bluuebunny/crossref_metadata_2025 huggingface dataset:
Davoceticept (ALPN-202), a PD-L1-dependent CD28 costimulator and dual checkpoint inhibitor, in combination with pembrolizumab in patients with advanced malignancies (NEON-2).
Authors: Patnaik Amita , Lakhani Nehal J. , McKean Meredith , Gainor Justin F. , Vo Buu Cathy , Dillon Stacey R. , Zayed Hany , Chisamore Michael Jon , Pluda James Michael , Peng Stanford L.
Published: June 2022

TPS2683

Background: Despite successes with checkpoint inhibition (CPI) in a wide range of tumors, most demonstrate primary or acquired resistance, warranting better therapeutic strategies. PD-1 is now recognized to effect much of its benefit by disinhibiting CD28 signaling – a mechanism expected to require intra-tumoral engagement of CD28 by its ligands CD80/CD86. Davoceticept (ALPN-202), a variant CD80 vIgD-Fc fusion protein, was engineered to provide tumor localizing PD-L1-dependent CD28 agonism, while inhibiting PD-L1 and CTLA-4. Davoceticept has demonstrated superiority to CPI-only therapies in both in vitro and in vivo tumor models, while also demonstrating additional benefit in combination with targeted PD-1 axis blockade (Lewis et al. (2019) J Immunother Cancer 7(S1): P467). The benefit appeared at least additive in models of poorly immunogenic tumors, suggesting the possibility of meaningful clinical benefit where CPI therapeutic efficacy is limited, such as noninflamed tumors. Single agent safety and tolerability of davoceticept has been demonstrated along with pharmacodynamic evidence of CD28 engagement with immune checkpoint inhibition (Moser et al. (2021) J Clin Oncol 39(s15): 2547). Methods: NEON-2 is an open-label dose escalation and expansion study of davoceticept combined with pembrolizumab in adults with advanced solid tumors or lymphoma that was initiated in June 2021 (NCT04920383). Eligibility includes tumors where single agent PD-(L)1 antagonists are SOC, are refractory or resistant to standard therapies (including approved CPIs), or have no standard or curative therapy. The study employs a standard 3+3 dose escalation design with two schedules, Q1W and Q3W of davoceticept. Pembrolizumab is given per label at 400 mg IV Q6W. Objectives include evaluation of safety and tolerability, identification of the recommended phase 2 dose(s) (RP2D), PK, PD, exploratory predictive biomarker analysis (i.e., PD-L1, CD28, CD80 and CD86 expression, as well as immunophenotyping of immune cell populations on treatment) and preliminary anticancer activity of davoceticept in combination with pembrolizumab. Disease assessments are evaluated by RECIST v1.1 for solid tumors or by Lugano Classification for lymphoma. Efficacy endpoints include ORR, duration of response and disease control rate. Once the RP2D combination is identified, tumor-specific expansion cohorts of ̃ 30- 35 patients will be performed, including histologies that have not been demonstrated to be CPI responsive, as well as those where CPIs are approved SOC. The 0.1 mg/kg cohorts have been completed without DLT. Enrollment to the 0.3 mg/kg cohorts began in September 2021. Clinical trial information: NCT04920383.
A first-in-human, multicenter, phase 1/2, open-label study of XTX202, a masked and tumor-selective recombinant human interleukin-2 (IL-2) protein, in patients with advanced solid tumors.
Authors: McKean Meredith , Powderly John D. , Duncan Meghan , Norman Teleen , Patel Ekta , O'Neil Jennifer , Lee George , Luptakova Katarina , Kaufman Howard E.
Published: June 2022

TPS2697

Background: High-dose interleukin-2 (IL-2) has been approved in metastatic renal cell carcinoma (RCC) and metastatic melanoma, and can result in durable complete responses, including cures. Its use has been limited by life-threatening treatment-related multisystem toxicities, consisting mainly of vascular leak syndrome. XTX202 is a masked, tumor-selective IL-2 that is designed to be pharmacologically inactive in non-tumor tissue when circulating systemically and unmasked by matrix metalloproteases (MMPs) found preferentially in the tumor microenvironment (TME). XTX202 is expected, therefore, to achieve a wider therapeutic index resulting in increased efficacy and lower toxicity compared to existing non-tumor selective IL-2 based-therapies. The IL-2 domain of the XTX202 molecule is modified to reduce binding to the high-affinity IL-2 receptor while maintaining binding to the intermediate-affinity IL-2 receptor, thereby decreasing activation of regulatory T-cells relative to wild-type IL-2, while still activating effector T cells. A masking domain is designed to pharmacologically inactivate IL-2 until it is activated by MMPs that are enriched in the TME. Cleavage at a protease cleavage site in the XTX202 linker by MMPs results in an active IL-2 moiety when the masking domain is released. XTX202 is designed with the goal of producing a localized anti-tumor immune response and limiting exposure of the active form of XTX202 in non-tumor tissue. Preclinically, XTX202 exhibited tumor-selective activity in mice without peripheral toxicities in non-human primates [O’Neil et al. ASCO 2021]. Methods: XTX202-01 trial (NCT05052268) is a first-in-human Phase 1/2 study to determine a recommended Phase 2 dose of XTX202 (Phase 1) and to evaluate the efficacy of XTX202 monotherapy in patients with metastatic RCC and unresectable or metastatic melanoma (Phase 2). Patients with advanced solid tumors are eligible for Phase 1 and will receive XTX202 monotherapy administered every 21 days in an accelerated and standard 3+3 dose escalation design. Phase 2 will consist of 2 parts: Part 2a will enroll patients with metastatic RCC who have received a prior tyrosine kinase inhibitor therapy and have been treated and progressed on an anti-PD-1 therapy. Part 2b will enroll patients with unresectable or metastatic melanoma who have received immune-checkpoint therapy with an anti-PD-1 therapy and an anti-CTLA-4 therapy to determine the efficacy of XTX202 monotherapy in this population. Enrollment to the study began in January 2022. Clinical trial information: NCT05052268.
ELU-FRα-1: A study to evaluate ELU001 in patients with solid tumors that overexpress folate receptor alpha (FRα).
Authors: Ma Wen Wee , Tolcher Anthony W. , Strauss James Fredric , Bekaii-Saab Tanios S. , Zhao Yujie , Perez Cesar Augusto , Hamilton Erika P. , Adams Gregory Paul , Reddick Catherine , Bayever Eliel
Published: June 2022

