bluuebunny/crossref_metadata_2025 huggingface dataset:
BMC128: A rationally designed live bacterial consortium for the potentiation of immune checkpoint therapy in solid tumors.
Authors: Maurice-Dror Corinne , Tirosh Osnat , Kruger Ben-Shabat Sheerli , Eshar Shiri , Plolonsky Omri , Davis Noa , Haber Elran , Meshner Shiri , Perets Ruth
Published: June 2022

TPS2685

Background: Immune-Checkpoint inhibitors (ICI) have transformed the treatment of solid tumors, specifically in cutaneous melanoma, clear cell renal cell carcinoma (ccRCC) and non-small cell lung cancer (NSCLC). Despite these advances, a significant proportion of patients do not respond to ICI and only a fraction of responding patients will experience durable responses. Recent reports have found that patients showing poor response to ICI are characterized by a reduced gut microbiome diversity, suggesting that the gut microbiome might affect immune activation by ICI. BMC128 is a live bacterial consortium of 4 bacterial strains predicted to induce anti-tumor immune function when given in conjunction with ICI. These strains were identified by analyzing data obtained from NSCLC and ccRCC patients presenting varied responses to ICI, using a proprietary computational discovery platform enabling high-resolution functional microbiome analysis. In pre-clinical studies, treatment with BMC128 potentiated the efficacy of ICI in breast cancer and melanoma mouse models, reducing tumor volume, increasing the number of responders, and demonstrating an increase in infiltrating immunocytes: CD4, CD8 and NK cells. Methods: In this phase I, first-in-human trial, patients with ccRCC, cutaneous melanoma and NSCLC-adenocarcinoma (EGFR/ALK wild-type), who previously progressed on PD1/PDL-1 inhibitors will be treated with BMC128 8*108 CFU BID in combination with Nivolumab at a fixed-dose of 480mg q4weeks in a 3+3 design, followed by a 9 patient expansion phase. No dose escalation is planned. The primary objective is to investigate the safety and tolerability of BMC128 in combination with Nivolumab. Enrollment is intended to start in Feb, 2022. Clinical trial information: 202122207. [Table: see text]
An open-label, non-randomized, multi-center phase I study evaluating the safety, tolerability, pharmacokinetics and preliminary efficacy of bi-ligand-drug conjugate CBP-1018 in patients with advanced solid tumors.
Authors: Li Kaiwen , Shi Yehui , Wu Junyan , Zhou Liyan , Ye Suiwen , Lai Xiuping , Huang Robert , Teng Yan , Yu Jiangang , Chai Xiaoyan , Huang Hai
Published: June 2022

TPS2694

Background: Folate-receptor 1 (FOLR1) and prostate specific membrane antigen (PSMA) are overexpressed on tumor and angiogenic endothelial cells in solid tumors, including prostate cancer, renal cell cancer and lung cancer. CBP-1018 is a first-in-class bi-ligand drug conjugate targeting to both FOLR1 and PSMA, with a tubulin inhibitor payload, monomethyl auristatin E (MMAE). We herein introduce its first-in-human study which is designed based on the significant anti-tumor potency and acceptable safety profile in nonclinical studies. Methods: This study is a phase Ⅰa/Ⅰb, multicenter, open-label study enrolling patients with advanced solid tumor relapsed after previous standard therapies. The primary objective is to assess CBP-1018 safety, tolerability, dose limiting toxicity and maximum tolerated dose. Preliminary efficacy including objective response rate, duration of response and progression-free survival will be observed. Pharmacokinetics, immunogenicity and biomarkers will be also evaluated. This study includes 2 parts: Ⅰa (Dose Escalation) and Ⅰb (Dose Expansion). CBP-1018 is administrated iv Q2W (4 weeks/cycle) in Ⅰa, with accelerated titration at lower doses (0.03 mg/kg and 0.06 mg/kg) and an i3+3 design at following doses (0.08 mg/kg, 0.10 mg/kg, 0.12 mg/kg and 0.14mg/kg, etc.). Subjects will be enrolled in 4 cohorts in Ⅰb: metastatic castration resistant prostate cancer, advanced renal cell cancer, advanced lung squamous cell cancer, and other advanced solid tumors. Efficacy will be assessed every 8 weeks (±7days) according to RECIST 1.1, PCWG3 and PSA assessment (only for prostate cancer). Treatment will be continued untill disease progression or intolerable toxicity. Enrollment has been started in Nov. 2021 and is ongoing. Clinical trial information: NCT04928612.
Phase 1 study of SGN-B7H4V, a novel, investigational vedotin antibody–drug conjugate directed to B7-H4, in patients with advanced solid tumors (SGNB7H4V-001, trial in progress).
Authors: Patnaik Amita , Lakhani Nehal J. , Xu Ping , Nazarenko Natalya N. , Call Justin A
Published: June 2022

