bluuebunny/crossref_metadata_2025 huggingface dataset:
Colon adjuvant chemotherapy based on evaluation of residual disease (CIRCULATE-US): NRG-GI008.
Authors: Dasari Arvind , Yu Guan , Kopetz Scott , Jacobs Samuel A. , Lucas Peter C. , Sahin Ibrahim Halil , Deming Dustin A. , Philip Philip Agop , Hong Theodore S. , Rojas-Khalil Yesenia , Loree Jonathan M. , Wolmark Norman , Yothers Greg , George Thomas J. , Lieu Christopher Hanyoung
Published: June 2023

TPS3634

Background: Currently, there are no biomarkers validated prospectively in randomized studies for resected colon cancer (CC) to determine need for adjuvant chemotherapy (AC). However, circulating tumor DNA (ctDNA) represents a highly specific and sensitive approach (especially with serial monitoring) for identifying minimal/molecular residual disease (MRD) post-surgery in CC patients (pts), and may outperform traditional clinical and pathological features in prognosticating risk for recurrence. CC pts who do not have detectable ctDNA (ctDNA-) are at a much lower risk of recurrence and may be spared the toxicities associated with AC. Furthermore, for CC pts with detectable ctDNA (ctDNA+) who are at a very high risk of recurrence, the optimal AC regimen has not been established. We hypothesize that for pts whose CC has been resected, ctDNA status may be used to risk-stratify for making decisions about AC. Methods: In this prospective phase II/III trial, up to 1,912 pts with resected stage III A, B (all pts) and stage II, IIIC (ctDNA+ only) CC will be enrolled. Based on the post-operative ctDNA status using personalized and tumor-informed assay (SignateraTM, bespoke assay), those who are ctDNA- (Cohort A) will be randomized to immediate AC with fluoropyrimidine (FP) + oxaliplatin (Ox) for 3-6 mos per established guidelines vs. serial ctDNA monitoring. Patients who are ctDNA+ post-operatively or with serial monitoring (Cohort B) will be randomized to FP+Ox vs. more intensive AC with addition of irinotecan (I) for 6 mos. The primary endpoints for Cohort A are time to ctDNA+ status (phase II) and disease-free survival (DFS) (phase III) in the immediate vs. delayed AC arms. The primary endpoint for Cohort B is DFS in the FP+Ox vs FP+Ox+I arms for both phase II and phase III portions of the trial. Secondary endpoints include prevalence of detectable ctDNA post-operatively, time-to-event outcomes (overall survival and time to recurrence) by ctDNA status, and the assessment of compliance to adjuvant therapy. Biospecimens including archival tumor tissue, as well as post-operative plus serial matched/normal blood samples, will be collected for exploratory correlative research. Active enrollment across the NCTN started in June 2022. NCT#: NCT05174169. Support: U10-CA-180868, -180822; UG1CA-189867; Natera, Inc. Clinical trial information: NCT05174169 .
The FOxTROT platform: Clinical trials and exploratory research for personalization of neoadjuvant (NA) therapy in locally advanced colon cancer (LACC)—ISRCTN83842641.
Authors: Williams Christopher , White Mark , Platt James Robert , Glasbey James , Bailey Lucy , Magill Laura , Wheatstone Peter , Cooper Libby , Beggs Andrew David , Braun Michael , Cairns David A. , Gilbert Alexandra , Tolan Damian , West Nicholas , Graham Janet Shirley , Morton Dion , Seligmann Jenny F.
Published: June 2023

TPS3636

Background: The FOxTROT1 trial demonstrated a significant reduction in 2-year (yr) recurrence with 6 weeks (wks) of oxaliplatin and fluoropyrimidine (OxFp) NA chemotherapy (NAC) in patients (pts) with LACC, establishing NAC as a new therapeutic option. The ongoing FOxTROT platform will refine and personalize NA therapy in LACC. FOxTROT2 is testing NAC in older pts and those with frailty, who are poorly represented in clinical trials. FOxTROT3 is assessing intensified NAC with modified FOLFOXIRI (mFOLFOXIRI; 5-fluorouracil, oxaliplatin, irinotecan) in fit pts. The FOxTROT platform will also test targeted treatments with established safety and efficacy in defined molecular subgroups. FOxTROT4 is investigating the efficacy and safety of NA encorafenib and cetuximab in BRAF-mutant pMMR LACC. Other arms in setup are shown in Table. Methods: FOxTROT platform trials are international, multicenter, open-label, phase II/III RCTs. Pts with resectable, cT3-4 N0-2 M0, biopsy-proven colon adenocarcinoma are eligible for recruitment. Pts whose age or frailty precludes mFOLFOXIRI can be considered for FOxTROT2. Pts suitable for mFOLFOXIRI can be considered for FOxTROT3. BRAF-mutant pMMR pts can be considered for FOxTROT4. Pts are randomized 2:1 between intervention and control arms. FOxTROT2 randomizes between 6 wks OxFp NAC (choice of 100% or 80% dose) vs proceeding straight to surgery. Adjuvant chemotherapy (AC) is per physician choice. Primary outcome is 3-yr DFS. 759 pts will be recruited over 5 yrs. FOxTROT3: 6 wks mFOLFOXIRI NAC vs 6 wks OxFp NAC. All pts receive AC but physicians may de-escalate mFOLFOXIRI to OxFp. Hierarchical co-primary endpoints: tumor regression grade (TRG) (blinded central assessment) and 3-yr DFS. 873 pts over 5 yrs. FOxTROT4: 6 wks NA encorafenib and cetuximab vs 6 wks OxFp NAC. AC is per physician choice. Primary outcome: TRG. 45 pts over 3 yrs. Secondary outcomes include: histopathological endpoints, downstaging, minimal residual disease by ctDNA, safety, toxicity, OS, surgical outcomes and patient-reported outcomes; and DFS in FOxTROT4. The FOxTROT platform opened 7th Feb 2022, funded by Yorkshire Cancer Research. At submission, 50 pts had been randomized at 23 centers. Trial design and management is conducted in partnership with patient representatives. A program of translational and radiomics research is running in parallel. International recruitment in France and India will commence in 2023 with additional international partners joining from 2024. Clinical trial information: ISRCTN83842641 . [Table: see text]
Neoadjuvant short-course radiotherapy followed by chemotherapy plus camrelizumab versus long-course chemoradiotherapy followed by chemotherapy for patients with locally advanced rectal cancer: A randomized, multicenter, open-label phase 3 trial (Union).
Authors: Lin Zhenyu , Zhang Peng , Hou Zhiguo , Tao Kaixiong , Zhang Tao
Published: June 2023

