bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II trial of XmAb20717 (vudalimab) in patients with advanced biliary tract cancers.
Authors: Chapin William Joseph , Agarwal Parul , DiCicco Lisa , Palmer Rayleigh , Cenou Nadia , Huang Alexander Chan Chi , Karasic Thomas Benjamin
Published: June 2023

TPS4184

Background: For patients with advanced biliary tract cancers (BTCs), gemcitabine and cisplatin has been the standard-of-care first-line therapy, with a median overall survival (OS) of 11.7 months. More recently, TOPAZ-1 demonstrated a modest, but significant overall survival benefit (HR 0.80; 95% CI 0.66 – 0.97) to the addition of durvalumab to gemcitabine and cisplatin with a median OS of 12.8 months. However, for patients without targetable molecular variants, second-line and beyond options are limited, with FOLFOX demonstrating an overall response rate (ORR) of 5% and increase in median overall survival by 0.9 months compared to active symptom control. In patients with advanced BTCs, combination immunotherapy approaches with PD-1 or PD-L1 plus CTLA-4 inhibitors have been associated with improved ORRs of 10.8% - 23% compared to ORRs of 3 – 7% observed with single agent PD-1 or PD-L1 inhibitors. XmAb20717 (vudalimab) is a novel, bispecific antibody targeting PD-1 and CTLA-4 which demonstrated an ORR of 14.1% in a phase I dose expansion cohort of patients with advanced malignancies, including patients that had experienced disease progression on prior immune checkpoint inhibitors. Methods: We initiated a single-arm, phase II clinical trial with a Simon two-stage mini-max design to evaluate the efficacy of XmAb20717, in terms of ORR, in patients with advanced biliary tract cancers previously treated with gemcitabine-based chemotherapy. In the first stage, 13 patients evaluable for efficacy will be accrued. If no responses are observed in these 13 patients, the study will be stopped for futility. Otherwise, 14 additional patients evaluable for efficacy will be accrued to total 27 evaluable patients. If 4 or more responses are observed in these 27 patients, then the null hypothesis will be rejected. XmAb20717 (10 mg/kg) is administered intravenously on days 1 and 15 of a 28-day cycle. Important inclusion criteria include that patients with FGFR2 fusions, NTRK fusions, or IDH1 mutations must have received molecularly targeted therapy unless contraindicated or refused. Patients are not eligible if they have received prior immune checkpoint inhibitor therapy. Correlative studies will include longitudinal peripheral blood collection for circulating immune cell profiling. As of January, 2023, 8 patients have been enrolled with enrollment ongoing. Clinical trial information: NCT05297903 .
NeoTACE: A multicenter, randomized study evaluating the efficacy and safety of neoadjuvant HAIC for TACE plus donafenib in BCLC B stage hepatocellular carcinoma outside of up-to-seven.
Authors: Wang Xiaodong
Published: June 2023

TPS4186

Background: Transarterial chemoembolization (TACE) is standard treatment for hepatocellular carcinoma (HCC) patients in BCLC B stage, while a number of studies demonstrated compromised effect of TACE for patients with large HCC or tumor burden outside of up-to-7. Recently, two phase 3 studies showed the survival benefit of Hepatic arterial infusion chemotherapy (HAIC) for large HCC and as neoadjuvant treatment for HCC outside of Milan criteria. A Phase 3 study also showed the survival benefit of donafenib for unresectable HCC compared with sorafenib. Here, we propose a prospective randomized study to investigate the benefit of HAIC as a neoadjuvant therapy for TACE plus donafenib in unresectable BCLC B stage HCC outside of up-to seven. Methods: This is a multicenter, open-label, randomized study designed to evaluate the efficacy and safety of neoadjuvant HAIC for TACE plus donafenib compared with TACE plus donafenib in BCLC B stage unresectable HCC outside of up-to-seven. Participants are randomized in 1:1 ratio to either Arm A, receiving 2-4 cycles neoadjuvant HAIC treatment plus donafenib initially, then TACE plus donafenib sequentially, or Arm B, just receiving TACE treatment plus donafenib. HAIC consisted of infusions of oxaliplatin (35 mg/m2 for 2 hours), followed by 5-fluorouracil (600 mg/m2 for 22 hours) on day1-3 every 4 weeks. The primary endpoint is PFS, and the secondary endpoints are OS, ORR, DCR, and adverse events. We hypothesize that neoadjuvant HAIC for TACE plus donafenib will improve PFS from 6 months to 11 months, with the hazard ratio of 0.55. With one-sided significance level of 0.05 and power of 0.8, the sample size for randomization will be 156. The study, registered with clinical trial ID of NCT05171166, started enrolment in Feb 2022. As of Oct 2022, 65 patients have been enrolled and 11 patients have been randomized. Clinical trial information: NCT05171166 .
ADJUBIL: A phase II study of immunotherapy with durvalumab and tremelimumab in combination with capecitabine or without capecitabine in adjuvant situation for biliary tract cancer.
Authors: Goetze Thorsten Oliver , Kochen Lisa , Vortmeyer Doerthe , Al-Batran Salah-Eddin , Habibzada Timorshah , Brunner Marius , Ettrich Thomas Jens , Gonzalez-Carmona Maria A , Kohne Claus-Henning , Modest Dominik Paul
Published: June 2023

