bluuebunny/crossref_metadata_2025 huggingface dataset:
Staccato pulse interleukin-2 (IL-2) in metastatic melanoma (MM) previously treated with checkpoint inhibitors (CPI).
Authors: Quan Walter , Gutierrez Leah I , Quan Kyle , Quan Francine Marie
Published: May 2019

e21022

Background: The CPI ipilimumab, nivolumab, and pembrolizumab have been adopted into common use for patients (pts) with MM. While their clinical activity is undeniable, a substantial fraction of pts treated with these agents experience disease progression. Additional approaches are therefore needed. Intravenous IL-2 given via daily single intravenous infusions (pulses) has been developed to mitigate toxicity while maintaining anticancer activity against MM. Staccato pulse IL-2 is based on three prior observations. Daily IL-2 schedules have previously been demonstrated to induce Lymphokine Activated Killer cell (LAK) activity [Mitchell, 1989]. LAK generated by IL-2 then subsequently exposed to more IL-2 display enhanced cytotoxicity in vitro [Hank, 1990]. Increased numbers of LAK are seen in pts with melanoma treated with daily IL-2 [Quan, 2011]. Methods: In this retrospective study, ten pts with MM were treated with IL-2 18 Million IU/M2 intravenously over 15-30 minutes on days 1-3 and 21.6 Million IU/M2 intravenously over 15-30 minutes on day 5 on an outpatient basis. Cycles were repeated every 3 weeks. Results: Characteristics: 8 females/ 2 males, median age-56 (range: 21-74), median ECOG-1 (0-1); common disease sites: lymph nodes (12), subcutaneous (6), lungs (5), soft tissue (4). Prior CPI: Ipilimumab (8); Pembrolizumab (5); Nivolumab (2). Common toxicities: nausea/emesis (8), myalgia/arthralgia (5), sinus/catarrhal symptoms (5), fatigue (5), and hypotension requiring intravenous fluids (5). No pts required hospitalization for toxicity related to therapy. Median number of cycles: 3 (2-8). Four pts have had partial responses (total response rate = 40%; 95% CI: 10-70%). The median duration of response exceeds 7.4+ months. One pt having had resolution of prior lung, lymph node, and peritoneal metastases (partial response of 24.5+ months) underwent surgical resection of the residual intraabdominal disease focus and is free of disease at 36.5+ months. Overall, responses have occurred in lung, lymph nodes, subcutaneous, bones, peritoneum, small bowel, and soft tissue sites. Conclusions: Staccato pulse intravenous IL-2 has activity in melanoma pts previously treated with CPI.
Real-world outcomes of advanced melanoma patients treated with pembrolizumab who have failed prior lines of therapy.
Authors: Ou Wanmei , Taymor Emilie , Diede Scott J. , Whitman Eric D.
Published: May 2019

e21031

Background: Pembrolizumab (PEM), a humanized antibody targeting programmed death-1 receptor, has been approved by FDA for the treatment of patients (pts) with advanced melanoma (AM) in the US since 2014. Real-world (RW) data supports the clinical effectiveness of 1L use of PEM, but there is limited information of PEM later line use. The study examined the RW outcomes of pts treated with PEM who have failed prior lines of therapy in US oncology clinical practices. Methods: Flatiron Health longitudinal database was used to identify adult pts with AM who received ≥1 dose of PEM in second line (2L) or later (3L+) between September 4, 2014 and May 31, 2017. Pts were followed up to May 31, 2018. Pts in clinical trials were excluded. Pt demographic, treatment, and clinical characteristics were described. Time on treatment (ToT) and overall survival (OS) were analyzed using the Kaplan Meier (KM) method, with the first dose of PEM as the starting point. Results: Two hundred thirty-six pts were included in the analysis, of which there were 171 2L and 65 3L+. Overall, median age at PEM initiation was 66 years; most were male (66.1%) and Caucasian (95.4%). 41.1% of pts’ tumors were confirmed BRAF mutant; 49.6% of pts’ tumors were confirmed BRAF wildtype; the rest was not tested or indeterminate. When data were available, 26.2% had an elevated lactate dehydrogenase (> ULN), 24.6% had brain metastases, and 25.5% had an ECOG performance status of > 1. At the time of analysis, pts were followed for a median of 12.5 months (mo, range, 0.1-44.6). Overall median ToT was 4.4 mo (95% CI, 3.5-5.3), with 4.7 and 4.4 mo in 2L and 3L+, respectively. Overall median OS was 16.8 mo (95% CI, 12.2-25.9), with 16.8 and 18.9 mo for 2L and 3L+ respectively. 1-year and 2-year survival, using the KM method, was 58.0% (95% CI, 51.2-64.1; 2L, 57.4%; 3L+, 59.6%) and 44.7% (95% CI, 37.9-51.3; 2L, 44.3%; 3L+, 46.1%) respectively. Conclusions: The study reports RW use of PEM in a large cohort of pts with AM who have failed initial therapy in US oncology clinical practices, with a heterogeneous study population compared to clinical trials. The findings of OS based on RW use suggest PEM is an effective treatment option for patients in later lines of therapy.
Markers of melanoma progression in the blood serum structure.
Authors: Shikhlyarova Alla I. , Kit Oleg I. , Shatokhina Olga N. , Akhmedova Amira A. , Przhedetskiy Yury Valentinovich , Pozdnyakova Viktoria V. , Khokhlova Olga V. , Przhedetskaya Viktoria , Lysenko E. P. , Goncharova Anna S. , Zhadobina Anastasia I. , Zhukova Galina V.
Published: May 2019