TPS3158

Background: ELU001 is a novel, first-in-class, new molecular entity described as a C’Dot Drug Conjugate (CDC). ELU001 consists of ̃12 folic acid targeting moieties and ̃22 exatecan topoisomerase-1 inhibitor payloads on Cathepsin-B cleavable linkers covalently bound to the surface of each silicon core/polyethylene glycol C’Dot nanoparticle. CDCs are small in size (̃6 nm), have a greater ability to penetrate into and through tumors as compared to ADCs, and are rapidly eliminated by the kidneys. The rapid systemic elimination is expected to lead to less toxicity than is observed with targeting platforms like ADCs that have a longer half-life in circulation. ELU001’s high avidity is believed to promote internalization into FRα overexpressing cancer cells, selectively delivering it’s ̃22 molecules of payload. The first-in-human clinical trial, ELU-FRα-1, is currently recruiting patients that have advanced, recurrent or refractory FRα overexpressing tumors considered to be topoisomerase 1 inhibitor-sensitive based on the literature, and, in the opinion of the Investigator, have no satisfactory therapeutic options available. Methods: This is a Phase 1 / 2 multicenter, open label clinical trial with two parts: Part 1 Dose Escalation and Part 2 Tumor Group Expansion Cohort(s). In Part 1, patients with cancer types with a high likelihood of having FRα overexpressing tumors based on historical data, (specifically, ovarian, endometrial, colorectal, gastric, gastroesophageal junction, triple negative breast, or non-small cell lung cancers, or cholangiocarcinoma), will be enrolled to the study. Patients will receive ELU001 on a weekly dose regimen (QW) (once a week for 3 weeks, 1 week rest) or every other week dose regimen (Q2W, with no rest between cycles). Retrospective analysis of FRα expression will be determined. Part 2 uses a Simon’s Two-Stage design to evaluate 4-6 tumor group expansion cohorts, each consisting of patients with specific tumor types (to be identified based on emerging data) that overexpress FRα (prospectively determined prior to enrollment). The primary objective for Part 1 is to identify the MTD/RP2D and for Part 2 is ORR. Dose Escalation will recruit about 25 patients per dose regimen (QW or Q2W). Dose Expansion will recruit about 15 patients per tumor group expansion cohort. Secondary objectives are anti-tumor activity (DOR, PFS, TFST, PFS2, OS), frequency, severity and tolerability of adverse events, PK, ADA, and FRα expression assessments. The study is actively enrolling in the US – Cohorts 1-2 have been completed without DLT. Enrollment to Cohort 3 began in December 2021. Clinical trial information: NCT05001282 .
Datopotamab deruxtecan (Dato-DXd) plus pembrolizumab in treatment-naive advanced/metastatic (adv/met) non–small cell lung cancer (NSCLC) with PD-L1 ≥ 50% and without actionable genomic alterations.
Authors: Levy Benjamin Philip , Reck Martin , Yang James Chih-Hsin , Cappuzzo Federico , Rawat Siddhartha , Xie Jingdong , Basak Priyanka , Felip Enriqueta
Published: June 2022

TPS3162

Background: First-line treatment with immunotherapy has significantly improved survival in patients with adv/met NSCLC. Pembrolizumab (pembro) as monotherapy has shown superior efficacy compared with chemotherapy in treatment-naive patients with advanced NSCLC and PD-L1 expression ≥50%, but most patients will ultimately experience progression. Dato-DXd is an antibody-drug conjugate (ADC) consisting of a humanized anti-TROP2 IgG1 monoclonal antibody attached to a topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavable linker. In the ongoing phase 1 TROPION-PanTumor01 study (NCT03401385; DS1062-A-J101), Dato-DXd 6 mg/kg monotherapy demonstrated an objective response rate (ORR) of 28% and a manageable safety profile in pretreated patients with NSCLC. In addition, preclinical studies showed that DXd ADCs combined with an anti–PD-1 antibody was more effective than monotherapy with either agent alone. The tolerability of Dato-DXd 6 mg/kg in combination with pembrolizumab was confirmed in the phase 1b TROPION-Lung02 trial (NCT04526691; DS1062-A-U102). Here we describe the phase 3 TROPION-Lung08 trial evaluating Dato-DXd combined with pembro in treatment-naive patients with adv/met NSCLC. Methods: TROPION-Lung08 (NCT05215340; DS1062-A-U304) is a global, randomized, open-label, phase 3 trial of Dato-DXd plus pembro vs pembro alone in treatment-naive patients with adv/met non-actionable oncogenic driven NSCLC with PD-L1 ≥50% (as determined by PD-L1 IHC 22C3 pharmDx assay). Approximately 740 patients will be randomized to receive pembro 200 mg plus Dato-DXd 6 mg/kg or pembro 200 mg alone every 21 days until discontinuation or 35 cycles of pembro. Randomization will be stratified by Eastern Cooperative Oncology Group performance status (0 vs 1), histology (squamous vs nonsquamous), geographic region (East Asia vs rest of world), and smoking status (former/current vs never). Patients must have stage IIIB/IIIC NSCLC ineligible for curative treatment or stage IV disease. Patients must not have received prior systemic therapy; if patients received neoadjuvant/adjuvant systemic therapy without immune checkpoint inhibitors, it must have been given ≥6 months before the diagnosis of adv/met disease. The primary endpoints are progression-free survival (assessed by blinded independent central review per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) and overall survival, with target hazard ratios of 0.65 and 0.75, respectively. Secondary endpoints include ORR, duration of response, time to response, disease control rate, safety, and antidrug antibody prevalence. Pharmacokinetic parameters, biomarkers, and patient-reported outcomes will also be explored. Clinical trial information: NCT05215340.
DELFI-L101: Development of a blood-based assay that evaluates cell-free DNA fragmentation patterns to detect lung cancer.
Authors: Mazzone Peter J. , Work Kyle , Velculescu Victor E. , Kotagiri Sonali , Sun Lee Ming , Dix Daniel , Jakubowski Debbie M , Leal Alessandro , Bach Peter Brian , Maddala Tara
Published: June 2022

