bluuebunny/crossref_metadata_2025 huggingface dataset:
Adrenal metastases in malignant melanoma, is it a privileged site?
Authors: Mushtaq Rao Rashid , Gao Dexiang , Raeburn Christopher , Tobin Richard P. , Robinson William
Published: May 2019

e21016

Background: Currently there is a very limited data reporting response of adrenal metastases to immunotherapy in patients with metastatic malignant melanoma. Certain sites in the body may serve as sanctuary sites due to tumor microenvironment. Lower response rates and shorter PFS are reported in malignant melanoma with liver metastases while higher objective response rates are seen with lung metastases. We hypothesized that adrenal glands are sanctuary sites for melanoma metastases and thus would have poor response to immunotherapy due to steroid production in the adrenals making microenvironment less optimum for the anti-tumor effects of immunotherapy. Methods: A retrospective single-institution chart review of all malignant melanoma with metastasis to adrenal gland treated at University Colorado Hospital from 2008 till 2018, with age ≥ 18 yrs of age who received at least one dose of immunotherapy. Immune-related response criteria (irRC) was used to assess the response to immunotherapy on the imaging. Kaplan Meier estimate, and Chi square test were used for statistical analysis. Results: Sixty-five patients met the inclusion criteria. Mean age of 61 yrs. with range from 25 to 90 yrs. 71% were males and 95% were Caucasians. Median duration of follow up was 51.3 months with range of 1.5-212 months. Forty-three percent were cutaneous, 35% unknown primary, 11% each with mucosal and ocular melanoma. Based on the category of malignant melanoma, 60% were metastatic, 12% nodular, 8% choroidal, 8% superficial spreading, 6% acral lentiginous and 6% other. BRAF mutations were present in 38%, wild type in 54% and unknown in 8%. NRAS was mutated in 18% and wild type in 17% and unknown in 65% of the patients. Comparison of response between adrenal metastasis and non-adrenal metastasis, showed that 71% adrenal metastases had progressive disease compared to 54% of non-adrenal metastases. The overall response rate (ORR) to immunotherapy was 15% in adrenal metastases compared to 20% of non-adrenal metastases. Disease control rate (DCR) was 29% in adrenal metastases compared to 46% non-adrenal metastases with p value = 0.015. Conclusions: The adrenal glands appear to be a sanctuary site for metastases in patients with malignant melanoma receiving immunotherapy. The reasons behind this are unclear but may be related to the microenvironment and local corticosteroid production suppressing the immune response. Preliminary data examining cellular responses in nine surgically removed adrenal metastases support this hypothesis and will be presented.
Progression and hyperprogression after anti-PD1 therapy for unresectable stage III or IV melanoma patients.
Authors: Colle Elise , Dalle Stéphane , Mortier Laurent , Guillot Bernard , Dutriaux Caroline , Leccia Marie Thérèse , Dalac Sophie , Legoupil Delphine , De Quatrebarbes Julie , Montaudié Henri , Arnault Jean-Philippe , Brunet-Possenti Florence , Saiag Philippe , Momenzadeh Mathieu , Dreno Brigitte , Porcher Raphael , Oriano Bastien , Lebbe Celeste
Published: May 2019

e21021

Background: Primary progression (PP) and secondary progression (SP) to anti-PD1 therapy (APD) are poorly described in advanced melanoma in real life practice. Hyperprogression with a deleterious effect is reported in many cancers but is poorly assessed in advanced melanoma. Methods: Characteristics of 793 patients treated by APD (nivolumab or pembrolizumab) between July 2014 and May 2018 were collected from MelBase, a prospective French biobank (NCT02828202).We considered: group A (progressive disease as best response), group AHP (hyperprogression) within group A patients (progression/death within 3 months with normal initial LDH and ECOG at baseline, and either ECOG increased from 0 to 3-4, either LDH increased from normal to elevated or both), group B SP (response or stable disease then progression). Characteristics for all and survival for patients alive at progression (AAP) were also described. Results: Median follow-up was 11.3 months (Q1-Q3 4.8–23.6). Characteristics at baseline are in the table. In group A, 14% patients died at progression; within 262 patients AAP, 17% continue APD (the same or switch), 15.1% (CI95 11.1-20.6) were alive 1-year after progression (1YAP); 20.5% for patients in first line and 11.5% for pretreated. In group AHP, 41% patients died at progression; within 48 patients AAP, 12% continue APD, 11.1% (CI95 7.8-13.6) were alive 1YAP. In group B, 11% patients died at progression; within 88 patients AAP, 36% continue APD, 10.3% (CI95 5.2-20.1) were alive 1YAP, 15.9% for patients in first line and 7.0% for pre-treated. Conclusions: Our study shows that PP and SP to APD differ at baseline, but have similar survival rates at progression, while mechanisms involved might be different, providing important landmarks to build second line trials. This study thus highlights the existence of hyperprogressors among which 41% patients died within 3 months, as well as describes their associated characteristics. [Table: see text]
Clinical heterogeneity of elderly melanoma patients in the real-world setting: Potential implications for treatment outcomes following immune based therapy.
Authors: Hegde Upendra P. , Parmar Harsh V , Stevenson Christina Elizabeth
Published: May 2019