TPS3638

Background: Short-course preoperative radiotherapy (SCPRT) and long-course chemoradiotherapy (LCCRT) are standard neoadjuvant treatments for locally advanced rectal cancer (LARC). Further, the RAPIDO trial found that SCPRT combined with consolidation chemotherapy produced better short- and long-term outcomes than SCPRT alone for patients with high-risk LARC. A phase 2, single-arm trial of neoadjuvant SCPRT followed by camrelizumab (an anti-PD-1 antibody) plus chemotherapy demonstrated promising short-term outcomes in patients with LARC. The Union trial is evaluating the efficacy and safety of neoadjuvant SCPRT followed by camrelizumab plus chemotherapy versus LCCRT followed by chemotherapy in patients with LARC. Methods: The Union trial is enrolling patients aged 18-75 with histologically confirmed clinical stage T3-4/N+ adenocarcinoma of the rectum, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and a tumor inferior margin less than 10 cm above the anal verge. Eligible patients are randomized in a 1:1 ratio to either arm A or arm B. Patients in arm A receive neoadjuvant treatment with SCPRT (a total of 25 Gy in 5 days) followed by camrelizumab (200 mg/m2 intravenous drip on day 1, every 3 weeks for 2 cycles) plus CAPOX (oxaliplatin 130 mg/m2 intravenous infusion over 2 hours on day 1, capecitabine 1000 mg/m2 oral twice daily, days 1–14, every 3 weeks for 2 cycles), surgery, and adjuvant treatment with camrelizumab plus CAPOX (6 cycles) followed by camrelizumab until the medication duration of camrelizumab reaches one year. Patients in arm B receive neoadjuvant treatment with LCCRT (capecitabine 825 mg/m2 twice daily, 5 days a week, combined with a total dose of 50.4 Gy in 28 days) followed by CAPOX (2 cycles), surgery, and adjuvant treatment with CAPOX (6 cycles). Randomization is stratified by clinical T stage (≤T3 vs T4) and clinical N stage (N0 vs N+). The primary endpoint is pathologic complete response (pCR). The secondary endpoints are 3-year event-free survival rate, overall survival, R0 resection rate, completion rate of neoadjuvant treatment, 3-year disease-free survival rate, tumor regression grading, safety, and quality of life. pCR is evaluated per the AJCC 8th Edition TRG scoring system as assessed by the blinded independent central review. Adverse events are graded by the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Quality of life is assessed by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30. This study began enrollment in July 2021 with a planned enrollment of 230 patients. Clinical trial information: NCT04928807 .
An open-label, multicenter study investigating RP3 oncolytic immunotherapy in combination with first- or second-line systemic atezolizumab and bevacizumab therapy in patients with locally advanced unresectable or metastatic hepatocellular carcinoma.
Authors: Bekaii-Saab Tanios S. , Yarchoan Mark , Ahmed Muneeb , Cohan David Michael , Ma Wen Wee
Published: June 2023

TPS4178

Background: Despite advances in treatment for unresectable hepatocellular carcinoma (HCC), long-term survival rates remain poor. The combination of bevacizumab (Bev) and atezolizumab (Atezo) is the preferred frontline therapy for advanced HCC, but a minority of patients (pts) respond, and secondary resistance usually occurs within months. HCC has an immune-suppressed tumor microenvironment, mediated by activated immune checkpoint signaling and angiogenesis pathways, which may contribute to therapeutic resistance. RP3 is a genetically modified herpes simplex virus type 1 (HSV-1) that expresses the fusogenic gibbon ape leukemia virus glycoprotein with the R sequence deleted (GALV-GP-R–), an anti–CTLA-4 antibody-like molecule, CD40 ligand, and 4-1BB ligand. The direct oncolytic effect coupled with immune stimulation by RP3 in the tumor microenvironment is intended to provide systemic antitumor activity and enhance therapeutic response to anti–PD-1/PD-L1 agents, such as Atezo. Preclinical data have demonstrated improved distribution of oncolytic HSV within tumors in combination with Bev, supporting the clinical combination of RP3 with Bev. This study will evaluate the safety and efficacy of RP3 combined with Atezo and Bev as first- (1L) and second-line (2L) systemic therapies for unresectable and advanced HCC. Methods: The 1L and 2L cohorts will each enroll up to 30 pts. Pts in the 1L cohort may not have received prior systemic treatment; pts in the 2L cohort must have progressed on or following one prior line of systemic therapy, which must have included a PD-1/PD-L1−directed agent. Key inclusion criteria include advanced, unresectable HCC with ≥1 measurable tumor of ≥1 cm in longest diameter, Child-Pugh Class A, and Eastern Cooperative Oncology Group performance status of 0−1. Key exclusion criteria include untreated esophageal and/or gastric varices with bleeding or at high risk for bleeding and macroscopic invasion of tumor into any major blood vessel(s) and/or main bile ducts. Pts with a history of medically refractory hepatic encephalopathy and/or hepato-renal syndrome are also excluded. Pts in the 1L cohort will receive 1200 mg Atezo and 15 mg/kg Bev every 3 weeks (Q3W) together with RP3 intratumorally Q3W for a total of up to 8 doses. Pts in the 2L cohort will receive RP3 every 2 weeks for 4 doses with Bev Q3W starting on cycle (C) 1 day (D) 1, then RP3 and Bev Q3W for up to 4 more doses with Atezo Q3W being added on C4D1. The primary endpoint is overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Secondary endpoints are safety, ORR using HCC modified RECIST, duration of response, complete response rate, and progression-free survival. Clinical trial information: NCT05733598 .
Autologous cytotoxic T-cell receptor T cell therapy (SCG101) against hepatitis B surface antigen phase I/II trial for patients with advanced hepatitis B-related hepatocellular carcinoma.
Authors: Abou-Alfa Ghassan K. , Yong Wei-Peng , Chang Stephen Lam , Fan Jia , Toh Han Chong , Yau Thomas , Choo SuPin , Wang Jing , Kusuma Nicole , Ma Christy , Qin Shukui
Published: June 2023