TPS3164

Background: Despite longstanding national recommendations, uptake of lung cancer screening in the US remains low. Barriers include access to lung cancer screening, costs, and concerns over potential harms like false-positives and radiation exposure. The DELFI technology evaluates fragmentation patterns of cfDNA using supervised machine learning to distinguish cancer from non-cancer [PMID30943338; 34417454; 31142840]. Methods: The DELFI-L101 is a case-control observational study (NCT04825834) prospectively enrolling at academic and community sites. Eligible participants (≥50 years of age) are individuals who currently smoke or previously smoked, with smoking histories of ≥20 pack-years. Individuals are ineligible if they had cancer treatment in the prior year or a history of hematologic malignancies or myelodysplasia. Cases are individuals with pathologically confirmed cancers (group A – lung, group C – non-lung). Controls are those without cancer (group B) as determined by low-dose computed tomography screening completed within 6 weeks of enrollment. Cases and controls are identified among enrollees from all participating sites. Total enrollment is estimated to be ̃2500 participants across all groups. Blood samples are collected at enrollment for DELFI analyses, which involves cfDNA isolation from plasma, low-coverage, whole-genome, next-generation sequencing, and machine learning methods. Clinical data (medical history, demographics, and diagnostic, surgery, imaging, and pathology reports, and/or other diagnostic information) are collected at enrollment and at 12 months post-enrollment. The primary objective is to train and test a classifier for the detection of lung cancer using the DELFI technology with other biomarkers and clinical features. Secondary objectives include the evaluation of classifiers to distinguish lung cancer from other cancers, modeling benefits and harms using performance estimates of these classifiers, and description of the analytical performance (eg, repeatability and reproducibility) of the DELFI technology and classifiers. The primary endpoint is the accuracy of lung cancer detection as measured by sensitivity, specificity, and the area under the receiver operating characteristic curve. Secondary endpoints include accuracy of tissue of origin classification, and adverse events associated with blood sample collection. The training and performance characterization of a DELFI classifier will further the development of an affordable, accessible, blood-based cancer detection tool with potential to overcome barriers to lung cancer screening. Clinical trial information: NCT04825834.
A phase 2 study of the MDM2 inhibitor milademetan in patients with TP53-wild type and MDM2-amplified advanced or metastatic solid tumors (MANTRA-2).
Authors: Dumbrava Ecaterina Elena , Hanna Glenn J. , Cote Gregory Michael , Stinchcombe Tom , Johnson Melissa Lynne , Chen Christopher , Devarakonda Siddhartha , Shah Naisargee , Xu Feng , Doebele Robert Charles , Gounder Mrinal M.
Published: June 2022

TPS3165

Background: Murine double minute 2 (MDM2) is a potent negative regulator of the tumor suppressor p53. MDM2 induces degradation of p53 and promotes tumorigenesis in solid tumors, and preclinical models have shown that inhibition of MDM2 can restore p53 tumor suppressor activity in TP53-wild type (WT), MDM2-amplified tumors. We performed a mutual exclusivity analysis of patients with solid tumors (n = 42,125; AACR Project GENIE) and found that the frequency of co-occurring TP53 mutations decreased with increasing MDM2 copy number. An MDM2 copy number of 12 was chosen as the threshold. An estimated 1.1% of solid tumors meet this molecular criteria, excluding glioblastomas, dedifferentiated liposarcomas, and intimal sarcomas where this signature is enriched. Milademetan (RAIN-32), an oral, selective MDM2 inhibitor, inhibits growth of TP53-WT/ MDM2-amplified cell lines and patient-derived xenograft models from varying tumor types. Furthermore, tumor regression was observed in 3/3 non-liposarcoma patients with MDM2 copy number > 12 in a phase 1 trial of milademetan. MANTRA-2 (RAIN-3202) is a phase 2, multicenter, single-arm, open-label, basket trial designed to evaluate the efficacy or clinical benefit of milademetan in TP53-WT solid tumors with MDM2 amplification (copy number ≥ 12). Methods: Eligible patients must be ≥ 18 years of age with histologically and/or cytologically confirmed locally advanced, incurable or metastatic solid tumors refractory to standard therapy. Local testing demonstrating TP53 WT and MDM2 amplification is required, defined as a MDM2 copy number ≥ 12 or 6-fold increase. Patients with well-differentiated/de-differentiated liposarcomas, intimal sarcomas, or primary central nervous system tumors are excluded. Prior treatment with an MDM2 inhibitor is not permitted. Patients receive milademetan 260 mg orally once daily on Days 1–3 and 15–17 of a 28-day cycle. Tumor response is evaluated by RECIST v1.1 at Weeks 8, 16, 24, and 32, and then every 12 weeks. Primary endpoint: objective response rate. Secondary endpoints include: duration of response; progression-free survival; growth modulation index; disease control rate; overall survival; safety; health-related quality of life scores. Exploratory endpoints include: biomarkers in blood and/or tumor tissue; pharmacodynamics; pharmacokinetics. Enrollment of 65 patients is planned to ensure that 57 patients have centrally confirmed TP53 WT and MDM2 copy number ≥ 12. The trial opened in November 2021 and is actively enrolling patients. Clinical trial information: NCT05012397.
A phase I trial of elimusertib in combination with cisplatin or with cisplatin plus gemcitabine in advanced solid tumors with an emphasis on urothelial carcinoma.
Authors: Leibrandt Ryan , Frankel Paul Henry , Beumer Jan Hendrik , Takebe Naoko , Yin Ming , Emamekhoo Hamid , Lara Primo "Lucky" N. , Gore Steven , Parikh Mamta
Published: June 2022