e21035

Background: Lack of prognostic markers of melanoma to assess its progression, metastasis (MTS), and treatment effectiveness, determines the feasibility of studying biophysical aspects of the transmission of events from cellular to extracellular environment. Receipt and circulation of pathological proteins of melanoma (M) in the blood carries important information, and its trap is the phase transition of biofluids into a solid state. The purpose of the study was to determine markers of melanoma at the supramolecular level in solid-state samples of the blood serum (BS). Methods: 240 samples of BS obtained prior to the surgery from 60 patients with M were studied. The preparations were prepared by the Shatokhina-Shabalin method by creating a closed "analytic cell": dehydration of a BS drop (10 mcL) under a cover glass at 20–240С, humidity 65–70%, for 72 hours. The folding of M proteins was assessed by a polarized light microscopy (Leica DM LS2 microscope, x400-640) using photo and video control and the Morphotest program. Results: The initial stages of M development were characterized by the early appearance of single combined melanoform crystals — anisotropic microspherolites (Mi) embedded in the center of a large anisomorphone (lAM). As M progressed, Mi aggregation with basic lAMs was enhanced. Anisotropy of Mi increased, revealing clear sectors filled with melanin. In the later stages of M growth, melanoform aggregations dominated with point, filamentous, and chained melanin structures. The manifestation of MTS was accompanied by the destruction of the aggregations and the filling of the analytic cell space with numerous Mi. Conclusions: Correspondence of crystallogenesis of M melanomorphic markers in BS in tumor progression allows using the studied supramolecular factors to predict the development of melanoma.
Prognostic differences and the effect of radiotherapy on survival in Merkel cell carcinoma: A retrospective analysis of a Swedish cohort.
Authors: Bjorn-Andtback Hannah , Masucci Giuseppe V. , Björnhagen-Säfwenberg Viveca , Lui Weng-onn , Villabona Lisa Elena Esther
Published: May 2019

e21047

Background: Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin cancer. The pathogenesis is linked to the immune system and Merkel cell polyoma virus (MCPyV) is present in about 80% of MCC. Reports have shown that patients with a virus-negative MCC have a worse prognosis. Adjuvant radiotherapy given after surgery has previously been shown to give a survival benefit in retrospective data. Our aim is to analyze clinical variables and their prognostic impact in a Swedish cohort. Methods: All patients with confirmed diagnosis of MCC referred to Karolinska University Hospital in Sweden from 1989-2018 were included and retrospective data was collected. Results: 113 patients were included. Median age at operation was 75.4 years (range 19-99); 64 (57%) were female. Treatment included surgery with (n = 46) or without adjuvant radiotherapy (RT). 43% of female patients and 37% of male patients received RT. Median overall survival (OS) was 2,6 years (range 0,1-25,8), for female patients 3,4 years (range 0,1-25,8) and for male patients 1,8 years (range 0,1-19,0). Median OS in surgery group was 1,8 years (range 0,4-25,8). With adjuvant RT median OS improved with 1,7 years (p = 0,0001) to 3,5 years (range 0,2-22,1), for female patients 4,0 years (range 0,2-22,1) and for male patients 2,0 years (range 0,3-8,8). MCPyV status was available in 53 patients. 74% were MCPyV positive, 26% negative. MCPyV gave no difference in OS, however when gender was added in to multivariate analysis, female patients with virus negative disease had better outcome than virus negative males (p = 0.03). In virus positive MCC there was no difference in OS between female and male patients. Conclusions: Our data confirms the positive impact of adjuvant radiotherapy on survival and illustrates the difference in outcome between female and male patients, with women having a better outcome. In the MCPyV group the tendency is that men with virus negative MCC has the worst outcome. Our findings indicate that MCPyV positive and negative MCC act as two different diseases and it also raises questions if there is a difference in the disease itself or the immune response towards MCC between male and female patients.
Tumor growth rate as an early indicator of the efficacy of anti-PD-1 immunotherapy in advanced melanoma.
Authors: Tang Bixia , Chi Zhihong , Sheng Xinan , Si Lu , Cui Chuanliang , Kong Yan , Yan Xieqiao , Li Siming , Mao Lili , LIAN BIN , Wang Xuan , Bai Xue , Zhou Li , Dai Jie , Guo Jun
Published: May 2019

e21050

Background: As immunotherapeutics take longer time to show clinical efficacy compared with chemotherapy and targeted therapy, it is critical to select patients with low tumor growth rate (TGR) prior immunotherapy as to get sufficient time for immunotherapeutics to play functions. However, which threshold of TGR before immunotherapy may be associated with good outcome remains unknown. Methods: Medical records from patients with advanced refractory melanoma prospectively treated in clinical trials (NCT02836795 and NCT03013101) of anti-PD-1 antibody toripalimab were analyzed. TGR was computed during the pretreatment period (reference) and the treatment period (treatment). Associations between TGR and objective response at the first evaluation, progression free survival (PFS), overall survival (OS) were computed. Results: We analyzed a total of 142 patients enrolled in these two clinical trials. Excluded for no measurable lesions in pretreatment period or incomplete imaging data through the pretreatment/treatment periods, a total of 90 patients could be explored for the relationship of TGR and the efficacy of anti-PD-1 antibody. TGR and hyperprogression were defined as Champiat S. used to make. The distribution of TGR is as follows: median 63.7 (range: -51~720). A total of 15 (16.7%), 41 (45.6%), 34 (37.8%) and 0 patients exhibited PR, SD, PD, CR, respectively. An association between lower TGR (TGR ≤55) and objective response was observed (P≤0.001). Among evaluable patients at week 8, 83.9% (13+34/56) and 26.5% (2+7/34) showed PR/SD from baseline tumor measurements for the group of TGR≤55 and TGR > 55, respectively. Median PFS was 5.5 0.9m in the group of TGR≤55 compared 1.8 0.4m in the group of TGR > 55 (P≤0.001). Median OS was not reached in the group of TGR≤55 group and was 15.9 1.8m in the group of TGR > 55 (p = 0·02). Two patients were confirmed pseudoprogression in the follow-up. The TGR of these two patients was lower than 55. Five patients experienced hyperprogression. The TGR of each patient was 9, 12, 54, 56, 78, respectively. Conclusions: Melanoma patients with TGR≤55 prior anti-PD-1 antibody therapy are more likely to benefit from this regimen. However, it could not predict patients who may develop hyperprogression after anti-PD-1 antibody therapy. Clinical trial information: NCT02836795 and NCT03013101.
Ingenol mebutate to treat lentigo maligna of the head (face and scalp): A prospective and multicenter single-arm phase 2 trial.
Authors: Montaudié Henri , Le Duff Florence , Butori Catherine , Hofman Veronique , Fontas Eric , Roger Coralie , Bahadoran Philippe , Perrot Jena-Luc , Desmedt Eve , Legoupil Delphine , Passeron Thierry , Lacour Jean-Philippe
Published: May 2019

