bluuebunny/crossref_metadata_2025_split huggingface dataset:
Trial in progress: Phase II activity trial of high-dose radiation and chemosensitization in patients with macrometastatic lymph node spread after sentinel node biopsy in vulvar cancer: Groningen International Study on Sentinel Nodes in Vulvar Cancer III (GROINSS-V III/NRG-GY024).
Authors: Gien Lilian Tran , Slomovitz Brian M. , Leitao Mario M. , Van Der Zee Ate , Creutzberg Carien L. , Reyners An K.L , Witteveen Petronella , Ayala-Peacock Diandra , Mayadev Jyoti , Leath Charles A. , Oonk Maaike 
Published: June 2022

TPS5624 Background: Early stage invasive squamous cell carcinoma of the vulva is treated by radical excision of the primary tumor combined with a sentinel node (SN) procedure for the groins. GROINSS-VI and GOG-173 demonstrated that if there is no metastasis to the SN, then standard of care is observation. GROINSS-VII/GOG-270 demonstrated that micrometastatic disease (<2mm) to the SN requires standard radiotherapy (50 Gy) without the need for an inguinofemoral lymphadenectomy (IFL). This study also found that patients with macrometastasis ( > 2mm) required IFL in order to have an acceptably low groin recurrence rate. However, IFL is associated with significant morbidity such as lymphedema, wound healing issues, and recurrent infections. It is hypothesized that for those with macrometastasis ( > 2 mm) in the SN, the efficacy of treatment can be increased by giving a higher dose of radiotherapy along with chemosensitization. Methods: This is an international multicenter single-arm phase II prospective clinical trial. The primary objective is to investigate the safety of replacing IFL by chemoradiation in early-stage vulvar cancer patients with a macrometastasis ( > 2mm) and/or extracapsular extension in the SN. The primary endpoint is the groin recurrence rate in the first two years after primary treatment. Secondary endpoints are short and long-term morbidity associated with the SN procedure and chemoradiation and quality of life as measured by EORTC-QLQc30. Patients with invasive ( > 1mm) squamous cell carcinoma of the vulva, stage T1, tumor size < 4 cm diameter and no suspicious lymph nodes by imaging of the groins will proceed with SN detection. Institutions enrolling patients must demonstrate prior surgical experience with SN detection with the submission of at least 10 successfully completed cases in vulvar cancer. Patients with SN metastases > 2mm and/or with extracapsular extension or those with > 1 SN with micrometastases will be eligible for this study. Treatment will consist of chemoradiation with a dose of 56 Gy to the groin combined with weekly cisplatin 40 mg/m2 IV on days 1, 8, 15, 21 and 29 of radiotherapy. One hundred and fifty-seven patients in Europe, United States and Canada will be enrolled. The study includes continuous monitoring of groin recurrences with stopping rules. Results of this trial may be practice changing and eliminate the need for IFL in all women with clinically early stage vulvar cancer. The study is currently open for enrollment. Clinical trial information: NCT05076942.
A phase 1/2 trial to evaluate the safety and antitumor activity of tipifarnib and alpelisib for patients with PIK3CA-mutated/amplified and/or HRAS-overexpressing recurrent/metastatic head and neck squamous cell carcinoma.