TPS4181

Background: The overall prognosis of patients with advanced Hepatitis B-related hepatocellular carcinoma (HCC) remains poor, and treatment options are limited. In an IIT study conducted in China (NCT05339321), SCG101 following lymphodepletion (cy-flu) as second-line setting or beyond in patients with Hep B-related HCC has shown acceptable safety profile, reduction in HBsAg levels (>1 log) and tumor control. A phase I/II trial has been initiated to evaluate safety and RP2D of autologous SCG101 T cell therapy in Hepatitis B virus-related HCC (NCT05417932). Methods: This multicenter, open-label, 3+3 dose-escalation phase I trial is ongoing across 7 sites in the United States, Singapore and Hong Kong SAR, and a parallel study is done in mainland China across 8 sites. Eligible patients have a histologically confirmed HCC, not amenable to curative intent (surgery or locoregional therapy) and failed ≥2 standard line of therapies, match any of HLA-A*02:01, *02:02, *02:03, *02:04, *02:07, *02:09,*02:16, have positive serum (or tumor) HBsAg, HBV-DNA <2000 IU/ml, BCLC B or C, CP≤7, with measurable disease at screening (mRECIST and RECIST v1.1), ECOG PS<1. Patients with CNS metastasis, prior liver transplant, autoimmune disease or prior cell therapy are excluded. SCG101 T cells is manufactured in Singapore under cGMP and ship to all study sites across the U.S, Singapore and Hong Kong SAR, while SCG101 T cells for the China sites is manufactured in SCG Cell Therapy’s China facility. Patients will receive a single dose of SCG101 T cell therapy following lymphodepletion (cy-flu). Endpoints include safety, MTD and RP2D. Secondary endpoints include ORR, DOR, PFS, OS, changes in serum HBsAg. Safety is monitored together with Data Review Committee. The study is actively enrolling, and the phase II portion of the trial is expected to be initiated by H2 2023. Autologous SCG101 T cell therapy may provide a new treatment option for patients with advanced Hepatitis B virus-related HCC. Clinical trial information: NCT05417932 .
Alliance A021804: A prospective, multi-institutional phase II trial evaluating temozolomide versus temozolomide and olaparib for advanced pheochromocytoma and paraganglioma.
Authors: Del Rivero Jaydira , Perez Kimberly , Geyer Susan Michelle , Khalil Maged F. , Vijendran Aishwarya , Kordaris-Corkill Andrea , Shergill Ardaman , Spencer Kristen Renee , Soares Heloisa P. , Lopez Charles D. , Nixon Andrew B. , Dueck Amylou C. , Meyerhardt Jeffrey A. , O'Reilly Eileen Mary
Published: June 2023

TPS4191

Background: Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are rare neuroendocrine tumors (NETs) that arise from chromaffin cells. Few antitumor therapies have been developed for patients (pts) with advanced PHEO/PGLs (APP). Potent poly (ADP-ribose) polymerase (PARP) is activated after DNA damage and regulates base excision repair, homologous recombination and non-homologous end joining. Inhibition of PARP enzymatic activity blocks PARP-mediated DNA repair, therefore PARP inhibitors can be directly cytotoxic to tumor cells which then permits synergy with agents that increase prevalence of single-strand breaks in tumor models. Temozolomide (TMZ) is an alkylating agent that induces single-strand DNA breaks and therefore is an optimal therapeutic pair with a PARP inhibitor. We are conducting a phase II multi-institutional study to evaluate the antitumor activity of TMZ and olaparib [OLA (a PARP inhibitor)] in patients with APP. Methods: Patients with APP with radiographic evidence of disease progression by RECIST v1.1 in the 12 months prior to registration can be enrolled in this phase II randomized study. Patients will be randomized in a 2:1 allocation with more patients to Arm 1. Arm 1 will receive TMZ 75 mg/m2 daily and OLA 200 mg twice daily on days 1-7 of a 21-day cycle. Arm 2 will receive TMZ 200 mg/m2 daily on days 1-5 of a 28-day cycle. Treatment on Arm 1 will continue for 13 cycles, followed by OLA maintenance until disease progression. Treatment on Arm 2 will continue for 13 cycles or until disease progression. The primary objective is to compare the progression-free survival between the two arms with a planned interim analysis for futility. Secondary endpoints include safety, response rate, and overall survival. Correlative endpoints include biochemical response and biomolecular markers (germline succinyl dehydrogenase mutations and tumor status of the repair enzyme methylguanine-DNA methyltransferase). We anticipate a null PFS median of approximately 5.4 months. We plan to accrue a total of 76 patients (randomized at a rate of 2:1 with more patients enrolled to the TMZ+OLA arm) in 38 months with a minimum follow-up of 2.5 months to achieve 56 PFS events. This design includes one interim analysis for futility using Rho Family spending functions (Rho = 2.5) and will yield 89% power to detect a hazard ratio (HR) of 0.5 (median PFS of 5.4 vs. 10.8 months) assuming exponential survival and using a one-sided log-rank test with type I error rate of 0.11. Clinical trial information: NCT04394858 .
LANTana trial protocol: An open label, single arm, phase Ib study to evaluate the effect of pre-treatment with ASTX727 (a demethylating agent) followed by lutetium Lu 177 dotatate in patients with progressive, metastatic neuroendocrine neoplasias (NENs).
Authors: Sharma Rohini , Ward Caroline , Naik Mitesh , Khan Saraih , Barwick Tara , Martinez Maria , Izadi Hooshang , Aboagye Eric O.
Published: June 2023