e21051

Background: Ingenol mebutate gel is indicated for the treatment of actinic keratoses. In vitro, it has been shown that ingenol mebutate can induce the apoptosis of melanoma cells, but robust clinical data are missing with only few case reports reported.The objectives of the current study was to assess the efficacy and safety of ingenol mebutate for the treatment of lentigo maligna (LM). Methods: We conducted a prospective, multicentre, and single-arm phase 2 trial (NCT02723721), from June 2016 to November 2017. This trial was planned according to Simon’s optimal two-stage design for a total sample size of 23 subjects. Adults with LM of the head were included. Ingenol mebutate gel 150 µg/g was applied daily for 3 consecutive days (one cycle). For patients having no remission or only partial remission at 2 months, a second cycle was done. Patients were evaluated 2 months after the (re)treatment and then every 3 months for 36 months if a complete response (CR) was obtained. The primary endpoint was the CR, defined as the complete clearing of the LM evaluated at 2 months clinically and histologically. Results: Twelve patients with a median age of 73 years were recruited. Only 2 achieved a CR; one patient relapsed during the first year following the treatment. Forty-seven adverse events related to ingenol mebutate were declared. Most were grade 3-4 (66%), but all were resolved without any sequelae. The mean maximum local skin reaction score was 12 (min: 3 – max: 22). These results should be interpreted with caution, because this study has limitations, such as the lack of a comparative arm and the heterogeneity of LM (size and localization). Conclusions: To our knowledge, we report the first prospective study evaluating the efficacy and safety of IM in patients with LM of the head. Unfortunately ingenol mebutate is not an effective treatment of LM in this indication at the concentration of 150 µg/g. Its use with a more intense regimen (more cycles and/or highest concentration (500 µg/g)) is also limited by a poor safety profile. Clinical trial information: NCT 02723721.
Somatic mutational profile of Merkel cell carcinoma treated with immune checkpoint blockade: Preliminary results from a planned multiplatform analysis.
Authors: Rosenbaum Evan , Kelly Ciara Marie , Barker Christopher Andrew , Adamson Travis , Kiesler Hannah , Hundal Jasreet , Paul Alexander J. , McLellan Michael D. , Walker Jason , Tap William D. , Coit Daniel G. , D'Angelo Sandra P.
Published: May 2019

e21064

Background: Merkel cell carcinoma (MCC) is an immunogenic neuroendocrine malignancy with promising responses to immune checkpoint blockade (ICB). Although ICB is standard of care in advanced MCC patients, approximately 50% of patients are resistant to ICB. Thus, it is crucial to identify biomarkers predictive of response. Methods: To understand the genomic landscape of MCC, we performed exome capture sequencing on 27 tumor and matched normal samples from 25 patients with MCC treated at Memorial Sloan Kettering. Herein, we report the analysis of 16 paired samples from 14 patients. Nonsynonymous, high-confidence somatic mutations were identified and tumor reads aligned to the Merkel cell polyoma virus (MCPyV) were quantified. Results: Tumor and matched normal samples were sequenced to a median target coverage depth of 53x and 79x reads, respectively. One sample was not analyzed due to inadequate coverage. The MCPyV genome was detected in 12 of 13 patients (92%). The median somatic mutation burden among analyzed samples was 19 nonsynonymous variants per exome (range: 8 - 120). No recurrent driver mutations were identified in any sample. Four samples lacked potential driver mutations and, among the remaining 11 samples, 36 putatively oncogenic mutations were detected in 33 genes (variant allele frequency: 0.08 – 1), including genes involved in the cell cycle checkpoint ( TP53, RB1), DNA damage repair ( ERCC4, FANCA, FANCD2), PI3K-AKT-mTOR ( PIK3CA, PIK3CG), and Notch ( NOTCH1, NOTCH2) pathways. One sample with undetected MCPyV DNA demonstrated loss of heterozygosity of both TP53 and RB1. Four samples contained strand coordinated clusters of mutations in more than 20 distinct gene regions, suggesting an APOBEC-high mutagenesis signature. Conclusions: The MCPyV genome was detected in most tumors analyzed and tumor mutation burden was low in such tumors, consistent with published literature. Analysis of an additional 11 sample pairs is ongoing, along with personalized neoantigen binding predictions on all samples. Immunohistochemistry (IHC) for PDL1 and CD8 expression is in progress. Associations between the aforementioned and response to ICB will be reported.
INFORM2 exploratory multinational phase I/II combination study of nivolumab and entinostat in children and adolescents with refractory high-risk malignancies: INFORM2 NivEnt.
Authors: van Tilburg Cornelis Martinus , Witt Ruth , Pajtler Kristian W. , Christoph Plass , Poschke Isabel , Platten Michael , Harting Inga , Sedlaczek Oliver , Freitag Angelika , Meyrath David , Taylor Lenka , Balasubramanian Gnana Prakash , Jäger Natalie , Pfaff Elke , Worst Barbara Christine , Milde Till , Pfister Stefan M. , Jones David T. W. , Kopp-Schneider Annette , Witt Olaf
Published: May 2019

