bluuebunny/crossref_metadata_2025 huggingface dataset:
Design and rationale of MASTERKEY-115 phase II trial of talimogene laherparepvec (T-VEC) with pembrolizumab (pembro) in patients with advanced melanoma who progressed on prior anti-programmed cell death-1 (anti-PD-1) therapy.
Authors: Chesney Jason Alan , Milhem Mohammed M. , Chaney Marya F. , Gokani Priya , Snyder Wendy , Robert Caroline
Published: May 2020

TPS10079

Background: Treatment options are limited for patients with advanced metastatic or unresectable melanoma, especially after anti-PD-1 failure. T-VEC is an intralesional oncolytic viral immunotherapy designed to selectively replicate in tumor cells and induce local and systemic antitumor response. Pembro promotes T cell activity by blocking PD-1 receptors. Combining T-VEC and pembro may produce robust antitumor activity by increasing T cell activation and blocking T cell inhibition, with a tolerable safety profile. The MASTERKEY-115 trial will evaluate safety and efficacy of T-VEC combined with pembro in patients with advanced melanoma who experienced progressive disease (PD) on prior anti-PD-1 therapy. Methods: NCT04068181 is a phase 2, open-label, single-arm, multicenter trial of T-VEC with pembro in patients with advanced melanoma and PD on prior anti-PD-1. The study is expected to enroll approximately 100 patients and comprises 4 cohorts. Cohorts 1 and 2 will receive anti-PD-1 in a locally recurrent or metastatic setting and experienced PD within 12 weeks of the last anti-PD-1 dose (Cohort 1: PD or stable disease prior to confirmed PD; Cohort 2: complete or partial response prior to confirmed PD). Cohorts 3 and 4 will receive adjuvant anti-PD-1 and were disease-free for < 6 months (Cohort 3) or ≥ 6 months (Cohort 4) prior to confirmed PD. Enrollment criteria include adults with histologically confirmed unresectable or metastatic stage IIIB–IVM1d melanoma, measurable and injectable disease, ECOG PS 0-1, and prior anti-PD-1 (≥ 2-3 consecutive cycles within 8 weeks, immediate prior treatment before enrollment). The primary endpoint is objective response rate per modified RECIST. Key secondary endpoints assess efficacy (objective response rate, best overall response, complete response rate, response duration, durable response rate, disease control rate, progression-free survival, overall survival), safety (incidence of treatment-emergent and treatment-related adverse events, abnormal laboratory tests), and time to subsequent anticancer therapy. The study began enrolling patients in January 2020 and enrollment is ongoing. Clinical trial information: NCT04068181.
A phase I study of Aurora kinase A inhibitor LY3295668 erbumine as a single agent and in combination in patients with relapsed/refractory neuroblastoma.
Authors: DuBois Steven G. , Kremer Jill D. , De Wilde Bram , Jacobsen Chad , Aerts Isabelle , Mosse Yael P. , Maris John M. , Lithio Andrew , Gosberg Andreas , Banks C.L. , Tate Courtney , Dowless Michele , Gong Xueqian , Stancato Louis , Bell-McGuinn Katherine M. , Park Julie R. , Pearson Andrew DJ , Marachelian Araz
Published: May 2020

TPS10561

Background: Aurora kinase A (AurA) has been implicated in high-risk neuroblastoma, including roles stabilizing and increasing expression of MYCN protein. AurA impacts the function of MYCN in mediating transcription in a cell cycle dependent manner, suggesting that neuroblastoma and other MYC/MYCN-driven tumors may be sensitive to AurA inhibition. LY3295668 is a selective AurA inhibitor. The lack of AurB inhibitory activity is hypothesized to minimize on-target hematologic toxicity associated with AurB inhibition. The molecule’s selectivity is intended to allow for continuous dosing at exposures associated with > 90% target inhibition at trough. In an analysis of LY3295668 antiproliferative effects in 560 cancer cell lines, neuroblastoma was among the most sensitive histologies tested. This screen also separately evaluated genomic predictors of response to LY3295668, with MYC/ MYCN amplification identified as among the strongest predictors of sensitivity to this agent. LY3295668 is currently being evaluated in early phase adult trials. The current trial (J10-MC-JZHD) was uniquely designed to hasten time to first-in-child oncology development for a rare unmet need of relapsed/refractory neuroblastoma patients. Methods: Study J1O-MC-JZHD (NCT04106219) is a multicenter, dual collaboration (NANT and ITCC), randomized, open-label, Phase 1 study of oral LY3295668 in children with relapsed/refractory neuroblastoma. A rolling 6 design will be followed for dose escalation in both a monotherapy cohort and a combination cohort testing LY3295668 together with cyclophosphamide and topotecan. The starting monotherapy dose will be equivalent to 80% of the adult maximum tolerated dose. Key eligibility criteria include recurrent/refractory neuroblastoma not amenable to curative treatment, age 2-21 years, mandatory archival tissue submission, ability to swallow capsules, and adequate hematologic and organ function. LY3295668 is administered in capsule form orally BID continuously. Primary objectives include assessments of safety and tolerability of study drug to identify RP2D as monotherapy and combination, and assess antitumor activity. Secondary objectives include assessment of the pharmacokinetic profile as monotherapy and in combination, and assessment of the relationship between study drug exposure and efficacy. Following determination of the RP2Ds, an expansion phase will randomize patients to monotherapy or to the combination arm. Enrollment began 16 Dec 2019 and is ongoing. Clinical trial information: NCT04106219.
A phase II trial of nivolumab (NIVO) + palbociclib (PAL) + anastrozole (ANA) in postmenopausal women and men with estrogen receptor (ER)+/human epidermal growth factor 2 (HER2)- primary breast cancer (BC): CheckMate 7A8.
Authors: Tolaney Sara M. , Jerusalem Guy , Salgado Roberto , Liu Xiaochun , Chen Tian , Zhang Hongxia , Roberts Mustimbo , Zardavas Dimitrios , Prat Aleix
Published: May 2020