Authors: Hanna Glenn J. , Perez Cesar Augusto , Ho Alan Loh , Gillison Maura L. , Adkins Douglas , Dayoub Ashley , Saunders Andrew , Leoni Mollie , Dale Stephen , Nie Kun , Dmitrienko Alex 
Published: June 2022

TPS6104 Background: Understanding connections between key cellular pathways is particularly important when selecting combinatorial cancer therapies. HRAS preferentially activates PI3K 5-fold more efficiently than KRAS, while KRAS is a more efficient activator of RAF (Yan et al. 1998). Further, mutant HRAS is insufficient for oncogenic transformation if it is unable to recruit PI3K in preclinical models (Gupta et al. 2007). Conversely, mutant PI3K requires RAS to drive tumor growth (Zhao and Vogt 2008). HRAS mutation/overexpression and PIK3CA mutations/amplifications account for up to 50% of head and neck squamous cell carcinoma (HNSCC). Recognition of these interdependencies was the basis for the evaluation of HNSCC PDX models which demonstrated additive or synergistic anti-tumor effects that confirmed the codependency of these pathways, thus providing robust rationale for investigating combined pathway inhibition in the clinic. The KURRENT trial is enrolling patients with HRAS and/or PIK3CA-dependent tumors who will receive combination treatment with tipifarnib (a potent and selective inhibitor of farnesyltransferase, a critical enzyme for HRAS activity) and alpelisib, a PI3K inhibitor. Methods: The KURRENT trial (KO-TIP-013, NCT04809233) is an ongoing multicenter, open-label, 2-cohort, phase 1/2 trial designed to evaluate the safety of the combination of tipifarnib and alpelisib, determine the recommended combination dose(s) regimen, and evaluate preliminary anti-tumor activity in patients with recurrent/metastatic (R/M) HNSCC whose tumors are dependent upon HRAS and/or PIK3CA signaling. The trial will enroll 40 HNSCC patients; 20 each into two biomarker defined cohorts (Cohort 1; PIK3CA; Cohort 2; HRAS). Participants must have documented treatment failure from at least one prior therapy in the R/M setting and have measurable disease by RECIST v1.1. At the starting dose level, participants will receive tipifarnib at 300 mg twice daily on days 1-7 and 15-21 and alpelisib 200 mg each morning continuously during a 28-day cycle. The trial will use an adaptive dose escalation design (based on a Bayesian logistic regression model) to characterize safety, tolerability, and clinical activity of the combination to identify the Optimal Biologically Active Dose (OBAD) while maintaining a dose limiting toxicity (DLT) rate < 33%. No formal interim analysis is planned as the model-based dose escalation process requires decisions based on real-time evaluation of aggregate toxicity and efficacy data. All observed/available data among each cohort will be evaluated before choosing the combination dose for a subsequent cohort. Enrollment into the PIK3CA cohort began in October 2021. Clinical trial information: NCT04809233.
A phase II study of pemetrexed and pembrolizumab in recurrent and/or metastatic salivary gland malignancies.
Authors: Price Katharine Andress Rowe , Foster Nathan R. , Fuentes Bayne Harry E. , Fazer Casey , Savvides Panayiotis , Zhao Yujie , McGarrah Patrick Walsh , Cooper Anna C. , Chintakuntlawar Ashish V. 
Published: June 2022

TPS6111 Background: Treatment options for recurrent and/or metastatic (R/M) salivary gland cancer (SGC) are limited with response rates to standard cytotoxic chemotherapy (CT) low at 10-30%, and responses to single-agent immune checkpoint inhibition (ICI) <10%. Current therapeutic agents used to treat R/M SGC have an unfavorable toxicity profile including cytotoxic CTs such as cisplatin and doxorubicin and the targeted therapy lenvatinib. Treatments with general applicability and acceptable side effect profile are urgently needed. Pemetrexed (PTX) is a multi-targeted anti-folate CT with an excellent safety and toxicity profile with promising responses reported in a case series of patients (pts) with R/M SGC (Viscuse P and Price K. Marked responses to pemetrexed chemotherapy for metastatic adenocarcinoma of the parotid gland: case series. Head Neck 2019;41(6):E99-103.). As the combination of PTX and pembrolizumab (PMB) showed enhanced responses and survival in pts with lung cancer, we hypothesize that PTX and PMB will have efficacy in pts with R/M SGC and that the combination will have improved anti-cancer activity compared with historical controls. Correlative studies on archived tissues include methylthioadenosine phosphorylase loss, PDL1 expression, and thymidylate synthase expression as potential biomarkers of response. Methods: MC200708 is a single institution (3-site), open-label, single arm phase II study of PTX and PMB in patients with R/M SGC. Pts will be treated in two cohorts: one for pts with adenoid cystic carcinoma (ACC) and the other for pts with all other types of SGC (non-ACC cohort). Eligible pts must be ≥18 years old, have a pathologically confirmed SGC that is not amenable to curative-intent therapy, ECOG 0-2, adequate organ function, and at least 1 measurable lesion by RECIST 1.1. Any number of lines of prior therapy is allowed; prior treatment with checkpoint inhibitors and/or PTX is allowed. Key exclusion criteria: serious medical co-morbidity or autoimmune disease, prior grade 3-4 adverse event (AE) or grade 2-4 lung AE with ICI, and uncontrolled brain metastases. Simon’s two-stage design will be used for each cohort separately given the expected difference in responses in pts with ACC and non-ACC. Primary endpoint is overall response rate. Secondary endpoints are progression free and overall survival and toxicity. All patients will receive the same treatment of PTX 500 mg/m2 IV + PMB 200 mg IV every 3 weeks until disease progression or treatment intolerance. Response assessments will occur every 3 cycles. Enrollment began July 2021 and 16 of the planned 45 patients (ACC cohort 9 of 20 pts, non-ACC 7 of 25) have been accrued. Clinical trial information: NCT04895735.