TPS3174

Background: Cisplatin, a well-established backbone of combination therapy of various advanced solid tumors, inhibits DNA synthesis by forming DNA cross-links and adducts. Despite the activity of cisplatin, tumor cells can either be refractory or develop resistance to treatment. Cisplatin has been demonstrated to cause cell cycle G2/M arrest, which may allow for DNA damage response (DDR) and repair. Ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad 3-related (ATR) protein kinases are key regulators of DDR, and contribute to maintaining genomic integrity in response to various exogenous and endogenous genotoxic insults like cytotoxic chemotherapy. In fact, cisplatin has been shown to transiently increase ATR expression. Inhibitors of ATR have been studied in combination with cisplatin both in vitro and in vivo, demonstrating enhanced activity. The oral small molecule ATR inhibitor elimusertib, which has been studied as a single agent in a Phase I study, has also demonstrated enhanced activity with cisplatin in vitro in lung cancer and bladder cancer cell lines. We sought to conduct a Phase I study evaluating the combination of elimusertib with cisplatin or with cisplatin and gemcitabine. Methods: In the first cohort, patients with histologically confirmed advanced solid tumors for which cisplatin-based therapy would be considered appropriate, who exhibit adequate organ function, and have received < 300 mg/m2 of cisplatin previously are treated with cisplatin on Day (D) 1 and with elimusertib on D2 & 9 of each 21-day cycle. The study follows a phase I queue (IQ) 3+3 dose escalation design, following standard practices for dose-limiting toxicity (DLT) impact on escalation, and when the maximum tolerated dose (MTD) is established with cisplatin alone, this will inform the first dose level of the next cohort, in which patients will be treated with cisplatin on D1, gemcitabine on D1 & 8, and elimusertib on D2 & 9 of each 21-day cycle. An expansion cohort will enroll urothelial carcinoma patients when the second MTD is established. The primary objective of the study is to evaluate the safety and MTD of elimusertib in combination with cisplatin, as well as in combination with cisplatin and gemcitabine. Secondary study objectives include evaluation of pharmacokinetics of elimusertib in these combinations, preliminary efficacy, and evaluating the association between ATM expression and responses to therapy. Currently, 6 patients have been enrolled to the first cohort of the study. Clinical trial information: NCT04491942.
A first-in-human phase I dose-escalation trial of the B7-H6/CD3 T-cell engager BI 765049 ± ezabenlimab (BI 754091) in patients with advanced solid tumors expressing B7-H6.
Authors: Falchook Gerald Steven , Patel Manish R. , Ulahannan Susanna Varkey , Maier Daniela , Hipp Susanne , Azuma Hisaya , Spigel David R.
Published: June 2022

TPS3175

Background: B7-H6 is a member of the B7 family of immune receptors, which is expressed in several solid tumors, but with little to no expression detected in normal tissues[Brandt et al. J Exp Med 2009;206.1495–503; Boehringer Ingelheim. Data on file]. BI 765049 is a novel IgG-like bispecific T-cell engager (TcE) designed to bind simultaneously to B7-H6 on tumor cells and CD3 on T cells, resulting in cytolytic synapse formation and tumor lysis. Preclinical studies have demonstrated that BI 765049 monotherapy induced dose-dependent antitumor activity in humanized in vivo CRC tumor models. Consistent with the mode of action, treatment with BI 765049 led to profound infiltration of T cells into the tumor tissue, which correlated with apoptosis and tumor shrinkage. The inflammatory tumor microenvironment created by treatment with the B7-H6/CD3 TcE also led to an increase of PD-1 on T cells and PD-L1 on the tumor cells [Hipp et al. AACR Annual Meeting 2021]. This upregulation of PD-(L)1 provides the rationale for combining BI 765049 with a PD1 inhibitor. Methods: NCT04752215 is a first-in-human, open-label, dose-escalation trial of BI 765049 ± the PD-1 inhibitor, ezabenlimab. Adults with advanced, unresectable and/or metastatic CRC, NSCLC, HNSCC, hepatocellular, gastric or pancreatic carcinoma are eligible. Patients must have progressed on, or be ineligible for, standard therapies. B7-H6 positivity must be confirmed at screening by central review (immunohistochemistry assay) in archived tissues/fresh biopsies (except CRC). Patients must have ≥1 evaluable lesion (modified RECIST 1.1) outside of the central nervous system and adequate organ function. The primary objective is to determine the maximum tolerated dose (MTD) or recommended dose for expansion of BI 765049 ± ezabenlimab, based on dose-limiting toxicities during the MTD evaluation period. Further objectives are to evaluate safety, tolerability, PK/PD, and preliminary efficacy of BI 765049 ± ezabenlimab. The trial will assess up to four intravenous dosing regimens: A (BI 765049 once every 3 weeks [q3w]); B1 (BI 765049 qw); B2 (BI 765049 qw with step-in dosing); C (BI 765049 + ezabenlimab q3w). Dose escalation will be guided by a Bayesian Logistic Regression Model with overdose control that will be fitted to binary toxicity outcomes using a hierarchical modelling approach to jointly model all dosing regimens. Treatment will be allowed to continue until confirmed progressive disease, unacceptable toxicity, other withdrawal criteria, or for a maximum duration of 36 months, whichever occurs first. Approximately 150–175 patients will be screened and ̃120 patients enrolled. As of January 2022, eight patients have been recruited in early dose-escalation cohorts. Clinical trial information: NCT04752215.
Phase III study to compare bevacizumab or cetuximab plus FOLFIRI in patients with advanced colorectal cancer RAS/BRAF wild type (wt) on tumor tissue and RAS mutated (mut) in liquid biopsy: LIBImAb Study.
Authors: Damato Angela , Damato Angela , Aschele Carlo , Ciardiello Fortunato , Maiello Evaristo , Siena Salvatore , Torri Valter , Dolcini Virginia , Gervasi Erika , La Grotteria Ilenia , De Simone Irene , Normanno Nicola
Published: June 2022