TPS1105

Background: Cyclin-dependent kinase 4/6 (CDK 4/6) inhibition coupled with ER signaling blockade is an efficient treatment approach for patients (pts) with metastatic hormone receptor-positive, HER2− BC. Preclinical data suggest synergistic activity of CDK 4/6 inhibition and PD-1 blockade; in a syngeneic mouse tumor model, improved efficacy and complete tumor regression were observed with phased administration of ABE + PD-L1 therapy. Methods: CheckMate 7A8 (NCT04075604) is a randomized, noncomparative, multicenter, phase 2 study evaluating PAL + ANA +/- NIVO in postmenopausal pts with ER+, HER2− primary BC. After determining safe doses for NIVO combination regimens in the safety run-in phase, pts will be randomized in a 4:4:3 ratio to 1 of 3 treatment arms (Table) stratified by PD-L1 expression, node status and tumor size. Following treatment, all pts will undergo surgery and safety follow-up. Eligible pts are postmenopausal women and men with newly diagnosed, untreated, histologically confirmed ER+, HER2− BC with primary tumor ≥ 2 cm; suitable for neoadjuvant endocrine monotherapy and surgery; ECOG PS of 0–1; have baseline tumor tissue available; willing to undergo on-treatment research biopsy and tissue collection at surgery. Primary endpoints are number of pts with occurrence of dose-limiting toxicity (safety run-in phase) and residual cancer burden 0–I rate by central assessment at time of definitive surgery (randomized phase). Secondary endpoints include safety and tolerability, pathologic complete response, objective response rate and breast-conserving surgery rate. Key exploratory endpoints include biomarkers indicative of pharmacodynamic changes and potentially predicting treatment sensitivity. Interim analyses are planned. The study is currently enrolling. Clinical trial information: NCT04075604 . [Table: see text]
[OPTIMAL 3] A phase III trial to evaluate the efficacy and safety of DHP107 (Liporaxel, oral paclitaxel) compared to Taxol (IV paclitaxel) as first line therapy in patients with recurrent or metastatic HER2 negative breast cancer (BC) (NCT03315364).
Authors: Kim Sung-Bae , Zhang Qingyuan , Sun Tao , Seo Jae Hong , Lee Keun Seok , Kim Tae-Yong , Tong Zhongsheng , Park Kyong Hwa , Moon Yong Wha , Wang Shusen , Li Wei , Yang Yaewon , Wang Jingfen , Wang Xian , Choi Jonggwon , Lee Ji Eun , Yoon Koung Eun , Chung Seongwuen , Xu Binghe , Sohn Joohyuk
Published: May 2020

TPS1106

Background: Paclitaxel is a microtubule-stabilizing drug used for various cancers including breast cancer (BC) and gastric cancer (GC). DHP107 is an oral paclitaxel solution formulated with non-toxic excipients using DH-LASED technology, which doesn’t require pre-treatment. DHP107 demonstrated comparable efficacy and safety to IV paclitaxel for patients with advanced GC (Ann Oncol 2018), and was market approved as the first oral paclitaxel in 2016 for GC in Korea. In previous OPTIMAL phase II study, the primary endpoint objective response rate (ORR) was 54.5% in HER2 negative metastatic BC (MBC) patients and 44.4% in triple negative BC (TNBC) patients. Disease control rate (DCR) was 90.9% by the investigators’ assessment. Toxicity was manageable (2019 ESMO). OPTIMAL phase III is being conducted in Korea, China and Eastern Europe based on this result and another phase II study (OPERA) is being performed in USA. Methods: OPTIMAL 3 study is a multinational, multi-center, randomized and open-label trial enrolling HER2 negative (HR+/HER2- or TNBC) recurrent or metastatic BC patients. Patients are randomized to either study (DHP107) or control group (IV paclitaxel) in a 1:1 ratio and stratified by disease free interval (DFI≤48 weeks vs >48 weeks), visceral metastasis status (visceral vs non-visceral) and country. Patients are administrated with DHP107 (200mg/m2 p.o. bid) or IV paclitaxel (80mg/m2 infused) on D1, 8, 15, q4wks. Tumor assessments are performed on every 8 weeks (±7 days) from C1D1 until disease progression (RECIST V1.1). Key inclusion & exclusion criteria are hormone receptor (ER/PR) positive or negative, HER2 negative, ECOG performance status ≤1 and no prior chemotherapy in recurrent or metastatic disease. The primary endpoint is progression free survival (PFS). Secondary endpoints include ORR, overall survival (OS), time to treatment failure (TTF), DCR, quality of life (QoL) and safety. Total target number of patients is 476 with an estimated 10% drop-out rate. The test is based on non-inferiority hypothesis (HR=1.33) with 80% power. The primary endpoint will be analyzed using a one-sided test at a 2.5% significance level, and other endpoints will be analyzed using a two-sided test at a 5% significance level, with 95% confidence interval. The first subject was enrolled in Jan 2019 and recruitment is ongoing and is expected to be completed in Dec 2020. Final results of this study will be announced by the end of 2022. Clinical trial information: NCT03315364 .
CONTESSA TRIO: A multinational, multicenter, phase (P) II study of tesetaxel (T) plus three different PD-(L)1 inhibitors in patients (Pts) with metastatic triple-negative breast cancer (TNBC) and tesetaxel monotherapy in elderly pts with HER2-metastatic breast cancer (MBC).
Authors: Tolaney Sara M. , Bondarenko Igor , Chan Arlene , Dacosta Noshir Anthony , Izarzugaza Yann , Kim Gun Min , Liu Mei-Ching , Perez Maria EVA , Lu Yen-Shen , Oliveira Mafalda , Ow Samuel Guan Wei , Pavic Michel , Rugo Hope S. , Schwartzberg Lee S. , Stradella Agostina , Tan Tira Jing Ying , Wright-Browne Vance , O'Connell Joseph P. , Wei Thomas , Mittendorf Elizabeth A.
Published: May 2020