TPS3155

Background: B7-H4, a B7 immune checkpoint ligand, is expressed at low levels in normal tissue and negatively regulates T-cell function by inhibiting T-cell proliferation and cytokine production. B7-H4 expression is elevated in solid tumors, including breast, ovarian, and endometrial cancers. Targeting B7-H4–expressing tumor cells may relieve B7-H4–mediated T-cell inhibition. SGN-B7H4V is a novel, investigational vedotin antibody–drug conjugate directed to B7-H4 with proposed mechanisms of action including monomethyl auristatin E (MMAE)-directed cytotoxicity, bystander effect, antibody-dependent cellular cytotoxicity, and antibody-dependent cellular phagocytosis. SGN-B7H4V elicited antitumor activity in cell line-derived xenograft models of triple-negative breast cancer (TNBC) and patient-derived xenograft models of TNBC and ovarian cancer (Gray et al 2021), providing a rationale to evaluate SGN-B7H4V in patients (pts) with advanced solid tumors. Methods: SGNB7H4V-001 (NCT05194072) is a phase 1, first-in-human, multicenter, open-label trial evaluating the safety, tolerability, pharmacokinetics (PK), and antitumor activity of SGN-B7H4V in pts with advanced solid tumors. This study includes 3 parts: dose escalation (Part A), dose and schedule optimization (Part B), and dose expansion in disease-specific cohorts and a biology cohort (Part C). Adult pts (≥18 years) with histologically/cytologically confirmed locally advanced unresectable or metastatic solid tumors including high-grade serous epithelial ovarian cancer, primary peritoneal cancer, fallopian tube cancer, human epidermal growth factor receptor 2-negative and hormone receptor-positive breast cancer, TNBC, endometrial carcinoma, squamous non-small cell lung cancer, cholangiocarcinoma, or gallbladder carcinoma, are eligible. Pts must have ECOG PS 0–1 and relapsed/refractory disease or be intolerant to standard-of-care therapies. Prior treatment with an MMAE-containing agent or a B7-H4–targeted agent is not permitted. Primary endpoints include the rate of adverse events, laboratory abnormalities, dose-limiting toxicities, and cumulative dose-level safety. Secondary endpoints are objective response rate (ORR), complete response rate, duration of objective response (DOR), progression-free survival (PFS), overall survival (OS), PK, and incidence of antidrug antibodies. Exploratory endpoints include pharmacodynamic (PD) analyses, PD and PK exposure measurements, B7-H4 characterization on malignant cells, and biomarker analyses. Safety and antitumor activity endpoints will be assessed using descriptive statistics. ORR will be analyzed by tumor type and dose. DOR, PFS, and OS will be estimated using the Kaplan–Meier method. Enrollment for Part A is ongoing in North America and is planned in Europe. Clinical trial information: NCT05194072.
Phase 1 study of SGN-ALPV, a novel, investigational vedotin antibody–drug conjugate directed to ALPP/ALPPL2 in advanced solid tumors (SGNALPV-001, trial in progress).
Authors: Lakhani Nehal J. , Friedman Claire Frances , Perez Cesar Augusto , Wehr Alison , McGoldrick Suzanne M. , LoRusso Patricia
Published: June 2022

TPS3159

Background: Alkaline phosphatase placental (ALPP) and ALPP-like 2 (ALPPL2) are proteins with 98% sequence similarity that are highly expressed in ovarian, endometrial, gastric, and testicular cancers. Restricted normal tissue expression and efficient lysosomal trafficking of ALPP and ALPPL2 highlight their potential as anticancer targets. SGN-ALPV is a novel investigational vedotin antibody–drug conjugate composed of a humanized anti-ALPP/ALPPL2 monoclonal antibody, a protease-cleavable linker, and the microtubule disrupting agent monomethyl auristatin E (MMAE). The proposed mechanism of action of SGN-ALPV is binding to ALPP/ALPPL2 on the cell surface, where it is internalized and trafficked to the lysosome. Lysosomal proteases cleave the linker to release MMAE into the cytoplasm, where it binds and disrupts the microtubule network, causing cell cycle arrest and apoptosis. Additional mechanisms of action of SGN-ALPV include immunogenic cell death and apoptosis of neighboring cells via the bystander effect. Promising preclinical data support the evaluation of SGN-ALPV in a clinical trial. Methods: SGNALPV-001 (NCT05229900) is a phase 1, open-label, multicenter study designed to evaluate the safety, tolerability, pharmacokinetics (PK), and antitumor activity of SGN-ALPV in patients (pts) with select advanced solid tumors. This study consists of 3 parts: dose escalation (Part A), dose and schedule optimization (Part B), and dose-expansion in disease-specific cohorts and a biology cohort (Part C). Adult pts (≥18 years) with confirmed ovarian, endometrial, non-small cell lung, gastric, cervical cancer, or testicular germ-cell tumors, relapsed or refractory to approved therapies, with measurable disease per RECIST v1.1 and an ECOG PS 0–1 are eligible. Primary endpoints include incidence of adverse events, laboratory abnormalities, dose-limiting toxicities, and cumulative safety. Secondary endpoints include estimates of antidrug antibodies, PK parameters, objective response rate, duration of response, progression-free survival, and overall survival. Exploratory endpoints are pharmacodynamic and biomarker measurements. Safety and antitumor activity endpoints will be summarized using descriptive statistics. Enrollment for Part A is ongoing in sites in North America and Europe. Enrollment for Parts B and C will be opened upon completion of Part A. Clinical trial information: NCT05229900.
Phase 1 study of patritumab deruxtecan (HER3-DXd; U3-1402) in combination with osimertinib in patients with advanced EGFR-mutated NSCLC.
Authors: Janne Pasi A. , Mostillo Joseph , Shrestha Pomy , Zhang Ruoyang , Fan Pang-Dian , Cantero Frédérique
Published: June 2022