Abemaciclib in metastatic or locally advanced anaplastic thyroid cancer.
Authors: Khanna Vishesh , Miles Cristy , Sundaram Vandana , Sheth Siddharth , Steffen Martina , Biedermann Savanna , Jun Dhayoung , Winters Elizabeth , Khan Saad A. 
Published: June 2022

TPS6112 Background: Anaplastic thyroid cancer (ATC) is a rare and lethal tumor of thyroid epithelium, with disease-specific mortality approaching 100%. ATC accounts for > 50% of the 1200 annual deaths attributable to thyroid cancer. In the pre-molecular era, treatment options were largely ineffective, reflected in a median overall survival of 3-4 months following diagnosis. Outcomes have improved in BRAF V600E-mutated ATC with the FDA approval of dabrafenib and trametinib (Subbiah et al. JCO, 2018). However, a significant need exists for patients with BRAF wild-type tumors and patients with BRAF-mutated tumors who progress following treatment with BRAF-directed therapies. Abemaciclib is a CDK4/6 inhibitor currently FDA-approved in combination with endocrine therapy for hormone-positive breast cancer. Genomic analyses of ATC have indicated the presence of an intact Rb (Retinoblastoma) expression as well as the existence of CDKN2A (the gene encoding human p16) mutations in up to 32% of patients with ATC (Khan et al., Head Neck, 2019). Moreover, Lee et al. in 2008 reported undetectable p16 levels in 24 out of 27 (89%) patients with ATC. Low p16 levels would be expected to result in accelerated S phase entry, leading to uncontrolled ATC growth. Finally, studies in mouse xenograft models have demonstrated that ribociclib (a CDK4/6 inhibitor) slows proliferation and induces apoptosis of ATC cells (Lee et al., Cancer Letters, 2018). These molecular alterations and pre-clinical data provide a mechanistic rationale by which to evaluate CDK4/6 inhibitors in ATC and, to date, no CDK4/6 inhibitors have been evaluated in thyroid cancer. Methods: This multicenter, single-arm Phase 2 study will evaluate the safety and efficacy of treatment with abemaciclib in patients with histologically confirmed unresectable or metastatic ATC, using an optimal Simon two-stage design. Patients with BRAF V600E+ ATC must have progressed on or have an intolerance to dabrafenib and trametinib. The study intervention is abemaciclib 200 mg orally twice daily. The primary endpoint is overall response rate at eight weeks from the start of treatment. Secondary endpoints include progression-free survival and overall survival. Currently, 6 patients have been enrolled. Planned genomic analysis will be conducted to identify potential predictive biomarkers. Clinical trial information: NCT04552769.
Phase II neoadjuvant pyrotinib combined with epirubicin and cyclophosphamide followed by docetaxel in HER2-low–expressing and HR-positive early or locally advanced breast cancer (PILHLE-001): A single-arm trial.
