bluuebunny/crossref_metadata_2025_split huggingface dataset:
Insight into the brain metastasis journey: Initial survey results from patients and caregivers.
Authors: Willmarth Nicole , Elder Scott , Fine Avery , Ahluwalia Manmeet Singh , Barnholtz-Sloan Jill , Brastianos Priscilla Kaliopi , Brat Daniel , Mehta Minesh P. , Page Robin , DeVitto Ralph , Robins Debbie 
Published: May 2019

2069 Background: Brain metastases (BM) are the most common central nervous system tumors in the US. Though the exact incidence is unknown, BM are estimated to occur in up to 10-20% of all cancers. Despite the high frequency, there is little systematic knowledge about how BM are typically diagnosed and treated. The American Brain Tumor Association (ABTA) seeks to understand the BM journey: symptoms, diagnosis, treatment, and end of life, through a survey of BM patients and caregivers. Methods: Two surveys were developed by the ABTA with vendor, PSB Research, after careful literature review. The surveys were reviewed by a panel of clinicians who treat BM patients. Online survey research was conducted between 8/13-9/16/18, with one survey for adults with BM (N = 237) and another for caregivers (N = 211). Respondents came from PSB’s panels and ABTA collaborators: LUNGevity, Melanoma Research Foundation and the Kidney Cancer Association. Results: Ninety percent of patients, and a similar number of caregivers, were surprised by the diagnosis, with only 20% of patients knowing about BM before diagnosis. Most caregivers were the adult child of a patient. The impact of the diagnosis was primarily emotional. Top concerns after diagnosis, for both patients and caregivers, were likelihood of treatment success and impact on quality of life. Although a majority of patients were happy with the quality of information given, they stated a need to receive a greater quantity of information about treatment success and options. Only 30% of patients were referred to a patient advocacy organization. When referred, information on treatment success rates and options was most sought. Conclusions: Direct patient and caregiver feedback provides valuable insight towards understanding the BM journey and resources needed to support patients and caregivers. A subsequent survey among oncologists and other clinicians, planned for spring of 2019, will add to these findings.
A phase II trial of bevacizumab in patients with recurrent solid tumor brain metastases who have failed whole brain radiation therapy (WBRT).
Authors: Kumthekar Priya , Dixit Karan , Grimm Sean Aaron , Lukas Rimas Vincas , Schwartz Margaret A. , Rademaker Alfred , Sharp Laura , Nelson Valerie , Raizer Jeffrey J. 
Published: May 2019

2070 Background: Brain metastases (BM) are the most common intracranial malignancy with overall a poor prognosis estimated at approximately 4 months from time of initial diagnosis for treated patients, and even lower after failing WBRT after which treatment options have been limited and outcomes poor. Methods: This is an open label phase 2 study where patients who have previously failed WBRT received bevacizumab at a dose of 10 mg/kg intravenously every two weeks until CNS disease progression with one cycle being defined as 4 weeks. The primary endpoint was objective radiographic tumor response as defined by modified Response Assessment in Neuro-oncology (RANO) criteria. Secondary endpoints included progression free survival (PFS) at 6 months, time to progression, time to response, duration of response, overall survival (OS), quality of life (QOL) as measured by the FACT-G and FACT-Br and safety. Results: A total of 27 patients were consented and registered to study of which 24 were evaluable for ORR (3 came off study prior to first follow up MRI brain). Medianage was 53 (range 27-73), median number of cycles was 5.5 (range 1-20) with a median follow up of 8.7 months (range 2.4-47.9mo). Of the 24evaluable patients, there were 6 Partial response, 16 stable disease and 2progressive disease. The 6 month PFS: 46% (95% CI: 25% - 67%) and median PFS was 5.3 months. Median OS was 9.5 months (95% confidence interval 6.3m – 15.0m). For the patients who completed sequential QOL assessments, there was no significant decline in QOL but there was a nonsignificant improvement in the FACT-Br scores. Overall, treatment was well tolerated with 3grade 3 adverse events seen: hypertension (n = 3), headache (n = 1) and thrombotic event (n = 1). Conclusions: For this WBRT failure BM population, we were able to show a 25% disease response to bevacizumab therapy along with good drug tolerability and no noted central nervous system bleeding. Improved survival as compared to historical controls was seen 9.5 m. Of the 24 evaluable patients, 81% (22/24) experienced clinical benefit defined as stable disease or better. Bevacizumab therapy could be a viable option for solid tumor BM patients who experience progression following WBRT, however a larger trial is required to confirm this data. Clinical trial information: NCT01898130.