TPS10065

Background: Immune checkpoint inhibition in children has shown limited success rates until now. This is most likely due to the fact that the vast majority of pediatric cancers are so-called immunologic cold tumors, and that patients have been enrolled in an unselected manner in single agent trials. Recently, it has been shown that the class I selective HDAC inhibitor entinostat has significant immune enhancing activity in vitro and in vivo. This is mediated through multiple mechanisms including depletion of myeloid-derived suppressor cells, activation of neoantigen transcription and increase of MHC expression. Methods: INFORM2 NivEnt is an exploratory nonrandomized, open-label, multinational and multicenter seamless phase I/II basket trial of nivolumab and entinostat in children and adolescents with relapsed, refractory or progressive high-risk solid and CNS tumors. Patients aged 6-21 will be allocated to the following biomarker-defined groups: high mutational load ( > 100 somatic SNVs/exome; group A), high PD-L1 mRNA expression (RPKM > 3; group B), focal MYC(N) amplification (group C), low mutational load and low PD-L1 mRNA expression and no MYC(N) amplification (Biomarker low group D). Phase I determines the recommended phase 2 dose for the combination for the age groups 6-11 and 12-21 years. Patients will receive nivolumab 3mg/kg every 2 weeks. Entinostat has 2 dose levels: 2mg/m2 and 4mg/m2 once per week. Patients can seamlessly enter the phase II which investigates activity (defined as best response during the first 6 cycles) in the 4 biomarker groups A-D. The duration of treatment is 12 cycles, preceded by 1 entinostat priming week. Interim analyses for futility will be performed after every 10 patients in each group. The study will enroll a maximum of 128 patients in Germany, The Netherlands, Sweden, France, Australia and additional countries under discussion. A comprehensive accompanying biomarker program will investigate a series of immune and epigenetic pharmacodynamic biomarkers. Clinical trial information: NCT03838042.
EMERALD: A randomized, open label, phase III trial to evaluate the efficacy and safety of elacestrant (RAD1901) versus investigator’s choice (IC) of endocrine therapy (ET) for ER+/HER2- advanced breast cancer (BC) following CDK4/6 inhibitor (CDK4/6i) therapy.
Authors: Bardia Aditya , Aftimos Philippe Georges , Jiang Hai , Bihani Teeru , Anderson-Villaluz Alfred T , Conlan Maureen G. , Kaklamani Virginia G.
Published: May 2019

TPS1104

Background: Estrogen receptor-positive (ER+) BC comprises ~70% of all BC and advanced/metastatic ER+ disease (mBC) remains a major clinical challenge. The addition of CDK4/6i to ET has improved progression-free survival (PFS); however, novel treatments are needed after progression. Putative mechanisms of endocrine resistance, such as ESR1 mutations (mESR1), also indicate the need for additional therapies. Elacestrant, an oral selective estrogen receptor degrader (SERD), demonstrated anti-tumor activity in preclinical models of ER+ BC, including models resistant to CDK4/6i and models with mESR1. An interim evaluation of a phase 1 trial ( NCT02338349 ) of elacestrant in heavily pretreated patients (pts) with mBC, demonstrated an overall response rate (ORR) of 27% with a PFS of 5.4 mo (Bardia, SABCS, 2017). Responses were seen in pts with prior CDK4/6i and with wild-type (WT) or mESR1. Methods: This is a multicenter, international, randomized, open-label, active-controlled phase 3 trial for post-menopausal women or men with mBC. Pts must have received 1-2 prior lines of ET, ≤1 line of chemotherapy for mBC, and have documented progression on a CDK4/6i. Pts with measurable disease (RECIST v1.1) or bone-only disease are eligible. Pts are randomized 1:1 to elacestrant (400 mg orally daily) or IC of fulvestrant or an aromatase inhibitor. Stratification factors include ESR1 mutation status (detected by ctDNA), prior fulvestrant treatment and presence of visceral disease. The primary endpoints are PFS by blinded independent review committee (IRC) in pts with mESR1 and in all pts (WT or mESR1). Secondary endpoints include: overall survival; PFS by IRC in WT, PFS by investigator review; ORR, duration of response, and clinical benefit rate; safety; pharmacokinetics; and quality of life. Approximately 466 pts will be enrolled to detect 340 PFS events in all pts (power ≥90%, hazard ratio (HR) = 0.667) and 160 PFS events in the mESR1 subset (power ≥80%, HR = 0.610), overall α level at 2-sided 5% using the Hochberg procedure. The EMERALD study is open for enrollment. Clinical trial information: NCT03778931.
A multicentered randomized phase II comparison of single-agent carboplatin versus the combination of carboplatin and everolimus for the treatment of advanced triple-negative breast cancer.
Authors: Fukui Jami Aya , Shapiro Charles L. , Ru Meng , Klein Paula , Fasano Julie , Bhardwaj Aarti , Irie Hanna , Mandeli John P. , Goel Anupama , Kumarley Neha , Gomes Joni , Shuman Nicholas , Francois Damien , Tiersten Amy
Published: May 2019