TPS3636

Background: KRAS, NRAS, and BRAF mutations are well-established negative predictive biomarkers of response to anti-EGFR monoclonal antibodies (MoAbs) in metastatic colorectal cancer (mCRC) patients (pts). In clinical practice, RAS/BRAF wild-type (wt) patients receive first-line therapy regimens containing anti-EGFR agents. However, tumor heterogeneity might drive primary and acquired resistance to anti-EGFR MoAbs. In fact, circulating tumor DNA (ctDNA) testing reveals RAS/BRAF mutations in approximately 10% of pts who resulted in wt at tumor tissue. In addition, 30% to 50% RAS wt pts develop, during the treatment with anti-EGFR MoAbs, RAS mut can be detected in the ctDNA several weeks before clinical progression. As today, it is not known whether revealing RAS mut in liquid biopsy (LB) earlier than the appearance of a clinical/radiological disease progression, could impact pts’ outcomes. Similarly, there are no data suggesting the best therapeutic approach in patients with RAS/BRAF wt tissue and mutated ctDNA. Methods: This is a phase III, randomized, open-label, comparative, multicenter study to assess the superiority of Bevacizumab (BEV) compared to Cetuximab (CET) plus FOLFIRI in treatment naïve mCRC RAS/BRAF wt on tumor tissue (TT) and mutated in plasma samples. RAS/BRAF wt pts on TT will undergo the first LB, and RAS mut pts will be randomized 1:1 to receive FOLFIRI/CET (control arm) or FOLFIRI/BEV (experimental arm). Instead, RAS wt pts at first LB will be treated with FOLFIRI/CET up to 8 cycles. Pts who have not progressed after 8 cycles of treatment will undergo a second LB. If RAS mut was detected, pts will be randomized 1:1 to continue FOLFIRI/CET or switch to FOLFIRI/BEV. If not, pts will continue FOLFIRI/CET outside the clinical trial. Pts will be treated until disease progression, unacceptable toxicity, or withdrawal of consent. Among 26 pts screened at the first LB, actually 1 KRAS mut and 1 BRAF mut pts were detected. The primary endpoint is the PFS Plasma samples will be analyzed for KRAS, NRAS, and BRAF mutations by Idylla ctKRAS and Idylla ctNRAS-BRAF-EGFGR. All samples will be also analyzed by NGS, in order to better evaluate the correlation of tumor heterogeneity with pts’ outcomes. Clinical trial information: EudraCT Number: 2020-005078-82, NCT04776655.
A phase 2 multicenter, open-label, randomized, controlled trial in patients with stage II/III colorectal cancer who are ctDNA positive following resection to compare efficacy of autogene cevumeran versus watchful waiting.
Authors: Kopetz Scott , Morris Van K. , Alonso-Orduña Vicente , Garcia-Alfonso Pilar , Reboredo Margarita , Fernandez Montes Ana , Maurel Joan , Paez David , Reinacher-Schick Anke C. , Höhler Thomas , Carrasco Javier , Galligan Barbara Marie , Manning Luisa , Preußner Liane , Tureci Özlem , Sahin Ugur
Published: June 2022

TPS3641

Background: Colorectal cancer (CRC) is one of the most commonly occurring cancers with high recurrence and mortality rate. Circulating tumor DNA (ctDNA) can be used as a marker of minimal residual disease after completion of surgical resection of stage II/III CRC, where detectable ctDNA levels (positive) post-AdCTx are associated with an increased risk of disease recurrence and novel therapies are needed. Autogene cevumeran is an investigational individualized neoantigen-specific immunotherapy that is designed to harness an immune response against patient-specific, tumor neoantigens. This clinical trial is in progress in patients with Stage II (high risk) / Stage III colorectal cancer who are ctDNA positive following resection. Methods: Autogene cevumeran is being evaluated in an open-label, Phase 2, randomized, controlled trial in patients with Stage II / III CRC patients who are ctDNA positive following resection. Patients are randomized to adjuvant therapy followed by autogene cevumeran compared to adjuvant therapy followed by watchful waiting. The primary endpoint is disease-free survival (DFS). The trial has a Biomarker Cohort of 15 patients who will receive autogene cevumeran irrespective of the ctDNA status to pursue exploratory objectives. The main study of the phase 2 trial consists of a randomized (1:1) design comparing the experimental arm (autogene cevumeran) with the observational arm (watchful waiting) in ctDNA positive CRC patients. A third Exploratory Cohort explores the efficacy and safety of autogene cevumeran in ctDNA positive CRC patients with early recurrence/relapse during or after completion of AdCTx. Patients enrolled onto the experimental group, the biomarker and exploratory cohorts will receive autogene cevumeran 6x q1w, followed by 2x q2w, followed by 7 “booster” doses q6w, to receive a total of 15 doses (dosed at 25μg). AEs are assessed according to CTCAE v5. DFS will be determined by an independent central radiology assessment. Key eligibility criteria include 1) Patients must have stage II/III rectal cancer or stage II (high risk)/III colon cancer that has been surgically resected (R0 confirmed by pathology report); 2) patients must be ctDNA positive following resection; and 3) at least 5 tumor neoantigens must be identified in the provided tumor sample for autogene cevumeran manufacturing (RNA lipoplex, RNA-LPX). ClinicalTrials.gov identifier: NCT04486378.
Blood-borne assessment of stromal activation in esophageal adenocarcinoma to guide tocilizumab therapy: A randomized phase II proof-of-concept study (NCT04554771).
Authors: Doeve Benthe , Pouw Roos E. , Van Berge Henegouwen Mark I. , Hulshof Maarten C.C.M. , Medema Jan Paul , Derks Sarah , Bijlsma Maarten F. , Van Laarhoven Hanneke W.M.
Published: June 2022

