bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase Ib/II study of BCL-2 inhibitor lisaftoclax (APG-2575) safety and tolerability when administered alone or combined with a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor in patients with estrogen receptor-positive (ER+) breast cancer or advanced solid tumors.
Authors: Kalinsky Kevin , Tolcher Anthony W. , Wang Shushen , Meric-Bernstam Funda , Winkler Robert , Li Mingyu , Sun Xuemei , Pan Wentao , Paudyal Bishnuhari , LIANG ZHIYAN , Lu Ming , Yang Dajun , Zhai Yifan 
Published: June 2022

TPS1122 Background: Various cancers evade apoptosis by overexpressing BCL-2 proteins. Investigational agent lisaftoclax (APG-2575) is a novel, potent, selective BCL-2 inhibitor, while palbociclib inhibits cyclin-dependent kinases (CDK) 4 and 6. In preclinical studies, palbociclib decreased proliferation of ER+ breast cancer cell lines by arresting them in the G1 cycle phase. Preclinical data demonstrate favorable, complementary effects of palbociclib when combined with a BCL-2 inhibitor and support this combination in patients with ER+/ human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer. Methods: This global multicenter open-label dose escalation and dose expansion study is assessing the safety of lisaftoclax monotherapy in patients with histologically or cytologically confirmed advanced solid tumors that have progressed on standard therapy or when combined with CDK4/6 inhibitor palbociclib in physiologically postmenopausal women with ER+/ HER2- metastatic breast cancer that has progressed or relapsed after treatment with a CDK4/6 inhibitor. This trial consists of 2 parts: a phase Ib dose escalation phase using a standard 3+3 design to determine the maximum tolerated dose (MTD) of lisaftoclax as a single agent in patients with solid tumors, as well as both the MTD and recommended phase 2 (RP2D) dose of lisaftoclax when combined with palbociclib in women with ER+/ HER2- metastatic breast cancer. Phase II of this study is a signal-seeking expansion of lisaftoclax at RP2D when combined with palbociclib in women with ER+/HER2- metastatic breast cancer. This phase is being conducted using Simon’s Minimax two-stage design. The primary objective for phase II is to determine clinical benefit response, and secondary efficacy endpoints include overall response rate, duration of response, time to response, and progression-free survival. Lisaftoclax is being administered orally once daily in a 28-day cycle at the assigned dose. Clinical trial information: NCT04946864.
MOTION: A randomized, phase 3, placebo-controlled, double-blind study of vimseltinib (DCC-3014) for the treatment of tenosynovial giant cell tumor.
Authors: Tap William D. , Wagner Andrew J. , Sharma Maitreyi G. , Vallee Marc , Michenzie Mary F. , Sherman Matthew L. , Ruiz-Soto Rodrigo , Stacchiotti Silvia , van de Sande Michiel A.J. , Gelderblom Hans 
Published: June 2022

TPS11590 Background: Tenosynovial giant cell tumor (TGCT) is a rare, locally aggressive neoplasm that occurs in the synovium of joints, bursae, or tendon sheaths. TGCT is caused by upregulation of the colony-stimulating factor 1 (CSF1) gene, resulting in aberrant CSF1 expression and the recruitment of CSF1 receptor (R)-dependent inflammatory cells. Resection is the primary treatment, but nonsurgical treatment options are necessary for patients with symptomatic TGCT not amenable to surgical resection. Vimseltinib is an oral switch control TKI specifically designed to selectively and potently inhibit CSF1R. In a Phase 1/2 study in patients with TGCT, vimseltinib showed encouraging antitumor activity with an overall objective response rate (ORR) of 42% in the cohort receiving 30 mg twice weekly (recommended phase 2 dose; Gelderblom et al, ESMO 2021 Poster). Vimseltinib was also well tolerated, and the majority of the common (≥15%) treatment-emergent adverse events (TEAEs) were Grades 1–2. Among these common TEAEs, the only Grade 3–4 event in the Phase 2, twice-weekly, 30-mg cohort was increased blood creatine phosphokinase (CPK); however, this elevated CPK was not associated with any symptoms (Gelderblom et al, ESMO 2021 Poster). Phase 1/2 efficacy and safety data support further development of vimseltinib; here, we describe the ongoing Phase 3 study for patients with TGCT not amenable to surgical resection. Methods: MOTION (NCT05059262) is a Phase 3, randomized, placebo-controlled, double-blind study that aims to evaluate the efficacy and safety of vimseltinib for the treatment of TGCT not amenable to surgical resection. Participants must be at least 18 years of age and have histologically confirmed and symptomatic TGCT for which surgical resection will potentially cause worsening functional limitation or severe morbidity. Prior CSF1R therapy is not permitted (previous imatinib and nilotinib is allowed). In Part 1 of the study, eligible participants will be randomized 2:1 to receive either vimseltinib 30 mg twice a week or matched placebo for 24 weeks. The primary outcome measure is ORR assessed by central read using Response Evaluation Criteria in Solid Tumors version 1.1 at 25 weeks. Secondary outcome measures include ORR per tumor volume score, range of motion, and patient-reported outcomes. Participants assigned to placebo in Part 1 will have the option to receive vimseltinib in Part 2, a long-term treatment phase in which participants will receive open-label vimseltinib. This international study plans to randomize 120 participants and is currently enrolling. Clinical trial information: NCT05059262.
Targeting adiposity and inflammation with movement to improve prognosis in breast cancer survivors (the AIM trial): Rationale, design, and methods.
Authors: Dieli-Conwright Christina Marie , Kang Dong-Woo , Wilson Rebekah M , Gonzalo-Encabo Paola , Norris Mary , Hans Marybeth , Tahbaz Meghan , Dawson Jackie , Nguyen Danny , Normann Amber , Yunker Alexandra G , Sami Nathalie , Uno Hajime , Ligibel Jennifer A. , Mittelman Steven D 
Published: June 2022

