bluuebunny/crossref_metadata_2025_split huggingface dataset:
Patient controlled analgesia (PCA) versus non-PCA intravenous hydromorphone titration for severe cancer pain: A randomized, controlled, multicenter, phase III trial, HMORCT09-1.
Authors: Lin Rongbo , Zhu Jinfeng , Feng Shuitu , Lin Sunzhi , Fu Jianqian , Yao Yongzhi , Hong Lixia , Xin Min , Chen Zhangshu , Cai Zhenyu , Li Chunxiang , Zhao Shen , Wu Qingyi , Yang Shangwang , Huang Cheng 
Published: May 2019

TPS11635 Background: The opioid dose for an individual with cancer pain to provide adequate relief of pain with an acceptable degree of side effects is variable. Opioid titration is a process to obtain the tailored dose. Conventional titration is administered by a clinician or nurse. PCA is that patients control cancer pain by self-administration of intravenous opioids using programmable pump. The aim of our study is to evaluate the efficacy of PCA titration versus conventional titration intravenously for severe cancer pain (10-point numerical rating scale, NRS ≥ 7). Injectable Hydromorphone was selected as pharmaceutical analgesics, which works as well as morphine and oxycodone and had similar side effects. Methods: This is currently enrolling patients (n=230) with severe cancer pain during previous 24 hours. Patients are randomized 1:1 and stratified by opioid intolerance or opioid tolerance into PCA or non-PCA titration. PCA titration using programmable pump: bolus hydromorphone at 0.5mg (for opioid intolerance) or hydromorphone dose equivalent to 10% to 20% of the total opioid taken in the previous 24 hours with a lockout time 15 minutes (for opioid tolerance) was administered by the patients educated. No basal infusion was set in the pump. Non-PCA titration administered by a nurse or clinician: Initial hydromorphone doses were same with PCA titration. Reassess pain at 15 minutes. Increased dose of hydromorphone by 50%-100% if pain unchanged or increased, or repeat same dose if pain decreased to NRS 4-6, or continue at current effective dose as needed over initial 24 hours. The primary endpoint is the time needed to successful titration was defined the time from the first dose of hydromorphone after randomization to achieve satisfied pain control. The satisfied pain control was defined NRS pain score ≤ 3 at rest in at least 2 consecutive assessment (15 minutes interval). The time needed to successful titration was extended to achieve satisfied pain control again if NRS pain score ≥ 7 after satisfied pain control within 24 hours. The failure of successful titration was defined that satisfied pain control does not achieve within 24 hours. Secondary endpoints include the percentage of patients titrated successfully, the mean NRS pain score of 24 hours, the total dose of hydromorphone titrated, and adverse events. Clinical trial information: NCT03375515.
Omega-3 fatty acids and ERPR(-) and HER2/neu(+/-) breast cancer prevention.
Authors: Kalu Chidimma , Woelke Sarah , Zhang Jianying , Belury Martha , Shen Rulong , Clinton Steven K. , Yee Lisa 
Published: May 2019

TPS1589 Background: The most aggressive breast cancer subtypes tend to be estrogen and progesterone receptor negative (ERPR(-)) and human epidermal growth factor receptor type 2 positive (HER2(+)). Women with these breast cancer subtypes (triple negative, ERPR(-)HER2(+)) tend to experience worse clinical outcomes and have a relatively higher risk of recurrence. Our previous research demonstrated that dietary omega-3 (n-3) fatty acids can significantly inhibit ERPR(-) HER2(+) tumorigenesis in MMTV-HER2/neu transgenic mice fed fish oil vs corn oil-based diets. The fish oil diet group developed 30% fewer breast tumors, had lower Ki67 expression, and experienced less mammary atypia relative to the corn oil diet group. Other studies involving diet, nutrition and breast cancer point to the potentially protective effect of an anti-inflammatory diet on the risk of developing ER(-) and HER2(+) breast cancer, further supporting the evidence that the ERPR(-), HER2(±) subtypes may be highly responsive to this bioactive nutrient. Methods: This is a double-blinded, randomized clinical trial of high dose (~5.4 g EPA+DHA) vs low dose (~0.9 g EPA+DHA in fatty acid mix of the typical American diet) of n-3 fatty acids in breast cancer survivors of ERPR(-), HER2(±) breast cancer. Eligible participants will take 5 capsules/day for 12 months, with cellular samples of breast epithelial and/or adipose tissue obtained by fine needle aspirations of the contralateral breast. The study aims to determine whether n-3 fatty acid supplementation will modify fatty acid metabolite content in breast adipose tissue, modulate cytomorphology and/or cell proliferation in breast epithelial cells, affect DNA methylation patterns, and modulate pro- vs anti-inflammatory gene expression patterns in breast adipose tissue. Correlative aims will evaluate possible associations between factors such as breast adipose tissue, red cell membrane fatty acid profiles, BMI, and reported dietary intake. Sample size of 40 participants per arm was calculated to provide at least 80% power to detect a statistically significant difference for each primary endpoint. This study focuses on women survivors of high risk breast cancer subtypes, specifically triple negative or ERPR(-)HER2(+) disease, who are currently without long term adjuvant options. Eligibility criteria include prior diagnosis of ERPR(-) stage 0 to III breast cancer, ≤5 years from completion of standard therapy.The study was closed to accrual in November 2018; less than 9 months of follow-up remain for active study participants. Clinical trial information: NCT02295059.
EORTC 1709/CCTG CE.8: A phase III trial of marizomib in combination with standard temozolomide-based radiochemotherapy versus standard temozolomide-based radiochemotherapy alone in patients with newly diagnosed glioblastoma.
Authors: Roth Patrick , Reijneveld Jaap C. , Gorlia Thierry , Dhermain Frederic , De Vos Filip Yves Francine Leon , Vanlancker Maureen , O'Callaghan Christopher J. , Le Rhun Emilie , Van Den Bent Martin J. , Mason Warren P. , Weller Michael 
Published: May 2019