TPS4166

Background: The tumor stroma is increasingly acknowledged to harbor tumor-promoting properties. Recently, we found that stroma activity measured by serum ADAM12 predicts response to chemoradiation in esophageal adenocarcinoma (Veenstra et al., Oncogenesis, 2018). Preclinically, the esophageal adenocarcinoma stroma was found to produce interleukin 6, which causes epithelial-to-mesenchymal transition of tumor cells. These mesenchymal tumor cells have a poor response to chemoradiation (Ebbing et al., PNAS, 2019). Therefore, stroma-derived interleukin 6 provides a potential new target to improve the treatment of esophageal adenocarcinoma. Tocilizumab is an interleukin 6 receptor inhibitor clinically used in rheumatoid arthritis and cytokine-release syndrome. In this phase II proof-of-concept clinical trial, we aim to demonstrate that stroma-targeting by tocilizumab in esophageal adenocarcinoma patients with highly activated stroma increases efficacy of chemoradiation measured by pathological response according to the Mandard criteria. Methods: BASALT is a multi-center, randomized, open-label phase II proof-of-concept clinical trial in patients with surgically resectable adenocarcinoma of the esophagus or gastroesophageal junction (NCT04554771). To assess efficacy of tocilizumab in addition to chemoradiation, 48 patients will be grouped for serum ADAM12 level with a cutoff of 203 pg/mL. Patients are then randomized in a 1:1:1:1 ratio to receive three cycles of tocilizumab every two weeks in addition to paclitaxel, carboplatin and radiation (Table). The sample size is based on the rule-of thumb estimate of 12 patients per arm. Tocilizumab will be given intravenously at a dose of 8 mg/kg with a maximum of 800 mg per dose. Efficacy will be assessed by pathological response to chemoradiation according to the Mandard criteria. Secondary endpoints are overall and progression free survival, safety and toxicity, feasibility and efficacy of interleukin 6 inhibition with serum interleukin 6 levels, immunohistochemistry and RNA-sequencing. Currently, 28 out of the 48 planned patients have been enrolled. Clinical trial information: NCT04554771. [Table: see text]
First-line lenvatinib plus pembrolizumab plus chemotherapy in esophageal squamous cell carcinoma: LEAP-014 trial in progress.
Authors: Sun Jong-Mu , Enzinger Peter C. , Adenis Antoine , Shah Manish A. , Kato Ken , Bennouna Jaafar , Doi Toshihiko , Hawk Natalyn Nicole , Yu Li , Shah Sukrut , Bhagia Pooja , Shen Lin
Published: June 2022

TPS4167

Background: Recent data from the KEYNOTE-590 study demonstrated the superiority of pembrolizumab plus chemotherapy compared with chemotherapy as first-line treatment for unresectable locally advanced recurrent or metastatic adenocarcinoma or squamous cell carcinoma of the esophagus, or advanced/metastatic Siewert type 1 adenocarcinoma of the gastroesophageal junction. Prior data also suggest promising antitumor activity of lenvatinib plus pembrolizumab in advanced solid tumors. LEAP-014 (NCT04949256) is a randomized, 2-part, open-label, phase 3 study that will evaluate the efficacy and safety of first-line lenvatinib plus pembrolizumab plus chemotherapy versus pembrolizumab plus chemotherapy in patients with metastatic esophageal squamous cell carcinoma (ESCC). Methods: Key eligibility criteria include histologically or cytologically confirmed metastatic ESCC, measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), and Eastern Cooperative Oncology Group performance status 0 to 1. In part 1 (safety run-in), ̃6 patients will be treated for induction with intravenous (IV) pembrolizumab 400 mg every 6 weeks (Q6W) for 2 cycles plus oral lenvatinib 8 mg daily (QD) plus IV 5-fluorouracil (FU; 4000 mg/m2 on days 1-5) plus IV cisplatin (80 mg/m2) (FP) for 4 cycles and treated for consolidation with pembrolizumab 400 mg Q6W for ≤16 doses plus lenvatinib 20 mg QD; patients will be closely monitored for 21 days after the first dose of study intervention for dose-limiting toxicities. In part 2 (main study), approximately 850 patients will be randomly assigned 1:1 to induction with pembrolizumab plus lenvatinib plus chemotherapy (FP or mFOLFOX6 [Q2W for 6 cycles {IV oxaliplatin 85 mg/m2 plus bolus IV 5-FU 400 mg/m2 plus continuous IV 5-FU 2400 mg/m2 plus IV leucovorin 400 mg/m2 or IV levoleucovorin 200 mg/m2}]) followed by consolidation with pembrolizumab plus lenvatinib (arm 1) or pembrolizumab plus chemotherapy (FP or mFOLFOX6; arm 2). Randomization will be stratified by PD-L1 combined positive score (CPS; ≥10 vs < 10), region (East Asia vs North America and Western Europe vs rest of world), and chemotherapy backbone (FP vs mFOLFOX6). Treatment will continue until disease progression, unacceptable toxicity, or withdrawal of consent. Tumor imaging assessment will be performed Q6W for ≤1 year and Q9W thereafter. In part 1, the primary end point is safety and tolerability. In part 2, the dual primary end points are overall survival and progression-free survival (per RECIST v1.1 assessed by blinded independent central review [BICR]); secondary end points include objective response rate and duration of response (per RECIST v1.1 assessed by BICR) and safety and tolerability. Enrollment in this trial is ongoing. Clinical trial information: NCT04949256.
AdvanTIG-206: Anti-TIGIT monoclonal antibody (mAb) ociperlimab (BGB-A1217; OCI) plus anti-programmed cell death protein-1 (PD-1) mAb tislelizumab (TIS) plus BAT1706 versus TIS plus BAT1706 as first-line (1L) treatment for advanced hepatocellular carcinoma (HCC).
Authors: Fan Jia , Ren Zhenggang , Hsu Chiun , Guo Yabing , Song Tianqiang , Wang Wentao , Chao Yee , Gao Yujuan , Li Vincent , Ferro Salvatore , Yen Chia-Jui
Published: June 2022