TPS4187

Background: Despite improvements in multidisciplinary management, patients with biliary tract cancer (BTC) have a poor outcome. Only 20% of patients are eligible for surgical resection with curative intent, with 5-year overall survival of less than 10% for all patients. Data regarding pure adjuvant chemotherapy in BTC’s are conflicting and the SOC of the western world is currently capecitabine according to the British BILCAP- trial, even though BILCAP was formally negative. Based on the positive data for durvalumab in the TOPAZ- 1 – trial in BTC and for STRIDE- regimen in HCC according to the Himalaya- data, evaluation of IO- combination in the adjuvant setting seems to be promising. Preclinical studies indicate that the antibody combination results in stronger and more durable anti-tumor effects than single therapies by synergistically modulating the immunosuppressive tumor microenvironment which is particularly rich in cholangiocarcinoma. The aim of this study is the assessment of the clinical activity of the anti-PD-L1 (programmed- death 1-ligand) antibody durvalumab and the anti-CTLA-4 (cytotoxic T- lymphocyte-associated antigen 4) antibody tremelimumab in combination with or without capecitabine in patients with respectable BTC in the adjuvant situation. This is a randomized phase II study as a proof-of-concept for a potentially larger research program. Methods: The ADJUBIL trial is an open-label, multicenter phase II study, including patients with BTC after curative surgery with no previous systemic treatment. Patients are randomly assigned to receive tremelimumab (300mg, one dose) plus durvalumab (1500mg every 4 weeks; STRIDE, for a maximum of 12 months), with or without capecitabine (for 8 cycles). Forty evaluable patients will be enrolled in the study (1:1) to receive anticancer treatment until disease recurrence or intolerable toxicities. Primary objective is to assess the anti-tumor activity of the treatment in both arms by the recurrence-free survival rate after 12 months (RFS@12). Secondary endpoints are recurrence-free survival, overall survival, toxicity, and quality of life. Exploratory endpoints: Explore predictive biomarkers for recurrence-free survival and overall survival. Study start of the ADJUBIL trial was in June 2021. By January 2023, 12 centers across Germany have been initiated and a total of 8 out of 40 planned patients (1:1) have been enrolled. The study is currently ongoing. Clinical trial information: EUCTR2021-002389-41 .
Durvalumab and tremelimumab for hepatocellular carcinoma in patients listed for a liver transplant.
Authors: Sohal Davendra , Abouelezz Khaled Fahmy , Moreland Katie , Quillin Ralph , Lemon Kristina , Rojan Adam , Olowokure Olugbenga Olanrele , Kord Ali , Shah Shimul
Published: June 2023

TPS4188

Background: Hepatocellular carcinoma (HCC) is an aggressive malignancy, developing most often in the setting of liver cirrhosis (Sohal et al Current Oncol Rep 2011; Gordan et al JCO 2020). For advanced disease, immunotherapy has now become standard of care – a combination of atezolizumab and bevacizumab has shown the best overall survival outcome so far (Finn et al NEJM 2020). For earlier stage disease, however, there is no systemic therapy standard. The best treatment for HCC in the setting of cirrhosis is a liver transplant allowing potential cure for both the cancer and cirrhosis. Nonetheless, 25-35% of patients fail to reach liver transplant because of disease progression while waiting for a transplant (Sinha et al, Hepatology 2019) and approximately 15% experience HCC recurrence after transplant (Mehta et al, Transplantation 2020). Taken together, this constitutes a large subset of this patient population who cannot achieve a cure. Given the success of immunotherapy in the advanced setting, it is imperative to study this in the pre-transplant setting, to improve the outcomes cited above. However, there is a theoretical risk of graft rejection with immunostimulatory treatment. Methods: This is a single-arm, open-label, Phase II, multicenter study designed to evaluate the safety and efficacy of durvalumab and tremelimumab for the treatment of HCC patients who have cirrhosis or portal hypertension and are eligible for listing for a liver transplant. Eligibility requirements include adult patients with HCC within UCSF criteria, a Child-Pugh score of up to 7, and ECOG PS of 0 or 1. Treatment includes an immunotherapy combination of 1 dose of tremelimumab and 5 doses of durvalumab for up to 4 months. After a minimum 28-day gap following the final durvalumab dose, patients undergo locoregional therapy per institutional standards. After a minimum 72-day gap from the end of immunotherapy, patients undergo liver transplant. Primary outcome is a binary endpoint, and it will be assessed in patients undergoing liver transplant. Historically, 10-20% of patients are expected to experience acute cellular rejection within 30 days of transplant. We propose that an observed proportion of 20% treatment failure will be a clear indicator of safety in this pilot study, whereas an observed proportion of 50% failure will be a clear indicator of failure. Using these guardrails, with at least 20 patients going to transplant, we will have 80.6% power to demonstrate a failure proportion of 20% (4 patients experiencing failure) versus a null of 50% (10 patients experiencing failure), with a one-sided alpha of 0.05. With 25 patients going to transplant, the power will increase to 86% (other parameters being the same). Clinical trial information: NCT05027425 .
An open-label window of opportunity trial to evaluate the activity of durvalumab and tremelimumab with platinum-based chemotherapy (gemcitabine and cisplatin) in intrahepatic cholangiocarcinoma.
Authors: Gbolahan Olumide B. , Akce Mehmet , Outlaw Darryl Alan , Williams Grant Richard , Reddy Sushanth , Denbo Jason , Kim Richard D. , El-Rayes Bassel F. , Rose J. Bart
Published: June 2023