Authors: Xia Yuan , Yang Wenqian , Yang Ya-Ping , Zhu Yingying , Zeng Yinduo , Qin Tao , Jia Shijie , Chen Jiayi , Gong Chang 
Published: June 2022

TPS620 Background: As a latent new subtype, HER2-low-expressing breast cancer has attracted increasing attention. However, HER2-low-expressing/HR-positive early or locally advanced breast cancer (E/LABC) has the lowest pathological complete response (pCR) rate among all types of breast cancer. Pyrotinib, a small-molecule HER1/HER2/HER4 tyrosine kinase inhibitor, combined with chemotherapy regimen showed excellent efficacy and safety in the treatment of patients with HER2-positive early, locally advanced and metastatic breast cancer. In-vitro experiment showed pyrotinib can significantly inhibit colony formation in breast cancer cell lines with different HER2 expression levels including HER2-positive and HER2-low-expressimg [immunohistochemistry (IHC) 2+/in situ hybridization (ISH) negative]. Therefore, the investigator-driven, ongoing PILHLE-001 trial has been conducted to evaluate the potential role of neoadjuvant pyrotinib plus chemotherapy in the treatment of HER2-low-expressing/HR-positive E/LABC, which may provide a novel neoadjuvant therapeutic strategy for these patients. Methods: PILHLE-001, as a single-arm, phase Ⅱ study, is the first trial to evaluate the efficacy and safety of neoadjuvant pyrotinib combine with chemotherapy in HER2-low-expressing (defined as IHC 2+ with ISH negative) and HR-positive (ER or PR > 1% stained cells) E/LABC (cT1c with histologically involved lymph nodes or ≥cT2). Patients who have HER2 IHC 1+, or severe heart diseases or basic gastrointestinal diseases are excluded. The trial has 80% power to detect true difference from previous reported pCR rate of 17.5%, to an expected pCR rate of 35% at two-sided alpha level of 0.05. Considering a drop rate of 10%, a total of 46 patients will be needed. Since May 19, 2021 until now, 19 patients have been enrolled. All eligible patients will receive pyrotinib 320mg orally daily with all chemotherapy cycles (epirubicin 90 mg/m² intravenously plus cyclophosphamide 600 mg/m² intravenously on day 1 for four 3-week cycles followed by docetaxel 100 mg/m² intravenously on day 1 for four 3-week cycle). The primary outcome is the rate of total pCR, defined as no residual invasive tumor cells in the breast and axillary nodes, regardless of ductal carcinoma in situ (ypT0/is ypN0) after neoadjuvant treatment. The secondary outcomes include Miller-Payne grade, residual cancer burden score, overall response rate, breast conservation rate, disease-free survival, overall survival, exploratory biomarkers and drug related safety. Primary efficacy outcomes will be analyzed in the intention‐to‐treat population and safety outcomes in the safety set population. Long-term efficacy outcomes will be assessed later with enough follow-up. Clinical trial information: NCT05165225.
Phase 1 study of LP-108 as monotherapy and in combination with azacitidine in patients with relapsed or refractory myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), or acute myeloid leukemia (AML).
