatic disease in nonclinical models of aggressive human cancers. A Phase 1b study in platinum resistant ovarian cancer showed no dose limiting toxicities and established a recommended Phase 2 dose of 15mg/kg administered every 2 weeks. Longer progression free survival (PFS) and overall survival (OS) times were observed in patients who had not been previously treated with bevacizumab. Furthermore, retrospective analyses demonstrated that serum soluble AXL to GAS6 ratio may identify patients more likely to respond to this therapy. Methods: Patients with high grade serous, platinum resistant ovarian cancer, who have received no more than 4 prior therapy regimens will be randomized 1:1 to AVB-500 + PAC or PAC + placebo. Patients will be stratified by recurrence after last platinum regimen (<3, 3-6 months), prior lines (1-2, 3-4), and prior bevacizumab (yes, no). The primary endpoint is PFS by RECIST v 1.1 as assessed by the investigator, with OS a key secondary endpoint. The study design is adaptive; with two interim analyses addressing conditional power in the bevacizumab treated subset, and in a serum soluble AXL, GAS6 biomarker subset, respectively, with interim results used to define the final target population. Simulations confirm a nominal one-sided type 1 error below 0.025, and show >90% statistical power for PFS under the following assumptions of PFS medians. Study recruitment began in Q1. Clinical trial information: NCT04729608.
FLORA-5: Front-line chemoimmunotherapy (Paclitaxel-Carboplatin-Oregovomab [PCO] versus chemotherapy (Paclitaxel-Carboplatin-Placebo [PCP]) in patients with advanced epithelial ovarian cancer (EOC)—Phase III double-blind placebo controlled multinational study.
Authors: Secord Angeles Alvarez , Gupta Sunil , Reddick Cathy , Chauhan Jyoti , Gill Sarah , Schorge John O. , Gold Michael , Tewari Devansu , Breed Christopher A , Braly Patricia S. , Kuo Dennis Yi-Shin , Modesitt Susan C. , Holloway Robert W.
Published: June 2021

TPS5606

Background: Oregovomab binds tumor-associated CA125 rendering the target antigen CA125 more immunogenic or “neoantigen-like” through altered and enhanced antigen processing and presentation to specific T cells. This phenomenon is hypothesized to bypass tumor-associated immune suppression when administered in combination with chemotherapy. In a randomized phase II study, immunization with oregovomab in a schedule-dependent combination with paclitaxel and carboplatin induced tumor immunity and demonstrated significant improvement in PFS (median (months) 41.8 PCO vs 12.3 PCP, HR 0.44 p = 0.0027, and OS median N.E. PCO vs 43.2 PCP HR O.34 (p = 0.0077)) in patients with previously untreated EOC. The FLORA-5, the definitive confirmatory global registration trial, is currently recruiting patients in the front-line setting. Methods: The study is a phase 3, multicenter, double-blind, placebo-controlled clinical trial. Optimally debulked patients with FIGO III/IV EOC and serum CA125 > 50 U/ml receiving adjuvant (Cohort 1) or neoadjuvant (Cohort 2) chemotherapy will be randomized post-surgery to paclitaxel and carboplatin with or without oregovomab. Patients with germline BRCA1/2 mutations will be excluded. Chemotherapy will be administered every 3 weeks in both cohorts. Oregovomab/placebo is administered simultaneously at cycles 1, 3, and 5 of chemotherapy with a single maintenance dose at 12 weeks following cycle 5 in Cohort 1. Neoadjuvant patients (Cohort 2) will be administered oregovomab/placebo post interval debulking surgery at cycles 4 and 6 with maintenance doses at 6- and 18-weeks following cycle 6. No other post front-line maintenance therapy is permitted. The primary objective is PFS determined by RECIST 1.1 criteria. Cohort 1 will recruit 372 patients with a 90% power to detect a difference with an alpha of 0.025 and a hazard ratio of 0.65 when 252 PFS events have been observed. Cohort 2 will be analyzed separately recruiting 232 patients with a 90% power to detect a difference with an alpha of 0.025 and a hazard ratio of 0.60 when 165 PFS events have been observed. An interim analysis for futility will be performed. Secondary objectives include OS, frequency and severity of adverse events, and quality of life. Exploratory objectives include iRECIST, TFST, TSST, PFS2, and evaluation of potential biomarkers. The study is actively enrolling in the US with 9 patients enrolled at time of submission. Centers in Europe, South America and Asia are expected to begin accruing shortly. Clinical trial information: NCT04498117.