TPS4192

Background: Neuroendocrine neoplasias (NENs) are characterised by the presence of somatostatin receptors (SSTR) on cell surface, in particular SSTR2. Somatostatin and its stable analogue (SSA) bind with high affinity to SSTR2. SSA can be radiolabelled, to both stage NENs using positron emission tomography (PET), and to deliver selective radiotherapy; peptide receptor radionuclide therapy (PRRT). PRRT consists of SSA linked to the long acting radionuclide. Radiolabelled SSA binds to SSTR2 and the complex is internalised delivering high dose radiation directly to the cancer. PRRT has been significantly improve survival outcomes and maintain quality of life in metastatic disease. Suitability for PRRT depends on presence of SSTR2 as determined by PET imaging, commonly with [68Ga]-dotatate-PET. 20% of patients will have low or no uptake on [68Ga]-dotatate-PET precluding PRRT. The upstream promoter region of SSRT2 is methylated, with percentage of methylation correlating with SSTR2 expression. We have shown that the use of the demethylating agent, guadecitabine, increases uptake on PET imaging in such that tumours previously negative on PET imaging, become positive, correlating with a dose dependent increase in tumoural SSTR2 expression. Combination guadecitabine and PRRT was well tolerated in vivo models of NETs. Overall aim was to utilise [68Ga]-dotatate-PET as a biomarker of SSTR2 re-expression following treatment with the demethylating agent, ASTX727, such that patients previously unsuitable for PRRT can receive therapy, improving clinical outcome. 1) Utilise [68Ga]-dotatate-PET to image epigenetic regulation of SSTR2 in response to ASTX727. 2) Evaluate clinical efficacy and safety of ASTX727 pre-treatment in combination with PRRT. 3) Explore impact on quality of life of combination therapy. Methods: 27 patients with no or equivocal uptake on [68Ga]-dotatate-PET will be enrolled. [68Ga]-dotatate-PET will be performed at baseline and after 8days of ASTX727 (oral, fixed dose 100mg cedazuridine + 35mg decitabine). If there is a significant increase in PET uptake, patients will receive combination ASTX727 and PRRT (Lutathera). Treatment will be repeated every 2months for 4 cycles. Response assessment (RECIST 1.1), tolerability and QoL will be assessed at start of each cycle. Tumour biopsies will be taken at baseline, and after cycle1 of ASTX727 (n=5), for SSTR2 methylation. Methylation will be correlated with PET uptake and outcome. LINE-1 methylation in peripheral blood monocytes will be assessed throughout. Current enrolment: 4. Clinical trial information: NCT05178693 .
Phase 1b/2 trial of pepinemab plus avelumab as second line combination immunotherapy for patients with metastatic pancreatic adenocarcinoma.
Authors: Ruffolo Luis I. , Fisher Terrence Lee , Evans Elizabeth E. , Mallow Crystal L. , Boise Megan , Foster Amber , Leonard John E. , Belt Brian A. , Yeh Jen Jen , Zauderer Maurice , Linehan David , Mulkerin Daniel
Published: June 2023

TPS4195

Background: Monotherapy with immune checkpoint inhibitors (ICIs) is not effective in metastatic pancreatic adenocarcinoma (PDAC), likely due to the unique immunosuppressive tumor microenvironment (TME) of PDAC, thus safe and novel strategies to overcome resistance and facilitate adaptive immune responses are a major unmet need. Preclinical and clinical studies demonstrated that antibody blockade of semaphorin 4D (SEMA4D) promotes tumoral infiltration and activation of DCs and CD8+ T cells and reverses immunosuppression, including attenuation of MDSC recruitment and function, leading to enhanced efficacy of ICIs without increasing toxicity. Pepinemab, a SEMA4D blocking antibody, in combination (combo) with avelumab provided clinical benefit in some patients with ICI-resistant and PD-L1-low NSCLC (NCT03268057). Pepinemab is also being evaluated in combo with pembrolizumab in patients with metastatic squamous cell carcinoma of the head and neck (NCT04815720). The principal goals of this proof-of-concept study are to investigate the safety, efficacy, and TME biomarker changes of treatment with the combo of pepinemab plus avelumab in patients with metastatic PDAC. Methods: This single-arm, open-label study (NCT05102721) is evaluating the safety, tolerability, and efficacy of pepinemab in combo with avelumab in patients diagnosed with metastatic PDAC who have either progressed on or are otherwise intolerant to first line chemotherapy. Patients must have received 5FU or gemcitabine-based first line therapy with evidence of intolerance or treatment failure, including progression both during or after completing first-line treatment. Accrual for the Phase 1b portion follows a Bayesian Optimal Interval Design (BOIN), beginning at the highest dose combo; 20 mg/kg pepinemab and 800 mg avelumab Q2W. Phase 2 begins after 16 subjects are enrolled at MTD, permitting a Simon’s two stage assessment of futility prior to closing the Phase 1b period. The primary objective for Phase 1b is tolerability, and the primary objective for Phase 2 is therapeutic efficacy compared to historical second-line systemic chemotherapy. The trial anticipates a total evaluable cohort of 40 subjects and is powered to detect a response rate of 23% or greater, with alpha set at 0.1 and 80% power. Exploratory objectives include robust correlative analysis of immune, stromal, and genomic profiling of baseline and on-treatment tumor biopsies to ascertain mechanisms of treatment response and failure. Patient reported outcomes are incorporated throughout the trial to assess disease specific symptoms associated with pancreatic cancer and cancer cachexia. One patient has been enrolled as of Feb 14, 2023. Clinical trial information: NCT05102721 .
A phase 1 study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of LB4330, a peptide fused to CLDN18.2 antibody targeting the tumor antigen associated CD8+t CELLS in patients with advanced solid tumors.
Authors: Liu Jiajian ,   L&L Team
Published: June 2023