TPS1111

Background: Chemotherapy treatments with robust efficacy that preserve quality of life are needed. T is a novel, oral taxane that has potential advantages over currently available taxanes, including: oral administration with a low pill burden and once every 3 week (Q3W) dosing; no observed hypersensitivity reactions; preclinical evidence of central nervous system (CNS) penetration; and improved activity against chemotherapy-resistant tumors. More than 600 pts have been treated with T in clinical studies. T had robust monotherapy activity in a P2 study in 38 pts with HER2-, HR+ MBC, with a confirmed objective response rate (ORR) per RECIST 1.1 of 45%. Methods: CONTESSA TRIO is a 2-cohort, multinational, multicenter, P2 study. In Cohort 1, 90 pts (potential expansion to up to 150 pts) with metastatic TNBC who have not received prior chemotherapy for advanced disease will be randomized 1:1:1 to receive T at 27 mg/m2 Q3W plus either: (1) nivolumab at 360 mg Q3W; (2) pembrolizumab at 200 mg Q3W; or (3) atezolizumab at 1,200 mg Q3W. Nivolumab and pembrolizumab (PD-1 inhibitors) and atezolizumab (a PD-L1 inhibitor) are approved for the treatment of multiple types of cancer; atezolizumab, in combination with nab-paclitaxel, was recently approved in the US for the treatment of metastatic TNBC. The dual primary endpoints for Cohort 1 are ORR and progression-free survival (PFS). A sample size of 30 pts in each PD-(L)1 inhibitor treatment group has approximately 70% power to detect an ORR difference of ≥ 35% between the treatment group with the highest ORR and the treatment group with the lowest ORR. Secondary endpoints include duration of response (DoR) and overall survival (OS). Efficacy results for each of the 3 PD-(L)1 inhibitor combinations will be assessed for correlation with the results of each of the 3 approved PD-L1 diagnostic assays. CONTESSA TRIO is the first randomized clinical study to compare 3 approved PD-(L)1 inhibitors. In Cohort 2, 40 elderly pts (potential expansion to up to 60 pts) with HER2- MBC who have not received prior chemotherapy for advanced disease will receive T monotherapy at 27 mg/m2 Q3W. The primary endpoint for Cohort 2 is ORR. A sample size of 40 will allow the ORR to be estimated with a maximum standard error of < 8%. Secondary endpoints include PFS, DoR and OS. Pts with CNS metastases are eligible for both cohorts. The study was initiated in March 2019. Clinical trial information: NCT03952325 .
NCI protocol 10250: A phase II study of temozolomide and olaparib for the treatment of advanced uterine leiomyosarcoma.
Authors: Ingham Matthew , Allred Jacob B , Gano Katherine , George Suzanne , Attia Steven , Burgess Melissa Amber , Boikos Sosipatros Alexandros , Bui Nam , Chen James Lin , Close Julia Lee , Seetharam Mahesh , Thaker Premal H. , Schwartz Gary K.
Published: May 2020

TPS11570

Background: Soft tissue sarcoma (STS) is a heterogenous malignancy of mesenchymal origin and includes more than 50 biologically distinct subtypes. Leiomyosarcoma (LMS), a neoplasm of smooth muscle origin, represents up to 20% of STS. The uterus is the most common site of origin in women. Advanced uterine LMS (uLMS) is initially treated with gemcitabine + docetaxel or anthracycline-based chemotherapy but overall survival remains < 24 mos. Besides recurrent alterations in RB1, TP53 and ATRX, insight into cancer biology of uLMS remains limited. Recently, whole exome and transcriptomic sequencing studies suggest uLMS harbors characteristic defects in the homologous recombination (HR) DNA repair pathway and thus features of BRCAness. HR-deficient cancers are unable to efficiently repair double-stranded DNA breaks and appear sensitive to treatment with poly ADP-ribose polymerase (PARP) inhibitors. In preclinical studies, the combination of temozolomide (T), an alkylating agent, and olaparib (O), a PARP inhibitor, was synergistic and markedly suppressed proliferation of uLMS models. A recent phase II study in small cell lung cancer defined the RP2D for T + O where the chief toxicity was myelosuppression. Methods: NCI Protocol #10250 is a single-arm, open-label, multi-center phase II clinical trial of T + O in patients with advanced uLMS. Eligible pts have ECOG PS ≤ 2, progression on ≥ 1 prior line of therapy and disease measurable by RECIST v1.1 and amenable to image-guided biopsy. Pts receive T 75 mg/m2 PO daily + O 200 mg PO BID on days 1-7 in 21-day cycles. The 1° endpoint is objective response rate (ORR). A one-stage binomial design is used to evaluate for an ORR ≤ 10% (null hypothesis) versus ≥ 35% (alternative hypothesis). The design calls for 22 patients. If 5/22 respond, the treatment is promising. This design yields 93% power and 1-sided type I error of 6%. 2° endpoints include progression free survival and safety. All pts undergo tumor biopsies pre-treatment and during cycle 2. Tissue is used for correlative analysis interrogating uLMS for features of BRCAness through (a) whole exome sequencing/RNAseq to evaluate for alterations in HR pathway component genes, (b) RAD51 foci formation by immunohistochemistry as a functional marker of HR pathway activity and (c) protein expression of Schlafen family member number 11 (SLFN11), an emerging biomarker for PARPi. Tumors are also evaluated for MGMT protein expression, a known determinant of sensitivity to T. The study opened to accrual 10/2019. Clinical trial information: NCT03880019.
The effect of longitudinal exercise programming in breast cancer patients.
Authors: Fukui Jami Aya , Cheng Shirley , Lim Shannon , Shepherd John , Yamada Paulette , Teranishi-Hashimoto Cheri
Published: May 2020

