bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase 1 pilot study with dose expansion of chemotherapy in combination with CD40 agonist and Flt3 ligand in metastatic triple-negative breast cancer.
Authors: Reddy Sangeetha M. , Carter Meredith , Chan Isaac , Hullings Melanie , Unni Nisha , Medina Jessica , Shakeel Shahbano , Armstrong Susan , Cade Lakeisha , Fattah Farjana J. , Ahn Chul , Fang Yisheng V. , Chen Nan , McArthur Heather L. , Sinclair Nicole , Yellin Michael Jay , O'Shaughnessy Joyce , Nanda Rita , Conzen Suzanne D. , Arteaga Carlos L. 
Published: June 2022

TPS1126 Background: Only a subset of patients with metastatic triple-negative breast cancer demonstrate response to currently approved PD-1 immune checkpoint blockade, and few have durable responses. Antigen presentation defects may be a reason for this low response because deficiency of antigen-presenting DC1 dendritic cells is associated with poor anti-tumor immunity. CD40 agonists are a class of agents that activate antigen presenting cells including dendritic cells and B cells and also repolarize macrophages. Flt3 ligand is a growth factor that increases dendritic cells. In line with this, we recently demonstrated in pre-clinical models that the combination of liposomal-doxorubicin chemotherapy, a CD40 agonist, and a Flt3 ligand improves outcomes of breast cancer compared to alternate combinations. Methods: This is a single arm phase I pilot study of liposomal-doxorubicin, CDX-1140 (CD40 agonist), and CDX-301 (Flt3 ligand) combination therapy in patients with metastatic or unresectable locally advanced metastatic triple-negative breast cancer. Patients will be randomized to 3 lead-in arms (triplet therapy, doublet immunotherapy only, liposomal-doxorubicin only) prior to receiving full triplet therapy with fresh tissue biopsies before and after the lead-in treatment. CDX-301 will be discontinued after 2 cycles; liposomal-doxorubicin and CDX-1140 will be continued until disease progression or clinically limiting toxicities. Primary endpoint is determination of a recommended phase 2 dose based on treatment-related adverse events including dose-limiting toxicities. Secondary endpoints include anti-tumor immune response after triplet therapy, after immunotherapy alone, and after liposomal-doxorubicin alone; median progression-free survival, overall response rate, duration of response, and clinical benefit rate. Key eligibility criteria are unresectable stage III or stage IV triple-negative breast cancer (ER ≤10%, PR ≤10%, HER2/neu negative), 1st to 3rd line metastatic treatment setting (1st line patients need to be PD-L1 negative by 22C3 assay), measurable disease by RECIST 1.1 criteria, consent for pre-treatment and on-treatment biopsies of amenable soft tissue tumor lesions, no prior treatment with an anti-CD40 antibody or a Flt3 ligand, no anthracycline treatment in the metastatic setting, no prior progression while on anthracycline-based therapy or within 6 months of completing neoadjuvant chemotherapy, and no history of non-infectious pneumonitis or current pneumonitis. This trial will enroll up to 45 patients across multiple sites. Clinical trial information: NCT05029999.
A randomized, placebo-controlled, phase 2 trial of INBRX-109 in unresectable or metastatic conventional chondrosarcoma.
Authors: Chawla Sant P. , Wasp Garrett Thomas , Shepard Dale Randall , Blay Jean-Yves , Jones Robin Lewis , Stacchiotti Silvia , Reichardt Peter , Gelderblom Hans , Martin-Broto Javier , Eckelman Brendan , Darling Michelle , Andrianov Vasily , Conley Anthony Paul 
Published: June 2022

TPS11582 Background: Chondrosarcomas (CS) are the third most common type of primary bone cancer after myeloma and osteosarcoma. Conventional CS represent 85–90% of all cases and are typically treated with surgical resection. However, there are no approved systemic treatment options for patients with unresectable or metastatic conventional CS, and outcomes remain poor. INBRX-109 is a precision-engineered, tetravalent death receptor 5 (DR5) agonist antibody designed to overcome the limitations of earlier-generation agonists and exploit the tumor-specific cell death induced by DR5 activation. DR5 is one of two pro-apoptotic receptors for the trimeric tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Early clinical activity of INBRX-109 was observed in an ongoing phase 1 trial and warrants further investigation. INBRX-109 has been granted an FDA fast-track designation for conventional CS. Methods: This is a multicenter, randomized, blinded, placebo-controlled phase 2 study in patients with unresectable or metastatic conventional CS, measurable disease by RECIST 1.1, and radiologic disease progression within 6 months prior to screening. Any number of prior lines of therapy are allowed, except for prior DR5 agonists. Patients must be ≥18 years of age and have an ECOG performance status of 0/1 and have archival or fresh tissue available. Approximately 201 patients will be randomized (2:1) to INBRX-109 (3 mg/kg intravenously, every 21 days) or placebo, stratified by histologic grade (Grade 1/2 vs 3), isocitrate dehydrogenase (IDH)1 R132/IDH2 R172 status (wildtype vs mutation), and line of systemic therapy (none vs prior). Treatment will continue until disease progression/unacceptable toxicity. Patients treated with a placebo will have the option to cross over to INBRX-109 upon disease progression. The primary endpoint is progression-free survival (PFS) by independent radiology review. Secondary endpoints are overall survival, PFS by investigator assessment, quality of life, overall response rate, duration of response, disease control rate, safety, pharmacokinetics, and immunogenicity. Adverse events will be recorded and graded by NCI CTCAE Version 5.0. Median PFS of 7.0 months is projected for INBRX-109 and 4.0 months for placebo (corresponding hazard ratio of 0.571); INBRX-109 will be declared superior if the 1-sided p-value from the stratified log-rank test is <0.025. More than 50 sites are planned across the US/Europe. The study is actively enrolling. Clinical trial information: NCT04950075.
Phase 1/2 study of devimistat in combination with hydroxychloroquine (HCQ) in patients with relapsed or refractory (R/R) clear cell sarcoma (CCS).
Authors: Agulnik Mark , Davis Elizabeth J. , Albert Catherine M. , Davis Lara E. , Pardee Timothy S. , Chugh Rashmi , Trucco Matteo M. 
Published: June 2022