TPS3161

Background: Although first-line treatment with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor osimertinib improved survival in patients (pts) with advanced/metastatic EGFR-mutated ( EGFRm) non-small cell lung cancer (NSCLC), therapy after acquired resistance to osimertinib remains an unmet need. HER3 is expressed in the majority of EGFRm NSCLCs. HER3-DXd is a novel, investigational, HER3-directed antibody-drug conjugate that demonstrated preliminary single-agent clinical activity in EGFRm NSCLC. In preclinical models of EGFRm NSCLC, osimertinib increased membrane HER3 expression, improved the internalization rate of HER3-DXd, and enhanced tumor growth inhibition by HER3-DXd. Therefore, HER3-DXd with osimertinib might improve outcomes in pts with disease that progressed with osimertinib therapy. This phase 1 study (NCT04676477; U31402-A-U103) evaluates HER3-DXd in combination with osimertinib in pts with advanced EGFRm NSCLC that has progressed with first-line osimertinib therapy. Methods: This is an open-label, 2-part study of HER3-DXd in combination with osimertinib. Pts are enrolling in North America, Europe, and Asia. Dose escalation enrolls pts with locally advanced/metastatic NSCLC with an EGFR-activating mutation (exon 19 del or L858R) and progression during or after osimertinib therapy. Pts receive HER3-DXd 1.6, 3.2, 4.8, or 5.6 mg/kg intravenously (IV) every 3 weeks (Q3W) in combination with osimertinib 40 or 80 mg orally (PO) once daily (QD). Pts are enrolled in each cohort guided by safety (dose-limiting toxicities) using a Bayesian logistic regression model. Primary objectives of dose escalation are to assess safety and tolerability of the combination and identify a recommended combination dose (RCD). In dose expansion, pts will be randomized 1:1 to receive either HER3-DXd and osimertinib at the RCD (arm 1, [≈60 pts]) or HER3-DXd 5.6 mg/kg IV Q3W (arm 2, [≈60 pts]). A third arm (arm 1b, [≈60 pts]) may be added to evaluate 2 provisional RCDs of HER3-DXd + osimertinib. The primary objective of dose expansion (arms 1, 2, and 1b) is to evaluate efficacy of the combination vs that of monotherapy. The primary endpoint is objective response rate (ORR) as assessed by blinded independent central review. Other efficacy endpoints include ORR by investigator and duration of response, disease control rate, time to response, progression-free survival, and overall survival. If the RCD includes an osimertinib dose of 80 mg PO QD, ≈30 pts with advanced EGFRm NSCLC without prior treatment will be enrolled and treated at the RCD in a separate cohort; the primary objective is to assess safety and tolerability. A tumor sample after progression with osimertinib (or prior to entry) is required for pts enrolled in dose expansion for retrospective evaluation of HER3 and biomarker analyses. Clinical trial information: NCT04676477.
Phase 1 study of KT-333, a targeted protein degrader, in patients with relapsed or refractory lymphomas, large granular lymphocytic leukemia, and solid tumors.
Authors: Starodub Alexander , Gollerkeri Ashwin , De savi Chris , Dey Joyoti , Agarwal Sagar , Donohue Sean , Perea Rachelle , Klaus Christine , Gollob Jared
Published: June 2022

TPS3171

Background: The signal transducer and activator of transcription 3 (STAT3) protein is activated by cytokines and growth factors resulting in tumor growth and promotion and hindering antitumor immunity. Approximately 70% of human cancers including both hematological malignancies and solid tumors exhibit increased levels of phosphorylated STAT3 (pSTAT3). There is evidence of constitutive activation of STAT3 through genetic mutations or aberrant cellular signaling pathways in tumors such as large granular lymphocytic leukemia (LGL-L), peripheral T-cell lymphoma (PTCL), and cutaneous T-cell lymphomas (CTCL). Hyperactivation of STAT3 has been reported in a variety of solid tumors. In several of these cancers, the levels of pSTAT3 and/or activated STAT3 have been shown to correlate with poor clinical prognosis. As with other transcription factors, selective inhibition of STAT3 has been proven to be difficult with conventional therapeutic approaches. KT-333 is a potent highly selective, heterobifunctional small molecule degrader of STAT3. In preclinical studies, durable tumor regressions were seen with weekly KT-333 administration in STAT3-dependent T cell lymphomas, and antitumor activity was seen in solid tumors in combination with anti-PD1 (ASH 2021, SITC 2021). Methods: KT-333 is being evaluated in an open-label, dose escalation (Phase 1a, n = 40) study in patients with lymphomas relapsed or refractory (R/R) to at least two prior systemic treatments or for whom standard therapies are unavailable. Dose escalation will be conducted by accelerated titration followed by a 3+3 design in ascending doses of intravenous KT-333 administered once weekly in 28-day cycles to evaluate safety and define the maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D) (primary endpoint). Secondary endpoints include pharmacokinetics (PK) in plasma and urine and preliminary pharmacodynamic effects (PD) of KT-333 using blood (peripheral blood mononuclear cells [PBMCs], plasma/serum) and tumor tissue. After confirming the MTD/RP2D in patients with lymphoma, patients with advanced solid tumors will be enrolled in a separate Phase 1a cohort at the MTD/RP2D. In Phase 1b (n = 80), patients with PTCL, CTCL, LGL-L (T-cell LGL-L or chronic lymphoproliferative disorder of natural killer-cells), or solid tumors R/R to at least one prior systemic standard of care treatment or for whom standard therapies are not available, will be enrolled in separate 20 patient cohorts. This will further characterize safety, PK, PD and evaluate the clinical activity of KT-333. Treatment with KT-333 will continue until disease progression, unacceptable toxicity, or patient refusal. KT333-TL-101 began enrolling in January 2022. Clinical trial information: NCT05225584.
Phase 2 study of trastuzumab deruxtecan in the neoadjuvant treatment for patients with HER2-positive gastric and gastroesophageal junction adenocarcinoma (EPOC2003).
Authors: Takahari Daisuke , Kawazoe Akihito , Machida Nozomu , Minashi Keiko , Yamagata Yukinori , Hara Hiroki , Wakabayashi Masashi , Komura Yu , Sato Akihiro , Kuwata Takeshi , Kojima Motohiro , Shitara Kohei
Published: June 2022