Phase I study of pembrolizumab in people with HIV and cancer.
Authors: Uldrick Thomas S. , Goncalves Priscila Hermont , Abdul Hay Mohammad Maher , Claeys Alisa J , Emu Brinda , Ernstoff Marc S. , Fong Lawrence , Kaiser Judith C , Kohrt Holbrook Edwin , Lacroix Andreanne , Lee Steve Young , Lundgren Lisa , Lurain Kathryn Anne , Parsons Christopher , Peeramsetti Sharavi , Ramaswami Ramya , Sharon Elad , Wang Chia-Ching Jackie , Yarchoan Robert , Cheever Martin A. 
Published: May 2019

2500 Background: People with HIV have been excluded from immuno-oncology (IO) studies. Anti- PD-1/PD-L1 therapies are approved for a growing number of cancers. We evaluated pembrolizumab (pembro) in people with HIV and cancer. Methods: CITN-12 is a multicenter phase 1 trial. Key eligibility: advanced cancer; ECOG ≤1; CD4 ≥100 cells/μL; ≥4 weeks antiretroviral therapy (ART), HIV viral load (VL) < 200 copies/mL. Exclusion: uncontrolled HBV/HCV, autoimmune disease. Participants (pts) accrued into CD4 based cohorts (C): C1 100-199; C2 200-350; C3 > 350 CD4 cells/μL. Pembro 200 mg IV administered Q3W for up to 35 doses. Adverse events (AE) evaluated by CTCAE. Immune related AE ≥ grade (Gr) 2 were events of clinical interest (irECI). Clinical benefit (tumor shrinkage or stable disease [SD] ≥24 weeks) was estimated. Data were locked for safety analysis and publication once C2 and C3 completed accrual and all pts completed ≥2 cycles. Accrual continued for 6 C1 pts and a new phase 1b Kaposi sarcoma (KS) cohort (C4). Results: 30 pts, characteristics: C1 (6), C2 and 3 (12 each), median (med) age 57 years (range 39-77), 28 men, 2 women, 60% White, 30% Black, 10% Hispanic. Med CD4 285 cells/μL (132 - 966). Cancers: KS (6), non-Hodgkin lymphoma (NHL) (5), non-AIDS defining (19) – most common: anal (6) and squamous cell skin (3). Prior radiation (19), med prior systemic therapies 2 (0-8). Safety observed over 183 cycles, med 5 (1-32). Treatment emergent AE ≥ possibly attributed to pembro mostly Gr 1-2, with 20% of pts having Gr 3. irECI: hypothyroidism (6), elevated AST/ALT (1), pneumonitis (3), rash (2), musculoskeletal (1).1 KS pt developed KSHV-associated multicentric Castleman disease (KSHV-MCD) and died of the AE. HIV was controlled and increasing CD4 counts were observed. Best response: complete (lung, 1), partial (NHL, 2), SD ≥24 weeks (KS, 2), SD < 24 weeks (13), progressive disease (10), not evaluable (2). Conclusions: Pembro has acceptable safety in cancer pts with HIV on ART and > 100 CD4 cells/µL, similar to patients without HIV. Anti-PD-1 may unmask KSHV-MCD and such KSHV-viremic patients should be excluded. Clinical benefit was noted in several tumor types. Anti-PD1 is appropriate for FDA-approved indications in this population. Patients with HIV meeting appropriate eligibility criteria should be included in IO studies. Clinical trial information: NCT02595866.
Determination of the recommended phase II dose of birinapant in combination with pembrolizumab: Results from the dose-escalation phase of BPT-201.