Authors: Walker Alison R. , Bergua Burgues Juan Miguel , Montesinos Pau , Bixby Dale , Daver Naval Guastad , Konopleva Marina , Anthony Stephen Patrick , Tan Fenlai , Chen Yi , Chen Yu , Shen Yue , Burke Patrick William 
Published: June 2022

TPS7071 Background: BCL2 inhibition as a means of targeting intrinsic apoptotic pathways that confer a survival advantage to leukemic blasts has become a key therapeutic strategy for patients with myeloid malignancies. LP-108 is an oral highly potent and selective inhibitor of BCL-2 with comparable or more potent in vitro inhibitory activity as compared to the FDA approved oral BCL-2 inhibitor venetoclax. We propose to investigate LP-108 as monotherapy and in combination with azacitidine in patients with relapsed or refractory (r/r) MDS, CMML or AML. Methods: The primary objectives of the trial are 1.) To determine the safety, tolerability and determine the maximum tolerated dose (MTD) and the recommended phase 2 dose / optimal biological dose (OBD) of LP-108 as a single agent (Arm 1) and in combination with azacitidine (Arm 2) in patients with relapsed/refractory MDS/CMML/AML; 2.) To characterize the pharmacokinetic profile of LP-108 as monotherapy and in combination with a fixed dose of azacitidine. The secondary objectives of the trial are 1.) To evaluate the objective response rate of LP-108 (monotherapy or combination therapy) in r/r MDS/CMML/AML as well as progression free survival, duration of response and overall survival. In Arm 1 patients will be enrolled according to a 3+3 design with escalating doses of LP-108 for a 28 day cycle (firs table). DLTs will be determined in the first 28 days. In Arm 2 patients will be enrolled according to a 3+3 design with escalating doses of LP-108 in combination with a fixed dose of azacitidine (second table). DLTs will be determined in the first 28 days. DLT for both arms is defined as some ≥ Grade 3 non-hematological toxicities or prolonged myelosuppression. Patients may continue treatment until disease progression, unacceptable toxicity, or per investigator discretion. Patients age ≥ 18 years with r/r MDS with excess or blasts or with high or very-high risk disease per the R-IPSS, or r/r MDS for Arm 2, r/r AML, or frontline older and/or unfit AML for Arm 2, or r/r CMML may enroll. Patients with prior hypomethylating agents or venetoclax exposure may enroll. The blast count at the time of starting therapy must be ≤ 30 x 109 cells/L. Hydroxyurea is allowed prior to and during treatment. Ejection fraction ≥ 50% is required. Calculated creatinine clearance shall be ≥ 30 mL/min. Strong CYP3A4 inducers and inhibitors are prohibited. Patients on weak/moderate azole antifungals were allowed to enroll. Enrollment to Arm 1 is complete and there have been no DLTs to date. Enrollment to Arm 2 is pending. Arm 1 Dose Escalation Scheme (LP-108 monotherapy). Clinical trial information: NCT04139434. [Table: see text][Table: see text]
Subcutaneous daratumumab (DARA SC) versus active monitoring in patients (pts) with high-risk smoldering multiple myeloma (SMM): Randomized, open-label, phase 3 AQUILA study.
Authors: Dimopoulos Meletios A. , Voorhees Peter M. , Goldschmidt Hartmut , Baker Ross I. , Shi Yingqi , Rousseau Els , Dennis Robyn Monet , Carson Robin L. , Rajkumar S. Vincent 
Published: June 2022

TPS8075 Background: Standard of care for SMM includes active monitoring until progression to multiple myeloma (MM); however, recent evidence suggests pts with high-risk features may benefit from early treatment. DARA is a human IgGκ monoclonal antibody targeting CD38 that is approved as monotherapy for relapsed/refractory MM (RRMM) or in combination with standard of care for RRMM or newly diagnosed MM. Results from the phase 3 COLUMBA study showed that DARA SC demonstrated similar efficacy to intravenous (IV) DARA but with a lower rate of infusion-related reactions and shorter administration time. Based on the promising single-agent activity observed with IV DARA in intermediate- or high-risk SMM pts during the phase 2 CENTAURUS study, we hypothesized that DARA SC may delay progression to MM versus active monitoring in pts with high-risk SMM. Methods: AQUILA is an ongoing, randomized, open-label, multicenter phase 3 study of DARA SC versus active monitoring in pts with high-risk SMM. DARA SC (DARA 1,800 mg + recombinant human hyaluronidase PH20 [rHuPH20; 2,000 U/mL; Halozyme]) is administered by manual injection over approximately 5 minutes at alternating locations on the abdomen weekly in Cycles 1 and 2, every 2 weeks in Cycles 3-6, and every 4 weeks thereafter until 39 cycles (28 days/cycle), up to 36 months, or until disease progression. Eligibility criteria include confirmed diagnosis of SMM for ≤5 years, factors indicating high risk of progression to MM (clonal bone marrow plasma cells [BMPCs] ≥10% and ≥1 of the following: serum M protein ≥30 g/L, IgA SMM, immunoparesis with reduction of 2 uninvolved Ig isotypes, serum involved:uninvolved free light chain ratio ≥8 to < 100, or clonal BMPCs > 50% to < 60% with measurable disease), and ECOG performance status ≤1. The primary endpoint is progression-free survival (PFS), assessed by an independent review committee, with disease progression defined according to International Myeloma Working Group diagnostic criteria for MM. Secondary endpoints include time to biochemical or diagnostic (SLiM-CRAB) progression, overall response rate, complete response rate, duration of response, time to response, time to first-line treatment for MM, PFS on first-line treatment for MM (PFS2), overall survival, and incidence of MM with adverse prognostic features. The study completed enrollment on May 6, 2019; 390 pts have been randomly assigned to DARA SC or active monitoring. The primary efficacy analysis will be performed after approximately 165 PFS events have been observed. Clinical trial information: NCT03301220.