TPS4172

Background: Treatment with PD-1/programmed death ligand 1 (PD-L1) inhibitors and anti-angiogenic agents has demonstrated significant survival improvements in patients with untreated HCC. T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is a co-inhibitory immune checkpoint receptor upregulated on T cells and natural killer cells in multiple solid tumors. OCI is a novel, humanized mAb that binds TIGIT with high specificity and affinity, blocking interaction with its ligands on tumor cells. TIS is an anti-PD-1 mAb that has demonstrated clinical activity in patients with previously treated, unresectable HCC (NCT03419897). BAT1706 is a similar biological product to the anti-angiogenic agent bevacizumab. OCI combined with TIS and BAT1706 could further enhance both anti-angiogenic and anti-PD-1 therapies for patients with HCC. Methods: AdvanTIG-206 is a Phase 2, randomized, open-label clinical study (NCT04948697). Patients aged ≥ 18 years with histologically confirmed advanced HCC that is not amenable to a curative treatment approach are eligible. Patients must have a Child-Pugh A score, ECOG PS ≤ 1, and have received no prior systemic therapy for HCC. Approximately 90 patients will be randomized 2:1 to OCI 900 mg combined with TIS 200 mg plus BAT1706 15 mg/kg (Arm A) or TIS 200 mg plus BAT1706 15 mg/kg (Arm B), all administered intravenously (once every 3 weeks [Q3W]). The primary endpoint is objective response rate as assessed by the investigator (RECIST v1.1). Radiological assessment of tumor response status will be performed Q6W for the first 48 weeks and Q12W thereafter. Secondary endpoints include duration of response, time to response, disease control rate, clinical benefit rate, and progression-free survival (all by investigator’s assessment), overall survival, safety, pharmacokinetics, and immunogenicity. Study enrollment is ongoing. Clinical trial information: NCT04948697.
ALTER-UC-001: Phase II trial of anlotinib plus everolimus as first-line treatment for advanced non–clear cell renal cell carcinoma.
Authors: Zhang Hailiang , Ye Ding-Wei
Published: June 2022

TPS4598

Background: For patients (pts) with recurrent or stage IV non-clear cell renal cancer (nccRCC), the medical treatment guidelines recommend the first choice to participate in clinical trials, or use TKI drugs such as sunitinib, and mTOR inhibitors such as everolimus. Anlotinib is a novel multi-target tyrosine kinase inhibitor (TKI). It’s antitumor targets include vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR) and c-kit. This a single-center, single-arm, phase II trial which will evaluate the efficacy and tolerability of anlotinib hydrochloride plus everolimus as first-line therapy in pts with nccRCC (NCT05124431). Methods: Key inclusion criteria are: age ≥18 years; histologically confirmed advanced nccRCC, advanced disease is defined as TNM stage IV, not available for surgery, locally recurrent or metastatic renal cell carcinoma; no prior systemic drug therapy for advanced disease; Eastern Cooperative Oncology Group (ECOG) performance status 0-1. Approximately 30 pts will be assigned to receive anlotinib hydrochloride: 12 mg every 21 days (14 days on treatment from Day 1-14, 7 days off treatment from Day 15-21) by oral, and everolimus 5mg qd, continued for up to 1 year (∼17 cycles ) or until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was objective response rate (ORR). Radiographic imaging will be performed every 6 weeks. Secondary endpoints included overall disease control rate (DCR), progression free survival (PFS), and over survival (OS). Adverse events will be monitored throughout the study and graded according to CTCAE V5.0. Recruitment have begun in Jan. 2022. Research Sponsor: Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Clinical trial information: NCT05124431.
A phase 1b/2 study of batiraxcept (AVB-S6-500) in combination with cabozantinib, cabozantinib and nivolumab, and as monotherapy in patients with advanced or metastatic clear cell renal cell carcinoma (NCT04300140).
Authors: Beckermann Katy , Shah Neil J. , Vogelzang Nicholas J. , Mao Shifeng S. , Ornstein Moshe Chaim , Hammers Hans J. , Gao Xin , McDermott David F. , Haas Naomi B. , Yan Hongxia , Esquibel Vanessa , Rangwala Reshma A. , Campbell Matthew T
Published: June 2022