TPS4189

Background: Following surgical resection, the rate of recurrence of intrahepatic cholangiocarcinoma (ICC) is high. Expert groups recommend preoperative systemic therapy, particularly for resectable ICC with features that portend a high risk of recurrence. Based on data from ABC-02 the combination of gemcitabine and cisplatin (GC) is often used. This provides an objective response rate (ORR) of only 20% in ICC. The addition of durvalumab, an anti-PDL1 inhibitor to GC improves overall survival (OS) in the metastatic setting and is associated with an ORR of about 30%. On the other hand, while the addition of nab-Paclitaxel to GC provides an ORR of 34%, it was not associated with an improvement in OS in biliary tract cancer. It is therefore rationale to continue to explore and optimize immune checkpoint inhibitor development in ICC. We designed this study to determine the activity of durvalumab (D) and tremelimumab (T) (anti-CTLA4 ICPI) in combination with GC in resectable ICC with high-risk features. We plan to explore tumor intrinsic and tumor microenvironment related factors that will be associated with response (or lack thereof) to ICPI. Methods: This is a multicenter open-label, window of opportunity trial of the combination durvalumab and tremelimumab in combination with GC in resectable ICC with high-risk features. Inclusion criteria includes patients ≥18years with radiologically measurable and biopsy proven ICC that is surgically resectable but with high risk features (based on multidisciplinary tumor board discussion). Prespecified high-risk features include tumor size >5cm, T1b-T4 lesion, multifocal tumors/tumor with satellite lesions, suspicious or involved lymph nodes (N1) and vascular involvement all thought to be technically resectable. Patients with extrahepatic metastasis will be excluded. D will be administered at 1500mg IV on Day 1 every 3 weeks for up to a maximum of 4 cycles. T, 300mg will be administered on Day 1 of cycle 1 only. G (1000mg/m2) and C (25mg/m2) will be administered by IV infusion on Days 1 and 8 every 3 weeks for a maximum of 4 cycles. The primary outcome measure is to demonstrate an ORR of 52%. Secondary objectives are to assess the feasibility and safety of the combination in ICC. Given the historical objective response rate of 25% and using one-sided exact test for single proportion, we will have 80% power to reject 25% ORR at α=0.05 when we observe ORR of 52% (Ho: Po=0.25 vs. Ha: Pa=0.52) from the study sample. The study is open at the O’Neal Comprehensive Cancer Center at the University of Alabama and will be open at other centers in the next few months. Clinical trial information: NCT04989218 .
A phase II, open-label pilot study evaluating the safety and activity of liposomal irinotecan (Nal-IRI) in combination with 5-FU and oxaliplatin (NALIRIFOX) in preoperative treatment of pancreatic adenocarcinoma: NEO-Nal-IRI study.
Authors: Rogers Sherise C. , Sahin Ilyas , Fabregas Jesus C. , Nassour Ibrahim , Ramnaraign Brian Hemendra , Hitchcock Kathryn , Hughes Steven J. , Lee Ji-Hyun , Kayaleh Omar Roger , Turk Anita Ahmed , Fan Z. Hugh , Russell Karen Bullock , DeRemer David L. , Allegra Carmen Joseph , George Thomas J.
Published: June 2023

TPS4190

Background: Neoadjuvant treatment for potentially curable pancreatic cancer (PDAC) is increasing in acceptability, but a standard regimen has yet to be established. Multiple studies have demonstrated feasibility and effectiveness of the FOLFIRINOX (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) regimen in the perioperative setting. However, FOLFIRINOX often requires dose modifications, delays and growth factor support due to excessive toxicity which can complicate care delivery when given neoadjuvantly. Liposomal irinotecan injection (Nal-IRI) is FDA approved with a well-tolerated safety profile in relapsed, refractory metastatic PDAC. The current study aims to substitute Nal-IRI for traditional irinotecan in the standard FOLFIRINOX regimen (NALIRIFOX) and to demonstrate safe and effective neoadjuvant delivery. Methods: This phase 2, open-label, multicenter single-arm study focuses on patients (pts) with operable PDAC without metastatic disease. Other key eligibility criteria include age ≥18 years, resectability confirmed by multidisciplinary GI tumor board (resectable vs. borderline), adequate cardiac, renal, hepatic function and ECOG performance status of 0 to 1. Pts receive NEO-N-IRI regimen as per Table every 2 weeks for four months followed by disease reassessment. Pts who remain surgical candidates will undergo surgical resection within 4 to 8 weeks following last dose of therapy. The primary endpoint is to assess safety and feasibility of regimen in perioperative setting. Secondary endpoints include R0 resection rate, clinical, biochemical and radiological response rate and patient-reported quality of life during treatment as measured by the NCI validated FACT-G scale. Enrollment continues to a maximum of 28 evaluable pts to demonstrate a reduction in historical 30-day postoperative complication rate. Microbiota specimens will be collected for exploratory analysis. Clinical trial information: NCT03483038 . [Table: see text]
Phase II trial of BXCL701 and pembrolizumab in patients with metastatic pancreatic ductal adenocarcinoma (EXPEL-PANC).
Authors: Weinberg Benjamin Adam , Gutierrez Martin , Tesfaye Anteneh A. , Tan Ming Tony , Noel Marcus Smith , He Aiwu Ruth , Mukherji Reetu , Marshall John , Gleim Jennifer , Bouker Kerrie , Weiner Louis M.
Published: June 2023

TPS4194

Background: Pancreatic ductal adenocarcinoma (PDAC) has limited therapeutic options and is thought to be a “cold” tumor that does not respond to immunotherapy, due to a tumor microenvironment (TME) consisting of a desmoplastic stroma and poor T cell infiltrate. BXCL701 is an oral synthetic dipeptide that competitively inhibits dipeptidyl peptidases DPP4, DPP8, DPP9 and fibroblast activation protein (FAP). BXCL701 exerts antitumor activity via inhibition of DPP8/9, which is associated with induction of proinflammatory cytokines, as well as inhibition of FAP, which disrupts tumor-stromal interactions. Preclinical xenograft models demonstrate synergy between BXCL701 and an anti-PD-1 monoclonal antibody, reducing tumor growth and promoting an increase in intratumoral CD4+ and CD8+ T cells and NK cells. The combination of BXCL701 and pembrolizumab is already being studied in a phase II trial in patients with prostate cancer (NCT03910660) and a multi-cohort basket study (NCT04171219). Methods: This is a phase II trial of BXCL701 administered at 0.2 mg PO BID days 1-7 and 0.3 mg BID days 8-14 during cycle 1 (21 days) followed by 0.3 mg BID days 1-14 every 21 days in all subsequent cycles, given with pembrolizumab 200 mg IV every 21 days (all cycles). The primary objective is to determine the 18-week progression-free survival rate (PFS18weeks) in patients with metastatic PDAC treated in the second-line setting. We estimate that historical 2nd-line PFS18weeks is 30% or less; using a Simon’s two-stage (minimax) design, a type I error rate of 0.05 and power of 80% when the true response rate of 50%, we will need 19 patients in stage 1 and 20 in stage 2 (a total of 39). We plan to enroll 43 patients to account for a predicted 10% drop out of unevaluable patients. Eligible patients must have metastatic PDAC and disease progression or intolerance to only 1 line of therapy for metastatic disease, without exposure to prior immunotherapy. Patients must have measurable disease amenable to serial biopsies. Correlative pharmacodynamic studies include imaging mass cytometry to examine 34 markers of the PDAC TME in tissue biopsies, as well as blood-based analyses of KRAS circulating tumor DNA, circulating markers of fibrosis, and IL-6. Enrollment began in Q1 2023. Clinical trial information: NCT05558982 .
ASCEND: A randomised, double-blinded, phase II study of gemcitabine and nab‐paclitaxel with CEND‐1/LSTA1 or placebo in patients with untreated metastatic pancreatic ductal adenocarcinoma.
Authors: Dean Andrew Peter , Price Timothy Jay , Sjoquist Katrin Marie , Gebski Val , Mumford Jan , Day Fiona , Yip Sonia , Bradshaw Nathan , Jackson Christopher G. C. A. , Padinharakam Shamsudheen , Lee Belinda , Burge Matthew E. , Tebbutt Niall C. , Steer Christopher B. , Lomma Chris , Lam Lyn , Lee Joanna , Chantrill Lorraine A. , Harris Marion
Published: June 2023