TPS4196

Background: PD-1/PD-L1-targeted immunotherapies have become critical roles in the treatment for many tumors. However, there is limited progress in pancreatic ductal adenocarcinoma (PDAC). PDAC is low immunogenicity. PDAC microenvironment is immunosuppressive. More than 70% PDACs have few or no CD8+ T cells around the tumor cell or in the tumor microenvironment (TME). Therefore, immunotherapy like PD-1/PD-L1 antibody alone is rarely effective for PDACs. Some cytokine or analogs may activate CD8+ T cells. An analog specifically activating tumor antigen associated (TAA) CD8+ T cells was designed and fused to anti-CLDN18.2 antibody. This specific bi-functional molecule LB4330 has high affinity to human anti-CLDN18.2 (14pM) and CD8+T cells. LB4330, as a novel, first-in-class molecule, may activate TAA CD8+ T cells in TME and has potential in alone or in combination with PD-1/PD-L1 mAb, for the treatment of advanced solid tumors, especially for Claudin 18.2 positive PDAC. Methods: This is a FIH, phase 1 study to evaluate the safety, tolerability, pharmacokinetics and immunogenicity of LB4330 in patients with advanced solid tumors (MEETCD8-001). The planned sample size is approximately 66 patients in two parts: part 1 dose escalation, will evaluate safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and determine the maximum tolerated dose (MTD) and/or the recommended phase 2 dose (RP2D). Part 2 dose expansion will further characterize the safety profile and preliminary tumor response in advanced gastric and gastroesophageal junction adenocarcinoma and PDAC with Claudin 18.2 expression. In dose escalation stage, patients will be recruited with advanced solid tumors who have failed standard treatment, or for whom standard treatment is not available or applicable at this stage. Exclusion criteria include a greater risk for gastric bleeding, irritable bowel syndrome with symptoms, active virus infections. The primary endpoints are incidence of dose limiting toxicities and adverse events, MTD, and recommended phase 2 dose. Secondary objectives will evaluate PK parameters, preliminary antitumor activity, and immunogenicity of LB4330. Tumor response will be assessed per RECIST and iRECIST every 2 cycles. The Phase I study in advanced solid tumors is ongoing. Enrollment in cohort 1 began in Nov 2022. Clinical trial information: NCT05707676 .
A phase III randomized trial of eribulin (E) with or without gemcitabine vs standard of care (SOC) for metastatic urothelial carcinoma (UC) refractory to or ineligible for PD/PDL1 antibody (Ab): SWOG S1937.
Authors: Sadeghi Sarmad , Plets Melissa , Lara Primo N , Tangen Catherine , Bangs Rick , Lerner Seth P. , Flaig Thomas W. , Petrylak Daniel P. , Thompson Ian M
Published: June 2023

TPS4608

Background: UC is 2nd most common genitourinary cancer. Current SOC offers platinum-based (PB) first line chemotherapy (chemo) with ddMVAC or gemcitabine-cisplatin (GC) regimens. For cisplatin ineligible patients (pts), SOC includes gemcitabine-carboplatin (GCa), and in select pts pembrolizumab. Erdafitinib is approved for pts with FGFR alterations and Enfortumab vedotin (EV) is approved for previously treated pts. A phase I/II CTEP study of eribulin (E) for metastatic UC (mUC) established the activity of E in UC with objective response rate (ORR) of 37.5% and a median progression free survival (PFS) of 4.1 months (mo) and median overall survival (OS) of 9.5 mo (N=150). A phase II CTEP study of gemcitabine-eribulin (GE) in cisplatin ineligible mUC showed an ORR of 50%, median OS of 11.9 mo and median PFS of 5.3 mo (N=24). The most common Grade 3-4 toxicities included: neutropenia 63%, anemia and fatigue 29%. Pts with liver metastases benefited from therapy with 5 responders in 7 pts for GE vs 12 out 49 E. Methods: This is a phase III, randomized 3 arm study comparing E vs. GE vs. SOC (docetaxel, paclitaxel, or gemcitabine). E is given at 1.4mg/m2 on day (D) 1 and 8 of a 21 D cycle. In the GE arm, gemcitabine is added to E at 1000 mg/m2 dose to D1 and D8. SOC follows standard dosing of the agents. There is no limit to the number/sequence of prior regimens. A simplified summary of eligibility criteria is presented here. All pts must have: received frontline systemic treatment such as PB chemo or a non-platinum regimen; received PD1/PDL1 Ab or be deemed ineligible for PD1/PDL1 Ab; received EV. Assuming a median OS for the SOC arm of 7 mo the study seeks to find at least a 50% increase in median OS to 10.5 mo (Hazard Ratio (HR) = 0.667). One-sided 0.0125 type I error to account for testing of two primary hypotheses (Each arm vs. SOC). 87% power to detect a 3.5 mo improvement in OS. We require 140 eligible (155 total) pts in each arm for a total of 465. The study was activated in Feb 2021 and accrual is ongoing. Clinical trial information: NCT04579224 .
A phase II trial with copanlisib plus avelumab as maintenance therapy for metastatic bladder cancer after platinum-based chemotherapy.
Authors: Farrukh Hizra , Zhu Zheng , Zhu Shaoming , Montgomery Robert Bruce , Meeks Joshua J , VanderWeele David James , Wong Yu-Ning , Lew Robert A , Pan Chong-xian
Published: June 2023