TPS4161

Background: Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate consisting of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. DESTINY-Gastric01 study showed significantly higher objective response rate with T-DXd than physician's choice of chemotherapy (51.3%, vs. 14.3%, Shitara K, et al. NEJM 2020) as well as prolonged overall survival (median 12.5 vs. 8.4 months, hazard ratio 0.59). Considering that high response rate or major pathological response (MPR), which is defined as the proportion of subjects with < 10% residual tumor may be associated with favorable survival outcomes after preoperative chemotherapy, T-DXd could be a promising neoadjuvant treatment for patients with gastric and gastroesophageal junction (GEJ) cancer. However, to our knowledge, there is no currently ongoing study of T-DXd as a neoadjuvant setting for patients with gastric and GEJ cancers. Methods: This is an open-label, single-arm, multicenter, investigator initiated phase 2 trial to evaluate antitumor activity of T-DXd as the neoadjuvant treatment for patients with HER2 positive gastric and GEJ adenocarcinoma. Eligible patients should have previously untreated locally advanced gastric and GEJ adenocarcinoma with clinical stage of T2-4 and/or N+ without distant metastasis. The main cohort will enroll patients with HER2 overexpression defined as immunohistochemistry （IHC）3+ or IHC2+/ in situ hybridization（ISH）+ by local assessment. According to the results of exploratory biomarker analysis of DESTINY-Gastric01 study (Shitara K, et al. ESMO-GI2021), patients with HER2-low expression (IHC1+ or 2+ with ISH negative) with HER2-extra cellular domein (ECD) higher than 11.6 ng/ml also will be enrolled into the exploratory cohort. Patients will receive 3 cycles of T-DXd (6.4mg/kg) by intravenous infusion every 3 weeks followed by surgery at 3 to 8 weeks after last T-DXd infusion.The primary endpoint is MPR rate. The threshold in the main cohort is defined as 20%, and the expected MPR rate was set at 45%. The minimum sample size of this trial is 23 patients in the main cohort (α- and β-error probabilities, 0.1 and 0.15, respectively). Total number of patients will be increased up to 27 patients depending on the enrollment. In addition, 10 patients will be recruited into the exploratory cohort. Secondary endpoints are pathologic complete response (pCR) rate, curative resection rate, and adverse event rate. Biomarker analyses including whole exome sequencing, RNA sequencing, proteomics, and ctDNA changes will also be conducted using pre- and post-treatment tumor and blood samples. Enrollment is ongoing at six sites in Japan from November 2021. Clinical trial information: NCT05034887.
GRECO-2: A randomized, phase 2 study of stereotactic body radiation therapy (SBRT) in combination with rucosopasem (GC4711) in the treatment of locally advanced or borderline resectable nonmetastatic pancreatic cancer.
Authors: Hoffe Sarah E. , Kim Dae Won , Costello James , Malafa Mokenge Peter , Aguilera Todd Anthony , Beg Shaalan Shaalan , Parikh Parag , Herman Joseph M. , Caster Joseph Michael , Ghaly Maged , Moser Elizabeth Charlotte , Terry Kara , Kurman Michael , Holmlund Jon
Published: June 2022

TPS4184

Background: While treatment of pancreatic cancer has advanced, survival rates remain low. Stereotactic body radiotherapy (SBRT; high dose per fraction radiation) may exhibit improved clinical outcomes in locally advanced pancreatic cancer but carries potential gastrointestinal toxicity risks (Zhong 2017). Rucosopasem (GC4711) is one of a class of investigational selective dismutase mimetics that rapidly and specifically converts superoxide to hydrogen peroxide (Riley 2006). Studies have shown that normal cells tolerate hydrogen peroxide fluxes better than cancer cells (Doskey 2016). As radiation response modifiers, dismutase mimetics have the potential to increase tumor control of SBRT without compromising radiation safety (El-Mahdy 2020, Sishc 2021). In a pilot phase 1/2 trial in patients with pancreatic cancer, avasopasem, a dismutase mimetic related to rucosopasem, nearly doubled median overall survival in patients receiving SBRT vs placebo plus SBRT. Improvements versus placebo were also observed in local tumor control, time to metastases, and progression-free survival. Altogether, these data support the hypothesis that rucosopasem may improve survival and the benefit-risk ratio of SBRT by improving efficacy without increasing gastrointestinal toxicity. Materials/Methods: GRECO-2 is a phase 2, multicenter, randomized, double-blind, placebo-controlled study (NCT04698915) to determine the effect of adding rucosopasem to SBRT on overall survival in patients with borderline resectable or locally advanced, unresectable nonmetastatic pancreatic cancer following initial chemotherapy with a FOLFIRINOX-based regimen or a gemcitabine doublet. Approximately 160 patients will be randomized (approximately 35 sites) to receive rucosopasem 100 mg or placebo via IV infusion over 15 minutes, prior to each SBRT fraction (5 x 10 Gy). Patients judged to be resectable will undergo surgical exploration within 8 weeks after SBRT. The primary endpoint is overall survival. Secondary endpoints include progression-free survival, locoregional control, time to metastasis, surgical resection rate, RO resection rate, best overall response, in-field local response, and safety (acute and late toxicities). Exploratory endpoints include PRO-CTCAE and CA19-9 normalization. This trial is now enrolling. Clinical trial information: NCT04698915.
A randomized phase II study of gemcitabine and nab-paclitaxel compared with 5-fluorouracil, leucovorin, and liposomal irinotecan in older patients with treatment-naïve metastatic pancreatic cancer (GIANT): ECOG-ACRIN EA2186—Trials in progress.
Authors: Dotan Efrat , Catalano Paul J. , Lenchik Leon , Boutin Robert , Yao Xin , Beg Shaalan Shaalan , Vijayvergia Namrata , Gatsonis Constantine , Zhen David Bing , Li Daneng , Wagner Lynne I. , Simon Melissa A. , Wong Terence Z. , O'Dwyer Peter J.
Published: June 2022