e21026

Background: Recent studies have indicated that immune checkpoint inhibitor treatment of metastatic melanoma is effective irrespective of older age. However, in the real world setting, not all older patients (pts.) diagnosed with high-risk cutaneous melanoma have same levels of immune function due to wide variation of older age and aging associated diseases that adversely influence it. Frailty associated with co-morbidities, autoimmunity, cancer, and their treatments are three such conditions that influence treatment outcomes following immune based treatment of melanoma in older subjects. To better understand this interaction between melanoma, aging-associated diseases and potential outcomes following immune checkpoint inhibitor treatment in the real world, we reviewed clinical data of elderly melanoma pts. from the University of Connecticut's Neag Cancer Center following an IRB approval. Methods: We retrospectively reviewed clinical characteristics of elderly pts. diagnosed with high-risk cutaneous melanoma (Stage IIC, III, IV) at the University of Connecticut from 2012-2019. Pts. over the age of 60 years were divided into two main groups: Group I ("Fit elderly") and Group II ("Elderly with immune suppressive conditions"). Group II pts. were further divided into three subgroups: A ("Co-morbidities and frailty"), B ("Autoimmunity and its treatment") and C ("Cancer and its treatment"). Results: From 2012-2019, a total of 56 elderly pts. diagnosed with high-risk cutaneous melanoma were stratified as the following: Group I - 31 pts. (55%) and Group II - 25 pts. (45%); among the Group II pts., Group A contained 14 pts. (56%), Group B 5 pts. (20%), and Group C 6 pts. (24%). The median age for all 56 elderly pts. was 77 yrs. (range 61 to 99). In Group I, the median age was 73 yrs. (range 61-91). In Group II, the median age was 82 years (range 66-99); A median age 85 yrs (range 66-99), B median age 78 yrs (range 66-86), and C 80.5 yrs. (range 66-86). 9 out of 56 pts. (16%) did not receive immune checkpoint inhibitor treatment, of which 7 pts. (56%) were frail and 2 pts. (22%) were non-frail. Conclusions: Our data indicate that the existence of significant clinical heterogeneity among high-risk elderly melanoma pts. encountered in the community setting reflects a wide spectrum of immune function. Larger studies stratifying elderly subjects by co-morbidities and immune suppressive conditions will help shed accurate light on clinical relevance of immune based treatment of melanoma in older subjects.
Combined BRAF and MEK Inhibition in Patients with unresectable or metastatic cutaneous melanoma: A meta-analysis of randomized controlled trials.
Authors: Biedny Adam , Chahine Adam , Abdalla Ahmed , Sidahmed Shima , Kheiri Babikir , Kafri Zyad , Hadid Tarik H.
Published: May 2019