TPS2072 Background: The standard treatment for patients with newly diagnosed glioblastoma comprises maximum safe surgery, radiotherapy (RT), and concomitant and up to six cycles of maintenance temozolomide (TMZ) chemotherapy (TMZ/RT→TMZ). Despite this intense therapy, the prognosis remains poor and there is an urgent need to develop new therapeutic options. Marizomib is a novel, irreversible and brain-penetrant pan-proteasome inhibitor. Following its successful assessment in phase I trials in patients with newly diagnosed as well as recurrent glioblastoma, marizomib is now being investigated in a phase III trial. Methods: EORTC 1709/CCTG CE.8 is a multicenter, randomized, controlled, open label phase III superiority trial. Eligibility criteria include histologically confirmed newly diagnosed glioblastoma and a performance status ≥70. Approximately a total of 750 patients will be enrolled and randomized 1:1. Stratification factors include institution, age, Karnofsky performance status and extent of surgery. The primary objective of this study is to compare overall survival in patients receiving marizomib in addition to standard of care (TMZ/RT→TMZ) with patients receiving standard treatment only. The testing strategy specifies the determination of this objective in both the intent-to-treat population and the subgroup of patients with tumors harboring an unmethylated MGMT promoter. Secondary endpoints include progression-free survival, safety, neurocognitive function and quality of life. The study is accompanied by a translational research program. The study will be opened at 50 EORTC sites in Europe and done as an intergroup collaboration with the Canadian Cancer Trials Group (CCTG) with 25 sites in Canada and additional sites in the US. Patient enrolment started in June 2018 and as of January 29, 2019, a total of 85 patients have been randomized. An update on the enrolment status will be provided at the ASCO conference. Clinical trial information: NCT03345095.
A phase I/II study of nivolumab plus or minus ipilimumab in combination with multifraction stereotactic radiosurgery for recurrent high-grade radiation-relapsed meningioma.
Authors: Huang Jiayi , Campian Jian Li , Gao Feng , Johanns Tanner Michael , Desjardins Annick , Wang-Gillam Andrea , Rubin Josh 
Published: May 2019