TPS4610

Background: Bladder cancer is the tenth most common malignancy and the fourteenth most common cause of cancer death worldwide. Currently, platinum-based chemotherapy followed by avelumab maintenance immunotherapy is the first-line standard of care for advanced bladder cancer (aBC). Even though maintenance avelumab therapy has improved overall survival, its efficacy is still disappointing with a response rate of less than 10% and progression-free survival benefit of 1.7 months. The phosphoinositide 3-kinase (PI3K) pathway harbors more activating alterations than any other growth signaling pathway in aBC. Furthermore, PI3K δ and γ are expressed by immune cells and regulate their function. Activation alterations along the PI3K pathway are putative molecular drivers and can possibly be targeted for the treatment of aBC. In preclinical studies, we found that a pan-PI3K class I inhibitor, copanlisib, potentiates anti-programmed cell death 1 (PD1) antibody in syngeneic bladder cancer mouse models with or without activation alterations along the PI3K pathway (Zhu S, J Immunother Cancer. 2021). We hypothesize that copanlisib potentiates avelumab as maintenance therapy for aBC. Methods: This is a multi-center, single-arm, open-label Phase II trial with a lead-in safety phase to determine the efficacy and toxicity of combination copanlisib and avelumab maintenance therapy in aBC. The major inclusion criteria are patients with aBC without disease progression after platinum-based chemotherapy and no contraindication for avelumab and copanlisib. With a type I error of 5% and power of 80% with a log-rank test, we will need 26 patients for this study. With an attrition rate of 10%, we will enroll 29 patients from four US Department of Veterans Affairs Medical Centers. Copanlisib will be administered through intravenous infusion (IV) at 60 mg on Day 1, 8 and 15, and avelumab will be administered 800 mg IV on Day 1 and 15 of each 4-week treatment cycle for up to 26 cycles. Imaging will be repeated every two cycles during first year of therapy and thereafter every 3 cycles or clinically indicated. The primary endpoint is progression-free survival (PFS). The secondary endpoints include CT or MRI determined radiographic overall response rate, toxicity, overall survival, and molecular correlative studies. Kaplan-Meier estimates will be presented together with median PFS with 2-sided 95% confidence intervals (CI). In particular, the PFS rates at 3, 6, 9, 12 and 15 months will be estimated with corresponding 2-sided 95% CIs. Adverse events will be assessed according to CTCAE v5. Tumor response is determined according to Response Evaluation Criteria in Solid Tumors version (RECIST) 1.1 criteria. This study is currently open for enrollment. Clinical trial information: NCT05687721 .
Phase 2 trial of intravesical cabazitaxel, gemcitabine, and cisplatin (CGC) for the treatment of non-muscle invasive BCG unresponsive urothelial carcinoma of the bladder.
Authors: DeCastro Guarionex Joel , Anderson Christopher B. , Abate-Shen Cory , Gray Jillian , Ingram Justin , Stein Mark N. , McKiernan James M.
Published: June 2023

TPS4616

Background: For patients with non-muscle invasive bladder cancer (NMIBC) unresponsive to Bacille Calmette-Guerin (BCG), multi-agent intravesical trials have been limited. The goal of this Phase 2 study is to investigate the efficacy of intravesical chemotherapy consisting of sequential cabazitaxel, gemcitabine, and cisplatin (CGC) in the salvage setting. Phase 1 results reporting on 18 subjects demonstrated adverse events limited to local Grade 1 and 2 toxicities. Partial funding support for the trial was provided by a pharmaceutical company. Methods: This is a Phase 2 trial (NCT02202772) presently enrolling patients with BCG unresponsive NMIBC as defined by the FDA who refuse or are ineligible for radical cystectomy. All patients undergo pre-treatment transurethral resection of bladder tumor (TURBT) and a 6-week regimen of intravesical cisplatin (100mg), gemcitabine (2gm), and cabazitaxel (5mg). Each drug is instilled weekly except for cisplatin, which is given every other week. Complete response is defined as having no evidence of cancer on post-induction biopsy and negative urine cytology at 3 months. Complete responders proceed with monthly and bimonthly maintenance therapy without cisplatin in the first and second years, respectively, for a total of 24 months. Results: To date thirty-one patients have been enrolled (with target accrual of 33), of whom seven are female. One patient withdrew consent before first evaluation cystoscopy. Mean age thus far is 72 years. All patients have previously received at least two prior induction cycles of BCG, and meet FDA criteria for BCG unresponsive disease. All patients have biopsy proven high grade disease at enrollment; 8 (27%) have high grade T1 disease; and 20 (67%) patients have CIS. Conclusions: Salvage options for BCG unresponsive NMIBC are limited. The CGC protocol has been demonstrated to be safe in a previous Phase 1 study, and accrual for this Phase 2 is near completion. Clinical trial information: NCT02202772 .
Phase 1b/2 dose expansion, open-label study to evaluate safety and anti-tumor activity of intravesical instillation of TARA-002 in adults with high-grade non-muscle invasive bladder cancer.
Authors: Sun Wei , Bandari Jathin , Zummo Jacqueline , Belani Khushboo , Brown Eppie , DiFiglia Andrea , Metcalf McKenna , Nanayakkara Nuwan
Published: June 2023