TPS4197

Background: LSTA1 is a novel cyclic peptide with high tumor vascular endothelium specificity that activates an endocytotic/exocytotic transport pathway on stroma and tumor. LSTA1 potentiates greater intratumoral access for co-administered or tethered anti-cancer agents, including small molecules, antibodies, and nanoparticles, leading to increased anti-neoplastic activity. Preclinical studies in solid tumor models have shown co-administrating LSTA1 is effective in augmenting the delivery and activity of multiple anti-cancer agents. LSTA1 has been evaluated in 31 patients in a Phase I study in metastatic pancreatic ductal adenocarcinoma (mPDAC) demonstrating an objective response in 59% of patients, a 79% disease control rate at 16 weeks with a median progression free survival (PFS) of ~9.9 months. No dose limiting toxicities were observed. The ASCEND study will determine whether LSTA1 when added to SOC chemotherapy is active and safe as first-line treatment of mPDAC, and whether an additional dose of LSTA1 administered approximately 4 hours after chemotherapy further improves anti-cancer activity. Methods: ASCEND is a randomized, double-blind, placebo-controlled phase II trial evaluating the safety and efficacy of LSTA1 3.2 mg/kg in combination with standard of care chemotherapy (nab-paclitaxel 125mg/m2 and gemcitabine 1000mg/m2 on days 1, 8, and 15, every 28 days) in patients with histologically proven, previously untreated mPDAC. A total of 155 subjects will be randomized 2:1 in favor of study intervention in two cohorts and stratified by age, ECOG status, presence of liver metastasis, and study site. Patients in cohort A receive single doses of LSTA1 or placebo, and for cohort B, two doses of LSTA1 or placebo spaced 4 hours apart. Tumour assessment occurs every 8-weeks from randomization until disease progression or commencement of a new anti-cancer therapy. The primary endpoint is PFS. Secondary endpoints include objective tumour response safety, overall survival, and patient reported outcomes. At 14 Feb 2023, 70 participants have been enrolled from Australian sites. Sites in Ireland and New Zealand are anticipated to open this year. Clinical trial information: NCT05042128 .
Phase 3 PANOVA-3 study: Tumor treating fields (TTFields) therapy concomitant with gemcitabine and nab-paclitaxel (GnP) for front-line treatment of locally advanced pancreatic cancer.
Authors: Babiker Hani M. , Macarulla Teresa , Philip Philip Agop , Becerra Carlos Roberto , Dragovich Tomislav , Picozzi Vincent J.
Published: June 2023

TPS4199

Background: Tumor Treating Fields (TTFields) therapy is a locoregional antimitotic treatment approved for newly diagnosed and recurrent glioblastoma GBM and pleural mesothelioma. TTFields (150 kHz) therapy, with/without chemotherapy, had antiproliferative and anticlonogenic activity in pancreatic cancer cell lines, and reduced tumor volume and weight more than chemotherapy alone in in vivo models. TTFields therapy with gemcitabine and nab-paclitaxel (GnP) was well-tolerated, with promising efficacy in metastatic and locally advanced pancreatic adenocarcinoma (LAPC) in the phase 2 PANOVA study (NCT01971281). LAPC prognosis remains poor despite available therapies, which can negatively impact quality of life (QoL). As such, there remains a need for effective and tolerable treatments. Methods: PANOVA-3 (EF-27, NCT03377491) is a prospective, randomized, phase 3 study investigating the efficacy and safety of TTFields therapy with GnP in patients with LAPC, with a planned enrollment of 556 patients. Key inclusion criteria are: a diagnosis of unresectable LAPC (per NCCN guidelines), ECOG PS of 0–2, and no prior treatment. Patients will be stratified by performance status and geographical region and assigned 1:1 to treatment groups to receive TTFields therapy + GnP or GnP alone. GnP will be administered at a standard dose per standard of care. TTFields therapy (150 kHz, 18h/day) will be delivered by the NovoTTF-200T System until local disease progression per RECIST v1.1. Usage will be tracked by the device. Follow-up will be performed every 4 weeks and computed tomography scans of the chest and abdomen will be taken every 8 weeks until disease progression. Patients will be followed every month until death. The primary endpoint is overall survival and key secondary endpoints include QoL, pain-free survival, and puncture-free survival, which will be compared between treatment groups. Other secondary endpoints include progression-free survival (PFS), local PFS, objective response rate, 1-year survival rate, rate of resectability, and safety. Guidance around usage, lifestyle integration and prevention and management of skin adverse events will be provided by Device Support Specialists and field personnel. Usage information will be provided to patients and physicians to facilitate discussions to optimize outcomes by maximizing time on therapy. Together, these novel support approaches aim to optimize patient usage and outcomes. The trial is currently recruiting at 149 sites, globally. The DMC last reviewed the trial in August 2022, and suggested that the trial continue as planned. Clinical trial information: NCT03377491 .
ARC-20: A phase 1 dose-escalation and dose-expansion study to investigate the safety, tolerability, and pharmacology of HIF-2α inhibitor AB521 monotherapy in patients with clear cell renal cell carcinoma and other solid tumors.
Authors: Choueiri Toni K. , Garmezy Benjamin , Paterson Elaine , Ghasemi Mohammad , Cheng Tzuling , Foster Paul G. , Hauke Ralph J. , Patnaik Amita
Published: June 2023