TPS12124

Background: Obesity and weight gain are significant concerns for breast cancer survivors. Obesity at diagnosis is an established negative prognostic factor and studies suggest that post-diagnosis weight gain may increase risk for recurrence and decrease disease free survival. Various interventions such as dietary modification, physical activity, individualized counseling, cognitive behavioral therapy, and combinations of these interventions have been studied in order to identify strategies for weight loss in breast cancer survivors. However, one of the main challenges have been to show sustainability in these interventions. Given the adverse consequences of weight gain after diagnosis, continued efforts to identify appropriate weight management interventions aimed at promoting overall health and long term survivorship are needed. Methods: We have opened an investigator initiated Breast Cancer Exercise Study that provides a tailored exercise program and body health assessments for breast cancer patients along their treatment journey. We are enrolling women diagnosed with breast cancer up to 2 years after their diagnosis into a two 12-week exercise program. Participants’ biometrics and physical assessments will be assessed at baseline to determine the appropriate exercise intensity to implement. Women will attend private 1:1, 90min sessions, 3 days/week. At the end of the initial 12-week program, biometric assessments are again performed and participants are then randomized to either: a) continue with individual exercise classes, 2 days/week or b) continue with group exercise classes, 2 days/week. The study follows their long term outcomes including cancer recurrence, exercise adherence as well as quality of life symptoms. The functional health assessment and subsequent personalized exercise program utilizes kinesiology students from University of Hawaii-Manoa during their clinical practicum and is based at our community partner facility the Rehabilitation Hospital of the Pacific. Body assessments and other biomarkers are evaluated through expertise at University of Hawaii Cancer Center. Collectively, our study exemplifies our partnership with community facilities, utilizes cutting edge research and incorporates local students, to provide an important health program for cancer patients all the while enriching our understanding of the unique patient population. The results of this project may help to develop standardized exercise protocols for breast cancer survivors and provide insights to other important health concerns. Clinical trial information: NCT04013568 .
Phase III TRIDENT trial: Radiation and temozolomide +/- tumor treating fields in newly diagnosed glioblastoma.
Authors: Shi Wenyin , Kleinberg Lawrence , Jeyapalan Suriya A. , Goldlust Samuel Aaron , Nagpal Seema , Reardon David A. , Combs Stephanie E , Roberge David , Nishigawa Ryo , Glas Martin
Published: May 2020

TPS2580

Background: Tumor treating fields (TTFields) is a non-invasive, regional antimitotic treatment approved as a standard of care for glioblastoma (GBM). In the EF-14 phase III trial, TTFields (200 kHz) plus temozolomide (TMZ) significantly increased the survival of patients with newly diagnosed GBM (ndGBM) without increase in systemic toxicity. TTFields-related AEs were mainly skin AEs. In preclinical models, TTFields increase the therapeutic effects of radiation therapy (RT). A pilot study showed that TTFields concomitant with RT and TMZ is well tolerated. The benefit of concomitant TTFields with RT and TMZ will be tested in this phase III TRIDENT randomized trial. Methods: TRIDENT is an international phase III randomized trial comparing standard RT with TMZ vs the triple combination of RT plus TMZ with concomitant TTFields. RT is delivered through the TTFields arrays. Patients in both arms will receive maintenance TTFields with TMZ. TTFields (200 KHz) will be delivered >18 hours/day using Optune. Patients will continue TTFields treatment until second recurrence. Patients with pathologically confirmed newly ndGBM, ≥ 18 years, KPS ≥ 70, either sex, post-surgery or biopsy, who are amenable for RT/TMZ therapy will be enrolled. Patients will be stratified by extent of resection and MGMT promoter methylation status. The primary endpoint is overall survival (OS). Secondary end points include: progression free survival (PFS; RANO), 1- and 2-year survival rates, overall radiological response (ORR; RANO), progression-free survival (PFS2, PFS6, PFS12); severity and frequency of AEs (CTCAE V5.0); pathological changes in resected GBM tumors post treatment; quality of life (EORTC QLQ-C30); and correlation of OS to TTFields compliance. The hypothesis is that concomitant TTFields with radiation and TMZ will significantly improve OS as compared to radiation and TMZ alone. The sample size is 950, with 475 in each arm to detect a HR <0.8 with a 5% type I error. Survival will be measured from the time of randomization until date of death. At the time of analysis, patients who are lost to follow-up or still on protocol follow-up will be censored at the last date known to be alive.
ZW25, an anti-HER2 bispecific antibody, plus chemotherapy with/without tislelizumab as first-line treatment for patients with advanced HER2-positive breast cancer or gastric/gastroesophageal junction adenocarcinoma: A phase 1B/2 trial-in-progress.
Authors: Oh Do-Youn , Chung Hyun Cheol , Im Young Hyuck , Yen Chia Jui , Chao Yee , Li ZheZhen , Wang Xin , Wang Jin , Li Huiyan , Kang Yoon-Koo
Published: May 2020