TPS4185

Background: Evidence-based data is lacking to guide the care of older adults with newly diagnosed metastatic pancreatic cancer (mPCA). As a result, treatment approach and the selection of chemotherapy regimens are often extrapolated from data from younger patients. Furthermore, vulnerable older adults are often treated with dose adjusted regimens with limited data to support this practice. EA2186 is a phase II randomized controlled trial, and the first prospective study aiming to define the optimal treatment approach of vulnerable older adults with newly diagnosed mPCA. Methods: Patients aged 70 years and over with histologically confirmed pancreatic adenocarcinoma, evidence of metastatic disease, ECOG PS 0-2 and adequate organ function, who are considered vulnerable are eligible for this trial (accrual target 184). This study utilizes a screening geriatric assessment which characterize patients as fit, vulnerable or frail by evaluating functional status, cognition and co-morbidities. Vulnerable patients according to this screening assessment are those with mild abnormalities in functional status, comorbidities and/or cognition, or older than 80 years of age. Those patients will be randomized to receive either modified Gemcitabine/Nab-Paclitaxel or dose-reduced 5-Fluorouracil Leucovorin and Liposomal Irinotecan every 2 weeks. A comprehensive geriatric assessment (GA) and quality of life (QOL) evaluation are completed prior to initiation of therapy for all randomized patients. Follow up will continue until disease progression or withdrawal, with repeated GA and QOL assessments at each disease evaluation. Overall survival is the primary objective, with secondary objectives including progression free survival, and response rate. Enrolled patients will be stratified by age 70-74 vs ≥75, and ECOG PS 0-1 vs 2. Additional endpoints of interest for older adults include: evaluation of risk factors identified through GA, and capturing toxicities of interest for this patient population (i.e. hospitalization, deterioration in PS, and falls). Correlative studies include assessment of pro-inflammatory biomarkers or aging in the blood (IL-6 and CRP) as well as imaging evaluation of sarcopenia and body composition as predictors of treatment tolerance. Clinical trial information: NCT04233866.
Precision Promise (PrP): An adaptive, multi-arm registration trial in metastatic pancreatic ductal adenocarcinoma (PDAC).
Authors: Picozzi Vincent J. , Duliege Anne-Marie , Collisson Eric Andrew , Maitra Anirban , Hidalgo Manuel , Hendifar Andrew Eugene , Beatty Gregory Lawrence , Doss Sudheer , Matrisian Lynn McCormick , Herena Pamela S , Fleshman Julie , Detry Michelle A. , Berry Donald A. , Simeone Diane M.
Published: June 2022

TPS4188

Background: The success rate of drug development in PDAC is disappointingly low.PrP is a transformative, adaptive platform clinical trial designed to continuously evaluate many novel therapeutic options while increasing the probability that patients (pts) are randomized to effective experimental therapies. It cultivates enhanced cooperation among groups representing pts advocacy, pharmaceutical companies, academia, and the FDA. This patient-centric study aims to become the largest Phase 3 registrational study in PDAC and represents a fundamental shift in drug development for PDAC in the United States (US). Methods: PrP (NCT04229004) is a platform clinical trial sponsored by the Pancreatic Cancer Action Network (PanCAN), developed based on the FDA 2020 guidance document regarding "complex innovative designs" in registration trials https://www.fda.gov/media/130897/download . It utilizes adaptive randomization and other Bayesian statistical innovations provided by Berry Consultants LLC, including the “time machine” which uses all previously randomized controls for each arm, suitably adjusted for line of therapy and the time period of the arm. Focused on 1st and 2nd line treatment of mPDAC, PrP uses an adaptive platform design with randomization to one of 2 control arms (gemcitabine + nab-paclitaxel (GA) or mFOLFIRINOX, 30% of pts) or experimental therapy (70% of pts). Candidate experimental arms are reviewed by an Arm Selection Committee based on validity of the treatment target and strength of the pre-clinical and clinical data. The primary endpoint is overall survival (OS). Pts undergo pre- and on-treatment biopsies with state-of-the-art genomic, transcriptomic, and immune analysis, along with a serial collection of blood-based research samples. Pts are managed using novel supportive care techniques; PrP contains 3 sub-protocols evaluating quality of life, sarcopenia, and actigraphy. PrP launched in 2020 and has enrolled > 130 pts; 30 US sites have been selected with 17 currently active. Current experimental arms include: (i) GA + Pamrevlumab, an anti-CTGF Ab, (ii) Racemetyrosine monotherapy, a cancer metabolism-based therapy (for follow-up of patients) and (iii) an immuno-oncology arm in activation. Other arms are in the planning stages. Compared to traditional designs, PrP offers several advantages: multiple investigational treatments evaluated in parallel over time; ̃175 pts per experimental arm required to initiate a regulatory registration; and continuous learning from every patient, resulting in significant savings of time and resources. PrP has created an entirely new learning environment for accelerating drug development in PDAC. Clinical trial information: NCT04229004.
Sequential first-line treatment with gemcitabine plus nab-paclitaxel (GA) followed by FOLFIRINOX (FFX) versus FFX alone in patients with metastatic pancreatic cancer (PC): GABRINOX-2 randomized phase 2 trial.
Authors: Portales Fabienne , Assenat Eric , Samalin Emmanuelle , Mazard Thibault , Adenis Antoine , Suchet Gallet Blandine , Fiess Catherine , Moussion Aurore , Delaine Stephanie , Grigorescu Florin , Gourgou Sophie , Ychou Marc
Published: June 2022