TPS4602

Background: Renal cell carcinoma (RCC) is one of the 10 most common neoplasms in the United States. Patients with clear cell RCC (ccRCC) commonly have inactivation of the von Hippel-Lindau tumor suppressor protein, resulting in accumulation of hypoxia-inducible factor alpha (HIFα) subunits (especially HIF-2α) and leading to tumor growth. AB521, an orally bioavailable small molecule inhibitor of HIF-2α, potently inhibits transcription of HIF-2α-dependent genes in cell lines and preclinical species. Single doses of AB521 (3 mg, 10 mg, 30 mg, and 100 mg) and multiple ascending doses of AB521 (15 mg, 30 mg, and 50 mg) have been previously studied in healthy volunteers. ARC-20 is a first-in-patient study to investigate the safety, tolerability, and pharmacology of AB521 monotherapy in patients with solid tumors and evaluate the clinical activity of AB521 in previously treated patients with ccRCC. Methods: ARC-20 (NCT05536141) is a phase 1, multicenter, open-label study. Eligible patients are adults with solid tumors with ≥1 measurable lesion(s) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and an Eastern Cooperative Oncology Group performance status of 0 or 1. ARC-20 has 2 stages, dose escalation and dose expansion. The dose escalation stage uses a standard 3+3 design and includes patients with pathologically confirmed solid tumors and no other available treatment options. Patients will be sequentially assigned to 1 of 4 cohorts evaluating doses of AB521 ranging from 20 to 200 mg/day. Intermediate dose cohorts may be evaluated based on emergent safety or pharmacologic data. The dose expansion stage will evaluate approximately 30 patients with histologically confirmed ccRCC who have received previous treatment for metastasis with an anti-programmed cell death protein 1 (anti-PD-1) therapy and a vascular endothelial growth factor (VEGF)-targeting tyrosine kinase inhibitor (TKI). Patients previously treated with a HIF-2α-targeting therapy are not eligible for dose expansion. Results from the dose-escalation stage will inform the dose and schedule used during dose expansion. Primary endpoints are the incidence of dose-limiting toxicity and adverse events. Secondary endpoints include objective response rate, AB521 plasma concentration, and AB521 pharmacokinetics. Exploratory endpoints include changes in expression of erythropoietin and other HIF-2α driven biomarkers in blood and tumor tissues, along with progression-free survival for ccRCC patients during dose expansion. Clinical trial information: NCT05536141 .
LITESPARK-024: Randomized phase 1/2 study of belzutifan with or without palbociclib for treatment of advanced renal cell carcinoma (RCC).
Authors: McDermott David F. , Peer Avivit , Agarwal Neeraj , Atkins Michael B. , Cornell Jerry , Perini Rodolfo F. , Grossmann Kenneth F. , Gurney Howard
Published: June 2023

TPS4603

Background: Immunotherapy is a standard-of-care first-line treatment for advanced clear cell RCC (ccRCC). However, many patients (pts) will develop resistance to first-line therapy, and effective second- and later-line treatment options are therefore needed. The von Hippel-Lindau ( VHL) gene is inactivated in approximately 90% of ccRCC cases and results in the constitutive activation of hypoxia-inducible factor 2α (HIF-2α), a key oncogenic driver in RCC. Belzutifan, a first-in-class HIF-2α inhibitor, has demonstrated antitumor activity with manageable safety in previously treated pts with advanced ccRCC. The cyclin-dependent kinase (CDK) pathway is also associated with poor clinical outcomes in ccRCC. In RCC cell lines, the CDK 4/6 inhibitor palbociclib inhibited cell growth. CDK 4/6 inhibition has shown synergistic antiproliferative effects with HIF-2α inhibition in HIF-2α–dependent VHL -/- RCC cell lines. Palbociclib could therefore potentially enhance the efficacy of belzutifan as combination therapy for previously treated pts with advanced RCC. Methods: LITESPARK-024 is a 2-part, open-label, multicenter, phase 1/2 randomized study (NCT05468697). Part 1 is intended to establish the recommended phase 2 dose (RP2D) of belzutifan + palbociclib using a modified toxicity probability interval design. After the RP2D is established, part 2 will directly compare the safety and efficacy of belzutifan monotherapy with belzutifan + palbociclib in pts with advanced ccRCC. In both parts, pts with measurable disease per RECIST v1.1, a KPS score of ≥70%, and histologically confirmed unresectable stage IV RCC with a clear cell component with disease progressing on or after receiving at least 2 systemic treatments (both an anti–PD-1/L1 monoclonal antibody and a VEGF receptor–targeted tyrosine kinase inhibitor, in sequence or in combination) will be enrolled. Up to 30 pts will be enrolled into 3 dose groups in part 1 and will receive belzutifan 120 mg once daily + palbociclib (75, 100, or 125 mg) daily for 21 consecutive days followed by 7 days off. In part 2, approximately 150 pts will be randomly assigned 2:1 to receive belzutifan 120 mg once daily + palbociclib RP2D (21 consecutive days/7 days off) or belzutifan 120 mg once daily. Pts will be stratified by IMDC risk (0 vs 1-2 vs 3-6) and sarcomatoid histology (yes vs no) at randomization in part 2. The primary end point for part 1 is to assess dose-limiting toxicities and adverse events and to determine the RP2D of belzutifan + palbociclib. The primary end point for part 2 is ORR per RECIST v1.1 by investigator assessment. Secondary end points for part 2 are CBR, DOR, and PFS per RECIST v1.1 by investigator assessment, OS, and safety and tolerability. Enrollment began in July 2022. Clinical trial information: NCT05468697 .
MAIN-CAV: Phase III randomized trial of maintenance cabozantinib and avelumab versus avelumab after first-line platinum-based chemotherapy in patients (pts) with metastatic urothelial cancer (mUC; Alliance A032001).
Authors: Gupta Shilpa , Ballman Karla V. , Galsky Matt D. , Morris Michael J. , Sridhar Srikala S. , Chen Ronald C. , Chan Timothy An-thy , Wen Yujia , Grivas Petros , Tan Alan , Baghaie Shiva , Rosenberg Jonathan E.
Published: June 2023