TPS1109

Background: Triple negative breast cancer (TNBC) is an aggressive disease with unmet clinical needs. Women with TNBC tend to be younger and demonstrate early recurrence, higher histological grade, higher rate of visceral metastasis and increased mortality rates when compared to hormone positive breast cancer. Prognosis for metastatic TNBC is especially poor. Due to lack of targeted therapies, there is no standard treatment of choice for triple negative breast cancer and chemotherapy remains the accepted standard. Many chemotherapeutic agents have been reported to have clinical activity either as single agent or in combination. Seventy percent of breast cancers with BRCA-1 germline mutations are triple negative, which suggests a shared carcinogenic pathway between them. In preoperative and metastatic settings, both TNBC and BRCA-1 associated breast cancers are particularly sensitive to DNA cross-linking agents such as platinum compounds due to defective DNA repair by homologous recombination. The recent TNT trial showed in patients with triple negative metastatic or recurrent locally advanced breast cancer with BRCA1/2 mutations, carboplatin resulted in a significantly higher overall response rate versus docetaxel (68% versus 33.3%; p=0.03). Triple negative breast cancers are associated with a high frequency of PTEN loss, which leads to mTOR activation. Moreover, it has been reported that mTOR activation may confer resistance to platinum agents such as cisplatin, a phenomenon that may be reversible by the addition of an mTOR inhibitor such as everolimus. There are reports of synergy between mTOR inhibitors and platinum compounds in pre-clinical and clinical data. Methods: We have opened a multi-centered randomized phase II trial comparing carboplatin AUC 4 q 3 weeks vs carboplatin AUC 4 q 3 weeks combined with daily 5 mg everolimus. 41 of planned 72 patients from the Mount Sinai Health System have been enrolled and are randomized in a 2:1 allocation. The primary objective is to compare progression-free survival in patients treated with carboplatin+everolimus to patients treated with carboplatin alone. Patients may have had up to 3 prior regimens for metastatic disease. Exploratory biomarker assessment is being done to identify markers of response. Clinical trial information: NCT02531932.
KX-ORAX-001: An open label, randomized, multicenter, phase III registrational study to determine the safety, tolerability, and tumor response of oraxol (HM30181A + oral paclitaxel) and its comparability to IV paclitaxel in patients with metastatic breast cancer (MBC).
Authors: Umanzor Funez Gerardo Antonio , Vassallo Rosa Haydee , Chivalan Castro Marco Antonio , Bejarano Suyapa A. , Ramirez Velasquez Julio Roberto , Kowalyszyn Ruben , Fein Luis Enrique , Cutler David , Goldfinch John , Moore Taryn , Kramer Douglas , Kwan Rudolf , Barrios Francisco
Published: May 2019

TPS1116

Background: Paclitaxel is used in multiple cancer types including the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within six months of adjuvant chemotherapy. Due to poor oral absorption, paclitaxel is administered IV and is associated with extra administration costs, inconvenience, burden for the patient, and hypersensitivity reactions to the solubilizing agent Cremophor EL. HM30181A is an intestinal P-gp pump blocker that, when administered orally with paclitaxel capsules (Oraxol), enhances paclitaxel absorption. Interim data from a phase I crossover study showed Oraxol (15-mg HM30181A + 205 mg/m2) 3 days/week had similar AUC0-∞ to IV paclitaxel 80 mg/m2 over 1 hour (Oraxol 5078 ng*hr/mL vs. IV paclitaxel 5652 ng*hr/mL), however the Cmax was substantially lower with Oraxol which may result in lower incidence of neuropathy. In a phase II single arm study of Oraxol in MBC 45.8% and 41.7% of subjects had PR or SD according to RECIST 1.1. Methods: KX-ORAX-001 is a, multi-national open-label, randomized (2:1 Oraxol to IV paclitaxel) phase III registration study comparing Oraxol (15-mg HM30181A + paclitaxel 205 mg/m2 daily x 3 days QW) to IV paclitaxel 175 mg/m2 over 3 hours every third week, in female patients with histologically- or cytologically-confirmed MBC for whom treatment with IV paclitaxel monotherapy has been recommended. The study is powered to demonstrate the superiority of Oraxol on confirmed tumor response rate vs IV Paclitaxel 175mg/m2 q3weeks. The primary efficacy endpoint is confirmed tumor response according to a blinded central radiologist using RECIST 1.1 criteria. The study is designed to enroll approximately 360 evaluable subjects. Two interim DSMB reviews were conducted at approximately 90 and 180 evaluable subjects for safety, futility, and efficacy. Enrollment was initiated Dec 2015 at 45 sites in Central and South America and enrollment has been completed. At final analysis, if there is an approximate difference of ≥10% favoring Oraxol, a p-value of 0.045 [2-tailed] will be achieved. Secondary endpoints are PFS and OS. Clinical trial information: NCT02594371.
A phase Ib trial of CB-839 (telaglenastat) in combination with radiation therapy and temozolomide in patients with IDH-mutated diffuse astrocytoma and anaplastic astrocytoma (NCT03528642).
Authors: Kizilbash Sani Haider , McBrayer Samuel , Port John , Reid Joel M. , Lanza Ian , Allred Jacob B , Chakravarti Arnab , Kunos Charles , Adjei Alex A.
Published: May 2019

TPS2075

Background: IDH mutant astrocytomas express high levels of 2-hydroxyglutarate (2-HG), an oncogenic metabolite which drives gliomagenesis. Excess 2-HG inhibits branched chain amino acid transaminase, which catalyzes glutamate synthesis from branched chain amino acids. This defect causes these tumors to become more reliant on glutaminase for glutamate biosynthesis from glutamine. CB-839 (telaglenastat) is a novel glutaminase inhibitor which is well tolerated in humans. McBrayer et al have recently demonstrated that CB-839 further depletes intracellular glutamate and glutathione in IDH mutant glioma cells, and enhances RT (radiation therapy) efficacy in an orthotopic glioma model. Methods: NCI #10218 is a CTEP supported phase I clinical trial investigating the safety and tolerability of CB-839 when combined with RT/TMZ (temozolomide) in patients with previously untreated IDH mutant grade II/III astrocytoma. Patients with grade II and III astrocytomas will be treated with 50.4 and 59.4 Gy of RT, respectively, with standard doses of concurrent TMZ. CB-839 will also be administered orally concurrently with RT, with doses escalated in cohorts based on a standard 3+3 design. After defining the maximum tolerated dose (MTD) of CB-839, an expansion cohort will evaluate the pre- and post-CB-839 therapy metabolome of patients with IDH mutant astrocytoma. Enrollment to this cohort will require measurable disease and patients will additionally be treated with a 7 day run-in of CB-839 at MTD prior to RT. The effect of CB-839 on the metabolome will be studied in both plasma (LC/MS/MS) and tumor (magnetic resonance spectroscopy), along with PK to confirm adequacy of systemic exposure. Preliminary data on neurocognitive endpoints will also be acquired. NCI #10218 is currently activated for enrollment to cohort 1. Clinical trial information: NCT03528642.
The "INSIGHT" Trial: Two new strata of an explorative, open-labeled phase I study evaluating the feasibility and safety of subcutaneous IMP321 injections (LAG-3Ig fusion protein, eftilagimod alpha) combined with either standard-of-care drug therapy or PD-L1 inhibition (avelumab) in advanced-stage solid tumor entities.
Authors: Mueller Daniel Wilhelm , Goetze Thorsten Oliver , Atmaca Akin , Rafiyan Mohammad-Reza , Weidmann Eckhart , Brandts Christian H. , Pabst-Giger Urs , Duex Markus , Kraus Thomas Werner , Stahn Simon , Eickhoff Regina , Al-Batran Salah-Eddin
Published: May 2019