e21030

Background: Malignant melanoma is a dangerous disease with increasing incidence. Over the past several years, medical advancements have allowed for markedly improved therapeutic options. In patients with BRAF V600E or V600K mutations, the use of various BRAF inhibitors in combination with MEK inhibitors have been approved for stage III unresectable and metastatic disease. Therefore, we aimed to evaluate the efficacy and safety of this combination in comparison to a single agent BRAF inhibitor. Methods: A comprehensive electronic database search was conducted for all randomized controlled trials (RCTs) comparing the clinical outcomes of combination BRAF inhibitor and MEK inhibitor versus BRAF inhibitor alone in patients with unresectable stage III or stage IV BRAF-mutated malignant melanoma. The primary outcome was progression-free survival (PFS). Secondary outcomes included overall survival (OS), overall response, and various selected adverse events. We calculated hazard ratios (HRs) and 95% confidence intervals (CIs) using a random-effects model at the longest follow-up period. Results: We included five RCTs with 2,113 total patients, with a mean age of 55.5 years and 56.1% male. The combination therapy of BRAF and MEK inhibitors showed superior results with regard to PFS (HR 0.57; 95% CI: 0.50-0.67; p < 0.001), OS (HR 0.69; 95% CI: 0.61-0.78; p < 0.001), and overall response (HR 1.32; 95% CI: 1.23-1.43; p < 0.001) when compared to BRAF inhibitor alone. Additionally, patients treated with combination therapy had a lower incidence of cutaneous squamous cell carcinoma (Risk Ratio: 0.22; 95% CI: 0.10-0.47; p < 0.001) and arthralgia (Risk Ratio 0.34; 95% CI: 0.15-0.74; p < 0.001). Patients who received combination therapy, however, had a higher incidence of diarrhea (risk ratio 2.53; 95% CI: 1.05-6.09; p = 0.04) and pyrexia (risk ratio 4.98; 95% CI: 2.27-10.92; p < 0.001). Conclusions: For patients with unresectable stage III malignant melanoma or metastatic malignant melanoma, combination therapy with BRAF inhibitor and MEK inhibitor was associated with superior PFS, OS, overall response, and lower incidence of cutaneous squamous cell carcinoma and arthralgia compared with BRAF inhibitor alone. The combination therapy, however, was associated with a higher incidence of diarrhea and pyrexia.
​obesity and metastatic melanoma: A national perspective from the pre-immune checkpoint inhibitor era.
Authors: Desai Aakash , Parmar Harsh V , Hegde Upendra P.
Published: May 2019

e21032

Background: There is an ongoing debate about correlation of obesity with favorable outcomes in patients with metastatic melanoma receiving treatment. Our study measured the differences in in-hospital outcome parameters such as length of stay (LOS), cost and mortality in patients with metastatic melanoma with respect to obesity. Methods: We used National Inpatient Sample (NIS) dataset from 2008 to 2014 to identify the diagnosis of Metastatic melanoma (ICD-9 code:172.9) among hospitalized patients. Data was matched and weighted to obtain a nationally representative sample for analysis. The AHRQ comorbidity measure of obesity was utilized to identify obesity as a coexisting medical condition that is not directly related to the principal diagnosis. Categorical and continuous variables were tested using Chi-square test and Student t-test respectively. Multivariate hierarchical regression was used for the analysis of primary outcomes of interest. Results: We identified a total of 1,809 cases of metastatic melanoma from 2008 to 2014. Among them, 908 (50.19%) were obese and 901 (49.80%) non-obese. 195 out of the 1,809 (10.77%) patients were treated with high dose infusion of IL-2. Overall, the mean LOS (≈6.03 days [non-obese] vs ≈5.72 days [obese], p = 0.949) and mean cost of hospitalization (16720.28$ vs 17639.95$, p = 0.428; mean difference of 919.67$) was not significantly different based on obesity as a comorbid condition. The mortality rate was found to be significantly lower in obese patients (41% vs. 59%, p = 0.017), but did not reach statistical significance on logistic regression analysis (OR:0.95, p = 0.130). Further subgroup analysis of patients with metastatic melanoma who received high dose IL-2, we found no significant differences in mean LOS (5.03 vs 7.03, p = 0.14) as well as mean cost of hospitalization (27432.72$ vs 41881.13$, p = 0.485) between non-obese and obese patients. However, the in-hospital mortality for patients undergoing high dose IL-2 therapy could not be studied given no cases of in-hospital mortality occurred in this subgroup. Conclusions: Our study demonstrates that there are no significant differences in in-hospital outcomes for patients with metastatic melanoma with respect to obesity, even in the subgroup of patients treated with IL-2 immunotherapy. Thus, there is a need for further studies to adequately understand the exact biological mechanism of obesity in metastatic melanoma, the influence of obesity on immunotherapy outcomes and its translation into patient care outcomes.
Quantitative assessment of tumor-infiltrating neutrophils to predict immunotherapy responses in metastatic melanoma.
Authors: Vera Aguilera Jesus , Flotte Thomas J. , Yi Eunhee S. , Kroneman Trynda , Suman VeraJean , Paludo Jonas , McWilliams Robert R. , Kottschade Lisa A. , Yan Yiyi , Block Matthew Stephen , Markovic Svetomir
Published: May 2019