TPS4609

Background: First-line platinum-based chemotherapy followed by maintenance avelumab (Av) is the current preferred standard of care in patients (pts) with mUC who do not progress after platinum-based chemotherapy. There is an unmet need to further improve outcomes by combining Av with an effective, non-cross resistant therapy with non-overlapping toxicity. CABO is an oral inhibitor of MET, VEGFR and TAM family receptors involved in tumor growth, angiogenesis and immune cell regulation and has shown efficacy in UC in combination with PD-1/PD-1L1 inhibitors. We hypothesize that CABO-Av combination will be synergistic in pts with mUC with an acceptable safety profile and will improve upon the benefit seen with Av maintenance in mUC. Methods: MAIN-CAV is a phase III randomized, multicenter, international trial for locally advanced/mUC pts (including N3 only disease) who do not progress after 4-6 cycles of any platinum-based chemotherapy (gem-cis, gem-carbo, MVAC or ddMVAC). 654 adult pts will be randomized 1:1 within 3-10 weeks (wk) after last dose of chemotherapy to receive Av 800 mg IV every 2 wk or combination of Av and CABO 40 mg orally daily for up to 2 yrs. Key eligibility criteria include ECOG PS 0-1, no prior use of immunotherapy (exception of BCG), no central nervous system metastases, no major surgery within 4 wk, no uncontrolled hypertension or cardiovascular disorders. Pts will be stratified based on 1) best response to 1L therapy: complete response vs partial response vs stable disease and 2) presence or absence of visceral metastases. The primary endpoint is overall survival (OS) with assumptions of one-sided alpha of 0.025, power of 80%, median OS of 21 months (mo) on Av arm and hazard ratio (HR) of 0.75, thus hypothesizing a median OS of 28 mo on CABO-Av combination arm. Key secondary endpoints include progression-free survival, safety, tolerability, and activity of CABO-Av compared to Av alone based on RECIST 1.1 and iRECIST criteria and PD-L1 status of pts’ tumors. Quality of life (QOL) will be assessed using EQ-5D-5L, PROMIS-Fatigue 4a, EORTC QLQ-C30, EORTC QLQ-BLM30 between pts on CABO-avelumab vs avelumab alone. Biomarkers of response and resistance to Av will be assessed using baseline archival tissues, baseline and serial blood, ctDNA, stool and urine. Imaging studies will test correlation of established and new radiomic signatures with OS, adverse events and QOL and incorporate both radiologic and biologic features to predict outcomes. This trial would be the first to systematically address whether adding a multitargeted TKI, CABO to Av leads to improved clinical outcomes compared to Av alone. Clinical trial information: NCT05092958 .
ALTER-UC-007: A prospective phase 2 study of anlotinib with gemcitabine and cisplatin or anlotinib with penpulimab as perioperative treatment for patients with muscle-invasive urothelial carcinoma (MIUC).
Authors: Zhang Hailiang , Zhu Yiping , Ye Ding-Wei
Published: June 2023

TPS4612

Background: Radical surgery involving cystectomy and nephroureterectomy is the standard of care for patients with localized muscle-invasive urothelial carcinoma (MIUC). In recent years, neoadjuvant- and adjuvant-containing multimodality therapies have gradually been adopted in attempt to eradicate micrometastatic disease and improve the outcomes achieved with radical surgery alone. This study aims to evaluate the efficacy and safety of anlotinib (a multi-target tyrosine kinase inhibitor of angiogenesis) with gemcitabine and cisplatin or anlotinib with penpulimab (a humanized anti-PD-1 IgG1 monoclonal antibody) as neoadjuvant and adjuvant therapy in patients with MIUC. Methods: In this open-label, prospective, phase 2 study, eligible patients include those with histologically confirmed clinical stage T1-T4N1-3M0, T3-4N0M0 MIUC (tumors of the bladder, renal pelvis, ureter and urethra) fit and planned for radical cystectomy, nephroureterectomy or ureterectomy. Main exclusion criteria are distant metastatic disease; prior chemotherapy, anti-angiogenic therapy, radiation therapy or immunotherapies; active autoimmune disease; uncontrolled hypertension or patients at high bleeding risk. Patients will be enrolled and receive treatment based on PD-L1 status in tumor tissue. The PD-L1 status of eligible patients will be centralized and assessed using an anti-PD-L1 antibody and an immunohistochemical (IHC) assay. PD-L1 positivity was defined as combined positive score (CPS) ≥1 (previously reported as and equivalent to CPS ≥1%). The study treatment is stratified into two cohorts based on PD-L1 expression levels. In cohort 1, the PD-L1 negative patients with MIUC will receive neoadjuvant anlotinib (12 mg orally QD D1-14 every 3 weeks) + gemcitabine (1000 mg/m2, intravenously [IV] on days 1 and 8) + cisplatin (35 mg/m2 IV on days 1 and 8) for a maximum of 4 cycles followed by radical surgery and 2 cycles of adjuvant treatment post-surgery. In cohort 2, PD-L1 positive patients will receive anlotinib (12 mg orally QD D1-14 every 3 weeks) + penpulimab (200 mg IV every 3 weeks) for a maximum of 4 cycles followed by radical surgery and 2 cycles of adjuvant treatment post-surgery. After the completion or discontinuation of the study treatment, safety follow-up and survival follow-up will be performed. Tumor imaging was performed by computed tomography (preferred) or magnetic resonance imaging at baseline, and every 6 weeks during treatment, then every 6 months through year 2. Objective response rate (ORR) is the primary endpoint. Secondary endpoints included pathological complete response rate (pCR), disease-free survival (DFS), overall survival (OS) and safety. Recruitment have begun in October 2022. Currently, the study is active with 1 participant has been enrolled. Clinical trial information: ChiCTR2200063085 .
Adding mitomycin (MM) to bacillus Calmette-Guérin (BCG) as adjuvant intravesical therapy for high-risk, non–muscle-invasive urothelial bladder cancer (NMIBC): BCGMM; ANZUP 1301.
Authors: Hayne Dickon , Stockler Martin R. , Martin Andrew James , McCombie Steve P , Zebic Danka Sinikovic , Bastick Patricia A. , Beardsley Emma Kate , Frydenberg Mark , Green William , Grummet Jeremy , Hawks Cynthia , Ischia Joseph , Mitterdorfer Andrew , Patel Manish , Roberts Matthew , Sengupta Shomik , Srivastav Ratnesh Kumar , Redfern Andrew David , Davis Ian D. ,   The Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP)
Published: June 2023