TPS2073 Background: There is currently lack of effective therapy for meningiomas that have relapsed despite surgery and radiation therapy (RT). Reirradiation have been used in selected cases, but the long-term clinical outcomes remained poor, especially for high-grade meningiomas. Preclinical data have suggested synergy between hypofractionated radiosurgery with immune checkpoint inhibitors such as PD1 and CTLA4 inhibitors. The purpose of this study is to evaluate feasibility and preliminary clinical efficacy of combining reirradiation using hypofractionated radiosurgery with concurrent nivolumab (PD1 inhibitor) plus or minus ipilimumab (CTLA4 inhibitor) for recurrent high-grade meningiomas. Methods: During the phase I portion, eligible patients will be treated according to treatment-escalation schema following the modified 3+3 design (Table). The maximum tolerated combination (MTC) will be the regimen at which ≤1/6 patients experience dose-limiting toxicity within 8 weeks of the start of study therapy. During the phase II portion, a total of 24 evaluable patients will be enrolled at the MTC using Simon’s MiniMax two-stage design. Key eligibility criteria include patients with recurrent grade II-III meningiomas after prior RT; age ≥ 18 years; ECOG score ≤ 2; measurable disease but ≤ 5 cm (or 20 cm3); prior radiation dose ≤ 70 Gy with at least 6 months interval; normal organ function; no active autoimmunity. The primary endpoints are to determine the MTC (phase I) and the objective response rate of the MTC (phase II). Secondary endpoints include safety, duration of response, progression-free survival, overall survival. Exploratory endpoints include developing an immune or molecular signature for predicting treatment response and resistance. The trial is actively enrolling and funded by the National Cancer Institute Experimental Therapeutics Clinical Trials Network (NCI-ETCTN). Treatment Escalation Schema. Clinical trial information: NCT03604978. [Table: see text]
A phase III trial-in-progress comparing tislelizumab plus chemotherapy with placebo plus chemotherapy as first-line therapy in patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma.
Authors: Xu Rui-hua , Arkenau Hendrik-Tobias , Bang Yung-Jue , Denlinger Crystal S. , Kato Ken , Tabernero Josep , Wang Jin , Li Jiang , Castro Henry , Moehler Markus Hermann 
Published: May 2019

TPS2655 Background: In patients (pts) with locally advanced or metastatic G/GEJ cancer, fluoropyrimidine- and platinum (plt)-based combination chemotherapy is first-line standard of care. Despite improvement in chemotherapy regimens, outcomes are poor and survival remains low. Tislelizumab, an investigational anti-PD-1 antibody, was engineered to minimize binding of FcγR on macrophages in order to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. Previous reports suggested tislelizumab, as a single agent and in combination with chemotherapy, was generally well tolerated and had antitumor activity in pts with advanced solid tumors, including G/GEJ cancer. Methods: This global, double-blind, randomized, phase 3 study (NCT03777657) is designed to compare plt/fluoropyrimidine + tislelizumab versus plt/fluoropyrimidine + placebo as first-line therapy for pts with locally advanced or metastatic G/GEJ cancer. Approximately 720 pts from 160 centers will be randomized 1:1 to receive tislelizumab (200 mg IV Q3W) or placebo (IV Q3W) in combination with chemotherapy. Oxaliplatin (130 mg/m² IV Q3W) plus capecitabine (1000 mg/m2 orally twice daily for 2 weeks) or cisplatin (80 mg/m² IV Q3W) plus 5-fluorouracil (800 mg/m2/day IV on Days 1–5 Q3W) will be used as backbone chemotherapy on an individual basis. Chemotherapy will be administered for up to 6 cycles; capecitabine maintenance therapy is optional for pts who received capecitabine and oxaliplatin. PD-L1 expression will be assessed using the VENTANA PD-L1 (SP263) assay. Progression-free survival and overall survival are primary endpoints in the intent-to-treat and PD-L1-positive analysis sets of the study. Secondary endpoints include overall response rate, duration of response, quality-of-life outcomes, and the safety/tolerability profile of combination therapy. Exploratory endpoints include disease control rate, time to response, and an analysis of potential predictive biomarkers including, but not limited to, PD-L1 expression. Clinical trial information: NCT03777657.
JAVELIN BRCA/ATM: A phase 2 trial of avelumab (anti–PD-L1) plus talazoparib (PARP inhibitor) in patients with advanced solid tumors with a BRCA1/2 or ATM defect.
Authors: Hyman David Michael , Zelnak Amelia B. , Bauer Todd Michael , Ulahannan Susanna Varkey , Ford James M. , Cesari Rossano , Hoyle Margaret , Chappey Colombe , Stewart Ross , Conte Umberto , Yap Timothy A 
Published: May 2019