Authors: Schilder Russell J. , Albertella Mark , Strauss James Fredric , Sydvander Malin , Le Dung T. , Norin Stefan , Mita Monica M. , Boström Emma , Fu Siqing , Basse Linda , Bethell Richard 
Published: May 2019

2506 Background: Birinapant is a bivalent SMAC mimetic targeting cIAP1. Synergistic effects of combining birinapant with immune checkpoint inhibitors have been demonstrated in preclinical models. Based on these observations, a clinical trial with birinapant and pembrolizumab was initiated (NCT02587962). Methods: Patients ≥18 years with advanced solid tumors without further suitable standard therapeutic options were eligible for inclusion. Birinapant (5.6-22 mg/m2) was administered IV on day 1 and 8 in addition to pembrolizumab 200 mg on day 1 in a 21-day cycle until disease progression using standard 3+3 dose-escalation. The primary objective was to determine the safety and tolerability of the recommended phase 2 dose (RP2D) of birinapant in combination with pembrolizumab. Secondary and exploratory objectives included antitumor activity assessed by RECIST 1.1 and iRECIST, pharmacokinetics and assessment of biomarkers including serum cytokines, cIAP1, PD-L1 expression and tumor infiltrating lymphocytes. Results: Nineteen patients were enrolled at 4 dose levels of 5.6 (n = 3), 11 (n = 3), 17 (n = 6) and 22 (n = 7) mg/m2. Most common tumors were pancreatic (n = 5), colorectal (n = 4), ovarian (n = 3) and sarcoma (n = 3). Median prior therapies were 4 (0-12). The most common AE related to any of the study drugs was rash occurring in 3 patients. Ten patients had 17 SAE's of which only one (stomatitis) was judged related to birinapant. Increased ALT/AST (G3/G2) leading to missed day 8 dose constituted a DLT at 22 mg/m2. Grade 2 lipase increases were seen in 2 patients. No cases of Bell’s palsy were detected. ORR by RECIST 1.1 was 5.6% (n = 1) in 18 evaluable patients. The responding patient had microsatellite stable colorectal carcinoma (MSS-CRC)) and remains on therapy 13+ months after first dose. By iRECIST, ORR was 11.1%. CBR (PR+SD) by RECIST was 22.2%. The exposure to birinapant generally increased with dose. The RP2D was determined to be 22 mg/m2. Conclusions: Birinapant and pembrolizumab is a safe and tolerable combination that has shown encouraging signals of efficacy. A phase 2 study evaluating efficacy of this combination in MSS-CRC is ongoing. Clinical trial information: NCT02587962.
Phase Ib study of MIW815 (ADU-S100) in combination with spartalizumab (PDR001) in patients (pts) with advanced/metastatic solid tumors or lymphomas.
Authors: Meric-Bernstam Funda , Sandhu Shahneen Kaur , Hamid Omid , Spreafico Anna , Kasper Stefan , Dummer Reinhard , Shimizu Toshio , Steeghs Neeltje , Lewis Nancy , Talluto Craig C. , Dolan Sinead , Bean Andrew , Brown Robert , Trujillo Damian , Nair Nitya , Luke Jason J. 
Published: May 2019

2507 Background: MIW815 (ADU-S100) is a novel synthetic cyclic dinucleotide that activates the STimulator of INterferon Genes (STING) pathway impacting tumor cells, tumor microenvironment, vasculature, tumor-associated fibroblasts, and priming APC and CD8+ T cells. Spartalizumab is a humanized IgG4 mAb that blocks the binding of PD-1 to PD-L1/2. Preclinical data support synergistic antitumor effects when MIW815 (ADU-S100) is combined with checkpoint inhibitors. Methods: In this Phase Ib dose escalation study, pts with advanced/metastatic solid tumors or lymphoma received MIW815 (ADU-S100) (intratumoral injections [50–800 µg] either weekly [3 weeks on/1 week off] or Q4W) and spartalizumab (400 mg IV Q4W). Injected and non-injected tumor biopsies were obtained at baseline and on treatment. Primary objectives are to determine safety and identify a dose/schedule for future studies. Preliminary activity, pharmacokinetics (PK), and pharmacodynamics (PD) are also being explored. Results: As of Jan 11, 2019, 66 pts (median age: 61 y) with various solid tumors or lymphomas have been treated. Treatment was discontinued in 49 pts (74%) due to disease progression (n = 28), pt/physician decision (n = 18), AE (n = 2), or death (n = 1). No DLTs were reported during the first cycle at any dose level. Most common (≥5 pts) treatment-related AEs (TRAEs) were injection site pain (12%), pyrexia (11%), and diarrhea (9%). Grade 3/4 TRAEs (in ≥2 pts) were increased AST and ALT (3% each). Serious TRAEs were pyrexia (3%), increased amylase, increased lipase, diarrhea, fatigue, hyperthyroidism, partial seizures, dyspnea, and pneumonitis (all 2%). Partial responses in pts with PD-1–naive TNBC and PD-1–relapsed/refractory melanoma have been observed. MIW815 (ADU-S100) plasma exposure generally increased in a dose-dependent manner with a rapid terminal half-life. Response data, PK and PD analyses will be presented. Conclusions: Thus far, MIW815 (ADU-S100) + spartalizumab has demonstrated antitumor activity in PD-1–naive TNBC and PD-1–relapsed/refractory melanoma. The combination is well tolerated, with no DLTs reported to date. The MTD has not been reached and dose escalation is ongoing. Clinical trial information: NCT03172936.