TPS2651

Background: The two new strata of the INSIGHT trial evaluate feasibility and safety of s.c. injections of IMP321 (eftilagimod alpha) in combination with either SOC first/second-line drug therapy (Stratum C) or in combination with an PD-L1 inhibitor (avelumab; Stratum D) in advanced stage solid tumors as well as to generate first efficacy data. This proof-of-concept data could build the basis for further clinical studies exploring the therapeutic potential of combinations of active immunotherapy using IMP321 with SOC drug therapies or immunotherapies targeting the PD-1/PD-L1 axis in various solid tumor entities. IMP321 is a MHC class II agonist that activates antigen-presenting cells (primary target cells) and then CD8 T cells (secondary target cells). Activation of the dendritic cell network and subsequent T cell recruitment at the tumor site with IMP321 may lead to enhanced anti-tumor CD8 T cell responses. Thus, especially combinations with PD-1/PD-L1 inhibitors might display interesting effects by activating immune cells and disabling immune inhibitory mechanisms at the same time. Methods: This is a prospective investigator initiated phase I trial consisting of four strata. New stratum C: Patients with solid tumors treated with SOC chemo- or targeted therapy in first or second line receive concomitant s.c. IMP321 injections. This combination is aimed to enhance the immune response against tumor cells compared to chemo-/targeted SOC therapy alone. New stratum D: Patients will receive avelumab i.v. q2w along with s.c. IMP321 injections. This combination is aimed to enhance efficacy by combining IMP321’s activating effects on immune cells with the release of immune inhibitory effects caused by interruption of the PD-1/PD-L1 axis. It is planned to enroll 20 patients in Stratum C and 12 patients in stratum D. Main efficacy endpoint is the overall response rate (RECIST 1.1). Overall recruitment has started; currently (Feb 2019) 14 patients have been enrolled. EudraCT: 2016-002309-20. Clinical trial information: NCT03252938.
A multicenter, open label, first-in-human study of an oncolytic viral vector expressing an agonistic anti-CD40 antibody (NG-350A) in patients with epithelial tumors (FORTITUDE).
Authors: Naing Aung , Ileana Dumbrava Ecaterina Elena , Murthy Ravi , Meric-Bernstam Funda , Fox Andrew , Krige David , Carter Jo , Champion Brian , Cockle Paul , Koetz Barbara , McElwaine-Johnn Hilary
Published: May 2019

TPS2668

Background: NG-350A is a transgene modified variant of the oncolytic platform virus enadenotucirev (EnAd) which expresses a fully human agonist anti-cluster of differentiation 40 (anti-CD40) antibody. The principal advantage of encoding anti-CD40 within an oncolytic virus is the ability to potentially achieve very high levels within the tumor coupled with direct cytotoxicity due to viral lysis and stimulation of the immune-system. NG-350A infects and selectively replicates in tumor cells. The anti-CD40 antibodies are expected to activate the patient’s own dendritic cells, macrophages and B-cells to drive CD4+ and CD8+ T-cell immuno-inflammatory responses and immune mediated tumor cell killing. EnAd is a tumor-selective chimeric Ad11/Ad3 group B oncolytic adenovirus developed using directed evolution. Phase I clinical studies have identified a well-tolerated systemic dose and regimen for EnAd monotherapy. EnAd shows a high level of selective replication and cell killing for a broad range of carcinoma cell lines (of epithelial origin) with little replication in normal and non-carcinoma cells. Methods: This first in human study will evaluate the safety, tolerability and preliminary efficacy of NG-350A together with virus kinetics, immunogenicity and other pharmacodynamic effects to elucidate the mechanism of action of NG-350A in patients with advanced or metastatic epithelial tumours. In the dose escalation phase up to 33 patients evaluable for dose-limiting toxicity will receive NG-350A by IV infusion on Day 1, 3 and 5 at 6 US sites. The first IV cohort in the dose-escalation phase will utilize the conventional ‘3+3’ design; thereafter dose recommendations will be based on a continual reassessment method. Following determination of the recommended phase 2 dose up to 20 patients will be treated in a dose-expansion cohort. In a parallel cohort, up to 12 patients will receive a single dose of NG-350A by intratumoural (IT) injection on Day 1 for direct delivery of high viral titres to tumor. Up to six patients are planned to undergo surgical resection of a tumor lesion to optimize translational research. Clinical conduct of the study was initiated in February 2019.
A phase II study for prostate cancer monitoring using 18F-DCFPyL and blood-based biomarkers.
Authors: Lim Emerson A. , Mintz Akiva , Stein Mark N. , Rai Alex J. , Mansukhani Mahesh M. , Aggen David Henry , Dallos Matthew , Hawley Jessica , Shaish Hiram A , Schwartz Lawrence Howard , Drake Charles G.
Published: May 2019