TPS2660 Background: Defects in DNA damage response genes, including BRCA1/2 and ATM, confer sensitivity to PARP inhibitors. Talazoparib is a potent, oral PARP inhibitor with a dual mechanism of action (PARP enzyme inhibition and PARP trapping). Avelumab is a human anti–PD-L1 IgG1 monoclonal antibody with a wild-type Fc region that has shown clinical activity in multiple tumor types. Preclinical and early clinical data suggest that combining a PARP inhibitor with an immune checkpoint inhibitor may provide improved activity. Methods: JAVELIN BRCA/ATM (NCT03565991) is an ongoing, open-label, multicenter, phase 2 trial assessing the combination of avelumab and talazoparib. Enrollment of ≈200 patients with a histologically confirmed locally advanced or metastatic solid tumor that has progressed on > 1 line of standard-of-care treatment for locally advanced or metastatic disease and has a germline or somatic defect in BRCA1 or 2 (cohort 1) or ATM (cohort 2) genes is planned. Patients with concomitant defects in > 1 gene ( BRCA1, BRCA2, or ATM) will be enrolled in cohort 1. Exclusion criteria include prior treatment with an immune checkpoint or PARP inhibitor, prior treatment with any other anticancer or radiation therapy within 2 weeks prior to enrollment, a known history of an immune-mediated or autoimmune condition, and known symptomatic brain metastases requiring steroids. The primary endpoint is confirmed objective response by blinded independent central review according to RECIST v1.1 and according to the Prostate Cancer Working Group 3 (PCWG3) for patients with metastatic castration-resistant prostate cancer (mCRPC). Secondary endpoints include safety; investigator-assessed confirmed objective response, time to tumor response, duration of response, and progression-free survival (per RECIST v1.1 and per PCWG3 for patients with mCRPC); overall survival; pharmacokinetic parameters; and potential predictive biomarkers. The study is currently enrolling patients at centers in the United States and Europe. Clinical trial information: NCT03565991.
Feasibility study of microbial ecosystem therapeutics (MET-4) to evaluate effects of fecal microbiome in patients on immunotherapy (MET4-IO).
Authors: Tan Tira Jing Ying , Butler Marcus O. , Hansen Aaron Richard , Hogg David , Sacher Adrian G. , Bedard Philippe L. , Ross Kendra , Chow Helen , Al-Kindy Aida , Boross-Harmer Sarah , Xu Wei , Coburn Bryan , Siu Lillian L. , Spreafico Anna 
Published: May 2019

TPS2664 Background: Differences in microbiome diversity and composition in immune checkpoint inhibitor (ICI)-responders vs non-responders have been demonstrated. Transplantation of responder feces in mouse models recapitulated the ICI-responsive phenotype. MET-4 is an oral alternative to fecal transplant consisting a well-defined mixture of intestinal bacteria isolated from healthy donor stool sample. We hypothesize that co-administration of MET-4 with ICI is safe and results in alterations of the gut microbiota. Methods: Three cohorts (n = 65) of subjects with any advanced solid tumor type treated with monotherapy anti- PD1/PD-L1 antibody outside of a therapeutic clinical trial will be enrolled. Group A: safety cohort of 5 subjects already on ICI will receive MET-4 in addition to standard of care (SOC) ICI. If < 2 subjects report adverse events of CTCAE grade ≥3 within 4 weeks at least possibly related to MET-4, this dose will be declared safe and groups B/C may start enrolling. Group B (n = 40): subjects with advanced solid tumors starting on ICI, randomized 3:1 to MET-4 plus SOC vs. SOC. Group C (n = 20): subjects with advanced solid tumors already on ICI with first unconfirmed disease progression randomized 1:1 to MET-4 plus ICI continuation vs. continuing ICI. Serial stool samples will be collected for taxonomic composition, diversity, metagenomics content and MET-4 species abundance. We anticipate the following analyses: 16S rRNA sequencing, shotgun metagenomics sequencing, qPCR, Nanostring nucleic acid detection and metabolomics profiling. Serial blood sampling for flow cytometry/CyTOF. Immune microenvironment of tumor specimen will be examined using immunohistochemistry. Other major inclusion criteria: willingness to provide correlative samples, RECIST v1.1 measurable disease and ECOG 0-2. Subjects unable to swallow oral medications are excluded. For the primary objective of cumulative relative abundance and changes of ICI-responsiveness associated species between baseline and day 12 MET-4, assuming a change of 0.5 standard deviation (SD) of microbial alpha diversity, our study will have ≥84% power to identify a significant difference given a significance level at 0.05 in group B. Assuming a change of 0.9 SD of microbial alpha diversity, we will have ≥83% power to identify a significant difference in group C. Response rates and progression free survival will be assessed per RECIST v1.1 and compared with historical data. Clinical trial information: NCT03686202.
Phase 1 trial of TLR9 agonist lefitolimod in combination with CTLA-4 checkpoint inhibitor ipilimumab in advanced tumors.
Authors: Reilley Matthew , Tsimberidou Apostolia Maria , Piha-Paul Sarina Anne , Yap Timothy A , Fu Siqing , Naing Aung , Rodon Jordi , Nguyen Ly Minh , Ager Casey , Meng Martin , Jayaprakash Priyamvada , Schmidt Manuel , Baumann Matthias , Meric-Bernstam Funda , Curran Michael A. , Hong David S. 
Published: May 2019