First-in-human study of REGN3767 (R3767), a human LAG-3 monoclonal antibody (mAb), ± cemiplimab in patients (pts) with advanced malignancies.
Authors: Papadopoulos Kyriakos P. , Lakhani Nehal J. , Johnson Melissa Lynne , Park Haeseong , Wang Ding , Yap Timothy A , Dowlati Afshin , Maki Robert G. , Lynce Filipa , Ulahannan Susanna Varkey , Kelly Karen , Sims Tasha Nicholle , Bredlau Amy-Lee , Bramble Derrick , Gonzalez Ortiz Ana , Zhu Min , Chen Huanyu , Karasarides Maria , Kroog Glenn 
Published: May 2019

2508 Background: We present initial safety, pharmacokinetics (PK), and efficacy from the dose escalation study of R3767, alone (mono) or in combination with cemiplimab (REGN2810), a PD-1 mAb (combo), in pts with advanced malignancies (NCT03005782). Methods: Pts who had progressed on prior therapy(ies) and/or for whom no therapy with clinical benefit was available were enrolled; most pts had received no prior anti-PD-1/PD-L1. Pts received R3767 1, 3, 10, or 20 mg/kg every 3 weeks (Q3W) ± cemiplimab 3 mg/kg or 350 mg Q3W IV for ≤51 weeks. Crossover from mono to combo was allowed at progression. R3767 PK were evaluated. Tumor measurements were performed Q6W for the first 24 weeks and subsequently Q9W. Data cut-off date was Aug 25, 2018. Results: Mono: 27 pts (median age: 66 yr; ECOG PS: 0 [n=4], 1 [n=23]) were treated. There were no dose-limiting toxicities (DLTs). The most common treatment-emergent adverse event (TEAE) was nausea (22.2%). Grade ≥3 immune-related adverse events (irAEs) of increased alanine and aspartate aminotransferases (each 3.7%) were reported. By investigator-assessment (per RECIST 1.1; INV), best response was stable disease in 11 pts. Combo: 42 pts (median age: 60 yr; ECOG PS: 0 [n=15], 1 [n=27]) were treated. One pt treated with R3767 3 mg/kg Q3W + cemiplimab 3 mg/kg Q3W experienced DLT of grade 4 elevated blood creatine phosphokinase, associated with grade 3 myasthenia syndrome and grade 1 elevated troponin. The most common TEAEs were fatigue (33.3%) and nausea (21.4%). Grade 3 irAE of hypothyroidism (2.4%) was also reported. By INV, 2 (both small cell lung cancer) combo pts and 2 (endometrial cancer and cutaneous squamous cell carcinoma) of 12 additional pts who crossed over from mono to combo had partial responses. PK: R3767 concentrations in serum increased in a dose-dependent manner and were unaffected by combo. Conclusions: The safety profile of R3767 ± cemiplimab was generally tolerable; PK was linear. Early efficacy signals were detected despite the difficult-to-treat pt population. Biomarker studies are ongoing. R3767 20 mg/kg or 1600 mg fixed dose equivalent Q3W as mono and combo were selected for further evaluation. Clinical trial information: NCT03005782.
Phase I trial of Claudin 18.2-specific chimeric antigen receptor T cells for advanced gastric and pancreatic adenocarcinoma.