TPS12140 Background: Obesity is considered a leading modifiable contributor to breast cancer mortality worldwide due to its association with increased recurrence and decreased overall survival rate. A central mechanism by which obesity stimulates cancer progression is through chronic, low-grade inflammation in adipose tissue. Exercise has shown potential in improving inflammation but has not been implemented with breast cancer survivors. Our hypothesis is that exercise designed to target chronic inflammation and associated sarcopenic obesity will improve prognosis in obese breast cancer survivors. Methods: The AIM trial is a prospective, three-armed, phase II randomized controlled trial investigating the effects of a 16-week supervised circuit aerobic and resistance exercise (CARE) program compared to a traditional aerobic and resistance exercise (TARE) program, and attention control (AC) group, on adipose tissue inflammation in 300 breast cancer survivors. Main inclusion criteria are histologically confirmed breast cancer stage 0-III, completion of chemotherapy and/or radiation, sedentary, centrally obese, and free from musculoskeletal disorders. The primary endpoint is adipose tissue inflammation as assessed by core biopsy and blood draw; secondary endpoint is sarcopenic obesity; and exploratory endpoints are physical fitness and function and patient reported outcomes. Participants randomized to the exercise groups participate in three weekly supervised exercise sessions for 16-weeks. Participants randomized to the attention control group are offered the CARE intervention after the 16-week period of observation. Discussion: This is the first randomized controlled trial examining the effects of exercise on adipose tissue inflammation in obese, breast cancer survivors. Results will contribute to a better understanding of exercise modality on adipose tissue inflammation that can potentially improve patient prognosis. Clinical trial information: NCT03091842.
A phase 0/surgical window-of-opportunity study in progress, evaluating evolocumab in patients with high-grade glioma or glioblastoma.
Authors: Singh Kirit , Foster Matthew , Miller Elizabeth S. , Gregory Simon , Weinhold Kent J. , Ashley David M. , Desjardins Annick , Low Justin , Peters Katherine B. , Severance Erin , Jaggers Denise , Friedman Henry S. , Johnson Margaret O. , Friedman Allan H. , Keir Stephen T. , Herndon James Emmett , Li Chuan-Yuan , Fecci Peter E. , Sampson John H. , Khasraw Mustafa 
Published: June 2022