TPS4190

Background: PC is a major health concern worldwide and a deadly disease due to its high metastatic behavior. In recent years, incremental progresses have been made with the use of new chemotherapy (CT) regimen in the metastatic setting. Thus, both PRODIGE 4/ACCORD11 (Conroy T, et al. 2011) and MPACT (Von Hoff D, et al. 2013) phase III trials established 2 new standard-of-care in the first line treatment of metastatic PC (mPC), demonstrating a survival benefit over gemcitabine monotherapy, with the use of FFX or GA. In the phase I/II GABRINOX trial (Assenat E, et al. ESMO Open 2021), we reported that sequential GA followed by FFX provided a high overall response rate (ORR) (64.9%) and a promising median progression-free survival (PFS, 10.5 months) and median overall survival (OS, 15.1 months), together with acceptable toxicity and remarkably low severe neurotoxicity rate (gr.3: 5.3%). To follow up these encouraging results in a controlled study, we aimed at comparing our experimental GABRINOX regimen to control FFX in the GABRINOX-2 randomized phase 2 trial (NCT05065801). Our primary objective is PFS, and our secondary objectives are tolerance, ORR, disease-control rate, OS, and Quality-of-life. Methods: Main inclusion criteria were as follows: Patients (pts) in good condition (ECOG PS ≤ 1), aged from 18 to 75 yo, with histologically or cytological proven mPC and at least one measurable metastatic target. Pts should have not been treated with (adjuvant) chemotherapy in the last 6 months. Eligible pts are randomized (ratio 1:1) either in the standard FFX group or in the experimental GABRINOX group where a GA (gemcitabine 1000 mg/m² and Nab-paclitaxel 125 mg/m², day 1-8-15) cycle alternates after a 2-weeks rest with a FFX cycle. To detect an increase in median PFS from 6.4 to 10.5 months (HR = 0.61) with a 80% power and a 5% α risk, 130 events are required among a total population of 210 pts. PFS was defined as the length of time between randomization and the onset of 1st documented progression (RECIST 1.1 criteria) or death. The study of quality of life will use the EORTC QLQ-C30 and QLQ-PAN26 self-reported questionnaires at baseline and every 2 months up to 12 months and then at 16, 20 and 24 months. Circulating DNA tests will be carried out at baseline and every 2 months until progression. All numerical variables will be expressed as medians and 95% CI, while PFS and OS will be estimated using Kaplan-Meier method. Multivariate analyses will use Cox proportional hazard model. Enrolment started in late 2021 and 3 patients were included so far. Clinical trial information: NCT05065801.
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. , Ramnaraign Brian Hemendra , Hitchcock Kathryn , Hughes Steven J. , Lee Ji-Hyun , Turk Anita Ahmed , Russell Karen Bullock , Nassour Ibrahim , El-Far Ahmad , Fabregas Jesus C. , Thomas Ryan M. , Sahin Ilyas , Allegra Carmen Joseph , DeRemer David L. , George Thomas J.
Published: June 2022

TPS4196

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 pre-op. Liposomal irinotecan injection (Nal-IRI) is FDA approved in combination with 5-FU/LV 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 multiD GI tumor board (resectable vs. borderline), adequate cardiac, renal, hepatic function and ECOG performance status of 0 to 1. Pts receive NALIRIFOX regimen as per the 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 pre-op 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 post-op complication rate. Clinical trial information: NCT03483038. [Table: see text]
SAMETA: An open-label, three-arm, multicenter, phase III study of savolitinib + durvalumab versus sunitinib and durvalumab monotherapy in patients with MET-driven, unresectable, locally advanced/metastatic papillary renal cell carcinoma (PRCC).
Authors: Choueiri Toni K. , Xu Wanning , Poole Lynne , Telaranta-Keerie Aino , Hartmaier Ryan , Powles Thomas
Published: June 2022