Authors: Zhan Xianbao , Wang Bin , Li Zonghai , Li Jie , Wang Huamao , Chen Longpei , Jiang Hua , Wu Meihong , Xiao Jun , Peng Xiaobo , Ma Hong , Feng Dan , Wang Dakun , Fu Qiang , Wang Mei , Shen Fengping , Hao Qiang , Zhang Linli , Xu Jing , Zhang Yingyi 
Published: May 2019

2509 Background: As a promising approach for some cancers, chimeric antigen receptor T cell therapy has limited success in solid tumors. Claudin18.2 (CLDN 18.2) is a stomach-specific isoform of Claudin-18, and highly expressed in gastric and pancreatic adenocarcinoma, the advanced form of both of which have urgent unmet medical needs. We previously developed and demonstrated ability of CLDN 18.2-specific CAR (CAR-CLDN18.2) T cells to eradicate CLDN 18.2-positive gastric cancer xenografts without obvious on-target off-tumor toxicity (Huang J. JNCI 2018). Methods: In this single-arm, open-label, first-in-human phase I pilot study (NCT03159819) to investigate the safety and explore the efficacy of the autologous CAR-CLDN18.2 T cells, patients with confirmed CLDN 18.2 positive advanced gastric or pancreatic adenocarcinoma aged 18 to 70 years received 1 or more cycles of CAR-CLDN18.2 T cell infusion(s) after lymphodepletion pretreatment (fludarabine and cyclophosphamide, with or without nab-paclitaxel) until disease progression or presence of intolerable toxicity. Adverse Event (AE) grade categorization is according to CTCAE 4.0, and tumor response was assessed per RECIST 1.1. Results: As of November 30th, 2018, 12 subjects with metastatic adenocarcinoma (7 gastric and 5 pancreatic) were treated with 1–5 cycles (total of 0.5 - 55 X 108) of CAR-positive T cells infusions. There were no serious adverse events, treatment-related death or severe neurotoxicity occurred in the study. No grade 4 AEs except for decreased lymphocytes, neutrophils and white blood cells. All cytokine release syndromes observed were grade 1 or 2. Among the 11 evaluable subjects, 1 achieved a complete response (gastric adenocarcinoma), 3 had partial responses (2 gastric adenocarcinomas and 1 pancreatic adenocarcinoma), 5 had stable disease and 2 had progression of disease. The total objective response rate was 33.3%, with median PFS of 130 days estimated using Kaplan-Meier method [95% CI (38, 230)]. Conclusions: This clinical study indicated that CAR-CLDN18.2 T cell therapy were safe and well tolerated and may have promising therapeutic efficacy in patients with advanced gastric and pancreatic adenocarcinoma. Clinical trial information: NCT03159819.
CX-072, a PD-L1 Probody therapeutic, as monotherapy in patients with advanced solid tumors: Preliminary results of PROCLAIM-CX-072.
Authors: Naing Aung , Thistlethwaite Fiona C. , Spira Alexander I. , Garcia-Corbacho Javier , Randhawa Manreet , Eskens Ferry , O'Neil Bert , Lavernia Javier , Uboha Nataliya Volodymyrivna , Hamid Omid , El-Khoueiry Anthony B. , Benson Beverly A. , Garner William , Huels Vanessa Jessica , Arkenau Hendrik-Tobias , LoRusso Patricia 
Published: May 2019

2513 Background: Anti-programmed cell death ligand 1 (PD-L1) immunotherapies have improved survival in many cancers, but immune-related adverse events (irAEs) have been observed, especially in combination therapy. CX-072 is an investigational Probody therapeutic directed against PD-L1, designed to be preferentially activated in the tumor microenvironment and to reduce irAEs. Methods: This is an ongoing phase 1/2a study (PROCLAIM-CX-072; NCT03013491) evaluating CX-072 in patients (pts) with metastatic or unresectable solid tumors with no further standard curative treatment options and with no prior anti-PD1, PD-L1 or anti-CTLA4 treatment. Pts were unselected for PD-L1 expression. We report preliminary results from expansion cohorts in anal squamous cell carcinoma (SCCA), cutaneous squamous cell carcinoma (cSCC), small bowel adenocarcinoma (SBA), triple-negative breast