TPS3154

Background: Assessing treatment response in castrate resistant prostate cancer (CRPC), remains a challenge due to the limited sensitivity and specificity of existing imaging modalities. Understanding prostate cancer biology with tumor biopsies does not address the issue of tumor heterogeneity or cellular degradation during the decalcification process of bone biopsies. Next generation positron emission tomography (PET) imaging and circulating biomarkers might provide additional insights on treatment responses and inform clinical decision-making earlier in therapy. 18F-DCFPyL (PyL) is a second-generation fluorinated PSMA PET tracer that has superior sensitivity and specificity to detect prostate cancer compared to standard imaging. Its role in assessing tumor response to therapy has not been evaluated. Circulating tumor DNA (ctDNA) in blood can provide tumor genomic information, while exosomes in serum and urine may provide data on the proteomic landscape of tumors. Methods: We are conducting a prospective study of 15 men with metastatic CRPC who are scheduled to start a new systemic therapy for their disease. Upon enrollment, subjects will have baseline assessments with standard cross-sectional imaging, 99mTc bone scan, and blood work. Standard scans will be performed every 8-12 weeks until progression of disease. PyL PET/CT scans and liquid biopsies (ctDNA and exosomes) will occur at baseline, 6 weeks after starting their new therapy, and at disease progression. Lesions seen on PET/CT images will be identified by a certified reader. The maximum standardized uptake value (SUVmax) will be measured and recorded in up to the five hottest lesions and normalized to a background SUVmean measured in the liver, spleen, kidney, mediastinum, and parotid glands. Changes in the normalized SUV from baseline to the 6-week PyL PET scan will be correlated to PSA response by the Pearson’s correlation coefficient. The Kaplan-Meier method will be used to evaluate progression free survival and overall survival dichotomized by the median value of SUV change. Blood for ctDNA and exosomes will be stored for future analysis. The study is open with two patients enrolled at the time of submission. One patient has completed his initial PyL PET/CT scan. Clinical trial information: NCT03585114.
Clinical Trial in Progress: The FLEX Big Data Platform explores new gene expression profiles and investigator-initiated protocols in early-stage breast cancer.
Authors: Untch Sarah , Srkalovic Gordan , Brufsky Adam , Crozier Jennifer A. , Habibi Mehran , Whitworth Pat W. , Cox Charles E. , D'Abreo Nina , Audeh William , Yoder Erin , Grady Ian
Published: May 2019

TPS3155

Background: Genomic signatures are revolutionizing the definition, identification, and treatment of breast cancer. To precisely stratify breast cancers into actionable subgroups, full genome expression data and matching clinical data must be aggregated into a large data set. Such a data set will accelerate research and discovery, especially for smaller patient subsets who are not as widely represented within the current body of literature. Methods: FLEX is a multicenter, prospective, population-based, observational trial for patients with Stage I, II, and III breast cancer. All patients with stage I to III breast cancer who receive MammaPrint, with or without BluePrint on a primary breast tumor are eligible for enrollment. The study’s primary aim is to create a large scale, population-based registry of full genome expression data matched with clinical data to investigate new gene associations with prognostic and/or predictive value. Secondary objectives include utilizing the shared study infrastructure to examine and generate hypotheses for targeted subset analyses and/or trials based on full genome expression data. The design of FLEX allows targeted sub-studies and sub-analyses to be added as appendices after the initial baseline study is opened. Patients enrolled in the initial study are also eligible for inclusion in sub-studies where they meet all criteria and additional consent is not required. Additional clinical data will be collected as specified in the appendix protocols. The FLEX collaborative platform allows participating investigators the opportunity to author their own sub-study protocols, as approved by the FLEX Steering Committee of their peers. 13 sub-studies have already been identified and are under development. Eligibility: The study will enroll a minimum of 10000 patients aged ≥18 years with histologically proven invasive stage I-III breast cancer who signed informed consent. Enrollment began April 2017 and 1506 patients have been enrolled. Clinical trial information: NCT03053193.
A window of opportunity trial of atorvastatin in p53-mutant and p53 wild type malignancies.
Authors: Telfah Mohammad , Iwakuma Tomoo , Bur Andres , Shnayder Lisa , Tsue Terry , Mazin Al-Kasspooles Mazin , Ashcraft John , Martin Benjamin , Al-Rajabi Raed Moh'd Taiseer , Kasi Anup , Khan Qamar J. , Lin Tara L. , Saeed Anwaar , Williamson Stephen K. , Chalise Prabhakar , Godwin Andrew K. , Reed Greg , Thomas Sufi , Komiya Takefumi , Baranda Joaquina Celebre
Published: May 2019