TPS4601

Background: Papillary renal cell carcinoma (PRCC) is the most common subtype of non-clear cell RCC and accounts for 10–15% of RCCs. Approximately 80% of PRCC cases are MET-driven, characterized by genomic abnormalities resulting in dysregulation of the MET signaling pathway, making these abnormalities a potential therapeutic target for treatment. Savolitinib is an oral, potent and highly selective MET tyrosine-kinase inhibitor (TKI) demonstrating preliminary clinical activity in advanced solid tumors, including in MET-driven PRCC, defined as presence of any of the following molecular alterations, in the absence of co-occurring fumarate hydratase mutations: chromosome 7 gain, MET amplification, MET kinase domain variations, or hepatocyte growth factor amplification. In the Phase III SAVOIR study, in PRCC, savolitinib monotherapy showed encouraging efficacy vs the multi-targeted TKI, sunitinib. In addition, non-clinical studies suggest a possible synergistic anti-tumor effect of MET-inhibitors and programmed cell death-ligand (PD-L1) inhibitors, such as durvalumab; emerging data from the Phase I/II CALYPSO study investigating savolitinib plus durvalumab shows a notable efficacy signal in patients with MET-driven PRCC. Following these findings, the SAMETA study (NCT05043090) is designed to evaluate the efficacy and safety of savolitinib in combination with durvalumab vs sunitinib and durvalumab monotherapy in PRCC. Methods: In this open-label, three-arm, multi-center, Phase III study, adult patients with unresectable, MET-driven and locally advanced/metastatic PRCC are eligible. An estimated 200 patients (25 countries, 165 centers) will be randomized in a 2:1:1 ratio into three treatment arms (A–C) with stratification by International metastatic RCC database consortium risk group & PD-L1 expression tumor status. Arm A: oral savolitinib 600 mg once daily (QD) plus intravenous (IV) durvalumab 1500 mg every 4 weeks (Q4W); Arm B: oral sunitinib 50 mg QD for 4 consecutive weeks, followed by a sunitinib-free interval of 2 weeks Q6W; Arm C: IV durvalumab 1500 mg Q4W. Study treatment continues until RECIST 1.1 disease progression or another discontinuation criterion is met. The primary endpoint is progression-free survival (by BICR; RECIST v1.1). Secondary endpoints include overall survival, objective response rate and duration of response. Safety (adverse events, vital signs, ECG, hematology and biochemistry parameters) will also be reported. The first patient was enrolled onto the study on 28 October 2021. Clinical trial information: NCT05043090.
A phase III randomized trial of eribulin (E) with or without gemcitabine versus 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 "Lucky" N. , Tangen Catherine , Bangs Rick , Lerner Seth P. , Flaig Thomas W. , Petrylak Daniel P. , Thompson Ian
Published: June 2022

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.
89Zirconium-labelled girentuximab (89Zr-TLX250) PET in patients with urothelial cancer (ZiPUP): A phase I trial of a novel staging modality for urothelial carcinoma.
Authors: Hayne Dickon , Gauci Richard , Al-Zubaidi Mohammed , Viswambaram Pravin , McCombie Steve P , Liow Elizabeth Chien Hern , Lenzo Nat , Ferguson Thomas , Antonini Paola , Meyrick Danielle , Hayward Colin , Redfern Andrew David
Published: June 2022

TPS4609

Background: Bladder cancer is a lethal disease with a rising incidence. The current standard imaging modalities for staging are either CT of the chest, abdomen and pelvis or FDG PET/CT. However, there are issues with using these modalities for staging. CT is known to have relatively low sensitivity for detecting low volume metastatic disease, while FDG is predominantly renally excreted and therefore has intense activity in the urinary tract, which limits its utility to detect bladder or upper tract lesions, or nodal metastases in close proximity to the urinary tract. Zirconium-89-Girentuximab (89Zr-TLX250) may have utility in the accurate staging of bladder and urothelial cancer, with less renal excretion as compared to FDG, however this has not previously been investigated. ZipUp is an investigator initiated trial. South Metropolitan Health Service WA is the trial sponsor. The study received funding and study drug support from Telix Pharmaceuticals Methods: ZiPUP is a single-arm, phase I trial examining the feasibility, safety, and utility of 89Zr-TLX250 PET/CT in patients either undergoing pre-operative staging of urothelial carcinoma or bladder cancer for curative intent, or with known metastatic urothelial carcinoma or bladder cancer. All participants will undergo 89Zr-TLX250 PET/CT and will need to have undergone recent FDG PET/CT for means of comparison. This trial aims to recruit 10 participants undergoing staging and 10 participants with known metastatic disease. The primary endpoint is effectiveness by assessing sensitivity and specificity in detecting lymph node metastases compared to FDG PET/CT; secondary endpoints are safety, tolerability, and feasibility. The first patient was enrolled in this single site study and the study is expected to be completed by December 2022. If 89Zr-TLX250 PET/CT is proven to be feasible, safe, and effective in staging urothelial cancer, it could improve the appropriate selection of treatment for patients with metastatic or primary urothelial carcinoma or bladder cancer. Clinical trial information: NCT05046665.
Trial in progress: A phase II switch maintenance study of live biotherapeutic MRx0518 and avelumab in patients with unresectable locally advanced or metastatic urothelial carcinoma (UC) who did not progress on first-line platinum-containing chemotherapy.
Authors: Shah Amishi Yogesh , Gao Jianjun , Rezazadeh Arash , Cole Suzanne , Jain Rohit K. , Stevenson Alex , Fyvie Gayle , Gaw Nina Jane , Pant Shubham
Published: June 2022