TPS3145

Background: ZW25 is a novel HER2-targeted antibody that binds two distinct extracellular domains of HER2, allowing for multiple mechanisms of action, including activation of ADCC and inhibition of ligand-dependent and -independent cellular growth. ZW25 is well tolerated and showed single-agent antitumor activity in patients (pts) with advanced HER2-positive cancers. Previous reports suggested that tislelizumab, an investigational anti-PD-1 antibody engineered to minimize binding of FcgR on macrophages in order to abrogate antibody-dependent phagocytosis, was generally well tolerated and had antitumor activity alone and in combination with chemotherapy in pts with advanced solid tumors. Combining HER2-targeted agents with chemotherapy has resulted in improved survival; the highly immunogenic nature of HER2 tumors has led to the development of therapies combining anti-HER2 therapies with immune checkpoint blockade. Methods: This open-label, two cohort phase 1B/2 study is designed to evaluate ZW25 plus chemotherapy ± tislelizumab as first-line therapy in pts (n≈50) with HER2-positive metastatic breast cancer (mBC; cohort 1) or advanced gastric/gastroesophageal junction adenocarcinoma (GC/GEJC; cohort 2). In cohort 1, pts with HER2-positive (IHC3+ or ISH amplified) mBC must be treatment-naïve for metastatic disease and will receive intravenous (IV) ZW25 30 mg/kg plus docetaxel 75 mg/m2 IV once every 3 weeks (Q3W). In cohort 2, treatment-naïve pts with HER2-positive (IHC3+ or IHC2+ with ISH amplification) advanced GC/GEJC will receive ZW25 30 mg/kg plus tislelizumab 200 mg IV and chemotherapy (CAPOX regimen: capecitabine 1000 mg/m2 twice daily and oxaliplatin 130 mg/m2 IV) Q3W. A safety lead-in phase is designed for the first six pts in cohort 2, followed by dose expansion after a safety monitoring committee review. Primary endpoints are the safety/tolerability profile and objective response rate; secondary endpoints include duration of response, time to response, progression-free survival, disease control rate, and overall survival. Clinical trial information: Registered, NCT number pending will provide as soon as available .
A phase Ia/Ib, open-label first-in-human study of the safety, tolerability, and feasibility of gene-edited autologous NeoTCR-T cells (NeoTCR-P1) administered to patients with locally advanced or metastatic solid tumors.
Authors: Chmielowski Bartosz , Ejadi Samuel , Funke Roel , Stallings-Schmitt Todd , Denker Mitch , Frohlich Mark Walter , Franzusoff Alexis J. , Abedi Mehrdad , Cristea Mihaela C.
Published: May 2020

TPS3151

Background: Neoepitopes (neoE) derived from private tumor-exclusive mutations represent compelling targets for personalized TCR-T cell therapy. An ultra-sensitive and high-throughput process was developed to capture tumor mutation-targeted CD8 T cells from patient blood. NeoTCRs cloned from the captured CD8 T cells, when engineered into fresh CD8 and CD4 T cells, effected killing of patients’ autologous tumor cells in vitro. These observations have been leveraged for the development of a fully personalized adoptive T cell therapy (NeoTCR-P1). A Phase 1 clinical trial testing NeoTCR-P1 in subjects with solid tumors is ongoing (NCT03970382). Methods: During the initial trial phase, escalating doses of NeoTCR-P1 T cells administered without and with IL-2 in the regimen, and following conditioning chemotherapy, will be evaluated in subjects with advanced or metastatic solid tumors (melanoma, urothelial cancer, colorectal cancer, ovarian cancer, HR+ breast cancer, and prostate cancer). The objective of the Phase 1a study is to establish a recommended Phase 2 dose. Primary endpoints include the incidence and nature of DLTs and overall process feasibility. The proliferation, persistence, and trafficking of NeoTCR-T cells will be characterized. In the expansion trial phase, preliminary anti-tumor activity of NeoTCR-P1 will be assessed in selected tumors. The combination of NeoTCR-P1 dosing plus nivolumab will be tested in a Phase 1b study. Conclusion: This is the first clinical study of an autologous, fully personalized adoptive T cell therapy directed against private tumor-exclusive mutations, generated without using recombinant viral vectors. Clinical trial information: NCT03970382 .
Alliance A151804: Establishment of a national biorepository to advance studies of immune-related adverse events.
Authors: Kozono David E. , Sharon Elad , Le-Rademacher Jennifer , Twohy Erin , Zemla Tyler J. , Wen Yujia , Watson Mark , Dib Elie G. , Kirkwood John M. , Lyman Gary H. , Naidoo Jarushka , Nixon Andrew B. , Mittendorf Elizabeth A.
Published: May 2020

TPS3154

Background: Immune-related Adverse Events (irAEs) are rare but serious sequelae of treatment with immuno-oncology (IO) therapeutics. These therapeutics, including monoclonal antibodies targeting programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), have had transformative effects on outcomes for patients (pts) with advanced cancers. Although most pts tolerate the therapies well, a few experience irAEs ranging in severity up to life-threatening. These irAEs involve diverse organs including the heart, kidney, liver and lung, and gastrointestinal, musculoskeletal, central and peripheral nervous systems. Because of the relatively low incidence and wide variety of irAEs due to various immunotherapies for multiple tumor types, establishment of an efficient centralized repository for acquisition and organized distribution of well-annotated biospecimens is vital for translational studies that improve understanding of the molecular pathogenesis and treatment of these significant toxicities. Methods: This multi-institutional study is open at sites across the National Clinical Trial Network to pts who received ≥ 1 IO therapeutics (e.g., CTLA-4, PD-1 or PD-L1 inhibitor) and experienced 1) ≥ 1 serious (grade 3–5) adverse events that are likely immune-related, 2) rare infection or 3) tumor hyperprogression. IrAEs of interest include myocarditis, colitis, hepatitis, nephritis, myositis, pneumonitis, meningitis/encephalitis, dermatitis, endocrinopathies and neuropathy. Pts may be on an NCTN or non-NCTN IO trial or be receiving standard-of-care therapy. Registration must occur ≤ 72 hours after confirmation of the irAE event. Clinical data are collected at registration, 1 month after registration and for up to 1 year. Biospecimens (tumor blocks, biopsies of inflammatory tissues used to establish irAE diagnosis, and serial blood samples for isolation of plasma, serum and peripheral blood mononuclear cells) are collected at 1-2 timepoints. Stool samples are collected from pts experiencing colitis. Imaging data are collected for pts with hyperprogression or pneumonitis. Goal accrual is 240 pts. Biospecimens and data will be made available to investigators following future submission and approval of proposals. Support: U10CA180821, U10CA180882, U24CA196171; U10CA180820 (ECOG-ACRIN); U10CA180888 (SWOG); U10CA180868 (NRG); https://acknowledgments.alliancefound.org; Clinical trial information: NCT04242095 .
Safety and efficacy of neoadjuvant intravesical oncolytic MV-NIS in patients undergoing radical cystectomy (RC) for urothelial carcinoma but ineligible for neoadjuvant cisplatin-based chemotherapy.
Authors: Leibovich Bradley C. , Miest Tanner , Young Paul R , Gonzalgo Mark L. , Boorjian Stephen A. , Tollefson Matthew K. , Karnes R. Jeffrey , Frank Igor , Lyon Timothy D. , Kroeninger Tessa , Naik Shruthi , Reckner Monica , Diaz Rosa M , Kaesshaefer Stephen , Whitelaw Ena , Brunton Bethany A , Newsom Alysha , Packiriswamy Nandakumar , Peng Kah Whye , Bexon Alice Susannah
Published: May 2020