cancer with skin lesions (TNBC), or undifferentiated pleomorphic sarcoma (UPS). Pts were treated with CX-072 monotherapy 10 mg/kg intravenously every 14 days. Results: As of 30 Nov 2018, 51 pts received CX-072 10 mg/kg monotherapy: SCCA (n = 9), cSCC (n = 5), SBA (n = 9), TNBC (n = 9), and UPS (n = 19). Median age was 63 y (range, 32-80), 67% were female, and pts had a median of 3 prior regimens (range, 1-12). Median treatment duration was 1.8 mo (range, 0.3-14.7). A grade 3/4 treatment-related adverse event (AE) was observed in 1 pt (2%; gr 3 generalized rash). No grade 3/4 irAEs were observed. Two pts discontinued treatment due to AEs: nausea (pt with SCCA) and sepsis (pt with SBA), neither treatment-related. Partial responses (confirmed and unconfirmed) were observed in cSCC (n = 1), TNBC (n = 2), and UPS (n = 1) (Table). Conclusions: CX-072 10 mg/kg monotherapy demonstrated anticancer activity in heavily pretreated pts with advanced solid tumors, including responses in cSCC, TNBC with skin lesions, and UPS, with a safety profile that compares favorably to historical controls. Clinical trial information: NCT03013491. [Table: see text]
Regorafenib plus nivolumab in patients with advanced gastric (GC) or colorectal cancer (CRC): An open-label, dose-finding, and dose-expansion phase 1b trial (REGONIVO, EPOC1603).
Authors: Fukuoka Shota , Hara Hiroki , Takahashi Naoki , Kojima Takashi , Kawazoe Akihito , Asayama Masako , Yoshii Takako , Kotani Daisuke , Tamura Hitomi , Mikamoto Yuichi , Sugama Ayako , Wakabayashi Masashi , Nomura Shogo , Sato Akihiro , Togashi Yosuke , Nishikawa Hiroyoshi , Shitara Kohei 
Published: May 2019

2522 Background: Immune suppressive cells such as regulatory T cells (Tregs) or tumor-associated macrophages (TAMs) may contribute to resistance to anti-PD-1/PD-L1 inhibitors (A-PD1). Regorafenib, a potent inhibitor of angiogenic and oncogenic kinases, reduced TAMs in tumor models. The combination of regorafenib plus A-PD1 exhibited superior tumor growth suppression compared to either treatment alone in murine models. Methods: In this study, we enrolled patients (pts) with previously treated, advanced GC or CRC. The pts received regorafenib plus nivolumab in a dose-finding phase to estimate the maximum tolerated dose (MTD). Additional pts were enrolled in a dose-expansion phase to further establish the safety and determine the preliminary efficacy. Regorafenib of 80 to 160 mg was administered once daily for 21 on 7 days off with intravenous nivolumab 3 mg/kg every 2 weeks. The primary endpoint was dose-limiting toxicity (DLT) during cycle one (4 weeks) to estimate the MTD and the recommended dose. Results: Fifty pts were enrolled (25 GC; 25 CRC) until October 2018. The median prior treatment line was 3 (range 2-8). During dose-escalation, 3 DLTs were observed with regorafenib 160 mg, including grade (G) 3 maculopapular rash, mucositis and proteinuria, while there was no DLT with 80 or 120 mg. In the dose expansion cohort with regorafenib 120 mg, the dose was reduced to 80 mg owing to frequent G3 skin toxicities. Grade ≥ 3 treatment related adverse events occurred in 17 pts; the common events ( > 5%) being rash (14%), palmar-plantar erythrodysesthesia (10%), and proteinuria (8%). Objective tumor response was observed in 19 pts (38%) including 11 MSS GC, 7 MSS CRC and 1 MSI-H CRC for response rates of 44% in GC and 29% in MSS CRC. Three of the 7 A-PD1 pretreated GC pts achieved a partial response. The pre- and post-treatment tumor samples showed a reduction of FoxP3hiCD45RA-Tregs fraction at the tumor response. Conclusions: The combination of regorafenib 80mg plus nivolumab had a manageable safety profiles and encouraging anti-tumor activity in MSS GC and CRC pts, which warrants further investigations in a larger cohort. Updated biomarker analysis will be presented. Clinical trial information: NCT03406871.