TPS4610

Background: Efficacy of avelumab for maintenance treatment of UC was investigated in the JAVELIN Bladder 100 study (NCT02603432), which led to the FDA approval of avelumab for maintenance treatment as the current standard of care for patients with locally advanced or metastatic UC that have not progressed with first-line platinum-based chemotherapy. Outcomes included median overall survival (OS) of 21.4 months (95% CI 0.56-0.86), median progression-free survival (PFS) of 3.7 months (95% CI 3.5-5.5) and objective response rate (ORR) of 9.7% (95% CI 6.8-13). MRx0518 is a novel, human gut microbiome-derived, single-strain, live biotherapeutic. It is a bacterium of the Enterococcus genus that was selected for development in solid tumor treatment for its strong in vitro and in vivo immunostimulatory activity. In vivo studies have shown that MRx0518 can inhibit tumor growth in different syngeneic cancer models as both monotherapy and in combination with immune checkpoint inhibitors. MRx0518 has been shown to reduce Treg and increase Th1 and Tc1 lymphocyte differentiation in vitro and increase intratumoral CD4+ and CD8+ T cells and NK cells in vivo. In clinical studies, preliminary data shows that MRx0518 monotherapy can increase anti-tumor TILs and systemic pro-inflammatory immune signaling molecules. This is a pilot study evaluating whether the addition of MRx0518 to avelumab in the maintenance setting of metastatic platinum-treated UC may improve outcomes. Methods: The study will enroll 30 patients with unresectable locally advanced or metastatic UC at multiple US centers. Patients must have measurable disease after a partial response or stable disease on 4-6 cycles of platinum-containing induction chemotherapy. Patients will receive 800 mg avelumab IV infusion every 2 weeks in combination with 1 oral capsule (10x1010 – 10x1011 CFU) MRx0518 twice daily until disease progression, patient withdrawal or unacceptable toxicity. Primary objectives are to assess safety of the combination, and effect on PFS at 6 months. Secondary objectives are to assess other efficacy measures including PFS, ORR, OS, duration of response, time to response, and disease control rate. Collection of paired research biopsies at baseline (after chemotherapy) and on treatment (after 8 weeks of MRx0518 + avelumab), plus longitudinal blood sampling, will allow investigation of immunological changes systemically both in the tumor and as potential predictive markers of response. Stool and urine samples collected before, during and after treatment will allow investigation of changes to the microbiome and metabolome. Recruitment is open, awaiting accrual. Clinical trial information: NCT05107427.
A phase II study of gemcitabine plus cisplatin chemotherapy in patients with muscle-invasive bladder cancer with bladder preservation for those patients whose tumors harbor deleterious DNA damage response (DDR) gene alterations (Alliance A031701).
Authors: Iyer Gopa , Ballman Karla V. , Atherton Pamela J. , Murray Katie , Kwok Young , Steen Preston D. , Baghaie Shiva , Rosenberg Jonathan E. , Morris Michael J.
Published: June 2022

TPS4615

Background: While a standard approach to muscle-invasive bladder cancer (MIBC) management involves neoadjuvant cisplatin-based chemotherapy (NAC) followed by radical cystectomy (RC), up to 50% of pts recur with metastatic disease. Moreover, removal of the bladder has a significant impact on pts’ quality of life. Pathologic downstaging to non-muscle-invasive disease (<pT2) or complete response (pT0) at RC is associated with long-term survival benefit. Somatic DDR gene alterations were shown to be enriched in pts who were pT0 at RC following NAC in multiple retrospective analyses. We hypothesize that MIBC pts with somatic loss-of-function alterations within specific DDR genes and clinical responses to NAC can be uniquely managed with a bladder-sparing approach consisting of close cystoscopic and radiographic surveillance, avoiding the toxicities of definitive local therapy. Methods: A031701 is a multicenter phase II trial that will enroll 271 pts with T2-T4aN0/xM0 MIBC diagnosed within 60 days prior to enrollment. Multifocal MIBC, tumors >5 cm by cystoscopic assessment, and Bacillus Calmette-Guérin (BCG)-refractory disease (beyond standard induction and maintenance) are not allowed. Intravesical chemotherapy is allowed. Pts must be eligible for cisplatin chemotherapy. Eligible pts will receive either standard dose or dose dense gemcitabine and cisplatin chemotherapy (investigator’s choice) with simultaneous genetic sequencing of pre-treatment transurethral resection specimens. Pts whose tumors contain deleterious alterations in any 1 of 9 pre-selected DDR genes ( ERCC2, ERCC5, BRCA1, BRCA2, RECQL4, RAD51C, ATM, ATR, and FANCC) and who exhibit T1 disease after NAC will undergo RC or chemoradiation therapy (investigator/patient choice). The primary endpoint is 3-year event-free survival in DDR-altered pts who undergo bladder sparing, defined as the proportion of pts without BCG-unresponsive non-muscle invasive recurrences, any >T2 recurrences, or any metastatic recurrences. Secondary endpoints include clinical response rate (<cT1) in patients with deleterious DDR gene alterations following NAC, bladder-intact survival, overall survival, pT0 rate in DDR-altered pts who elect to undergo RC, pT0 rate in pts without DDR gene alterations, 3-year RC rate in pts with DDR gene alterations, and proportion of pts undergoing intravesical management for in-bladder recurrences. The study opened for enrollment in September 2018. Support: U10CA180821, U10CA180882. Clinical trial information: NCT03609216.