TPS11595 Background: CCS of the soft tissues is a rare and aggressive subtype of sarcoma that often starts in the tendons of the arms or legs. It is molecularly characterized by t(12;22)(q13;q12) translocation, resulting in EWSR1-ATF1 or EWSR1-CREB1 gene fusion. Despite reports of occasional responses to systemic therapies, currently available therapies have shown limited efficacy in advanced CCS. Therefore, there is a significant unmet medical need for more active agents in CCS. Devimistat is a stable intermediate of a lipoate analog that inhibits pyruvate dehydrogenase and α-ketoglutarate dehydrogenase enzymes of the tricarboxylic acid (TCA) cycle preferentially within the mitochondria of cancer cells. Devimistat induces autophagy in cancer cells. In a metastatic mouse model of CCS, treatment with devimistat in combination with chloroquine significantly suppressed tumor growth (Egawa et al, 2018). Based on this data, we hypothesized that inhibition of autophagy with HCQ may sensitize cancer cells to devimistat with increased efficacy and acceptable toxicity. Given its expected synergy, we have initiated a single-arm phase I/II prospective, multicenter, open-label, non-randomized study to evaluate maximally tolerated dose (MTD), safety, and efficacy of devimistat in combination with HCQ in patients with R/R CCS. Methods: In the phase 1 portion of the study, patients with R/R CCS and other fusion-positive R/R sarcomas will be enrolled and a standard 3+3 design will be followed to evaluate toxicity, MTD, and recommended phase 2 dose. There will be two patient groups based on weight, and dose escalation will be conducted separately for each group. Starting dose of HCQ will be 5mg/kg PO BID for patients < 45 kg and 200 mg PO BID for patients ≥45 kg on days 1 through 5 of every 28 days. The first dose of HCQ each day will be followed 2 hours later by 1,000 mg/m2 devimistat (for patients < 45 kg) and 2,000 mg/m2 of devimistat (for patients ≥ 45 kg) administered over 2 hours. A maximum of 36 patients will be enrolled for the phase I portion, 18 for each patient group. In the phase 2 portion of the study, only relapsed or refractory CCS patients will be enrolled, and the response rate will be determined using RECIST 1.1. In phase 2, pharmacokinetics, duration of response, clinical benefit rate, progression-free survival, overall survival, safety, and patient-reported outcomes will also be assessed. This portion of the study will utilize Simon’s admissible two-stage design with 29 patients. This study started enrolling participants in November 2021 and has dosed six patients to date. The first two dose-escalation cohorts for patients ≥45 kg have been completed without DLT and the third dose level will be opening shortly. Clinical trial information: NCT04593758.
A randomized phase III clinical trial of yoga for chemotherapy-induced peripheral neuropathy treatment.
Authors: Han Katherine , Dooley Andee , Piulson Lauren , Seluzicki Christina , Zhi Wanqing Iris , Bao Ting 
Published: June 2022

TPS12146 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common, painful, and debilitating side effect of many standard chemotherapy regimens. Patients with CIPN typically experience pain, paresthesia, and muscle weakness, and may exhibit significant functional decline and worsened quality of life. Our prior study showed more than half of breast cancer survivors experience persistent CIPN up to a mean duration of 5.6 years, which is associated with a doubled fall risk. Identifying nonpharmacological approaches to reduce CIPN symptoms and improve cancer survivors’ outcomes is urgently needed. Yoga is a meditative movement therapy that that includes stretching, and flexibility and balance training. Our pilot study (NCT03292328) demonstrated that yoga reduced CIPN-related symptoms, and improved quality of life and functional reach scores compared to waitlist control. We hypothesize that yoga can reduce CIPN symptoms, improve function, and reduce the risk of falls. Methods: We are conducting a three-arm randomized education and usual care-controlled trial in cancer survivors with chronic CIPN pain at Memorial Sloan Kettering Cancer Center (MSK), New York, NY. Participants in the intervention arm will receive twice-weekly one-hour Hatha yoga classes virtually or in-person taught by MSK instructors, and practice yoga at home daily for eight weeks. Participants in the education control arm will receive one-hour virtual education classes twice per week taught by an MSK mind-body therapist for eight weeks. Participants in the usual care arm will continue their usual care for CIPN for eight weeks. The primary endpoint is the Brief Pain Inventory-Short Form (BPI-SF) average pain item at weeks 8 and 24. Secondary outcomes include the Neuropathic Pain Scale (NPS), Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx), Patient-Reported Outcomes Measurement Information System (PROMIS) Global Health outcome measure, Brief Fatigue Inventory (BFI), Insomnia Severity Index (ISI), Hospital Anxiety and Depression Scale (HADS), QLQ-CIPN-20, Functional Assessments, and quantitative sensory testing (QST) at weeks 0, 4, 8, 12, 18, and 24. Eligibility criteria included: 1) Moderate-to-severe CIPN pain, defined by a score of 4 or greater on a 0-10 numerical rating scale; 2) completion of neurotoxic chemotherapy at least three months prior; 3) no changes in anti-neuropathy medications within three months of enrollment; and 4) changes in balance and functionality. We have accrued five participants as of February 2022 with a total accrual target of 268 participants. We anticipate completing accrual in March 2025. Funding resource: NIH R01CA251470. Clinical trial information: NCT05121558.
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.