TPS4599

Background: In clear cell renal cell carcinoma (ccRCC) the constitutive expression of hypoxia induced factor 1-α leads to increased expression of AXL. AXL overexpression has been associated with the development of resistance to VEGF inhibitors and suppression of the innate immune response through inhibition of macrophage-driven inflammation. Batiraxcept is a recombinant fusion protein dimer containing an extracellular region of human AXL combined with the human immunoglobulin G1 heavy chain (Fc), which demonstrates highly potent, specific AXL inhibition. In preclinical studies using the 786-O, M62, and SN12L1 tumors, batiraxcept monotherapy resulted in a significant reduction of tumor growth compared to control. In healthy volunteer and ovarian cancer clinical studies, batiraxcept was well tolerated with no dose-related adverse events, and a maximum tolerated dose was not reached. Therefore, batiraxcept could be tested as either a monotherapy or in combination with standard of care drugs in patients with metastatic ccRCC. The Phase 1b dose-escalation portion of this study evaluated batiraxcept in combination with standard of care cabozantanib in patients who progressed on or after first line therapy. No DLT was observed at either of two batiraxcept doses evaluated. The recommended Phase 2 dose of batiraxcept has been identified as 15 mg/kg every 2 weeks (q2w) with cabozantinib 60 mg based upon safety, PK/PD, and preliminary efficacy data. Methods: This Phase 2, multi-center, open-label study includes three parts: Part A) batiraxcept 15 mg/kg q2w in combination with cabozantinib 60 mg daily for ccRCC subjects who have progressed on or after one line of therapy, n=25. Part B) batiraxcept 15 mg/kg q2w with cabozantinib 40 mg daily and nivolumab at the investigator’s choice (240 mg q2w or 480 mg q4w) for first line treatment of advanced or metastatic ccRCC subjects, n=20. If no safety signals are observed in the first 6 subjects enrolled, 10 subjects will be enrolled in the first stage of a Simon 2-stage minmax statistical design. If ≥ 6/10 subjects achieve PR or CR, stage 2 will open to enroll up to 20 total subjects. Part C) batiraxcept 15 mg/kg q2w monotherapy for subjects with advanced/metastatic ccRCC ineligible for curative intent therapies, n=10. The primary objective for each arm is objective response rate by RECIST v1.1. Secondary objectives include safety, duration of response, clinical benefit rate, progression free survival by RECIST v1.1, and overall survival. Exploratory objectives include pharmacokinetic and pharmacodynamic assessments. The Phase 2 portion of this Ph1b/2 study is currently enrolling. Clinical trial information: NCT04300140.
A phase II clinical trial of neoadjuvant sasanlimab and stereotactic body radiation therapy as an in situ vaccine for cisplatin-ineligible muscle invasive bladder cancer (RAD VACCINE MIBC).
Authors: Satkunasivam Raj , Lim Kelvin , Teh Bin S. , Esnaola Nestor F. , Slawin Jeremy , Zhang Jun , Miles Brian , Brooks Michael Austin , Anis Maryam , Muhammad Taliah , Farach Andrew M. , Chen Shu-Hsia , Efstathiou Eleni , Sonpavde Guru P.
Published: June 2022

TPS4611

Background: The utilization of neoadjuvant immune checkpoint inhibitor (ICI) therapy, including anti-PD1/L1 agents, prior to radical cystectomy (RC), is an emerging paradigm in muscle invasive bladder cancer (MIBC). Pathologic complete responses (pCR) have been observed in 25-40% of patients with neoadjuvant PD1/L1 inhibitor monotherapy for cisplatin-ineligible MIBC. In situ vaccination using stereotactic body radiation therapy (SBRT) may augment T-cell responses to tumor-specific antigens through immunogenic cell death. Sasanlimab (PF-06801591) is a humanized IgG monoclonal antibody that targets PD-1 selectively, for which there are both Phase 1 data and ongoing Phase 3 trials in early-stage urothelial carcinoma. There exists a strong rationale to evaluate a novel strategy of combination neoadjuvant ICI therapy with SBRT as an in situ vaccine to improve loco-regional control and decrease the risk of distant recurrence in cisplatin-ineligible patients with MIBC. Methods: This is a prospective, investigator-initiated, single-arm, single-institution, phase II trial that evaluates neoadjuvant sasanlimab in combination with SBRT as neoadjuvant therapy for patients with MIBC before RC. Eligibility requires patients to be cisplatin-ineligible (one of the following: ECOG-PS=2, creatinine clearance <60 ml/min, or comorbidities such as hearing loss or neuropathy) or those who refuse cisplatin-based chemotherapy. Sasanlimab (300 mg) will be administered subcutaneously on Day 1 of each 28-day cycle for a total of 2 cycles, in combination with SBRT to the primary tumor at a dose of 24Gy given in 3 fractions, starting on Day 1 of Cycle 2 with a 48-hour interval between fractions. The combination treatment will be assessed by using a Simon’s 2-Stage design, which the first 10 patients are enrolled as a safety lead-in to evaluate the safety and feasibility. Futility analysis will be performed after a total of 18 patients. The primary endpoint is pCR rate after neoadjuvant sasanlimab/SBRT, followed by RC. If pCR is observed in 4 or fewer patients, further enrollment of patients may be stopped with the conclusion that pT0 cannot be 40% or greater. Otherwise, an additional 15 patients will be accrued in stage II, resulting in a total of 33 patients. Secondary endpoints include adverse events, surgical complication rates, health related quality-of-life, overall survival, and recurrence free survival. Exploratory endpoints include analysis of and association with pCR of the tumor/germline genetic signatures, circulating tumor DNA, tumor PD-L1 expression, blood cytometry time-of-flight analysis to identify immune response. Enrollment opened on February 15, 2022. Clinical trial information: NCT05241340.