e21039

Background: Tumor-infiltrating neutrophils (TINs) and their myeloid precursors play an important role in cancer biology. While activated neutrophils have been shown to kill tumor cells, there is growing evidence that neutrophils may also support tumor progression by impairing T cell-dependent anti-tumor immunity. We hypothesized that low TINs would be associated with better responses to immunotherapy (IO). Methods: Pretreatment biopsies from 15 metastatic melanoma (MM) pts treated with anti-CTL4 and anti-PD-1 therapy from 2012-17 were collected and stained with myeloperoxidase (MPO). Slides were scanned at 40x magnification on the Aperio ScanScope AT Turbo brightfield instrument (Leica Biosystems) at a resolution of 0.25 microns per pixel. To indicate the region of analysis, the digital pen tool was used to trace a minimum 85% of tumor. Ten fixed-sized boxes were placed on the hottest staining region in a second annotation layer on the image. The boxes equaled 1mm2 in total area. If the tumor tracing had an area of 1mm2, or less, boxes were not placed on the image. The selected tissue was analyzed using an Aperio imaging quatification algorithm . The number of 3+ cells were considered positive for neutrophils and used in subsequent calculations. Quality control review was performed on a subset of cases by Anatomic Pathologists. Response to therapy was assessed using the Response Evaluation Criteria In Solid Tumors (RECIST). Overall survival (OS) was calculated using the Kaplan Meier method. Results: The median number of treatment lines before the biopsy was 1 (range 0-2). The treatment immediately following the biopsy consisted of ipilimumab (n = 10, 66.6%), pembrolizumab (n = 4, 26.6%), ipilimumab/nivolumab (n = 1, 6.6%). The median number of neutrophils in the biopsy hotspot was 92/mm2 (range 6-219) for the entire cohort. For patients achieving PR and CR after 4 cycles of therapy, the median neutrophils were 36/mm2 (IQ 14-78) while the median was 106/mm2 (IQ 60-138) for patients who had progressive disease,( p = 0.04). There was no correlation between the numbers of neutrophils in the biopsy with the absolute neutrophil count in the peripheral blood (R value: 0.012). Conclusions: Decreased TINs are significantly associated with better responses to IO in MM pts. Measurements of TINs may help to select patients who are likely to benefit from anti-CTL4 and anti-PD-1 therapy. Additionally, exploration of whether combining therapies that decrease neutrophils intratumorally should be explored.
Outcomes in MAGE+ cutaneous squamous cell carcinoma with perineural invasion treated with surgery followed by postoperative radiation therapy.
Authors: Stevenson Mary , Santana Alexis , Doudican Nicole Adell , Canavan Theresa N , Pavlick Anna C. , Carucci John
Published: May 2019