TPS4617

Background: Adjuvant intravesical BCG decreases disease recurrence and progression in high-risk, NMIBC, however recurrence occurs in 30% of those affected, despite optimal therapy. Meta-analyses evaluating addition of intravesical MM to BCG showed lower rates of recurrence and cancer-specific mortality in people with NMIBC who received combination regimens. Phase 3 randomized trials to definitively test this combination are lacking. The BCGMM trial (NCT02948543) will determine the effects of adding MM to the standard BCG after resection of high-risk NMBIC. This is the largest study evaluating this approach in high-risk NMIBC, is of particular relevance given the current BCG shortage, and has the potential to change global practice. Methods: This open-label phase 3 trial is randomizing 500 participants stratified by stage, site of disease, and presence of carcinoma in-situ, in a 1:1 ratio to Arm A (BCG induction weekly x6 then monthly x10) or Arm B (BCG weeks 1, 2, 4, 5, 7, 8; months 4, 5, 7, 8 + MM weeks 3, 6, 9; months 3, 6, 9, see figure below). This provides 85% power to detect an absolute improvement of 10% in 2-year disease free survival (DFS) at 2p = 0.05. Stage 1 (n = 130) was to determine rates of treatment completion, activity reflected by cystoscopic findings at 3 months, adverse events, resource use, and health related quality of life, established feasibility. Stage 2, including an additional 370 participants, will provide information on DFS, time to recurrence and progression, overall survival, and identification of potential predictive biomarkers, is estimated to complete accrual by Q2 2023. Progress As of Jan 2023, 484 of 500 planned participants have been recruited from 16 Australian and 1 UK site. In stage 1, successful treatment completion, defined as 75% or more of planned treatment doses, was achieved by 76% in the experimental group (BCGMM) versus 60% in the control group (BCG alone). Clinical trial information: NCT02948543 .
CLIMATE: Assessing the clinical utility of miR-371a-3p as a marker of residual disease in stage 1 testicular germ cell tumour (TGCT) following orchiectomy: ANZUP 1906.
Authors: Conduit Ciara , Grimison Peter S. , Lewin Jeremy Howard , Hansen Aaron Richard , Lynam James F. , Weickhardt Andrew James , Parente Phillip , Campbell David Colin , Hong Wei , Marx Gavin M. , Heron Orlaith Mary , Kuchel Anna , McJannett Margaret Mary , Cusick Thomas , Fontela Antoinette , O Haire Sophie , Zlatic Kristina , Davis Ian D. , Tran Ben ,   The Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group
Published: June 2023

TPS5100

Background: There is impetus to identify biomarkers in TGCT to help select those at high-risk of relapse following orchiectomy and target interventions to prevent over-treatment. miR-371 has been shown to reliably predict presence of active malignancy with higher accuracy than currently available biomarkers. More clinical evidence is required to ascertain its clinical utility as a marker of microscopic disease to guide treatment recommendations in stage 1 TGCT and other settings. Methods: CLIMATE ANZUP1906 (ACTRN12622000247774) is a prospective, single-arm, non-interventional cohort study recruiting adults with clinical stage 1 TGCT entering active surveillance. Eligible participants are recruited within six weeks of orchiectomy and are willing to undergo active surveillance in accordance with the Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group Surveillance Recommendations (or similar), without adjuvant treatment. Participants with metastases, non-testicular primaries, or history of contralateral TGCT are ineligible. Serum, plasma, and buffy coat samples are collected at consent and every three months until 24 months (and at relapse, if applicable). miR-371 will be assessed using established protocols. Clinical data, including treatment(s), surveillance, and relapses are captured in Australia’s national TGCT registry, iTestis. Archival tissue from diagnosis ± relapse is identified for future translational research. The primary endpoint for CLIMATE is 12-month relapse-free survival of miR-371 positive/negative groups. Key secondary endpoints include miR-371 during surveillance and at relapse, concordance between serum/plasma miR-371 and archival tissue, and health economic analyses. Prior studies suggest ~20% of post-orchidectomy miR-371 samples are positive. A sample size of 200 participants will result in 20 relapses, 160 non-relapses and 20 individuals lost to follow-up, and will permit description of the primary endpoint. Patient-level data from CLIMATE will contribute to a joint analysis of parallel trials evaluating miR-371 in this setting, COG AGCT1531 and SWOG1823. The first participant was recruited to CLIMATE in February 2022. 9/12 study sites in Australia and New Zealand have been activated and 47/200 (24%) have been enrolled. Recruitment is expected to take 36 months, followed by a further 24 months follow-up. Clinical trial information: ACTRN12622000247774 .
P3BEP (ANZUP 1302): An international randomized phase 3 trial of accelerated versus standard BEP chemotherapy for male and female adults and children with intermediate and poor-risk metastatic germ cell tumours (GCTs).
Authors: Zebic Danka Sinikovic , Tran Ben , Martin Andrew James , Pashankar Farzana D. , Mazhar Danish , Huddart Robert A , Wheater Matthew , Walpole Euan Thomas , Dunwoodie Elaine , Feldman Darren R. , Birtle Alison Jane , Wyld David , Lawrence Nicola Jane , Stockler Martin R. , Grimison Peter S. ,   Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP)
Published: June 2023