TPS3172

Background: Bladder cancer is a leading cause of cancer death in the United States. Over 90% of bladder cancer cases are urothelial carcinomas (UC) that may present as a non-muscle-invasive (NMIBC) or muscle-invasive disease (MIBC). Standard of care for NMIBC includes transurethral resection of bladder tumor (TURBT), intravesical chemotherapy and immunotherapy with Bacillus Calmette-Guerin (BCG). Patients (pts) with high-grade BCG-refractory NMIBC or MIBC undergo RC, which involves complete bladder removal and pelvic lymphadenectomy. RC severely impacts quality of life with significant morbidity. Oncolytic viruses are showing promise in UC, and MV-NIS has proven efficacy in other tumor types. MV-NIS is an investigational oncolytic measles virus with an excellent safety profile, irrespective of route of administration (n > 100). MV-NIS-related adverse events are limited to infusion reactions and transient CBC changes, and little local toxicity is anticipated with intravesical therapy. Clinical efficacy of this oncolytic may be related to absence of measles immunity. Based on this, the clinical strategy for MV-NIS is focused on targeting immune-privileged sites via intra-tumoral or intravesical routes, alone or in combination with checkpoint inhibitors. We hypothesize that intravesical therapy with oncolytic MV-NIS can improve clinical outcomes for (a) BCG refractory NMIBC pts to avoid or delay the need for RC; and (b) MIBC pts undergoing RC. Methods: This study is enrolling pts undergoing RC who are ineligible to receive neoadjuvant chemotherapy. The trial has 2 stages to (a) determine the safety and tolerability of intravesical MV-NIS, and (b) assess preliminary efficacy. Part (a) includes 4-24 pts in a timing cohort with doses administered at increasing durations (1-4 weeks) prior to RC to establish safety of a single MV-NIS dose. Part (b) includes an expansion cohort (n = 12) to evaluate the safety and efficacy of 2 intravesical doses of MV-NIS at 2-week intervals prior to RC. Safety is assessed using NCI-CTCAE V5 and Clavien-Dindo grading of operative complications. The efficacy endpoint is pathologic stage at time of RC (pT0 rate), which can be compared to pre-study TURBT stage. Additional exploratory studies include PK and PD analyses in urine, blood and tumor. Enrollment is ongoing at 2 Mayo Clinic sites (Rochester, MN and Jacksonville, FL) and the study has now progressed from the timing cohort into the expansion cohort. Clinical trial information: NCT03171493 .
A phase I trial of aerosol gemcitabine for the treatment of patients with solid tumors and lung metastases.
Authors: Gordon Nancy Beatriz , Kleinerman Eugenie , Sheshadri Ajay , Blanco David , Yedururi Sireesha , Morani Ajaykumar , Gill Jonathan Benjamin , Harrison Douglas James , Herzog Cynthia E. , Livingston J Andrew , Benjamin Robert S. , Gorlick Richard Greg , Mireles Maria E , Kawedia Jitesh D , Daw Najat C.
Published: May 2020

TPS3645

Background: Pre-clinical studies of aerosol gemcitabine (GCB) in mice and dogs with osteosarcoma (OS) lung metastases demonstrated therapeutic efficacy. Aerosol GCB administered once weekly proved to be safe in adults with lung cancer. Direct delivery of GCB to the lungs via inhalation may offer higher drug concentration in the tumor with fewer side effects. We initiated a Phase I study to evaluate the feasibility and safety of aerosol GCB treatment in patients >12 years with solid tumors and lung metastases (2015-0720- NCT03093909). Methods: Eligibility criteria: 1) Diagnosis of solid tumor with lung metastases, 2) willing to comply with protocol therapy, 3) adequate organ function, 4) patient age > 12 and < 50 years, 5) good performance status, 6) resolution of all acute toxic effects of any prior anti-cancer therapy, and 7) no radiotherapy within 2 weeks. Patients who previously received systemic GCB are eligible. Objectives: To determine the maximum tolerated dose (MTD) and toxicities of aerosol GCB, to evaluate for drug spillover into the circulation, and to preliminarily assess the anti-tumor activity. Correlative studies include effect of aerosol GCB on immune cell infiltration in the lung, autophagy, apoptosis, heat shock protein 27, evidence of DNA strand breaks (gH2AX) and expression of human equilibrative nucleoside transporter-1.Aerosol GCB is administered via a breath-induced nebulizer twice a week in 28-day cycles. A maximum of 6 dose levels will be studied; the starting dose is 0.75 mg/kg twice weekly. If no progressive disease or unacceptable treatment-related toxicity, patients may continue for 12 cycles. The study uses the accelerated titration method for the first 2 dose levels then the 3+3 design for the remaining dose levels. After determining the MTD, we will evaluate the defined MTD in an expansion cohort of 14 patients with relapsed OS. Symptoms, pulse oximetry, and pulmonary function are assessed prior to each nebulized dose using remote spirometry that allows raw numbers and flow-volume curves to be uploaded and transmitted via bluetooth to an android tablet provided to patients. Data is transmitted to a web portal and captured in a HIPAA-compliant web-based database (REDCap) that is accessible to the research team. Results: To date, the study enrolled 4 patients and accrual is ongoing at dose level 3. Conclusions: This study will provide information on the feasibility and safety of aerosol GCB. If proven to be feasible and safe, it can potentially offer a novel approach to treat metastatic OS to the lungs while minimizing systemic toxicity. Clinical trial information: NCT03093909 .
SGN228-001: A phase I open-label dose-escalation, and expansion study of SGN-CD228A in select advanced solid tumors.
Authors: Patnaik Amita , Meric-Bernstam Funda , Rocha Lima Caio Max Sao Pedro , Robert Francisco , Dowlati Afshin , Kindler Hedy L. , Davar Diwakar , Powell Steven Francis , Garfin Phillip M. , Balmanoukian Ani Sarkis
Published: May 2020