TPS2076 Background: High-grade gliomas (HGGs) are immunologically ‘cold’ tumors. This phenomenon is partly due to reduced expression of major histocompatibility class (MHC) I on the surface of tumor cells, which prevents CD8+ cytotoxic T lymphocyte activity (CTLs). Blockade of proprotein convertase subtilisin/kexin type 9 (PCSK9) increases MHC class I expression, enhances CTL tumoral infiltration, and potentiates checkpoint inhibition in vivo. Evolocumab is an FDA-approved fully human IgG2 monoclonal antibody PCSK9 inhibitor which is clinically indicated for hyperlipidemia. This study seeks to determine whether evolocumab can cross the blood-brain barrier (BBB) and enhance MHC I expression on resected tumor cells, serving as a potential future adjunct for immunotherapy. Methods: This study will enroll ten patients over 18 years who have newly diagnosed or recurrent HGG. These patients will also need to be undergoing resection of their tumor as part of their planned treatment pathway. Following informed consent, patients will receive evolocumab (420mg, subcutaneously) 7-14 days before surgical debulking of the tumor. We will collect tissue which is not required for histological tumor analysis and compare it with a contemporaneous matched control cohort. This will consist of resected tumor specimens from patients not treated with evolocumab. Quantification of the drug will be performed using mass spectroscopy, flow cytometry, and single-cell sequencing. The primary objective of this study is to evaluate whether evolocumab can cross the BBB and be measured in resected tumor specimens taken from patients with HGG. Secondary objectives include an analysis of lipid metabolism and MHC-I expression on the tumor via flow cytometry and CITEseq. Wilcoxon rank-sum test or a two-sample t-test, will compare groups for these endpoints. Exploratory analyses will determine if evolocumab leads to changes in tumorigenic pathways and the immune profile of tumor infiltrating lymphocytes (TILs). Bioinformatic analyses will be performed using protein set enrichment, gene ontology (GO) annotations, and search tools from the retrieval of interactive genes/proteins (STRING). Progress: The study was activated on 10/04/2021 (NCT04937413) and at the time of submission has enrolled 5 participants (4 to control arm, 1 to intervention arm). Clinical trial information: NCT04937413.
ARTISTRY-3: Effect of nemvaleukin alfa with a less frequent IV dosing schedule as monotherapy and in combination with pembrolizumab and impact on the tumor microenvironment (TME) in patients (pts) with advanced solid tumors.
Authors: Piha-Paul Sarina Anne , Elliott Corrine F. , Du Yangchun , Graham Julie R. , Desai, MD Monali , Wang Yan , Dalal Rita P. , Lakhani Nehal J. 
Published: June 2022

TPS2684 Background: Nemvaleukin alfa (nemvaleukin, ALKS 4230) is a novel engineered cytokine that selectively binds the intermediate-affinity interleukin-2 (IL-2) receptor, preferentially activating and expanding antitumor CD8+ T cells and NK effector cells, with minimal effect on regulatory T cells. Nemvaleukin was designed to leverage antitumor effects of the IL-2 pathway while limiting typical IL-2‒associated toxicity. In ARTISTRY-1, the recommended phase 2 dose (RP2D) for nemvaleukin monotherapy of 6 µg/kg IV on days 1 to 5 of a 21-day cycle elicited durable and deep responses in pts with advanced melanoma and renal cell carcinoma (Boni et al. ASCO 2021:abstr 2513). Responses with nemvaleukin plus pembrolizumab were also observed in platinum-resistant ovarian, breast, cervical, gastrointestinal, and genitourinary cancers. ARTISTRY-3 will investigate the effects of nemvaleukin as monotherapy and in combination with pembrolizumab on the TME in pts with advanced solid tumors, and in an additional cohort (Cohort 2), to further assess a less frequent IV dosing schedule for nemvaleukin. Methods: The phase 1/2, open-label ARTISTRY-3 (NCT04592653) study will enroll adults (≥18 years) with select advanced solid tumors, ≥1 accessible lesion for biopsy, ≥1 target lesion (per RECIST v1.1), ECOG PS of 0 or 1, estimated life expectancy of ≥3 months, adequate hematologic reserve, and adequate hepatic and renal function. Primary objectives: to evaluate effects of nemvaleukin monotherapy on the TME (Cohort 1) and to determine RP2D for less frequent dosing schedule (Cohort 2). Additional objectives are to evaluate: efficacy, safety, immunogenicity, and pharmacokinetics of nemvaleukin monotherapy; effects of nemvaleukin plus pembrolizumab on the TME; and correlative biomarkers of nemvaleukin as monotherapy and combination. Following the protocol amendment, additional pts enrolled in Cohort 1 will receive lead-in monotherapy at a dose selected based on results from Cohort 2, and pre- and on-treatment biopsies will be collected for TME assessments. Subsequent cycles will be administered in combination with pembrolizumab, and a biopsy may be collected at cycle 4 or 5. Tumor types eligible for Cohort 2 are selected based on activity observed in the ARTISTRY-1 study. A quantitative system pharmacology model was applied to identify a less frequent schedule for nemvaleukin monotherapy and combination. Cohort 2 will initially assess safety and tolerability of nemvaleukin at 1 dose per 21-day cycle. Two doses per 21-day cycle may be implemented to achieve optimal PK/PD parameters. Bayesian optimal interval design methodology with open enrollment will be applied to facilitate dose escalation decisions. Clinical trial information: NCT04592653.
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.