TPS4618

Background: Bladder cancer is the most common malignancy involving the urinary system, with over 700,000 individuals living with bladder cancer in the US in 2019. In the US, approximately 80,000 new cases and 18,000 deaths occur each year due to bladder cancer. Approximately 70% of new urothelial bladder cancer cases are classified as non-muscle invasive bladder cancer (NMIBC). With the current Bacillus Calmette-Guerin (BCG) shortage and limited effective alternate therapies, there continues to be a significant unmet need for treatment options for patients with NMIBC. TARA-002 is being developed for intravesical instillation for the treatment of high-grade (HG) NMIBC. TARA-002 is a lyophilized biological preparation for instillation containing cells of Streptococcus pyogenes (Group A, type 3) Su strain treated with benzylpenicillin. The chemical characteristics of TARA-002 are intended to be comparable to OK-432. Therefore, nonclinical and clinical evidence with OK-432 and TARA-002 support the ADVANCED-1 study (dose escalation Phase 1a [NCT05085977] and dose expansion Phase 1b/2 [NCT05085990]). The dose for the planned Phase 1b/2 study (ADVANCED-1-Ph1b/2) will be based on the recommended Phase 2 dose (RP2D) established in the Phase 1a study. Methods: ADVANCED-1-Ph1b/2 is a Phase 1b/2, dose expansion, open-label study of intravesical instillation of TARA-002 in adults with HG carcinoma in situ (CIS) NMIBC. The purpose of this study is to evaluate the safety and anti-tumor activity of TARA-002 administered intravesically for the treatment of subjects with CIS NMIBC (± Ta/T1) with active disease. The study includes approximately 102 eligible male and female subjects ≥ 18 years of age enrolled in 2 cohorts based on their prior BCG experience. Cohort A includes subjects unable to obtain BCG or subjects who have not received BCG in the last 24 months prior to CIS diagnosis, and Cohort B includes subjects with CIS who are BCG unresponsive after completion of adequate BCG therapy (at least 5 of 6 doses of an initial induction course plus either at least 2 of 3 doses of maintenance therapy or at least 2 of 6 doses of a second induction course). Those with current or a history of penicillin allergy or current evidence of any condition, therapy, or laboratory abnormality that might confound the results are excluded. The overall study duration is 6 months/24 weeks per subject for Ph1b/2-Cohort A (includes induction, reinduction [if applicable]), and 24 months/96 weeks per subject for Ph1b/2-Cohort B (includes induction, reinduction [if applicable], maintenance until 18 months). The ADVANCED-1 study started in March 2022. Phase 1a is open for enrollment. Phase 1b/2 is expected to begin enrollment in May 2023. Clinical trial information: NCT05085977 ; NCT05085990 .
GUIDE: A randomized non-comparative phase II trial of biomarker-driven intermittent docetaxel versus standard-of-care docetaxel in metastatic castration-resistant prostate cancer (ANZUP 1903).
Authors: Conduit Ciara , Mak Blossom , Qu Wenjia , Yeung Theresa , Bressel Mathias , Cusick Thomas , Dhillon Haryana M. , De Abreu Lourenço Richard , Underhill Craig , Torres Javier , Crumbaker Megan , Honeyball Florian , Linton Anthony , Sewak Sanjeev , Chau Nguyen Minh Hieu , Allen Ray , Davis Ian D. , Clark Susan J. , Horvath Lisa , Mahon Kate Lynette ,   The Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP)
Published: June 2023

TPS5099

Background: Docetaxel improves survival in people with metastatic castration resistant prostate cancer (CRPC) but is associated with toxicities which impact tolerability, particularly for patients who may be older and often with multiple co-morbidities. Biomarker-driven de-escalation of docetaxel chemotherapy may allow improved balance of cancer control and quality of life against toxicity. In patients with metastatic CRPC receiving docetaxel, a reduction to undetectable levels in circulating promoter methylated glutathione S-transferase Pi-1 ( mGSTP1) DNA after 2 cycles of chemotherapy is associated with improved overall survival1. This study aims to determine the efficacy and safety of intermittent docetaxel chemotherapy guided by the presence or absence of circulating mGSTP1 DNA in patients with metastatic CRPC. Methods: GUIDE (NCT04918810) is a randomized, two-arm, non-comparative phase 2 trial recruiting 120 patients at eight Australian centres. Patients with Prostate Cancer Working Group-3 defined metastatic CRPC who are commencing docetaxel 75mg/m2 q3w will be pre-screened for detectable mGSTP1 at baseline +/- following two cycles of treatment. Those with detectable plasma mGSTP1 at baseline that becomes undetectable after two cycles of chemotherapy will be eligible for GUIDE. Prior to Cycle 4 of docetaxel, these patients are randomized 2:1 to one of two treatment arms: Arm A (cease docetaxel and reinstitute if mGSTP1 becomes detectable) or Arm B (continue docetaxel 75mg/m2 q3w in accordance with clinician’s usual practice) (Figure 1). The primary endpoint is radiographic progression-free survival (rPFS). Secondary endpoints include time on treatment holidays, safety, patient-reported outcomes, overall survival, health resource use and cost associated with treatment. This study is powered to detect a rPFS curve with at least 50% rPFS at 12 months using a one-sided log-rank test with 2.5% alpha and 90% power. 3 of planned 120 patients have been enrolled. This novel study is the first to prospectively test the clinical utility of a circulating epigenetic biomarker ( mGSTP1) in clinical decision-making in prostate cancer, building upon existing data supporting analytical and clinical validity. We anticipate that this novel biomarker will safely guide treatment de-escalation and improve the quality of survival for a group of patients with metastatic CRPC. Clinical trial information: NCT04918810 .
A study of prospective monitoring of patients with recurrent prostate cancer using serial PSMA imaging (18F-DCFPyL).
Authors: Atiq Mohammad O. , Lindenberg Liza , Mena Gonzalez Esther , Turkbey Baris , Karzai Fatima , Hausler Megan , Cordes Lisa M. , Williams Monique , Hankin Amy , Gulley James L. , Figg William Douglas , Choyke Peter L. , Madan Ravi Amrit
Published: June 2023

TPS5101

Background: 18F-DCFPyL PSMA PET imaging is now FDA approved for patients with high-risk prostate cancer and those with biochemically recurrent prostate cancer (BCR). BCR has been traditionally defined as a rising PSA after definitive surgery and/or radiation have not been curative in patients without tumor findings on a CT or Tc99 bone scan. There are an estimated 25,000-50,000 new cases of BCR in the US annually. BCR patients are usually managed conservatively, often with surveillance since there is no data demonstrating interventions improve survival. Although 18F-DCFPyL will be able to detect disease at the micrometastatic/subclinical level, there is limited prospective data on how these patients should be managed. While great enthusiasm exists to utilize radiation or ADT-based regimens extrapolated from a more advanced disease state, the natural history of subclinical disease seen on 18F-DCFPyL remains unclear (Madan RA et al. J Clin Oncol 2022). Methods: The primary objective of this study is to monitor patients with recurrent prostate cancer to learn about the natural history of 18F-DCFPyL PET positive disease in this patient population. Eligible patients include those who have had prior definitive surgery or radiation, current PSA ≥0.50 ng/mL, testosterone > 100 ng/mL, no evidence of soft tissue disease on CT scan/MRI and no bone lesions on bone scan. Patients will undergo initial imaging with 18F-DCFPyL scans. Those with negative findings on the initial scan will have annual repeat 18F-DCFPyL scans. Patients with positive initial scans will be scanned every 6 months. All patients will have PSA testing every 3 months and will undergo annual CT and Tc99 bone scans. Up to 250 patients will be followed for 5 years or until off-study criteria is met (including new findings on CT/bone scans consistent with metastatic disease or continuous systemic prostate cancer therapy for more than 6 months). In addition to monitoring the imaging changes, we will evaluate patterns of progression on 18F-DCPyL scans over time, analyze PSA doubling time in context of 18F-DCFPyL changes and evaluate circulating biomarkers. ClinicalTrials.gov Identifier: NCT05588128. Clinical trial information: NCT05588128 .
First-in-class oral innate immune activator BXCL701 combined with pembrolizumab, in patients with metastatic castration-resistant prostate cancer (mCRPC) of small cell neuroendocrine (SCNC) variant: Randomized phase 2b trial.
Authors: Aggarwal Rahul Raj , Zhang Jingsong , Monk Paul , Zhu Xinhua , Costin Dan , Petrylak Daniel P. , Borderies Pascal , Deshpande Rashmi Majali , Hafeez Amir , O'Neill Vincent J. , Tagawa Scott T.
Published: June 2023