Birtamimab in patients with Mayo stage IV AL amyloidosis: Rationale for confirmatory affirm-AL phase 3 study.
Authors: Gertz Morie A. , Sanchorawala Vaishali , Wechalekar Ashutosh D. , Ando Yukio , Koh Youngil , Nie Christie , Sheng Xiaohua , Conrad Ansgar , Kastritis Efstathios 
Published: June 2022

TPS8076 Background: Light chain (AL) amyloidosis is a progressive and typically fatal disorder caused by misfolded AL protein produced by plasma cells. Birtamimab is a monoclonal antibody designed to neutralize circulating soluble and deposited insoluble amyloid, thus promoting phagocytic clearance. In 2018, the phase 3 VITAL study in newly diagnosed, treatment-naive patients was terminated based on futility analysis of the primary endpoint (time to all-cause mortality [ACM] or time to cardiac hospitalization > 90 days after first study drug infusion); the final hazard ratio (HR) numerically favored birtamimab + standard of care (SOC) over placebo + SOC (0.835 [95% CI: 0.5799, 1.2011]; p = 0.330). Post-hoc analysis of ACM over 9 months revealed a substantial survival benefit (HR = 0.413 [95% CI: 0.191, 0.895]; p = 0.025) in patients at high risk for early death (Mayo Stage IV). Post-hoc analyses of secondary endpoints in this subgroup indicated meaningful improvements in health-related quality of life (assessed with 36-Item Short Form Health Survey version 2; SF-36v2) and 6-minute walk test (6MWT) distance with birtamimab + SOC (p < 0.05) at 9 months. Methods: The phase 3, double-blind, placebo-controlled AFFIRM-AL study (NCT04973137) will enroll up to 150 Mayo Stage IV patients with newly diagnosed, untreated AL amyloidosis. Patients will be randomized (2:1) to 24 mg/kg intravenous birtamimab or placebo every 28 days. Both arms will receive concomitant chemotherapy with a first-line bortezomib-containing regimen, with or without daratumumab (D), at the discretion of the investigator. Patients will be stratified at randomization based on their 6MWT distance ( < 300 vs ≥300 meters) and initiation of D. The primary efficacy endpoint is time to ACM. Secondary endpoints are change from baseline to month 9 in the physical component summary of the SF-36v2 and 6MWT distance. This trial is powered at a significance level of 0.1 under a Special Protocol Assessment (SPA) with the U.S. Food and Drug Administration (FDA). Given the > 50% relative risk reduction for ACM observed in the post-hoc analysis of VITAL for patients with Mayo Stage IV disease, the AFFIRM-AL study is designed to confirm this effect of birtamimab. Approximately 130 global sites are planned; site initiation and patient randomization are underway. Conclusion: Treatments that improve survival in AL amyloidosis are needed, particularly for patients with advanced cardiac involvement, as median overall survival for those with Mayo Stage IV disease is ̃6–9 months. The AFFIRM-AL study is designed to confirm the survival benefit observed in the VITAL study in patients with Mayo Stage IV AL amyloidosis. Clinical trial information: NCT04973137.