TPS2669 Background: Drugs targeting pathogen associated molecular patterns are an attractive strategy to stimulate the immune system. Toll-like receptors (TLR) have generated significant interest as an effective means of stimulating the immune system that result in the killing of tumor cells. TLR-9 agonists can function to promote an early immune response and are an appealing partner for combination with checkpoint blockade to improve immune activation. Lefitolimod (MGN1703) is a covalently closed dumbbell-shaped DNA molecule that functions as a TLR-9 agonist. We developed a clinical trial combining lefitolimod with ipilimumab (anti-CTLA4) in patients with advanced malignancies. In the dose-escalation phase 19 patients were enrolled and no DLTs were encountered. Safety data and maximum planned dose level of lefitolimod at 120mg weekly and ipilimumab 3mg/kg every 3 weeks was previously presented. Adverse events related to the combination included fatigue, appetite loss, rash, and anemia. Methods: This trial (NCT02668770) was designed to evaluate the safety profile and maximum tolerated dose of lefitolimod with ipilimumab. A 3+3 trial design was used to establish safety of the combination at each dose level and guide the decision to escalate dose. Lefitolimod is administered via subcutaneous (SC) injection weekly while ipilimumab is given at 3mg/kg intravenous on day 8 of each 3 week cycle. Lefitolimod starting dose was 15mg SC weekly with 3 dose level escalations up to 120mg SC weekly. Patients receive treatment for 4 cycles (total 12 weeks) with the combination, and those with stable disease or response were eligible to remain on lefitolimod therapy for up to 1 year. Eligible patients have a metastatic or unresectable solid tumor refractory to standard therapies, ECOG ≤ 2, and normal organ and bone marrow function. Patients are allowed to have received prior checkpoint blockade agents. Enrollment in expansion cohorts in ongoing. To better understand relevant immunologic changes associated with treatment, paired pre- and post-treatment biopsies of target lesions and peripheral blood collection during treatment is required for target expansion cohort patient populations. In addition to evaluating target patient populations at the combination dose established during escalation, an expansion cohort for patients with cutaneous metastases involves combination treatment with intratumoral delivery of lefitolimod. Clinical trial information: NCT02668770.
A phase I/II multiple expansion cohort trial of MRTX849 in patients with advanced solid tumors with KRAS G12C mutation.
Authors: Papadopoulos Kyriakos P. , Ou Sai-Hong Ignatius , Johnson Melissa Lynne , Christensen James , Velastegui Karen , Potvin Diane , Faltaos Demiana , Chao Richard C. 
Published: May 2019

TPS3161 Background: RAS proteins are part of the family of small GTPases which regulate intracellular signaling pathways responsible for cell growth, migration, survival and differentiation. Oncogenic point mutations in RAS in codons 12, 13, and 61 occur in up to one-third of all human cancers and result in constitutive activation of RAS signaling, playing a key role in uncontrolled cellular growth and malignant transformation. Mutant KRASG12C in particular comprises approximately 14% of lung adenocarcinoma and 4% of colon adenocarcinoma, and less commonly in certain other types of cancer. For decades, KRAS was considered undruggable due to its high affinity for GTP/GDP and the lack of a clear binding pocket. Recent discoveries have enabled the development of compounds, including MRTX849, that covalently bind to KRASG12C at the cysteine at residue 12, lock the protein in its inactive GDP-bound conformation, and inhibit KRAS-dependent signal transduction. MRTX849 is a potent, orally-available, mutation-selective small molecule covalent inhibitor of KRASG12C. MRTX849 inhibits KRASG12C signaling in cell lines harboring this mutation, and results in tumor regression in a broad spectrum of KRASG12C animal models. Methods: This multi-center, Phase 1/2, multiple expansion cohort trial evaluates the safety, pharmacokinetics (PK), metabolites, pharmacodynamics, and clinical activity of MRTX849 in patients with advanced solid tumor malignancies with a KRAS (p.G12C) mutation. The study starts with an evaluation of dose and regimen of MRTX849 using a combination of the accelerated titration and modified toxicity probability interval designs, with MRTX849 initially administered once daily in a continuous regimen expressed in 3-week cycles. As potentially viable regimens are identified, Phase 1b expansion cohorts will be opened to provide greater safety and PK data for determination of the recommended Phase 2 dose (RP2D) and regimen. In Phase 2, separate cohorts of patients by histological diagnosis, including non-small cell lung cancer, colorectal, and other solid tumors, will be enrolled and evaluated for clinical activity using a predictive probability design. The study is open for enrollment, and recruitment is ongoing. Clinical trial information: NCT03785249.