TPS5102

Background: Bleomycin, etoposide, and cisplatin (BEP) given 3-weekly x 4 remains standard 1st line chemotherapy for intermediate or poor risk metastatic GCT. Accelerating standard regimens by shortening the cycle length to 2-weekly improved cure rates in other cancers. P3BEP will determine effects of accelerated versus standard BEP in this setting. This is the first international, randomized trial of chemotherapy for intermediate and poor-risk metastatic GCT to include adults and children of both sexes. Methods: This open label, randomized, phase 3 trial is conducted seamlessly in 2-stages. The primary endpoint for stage I (n = 150) was favourable response; and for stage 2 (n = 500) is progression free survival at 2 years (PFS2y). These sample sizes provide > 80% power with a 2-sided type I error rate of 5% to detect an absolute improvement of 21% in the favourable response rate (stage 1) and of 7% in the PFS2y (stage 2). The target population is males and females aged 11 to 45 with intermediate- or poor-risk metastatic GCT of the testis, ovary, retroperitoneum, or mediastinum. Participants are randomized (1:1) to 4 cycles of standard BEP (q3w) or accelerated-BEP (q2w) with cisplatin 20mg/m2 D1-5, etoposide 100mg/m2 D1-5, bleomycin 30 KIU weekly x 12, and pegylated G-CSF D6 or filgrastim daily (Figure 1). Study assessments occur at 30 days after completing chemotherapy, 6 months from randomisation, and after completion of all post-chemotherapy treatments (e.g. surgery). Tumour and blood samples are collected for translational substudies. Progress - As of Jan 2023, 241 participants have been recruited from 22 ANZ sites, 16 UK sites (led by Cambridge Clinical Trials Unit), and 55 USA sites (led by Children’s Oncology Group). The first planned interim analysis for safety (n = 76) identified no safety concerns. The stage I analysis of safety and activity (response rate) for the 1st 150 patients was reviewed by the IDSMC, which recommended continuation of the trial as per protocol. Clinical trial information: NCT02582697 .
SWOG S1823/CCTG GCC1: Translational observational investigational study of the liquid biomarker microRNA 371a-3p in newly diagnosed germ cell tumours—Real-world trial design, rapid accrual, and robust secondary use of data opportunities.
Authors: Morin Coulombe Antoine , Ozgun Guliz , Johnson Rebecca , Lewis Mark Andrew , Adra Nabil , Eggener Scott E. , Roth Bruce J. , Ryan Christopher W. , Porter Christopher , Millard Fred , Jang Thomas , Hamilton Robert James , Einhorn Lawrence H. , Kollmannsberger Christian K. , Arnold Kathryn B. , Blanke Charles David , Daneshmand Siamak , Nichols Craig R. , Nappi Lucia , Harzstark Andrea
Published: June 2023

TPS5103

Background: With the discovery of the very promising, germ cell malignancy (GCM) specific, liquid biomarker microRNA 371a-3p (miR371), the investigative trajectory has markedly accelerated. With its outstanding, previously-reported specificity and positive predictive value, miR371 likely will become a powerful tool for clinical decision-making. The primary objective of SWOG S1823/CCTG GCC1 [NCT03067181] is to define the operating characteristics of plasma miR371 expression at the time of clinical relapse for low/moderate risk non-seminoma GCM patients on active surveillance. Methods: S1823 is a prospective, observational, adult GCM translational trial which is actively accruing. Broad eligibility includes all newly diagnosed adult GCM patients. Patients are assigned to low (<25% risk of relapse), moderate (25-90% risk of relapse) or high (≥90% risk of harboring active GCM) risk groups. Pragmatic logistics include using Streck tubes and centralized processing for miR371 sample processing and analytics. Research samples were drawn at the time of routine blood draws minimizing patient burden. Source documents are submitted along with case report forms. This data-gathering model gives an important data quality-control check. S1823 began in July 2020 and has since accelerated its accrual to consistently predicted new enrollments of 20-30 cases/month. As of January 2023, the study enrolled 389 low-risk, 114 moderate-risk and 146 high-risk patients (657 total). Interim analysis is planned at the time 40 non-seminoma GCM patients have relapsed and is anticipated in late 2023 to early 2024. 404 centers have opened S1823. 3 Canadian centers have enrolled >10 patients (range 11-51). 17 USA institutions have enrolled >10 patients (range 11-112). In North America, 9 of the 12-storied GCM clinical research programs have had robust participation. The leading accruing organization was the Kaiser Permanente system where 112 patients have been enrolled. In Canada, all population centers contributed proportionally. In the USA, the dominant enrollment comes from the west coast and mid-west. Proportional enrollments have been seen in Hispanic and Asian populations. The entire study provides rich opportunities for a variety of secondary use and patterns of care projects that will begin to roll out over the next year. Clinical trial information: NCT03067181 . [Table: see text]