e21043

Background: Perineural invasion (PNI) is associated with a high risk for recurrence and metastasis from cutaneous squamous cell carcinoma (cSCC). Recommendations vary regarding use of post-operative radiation therapy (PORT). Biomarkers for poor outcome from cSCC with PNI are lacking. We aimed to evaluate outcomes in high-risk cSCC with PNI treated surgically +/- PORT and to evaluate tissue from the primary tumor to identify biomarkers for highest risk. Methods: We conducted a retrospective chart review of PNI SCC patients seen between 2005 and 2014. We compared outcomes for surgery vs. surgery plus PORT. Gene expression from tumor debulk was evaluated via Nanostring. MAGEA3 function was evaluated using PAM 212 SCC cells in a BALB/c mouse model. CRISPR-Cas9 MAGEA3 PAM 212 knockouts were developed to assess role of MAGEA3 in SCC growth. Results: Thirty-two patients with PNI SCC were identified. All were treated surgically, and 18/32 elected to undergo PORT. Nodal metastases were noted in 5/14 patients who did not undergo PORT, whereas no metastases were noted in any patient who underwent PORT. Thus, surgery plus PORT was associated with better outcome than surgery alone (P < 0.01). Local recurrence was not observed in any patients treated by surgery, including 30 patients treated by Mohs micrographic surgery (MMS). MAGEA3 was highly expressed in PNI SCC. MAGEA3 expression in PAM 212 SCC was associated with tumor growth and increased expression of cyclins A, B, and E. CRISPR-Cas9 MAGEA3 PAM 212 knockouts exhibited reduced growth in BALB/c mice. Conclusions: MAGEA3 expression is increased in human PNI SCC. We can mitigate against worst case outcome with surgery plus PORT. MAGEA3 merits further investigation as a potential biomarker for best candidates for surgery plus PORT.
Consensus gene expression analysis to identify key hallmarks of cancer in malignant melanoma.
Authors: O'Connor Emma , Parkes Eileen E. , Galligan Leeona , Bradford James , Lambe Shauna , Logan Gemma E , Walker Steven M. , McCabe Nuala , Harkin Paul D , Kennedy Richard D. , Knight Laura A.
Published: May 2019

e21045

Background: Traditionally gene expression signatures (GES) are used individually to classify patients into subgroups. Signatures targeting the same biology are often developed independently and may not classify identically. We developed the claraT software tool that uses consensus between multiple published GES categorised by the Hallmarks of Cancer (Hanahan & Weinberg, 2011) to classify cancers. As metastatic melanoma represents poor prognostic disease (5-yr survival 15-20%), we applied claraT to the TCGA melanoma dataset to identify targetable biologies, validated in a cohort of melanoma patients treated with Ipilimumab. Methods: TCGA RNA-seq data ( n= 472) was analysed using the claraT platform including GES for immune ( n= 14), angiogenesis ( n= 9) and epithelial-mesenchymal transition (EMT) ( n= 12) Hallmarks. Samples were clustered for the combined and individual Hallmarks. Median progression-free (PFS) and overall-survival (OS) differences were analysed across identified subgroups. Analysis was validated in an Ipilimumab treated melanoma dataset ( n= 42) (Van Allen, 2015). Results: Clustering the combined Hallmarks identified 4 subgroups in the TCGA cohort: 1) Immune active, 2) Immune-EMT active, 3) EMT-Angiogenesis active, 4) All inactive. Groups 1&2 had significantly improved OS compared to Groups 3&4 (HR = 0.50, p< 0.0001). Clustering using single Hallmarks revealed that immune-positive tumours had significantly improved OS (HR = 0.53, p< 0.0001) compared to immune-negative tumours. Angiogenesis-negative tumours displayed improved PFS (HR = 0.73, p= 0.03) and OS (HR = 0.53, p <0.0001) compared to angiogenesis-negative tumours. Interestingly the EMT Hallmark was not found to be individually prognostic. When validated in the Ipilimumab treated dataset, patients classified as immune-positive had improved OS (HR = 0.357, p= 0.010) when compared to immune-negative. Similar trends were also observed for angiogenesis and EMT Hallmarks. Conclusions: This study demonstrates how simultaneous analysis of multiple GES ( n= 35 in this study) can identify robust biologies through consensus expression. This platform may have value in the identification of reliable biomarkers for clinical trials and could inform how combination therapies targeting key biologies may be used in cancer treatment.
Postoperative radiotherapy in resected sinonasal mucosal melanoma.
Authors: Zhou Li , Cui Chuanliang , Lian Bin , Wang Xuan , Chi Zhihong , Si Lu , Sheng Xinan , Kong Yan , Mao Lili , Yan Xieqiao , Tang Bixia , Guo Jun
Published: May 2019