TPS3165

Background: Mutations in p53 contribute to tumor progression. A rational approach is to destabilize mutant (m) p53. The group at the University of Kansas Cancer Center screened compounds that suppress m p53 in a preclinical model. Luciferase-based reporter assay identified statins as suppressors of m p53 expression. In vitro validation assay demonstrated atorvastatin (A) suppressed m p53 level and cell growth selectively; and depletion of mevalonic acid lead to degradation of m p53. These effects were limited to mutations in the conformation of p53, while wild-type and DNA contact mutations were not as sensitive to statin-induced degradation of p53. M p53 xenograft model confirmed that A could suppress tumor growth at a concentration that can decrease LDL level. The primary objective of this trial is to determine if A decreases the level of conformational m p53. The secondary objective is to assess the effects of A on Ki-67 and caspase-3 in conformational m p53 tumors. Methods: This is an open-label, window of opportunity pilot trial to see if A given for 1 to 4 weeks at a dose of 80 mg/day is sufficient to reduce the levels of conformational m p53 in the tumor tissues. Subjects with new diagnosis of malignancy with a planned surgical therapy, and subjects with previously treated AML, in between treatment regimens, are eligible. Tissues from solid tumors, and bone marrow or peripheral blood samples from AML will be used to screen for m p53 by immunohistochemistry (IHC). Subjects will receive A at 80 mg/day po for 1 to 4 weeks. Pharmacokinetics at pre-dose and 1-hour post-dose on Day 1 and on the day of surgery will be done. Mutational analysis using exome sequencing technique will be done on m p53. Using IHC, the amount of p53 in pre-treatment and post-treatment samples will be measured and compared simultaneously. The levels of Ki67 and caspace-3 will be tested and compared between pre-treatment and post-treatment samples in subjects with conformational m p53, between conformational and non-conformational m p53, and in wild-type p53 tumors. The trial is actively enrolling subjects. The results of this trial will determine further investigations on the role of atorvastatin in tumors with p53 mutations in a placebo-controlled, randomized trial. Clinical trial information: NCT03560882.
Leeomic: A comprehensive proteomic analysis towards discovery of predictive patterns of protein expression to ribociclib sensitivity and resistance—A compLEEment-1 Canadian correlative sub-study.
Authors: Chia Stephen K. L. , Henning Jan-Willem , Warner Ellen , Song Xinni , Joy Anil A. , Califaretti Nadia , Desbiens Christine , Zarate Juan Pablo , Haftchenary Sina , Perri Sabrina R. , Morin Gregg B.
Published: May 2019

TPS3170

Background: Despite developments in the treatment of advanced hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer, primary or acquired resistance eventually occurs in all cases and there is still very limited understanding of the mechanisms of resistance to therapy. LEEOMIC is a sub-study of the main CompLEEment-1 ( N = 3255 patients enrolled, CLEE011A2404 v03) trial, an open-label, phase 3b study evaluating ribociclib + letrozole as first-line therapy in an expanded advanced breast cancer patient population which recruited over 250 Canadian patients. The purpose of this Canadian correlative sample collection study is to explore the mechanisms of response and resistance to ribociclib in combination with letrozole through proteomic and ctDNA analysis. Methods: The British Columbia Cancer Research Centre team developed a novel and optimized MS/MS platform called SP3-Clinical Tissue Proteomics (SP3-CTP) to perform in-depth proteome profiling ( > 8,000 proteins) from formalin fixed paraffin embedded (FFPE) material (10-micron section). SP3-CTP analysis of the proteome of the study patients who did not achieve clinical benefit (primary resistance: progression within 3 months of treatment) will be compared to the proteome of the sub-group of prolonged responders (time to progression of 22 months or more) in order to identify biomarkers that can predict response or de-novo resistance to therapy. Archival tumor biopsies (primary or metastatic) collected from the study will be submitted for proteomic analysis to identify proteomic expression levels that may serve as predictor of response. It is anticipated that over 150 samples will be collected. If available, blood samples taken at time of progression or end of treatment will also be analyzed for ctDNA for genetic profiling and to study if there is any correlation between genetic mutations and response or resistance to therapy. Currently, both tissue and blood samples are being collected and no analysis has been conducted thus far. Clinical trial information: NCT03613220.
TENERGY: Multicenter phase II study of atezolizumab monotherapy following definitive chemoradiotherapy with 5-FU plus cisplatin in patients with locally advanced esophageal squamous cell carcinoma.
Authors: Bando Hideaki , Kotani Daisuke , Tsushima Takahiro , Hara Hiroki , Kadowaki Shigenori , Kato Ken , Chin Keisho , Yamaguchi Kensei , Kageyama Shun-ichiro , Hojo Hidehiro , Wakabayashi Masashi , Fukutani Miki , Togashi Yosuke , Fuse Nozomu , Nishikawa Hiroyoshi , Kojima Takashi
Published: May 2019

TPS4141

Background: The standard treatment for patients with unresectable locally advanced esophageal squamous cell carcinoma (ESCC) is definitive chemoradiotherapy (CRT) using 5-FU plus cisplatin. However, complete response (CR) rates are only 11% to 25%, and median overall survival (OS) is 9 to 10 months. The improved therapeutic efficacy of combining immunotherapy with radiation has been gaining interest. Our basic research suggested that sequential treatment with anti-PD-L1 agents soon after completion of CRT is the best combination. Twelve months of anti-PD-L1 antibody following platinum-based CRT significantly improved progression-free survival (PFS) and OS in patients with locally advanced non-small cell lung cancer (Antonia SJ, et al. N Engl J Med. 2018). Based on this background information, we have planned a phase II clinical trial to evaluate the safety and efficacy of atezolizumab monotherapy following definitive CRT in patients with locally advanced ESCC. Methods: The main inclusion criteria are unresectable locally advanced ESCC without distant metastasis, completion of treatment with 60 Gy of radiation plus two concomitant cycles of chemotherapy (cisplatin 70 mg/m2 on day 1 and 5-FU 700 mg/m2 on days 1–4, every 28 days), and adequate organ function. Within 4 weeks after CRT, patients will be registered in the study and started on 1200 mg of atezolizumab every three weeks until 12 months or disease progression. The primary endpoint is the CR rate by the investigator’s assessment. Overall response rate, PFS, OS, treatment-related adverse events, and CR rate by central assessment are secondary endpoints. A total of 50 patients will be enrolled, including 40 with primary locally advanced ESCC and 10 with postoperative loco regionally recurrent ESCC. As an exploratory biomarker study, biopsies from the primary site and blood collections will be performed at 3 time points (before CRT, after CRT, and four weeks after the start of atezolizumab). We will analyze the phenotype of immune-competent cells, neoantigens, tumor mutation burden, PD-L1 status, and Human Leukocyte Antigen haplotyping. Clinical trial information: UMIN000034373.