TPS3652

Background: SGN-CD228A is an investigational antibody-drug conjugate (ADC) that targets CD228, a cell-surface oncofetal protein with prevalent expression in several types of cancer and limited expression on normal tissues. SGN-CD228A consists of a humanized IgG1 anti-CD228 monoclonal antibody conjugated to an average of 8 molecules of monomethyl auristatin E (MMAE) via a PEGylated β-glucuronidase cleavable linker. MMAE is a well-studied and highly active chemotype with an established safety profile. The proposed mechanism of action involves binding CD228 on cell surfaces, ADC internalization, and trafficking to lysosomes. MMAE is then released through β-glucuronidase cleavage of the glucuronide MMAE linker. MMAE then binds tubulin, which disrupts microtubule networks and causes cell cycle arrest and apoptosis. Methods: SGN228-001 (NCT04042480) is a phase 1, open label, multicenter, dose escalation, and expansion study enrolling up to 240 subjects to evaluate the safety, tolerability, PK, and antitumor activity of SGN-CD228A in select advanced solid tumors. Eligible subjects are ≥18 years of age and have metastatic cutaneous melanoma, malignant pleural mesothelioma, human epidermal growth factor receptor 2-negative metastatic breast cancer, advanced non-small cell lung cancer, metastatic colorectal cancer, or advanced pancreatic ductal adenocarcinoma. Subjects must have relapsed, refractory, or progressive disease, and should have no appropriate standard therapy available. Measurable disease per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1), Eastern Cooperative Oncology Group (ECOG) performance status score of ≤1, and adequate renal, hepatic, and hematologic function are required. The study includes dose escalation and dose expansion, with multiple disease-specific dose expansion cohorts and a biology cohort. Dose escalation will be conducted using the modified toxicity probability interval method (Ji 2010) to evaluate the safety and identify the maximum tolerated dose of SGN-CD228A. Following dose escalation, disease-specific expansion cohorts and a biology cohort (to evaluate exploratory biomarkers) are planned. Response assessments will be conducted every 6 weeks per RECIST v1.1 and all subjects will be followed for safety. Pharmacokinetics and markers of pharmacodynamics will be assessed regularly. Key efficacy endpoints include objective response rate, progression-free survival, and duration of objective response. Enrollment is ongoing in the US and planned in Europe. Clinical trial information: NCT04042480 .
BT5528-100 phase I/II study of the safety, pharmacokinetics, and preliminary clinical activity of BT5528 in patients with advanced malignancies associated with EphA2 expression.
Authors: Bendell Johanna C. , Wang Judy Sing-Zan , Bashir Babar , Richardson Debra L. , Bennett Gavin , Campbell Carly , Hennessy Meliessa G. , Jeffrey Phil , Kirui Julius , Mahnke Lisa , Shapiro Geoffrey
Published: May 2020

TPS3655

Background: BT5528 is a Bicycle Toxin Conjugate (BTC), comprising a bicyclic peptide targeting the tumor antigen EphA2, linked to a cytotoxin (monomethyl auristatin E [MMAE]) via a tumor microenvironment cleavable linker. Bicycles are a novel class of chemically synthesized constrained peptides, developed by Bicycle Therapeutics. EphA2 is reported to be overexpressed in a range of solid tumors, contributes to oncogenesis, tumor-associated angiogenesis and metastasis. Intracellular EphA2 signaling converges on pathways that are integral to cell growth, proliferation, migration and invasion. Increased EphA2 expression has been identified as a resistance mechanism to EGFR Tyrosine Kinase Inhibitor based therapy. BT5528 mechanism of action is dependent on tumor penetration, target binding and release of MMAE toxin payload. BTCs offer advantages over antibody-toxin conjugates exhibiting rapid penetration of dense tumors and decreased extra-tumor exposure. BT5528 exhibited a favorable preclinical profile supporting the initiation of a first-in-human study to investigate safety and efficacy of BT5528 in indications with evidence of EphA2 expression including non-small-cell lung cancer (NSCLC), ovarian cancer, triple-negative breast cancer (TNBC), gastric/upper gastrointestinal (GI), pancreatic and urothelial cancers. Methods: BT5528-100 (NCT04180371) is a Ph I/II study to evaluate safety and tolerability of weekly BT5528 alone and in combination with Q4W nivolumab. Each dose escalation utilizes a 3+3 design which converts to a Bayesian design to determine MTD or MAD and RP2D for BT5528 with and without nivolumab. Eligible patients must have advanced solid tumors associated with EphA2 expression which have recurred after exhausting standard treatment options. Patients must have available tumor tissue and acceptable hematologic and organ function, with exclusions for uncontrolled brain metastases, thromboembolic events, bleeding disorders, uncontrolled hypertension, CYP3A4 inhibitors/inducers or, for the nivolumab cohorts, autoimmune disease. On-study tumor and blood samples will be collected for biomarker evaluations including tumor EphA2 expression, ADA, and candidate response biomarkers for BT5528 alone and combination with nivolumab. Pharmacokinetic data will be reported for C1D1 and D15 for BT5528 and MMAE. The expansion phase will enroll specific tumor types to evaluate clinical activity of BT5528. Enrollment is ongoing. Clinical trial information: NCT04180371 .
A first-in-man phase I/II study of OBI-3424, an AKR1C3-selective bis-alkylating agent prodrug, in subjects with advanced cancer, including hepatocellular carcinoma (HCC) and castrate-resistant prostate cancer (CRPC).
Authors: Tsimberidou Apostolia Maria , Verschraegen Claire F. , Hsu Pei , Pearce Tillman E.
Published: May 2020