TPS5109

Background: BXCL701 (talabostat), oral small molecule inhibitor of dipeptidyl peptidases (DPP)—primarily DPP8/9 & DPP4—triggers inflammasome to alert and prime immune cells, leading to induction of IL-18 & IL-1ß, bridging innate & adaptive immunity. BXCL701 + pembrolizumab evaluated in a Phase 2 study, in mCRPC patients with SCNC. SCNC is highly proliferative and aggressive with limited duration of response to platinum-based chemotherapy. Final results of Phase 2a presented at ASCO GU 2023 (abstract #176) after enrollment of 28 evaluable SCNC patients. 7 (25%) patients achieved a composite response, primary endpoint of trial. In patients with measurable disease (n = 25), RECIST 1.1-defined partial response (PR) observed in 5 (20%) patients (4 confirmed PR + 1 uPR). Disease control rate (complete response + PR + stable disease) was 48% (12 patients). Median duration of response for both composite responses and RECIST-defined PRs was 6+ months as of data cutoff on 19-DEC-22. 6 / 34 patients (18%) in safety population experienced serious adverse events (SAEs) possibly related to BXCL701 or pembrolizumab, and 6 (18%) patients discontinued any drug due to an AE. No evidence found that BXCL701 potentiates immune-related AEs related to immune checkpoint inhibitors. DPP9 overexpression was identified as a potential predictive biomarker for BXCL701 response; biomarker evaluation is ongoing and additional findings will be presented at an upcoming medical meeting. Since SCNC cohort showed encouraging efficacy in Phase 2a, the Phase 2b portion of study was initiated to evaluate SCNC variant in a potential registrational randomized study. Methods: Patients with any SCNC histopathological features, either de novo or treatment-emergent including mixed SCNC, are randomized 2:1 to receive BXCL701 + pembrolizumab (n = 40) or BXCL701 monotherapy (n = 20). Patients are required to have progression by PCWG3 on ≥1 prior line of cytotoxic chemotherapy (patients who either have refused chemotherapy or are considered unsuitable for chemotherapy also permitted entry with prior approval by sponsor). Patients receive pembrolizumab (200 mg IV q3week Day 1) + BXCL701 or BXCL 701 alone (0.2 mg BID Days 1-7 with step-up to 0.3 mg BID Days 8-14, and 0.3 mg BID Days 1-14 of subsequent 21-day cycles). Primary endpoint is response rate defined by RECIST 1.1 criteria. Secondary objectives are ≥-50% decline in PSA from baseline, OS, duration of response, rPFS, and PSA PFS. Exploratory biomarkers and changes in relevant immune effector cells are also evaluated. Phase 2a activity threshold for accrual was met. ClinicalTrials.gov Identifier: NCT03910660. Clinical trial information: NCT03910660 .
APPROACH trial: Multimodal approach in patients with mHSPC: A pragmatic, randomized, phase 3 trial of androgen-deprivation therapy (ADT) plus apalutamide (APA) versus ADT plus apalutamide (APA) and local treatment—Meet-URO 29 study.
Authors: Guadalupi Valentina , Rametta Alessandro , Verzoni Elena , Claps Melanie , Sepe Pierangela , Stellato Marco , Bottiglieri Achille , Catanzaro Mario , Avuzzi Barbara , Sighinolfi Maria Chiara , Rocco Bernardo , Jereczek Barbara , Di Maio Massimo , Nicolai Nicola , De Braud Filippo G. , Procopio Giuseppe
Published: June 2023

TPS5115

Background: it is reasonable to offer radiotherapy (RT) to improve outcomes for patients with newly diagnosed M1 prostate cancer with < 5 bone metastases (HORRAD) or low volume disease (STAMPEDE) (Burdett, S et al., Eur. Urol. 2019). Data from clinical randomized trials evaluating feasibility and overall benefit of cytoreductive radical prostatectomy (cRP) in oligometastatic ormone sensitive patients are not available. The rationale for performing cytoreductive radical prostatectomy is to eliminate lethal clones ofcastration-resistant intraprostatic PCa, which can favor the process of metastasis (A Heidenreich et al. Current Opinion in Urology 2020), in order to improve OS and PFS and to prevent local progression and correlated events. Methods: APPROACH is an Italian multicenter study, which is enrolling ~566 pts with oligometastatic hormone sensitive prostate cancer who are candidates to receive treatment with apalutamide. After 6 months from the start of treatment, patients will be randomized 1:1 to receive local treatment or not in addition to apalutamide (investigator's choice between primary radiotherapy and cytoreductive prostatectomy). Primary end point: To determine whether treatment with apalutamide plus ADT for 6 months followed by locoregional treatment with radiotherapy or radical prostatectomy has better efficacy than treatment with apalutamide plus ADT alone in terms of radiographic progression-free survival (rPFS). Secondary end points: To evaluate tumor shrinkage after locoregional approach and to evaluate short and long-term side effects after locoregional surgery or RT, time to PSA progression, time to castration resistance, cancer specific survival, overall survival and quality of life according to EPIC-26 and EQ-5D-5L questionnaires. Clinical trial information: NCT05649943 .