TPS3658

Background: Aldo-keto reductase family 1 member C3 (AKR1C3) modulates cellular differentiation and proliferation through indirect regulation of ligand access to hormone and nuclear receptor signaling. AKR1C3 is expressed at high levels in various human cancers, including HCC. In prostate cancer cells exposed to anti-androgen therapies, AKR1C3 is adaptively upregulated. CRPC is a potential indication for this targeted alkylating agent. AKR1C3 tumor expression is associated with poor patient survival and resistance to cancer therapies. OBI-3424 is a nitro-benzene prodrug of a nitrogen mustard that can be selectively cleaved in the presence of AKR1C3 enzyme into a bis-alkylating agent capable of forming intra- and inter-strand crosslinks with DNA, thereby resulting in cell death. The selectivity of OBI-3424 for AKR1C3 distinguishes it from traditional alkylating agents, which are nonselective. The primary objectives of the study are to evaluate the safety and tolerability of single-agent OBI-3424. The dose-escalation phase will determine the dose-limiting toxicities (DLT), maximum tolerable dose (MTD), and recommended Phase 2 dose (RP2D) of OBI-3424 through assessment of PK of OBI-3424 and OBI-2660 in plasma and urine. After determining the maximum tolerated dose (MTD), the study will enroll subjects with advanced HCC or CRPC, two tumor types with a high likelihood of overexpression of AKR1C3, into the dose expansion portion of the study according to a Simon two-stage phase 2 design. This phase is designed to assess the objective response rate, and progression-free survival in patients with HCC and CRPC. Immunohistochemistry assays are being developed to assess tumor expression of AKR1C3 for this study. The clinical safety and relationship of efficacy to AKR1C3 tumor expression will serve to guide further clinical development of OBI-3424 in these two unmet need settings. Methods: Based on the toxicology and PK results in cynomolgus monkeys, the starting dose is one sixth of the human equivalent dose of the highest non-severely toxic dose observed. Doses of 1, 2, 4, 6, 8, 12, and 14 mg/m2 will be used. OBI-3424 is administered intravenously (IV) over 30 minutes on days 1 and 8 of each 21-day cycle. Subjects without clinically significant disease progression may continue on treatment for up to 2 years, if they do not experience a DLT or other significant toxicity. Clinical trial information: NCT03592264 .
SKB264 ADC: A first-in-human study of SKB264 in patients with locally advanced unresectable/metastatic solid tumors who are refractory to available standard therapies.
Authors: Liu Yongheng , Lian Wei , Zhao Xi , Diao Yina , Xu Jian , Xiao Liang , Qing Yan , Xue Tongtong , Wang Jingyi
Published: May 2020

TPS3659

Background: Elevated expression of trophoblast antigen 2 (TROP2) is often associated with invasion/aggression, progression, and metastasis of many different tumor types. Efficacies of anti-TROP2 ADC have been demonstrated both pre-clinically and in the clinical trials. SKB264 is being developed as a further optimized TROP2-targeting ADC with a proprietary cytotoxic, belotecan-derived payload and novel stable conjugation chemistry to achieve average DAR (Drug Antibody Ratio) of 7.4. Release of payload upon SKB264 internalization is in a TROP2 expression dependent manner. Extensive preclinical studies demonstrated antitumor activity of SKB264 in vitro, in xenograft and patient-derived xenograft (PDX) animal models. In addition, safety studies have demonstrated a good safety profile to allow SKB264 to be studied in clinical trials. Methods: SKB264-01 is a global open label multicenter study. The study is divided into 2 parts, the phase I is to determine the safety profile, define MTD and/or the RP2D, and characterize DLTs of SKB264. Dose escalation and MTD identification will be directed using a Bayesian logistic regression model (BLRM) with overdose control. The phase II is to evaluate efficacy and obtain clinical activity data of SKB264 as a monotherapeutic agent at the RP2D in each of the designated Phase II cohorts and overall (n = 16 per cohort; n = 48 for entire Phase II part). Objective response rate (ORR) will be continuously evaluated in each cohort using a Bayesian hierarchical model. TROP2 assessments will not be performed prior to enrollment but it will be assessed retrospectively. Confirmation of TROP2 expression by immunohistology or other methods is not required, but the Sponsor will request tissue specimens from archived materials for determination of TROP2 expression. The patient must have, in the judgment of the investigator, historically documented, incurable, locally advanced or metastatic cancer that are refractory to standard therapies of one of the following types: i. ovarian epithelial cancer, ii. gastric adenocarcinoma, iii. pancreatic adenocarcinoma, iv. triple negative breast cancer, v. bladder cancer. Patient will receive study drug as a single IV infusion at the prescribed dose level at each administration. Cycles will continue until disease progression or unacceptable toxicity. Adverse Events (AE) will be graded according to CTCAE V.5.0. Responses will be evaluated according to RECIST V1.1. The enrollment will began in Mar 2020 in USA sites. Clinical trial information: NCT04152499 .