e21059

Background: Mucosal melanoma is rare but highly aggressive. Sinonasal melanoma comprised approximately 26% of the whole mucosal melanoma. Complete surgery plus postoperative radiotherapy is often recommended for early-stage sinonasal melanoma patients. However, the role of postoperative radiotherapy is still disputable. Methods: Mucosal melanoma patients with stage I-III sinonasal primaries which were completely resected were enrolled as part of the multicenter, randomized, controlled, phase 3 trial for the comparison of adjuvant chemotherapy (TMZ plus DDP 6 cycles) with high-dose interferon (HDI, 1 year) (NCT03435302). Postoperative radiotherapy was recommended in the trial for their own choice, prescribed as GTV 60-70Gy/CTV 60Gy/30f. Patients were divided into two groups, those who completed adjuvant radiotherapy after surgery (group S+R, n = 41) and those who received surgery alone (group S, n = 32). Results: Seventy three patients were enrolled from Feb 2014 to Jun 2016. Two groups were balanced regarding to age, gender, and adjuvant therapy of either HDI or chemotherapy. There are more locally advanced patients in Group S, namely T3-4 or N positive ( P= 0.001). At a median follow-up of 31.2 months (range: 5.3-60.0m), the median RFS was not reached in the S+R group, as compared with 17.1 months (95% CI: 2.3-31.9m, P= 0.008) in the S group. The median DMFS was 27.2 months (95% CI: 19.3-35.1m) in the S+R group, as compared with 24.8 months (95% CI: 13.9-35.7m, P= 0.475) in the S group. Patients in the S group had an increased probability of locoregional recurrence as a first event (46.7% vs. 14.6%), while patients in the S+R group are more likely to have metastases first (41.5% vs. 12.5%). Estimated OS was 46.8 months in the S+R group and 37.3 months (95% CI: 20.8-53.8m, P= 0.097) in the S group. T&N staging also had an influence on RFS, DMFS, and OS. In COX multivariate analysis, T&N staging was the only significant prognostic factor. Common toxicities included mucositis, dermatitis, nausea, and leukopenia. Conclusions: This study suggested that postoperative radiotherapy improved local-regional control rate and might had no effect on DMFS. OS was better in radiotherapy group but still mostly depends on T&N staging. More prospective data are needed for this subtype of melanoma. Clinical trial information: NCT03435302.
B-PRECISE-01 Study: A phase Ib trial of MEN1611, a PI3K Inhibitor, combined with trastuzumab ± fulvestrant for the treatment of HER2-positive advanced or metastatic breast cancer.
Authors: Piccart-Gebhart Martine J. , Aftimos Philippe Georges , Duhoux Francois P. , Wildiers Hans , Isambert Nicolas , Campone Mario , Tosi Diego , Varga Andrea I. , Boni Valentina , Doger Bernard , Corbacho Javier Garcia , Jimenez-Rodriguez Begona , Ruiz Borrego Manuel , Saura Cristina , Arkenau Hendrik-Tobias , Wardley Andrew M. , Troconiz Inaki F , Binaschi Monica , Simonelli Cecilia , Pellacani Andrea Ugo
Published: May 2019

TPS1101

Background: MEN1611 is a potent, selective class I inhibitor of PI3K, a key enzyme in the transduction of various extracellular growth factor signals essential for cell survival and apoptosis. The discovery in human cancers of frequent PIK3CA mutations, that have been linked to a worse outcome in advanced HER2-positive breast cancer, makes PI3K an attractive therapeutic target. Preclinical and clinical evidences support the development of MEN1611 in combination with other agents in the context of solid tumors. Methods: B-PRECISE-01 is an open-label, multicenter, phase Ib dose escalation study in patients with PIK3CA mutant tumors, HER2-positive advanced or metastatic breast cancer which has progressed after at least 2 lines of anti-HER2 based therapy. PIK3CA mutations are assessed centrally by real-time PCR assay in DNA derived from archived tumor samples. MEN1611 will be administered orally BID for continuous 28-day cycles until disease progression, in combination with weekly IV infusions of trastuzumab. In addition, HR-positive postmenopausal patients will also be treated with fulvestrant. After the completion of the dose escalation phase (Step 1), the study will continue in an expansion cohort (Step 2) testing the Recommended Phase 2 dose (RP2D) in a total of 15 patients in each of the treatment groups. The primary study objective is to assess combination safety and select RP2D. Secondary objectives include assessment of pharmacokinetics and pharmacodynamics, preliminary clinical activity of MEN1611 in combination with trastuzumab +/- fulvestrant, and correlation with PIK3CA mutations and other relevant cancer genes mutational status. Adverse events will be graded according to NCI CTCAE v4.03. Responses will be evaluated according to RECIST v1.1. Study variables will be presented by dose-cohort and overall using appropriate descriptive statistics. The enrollment began in July 2018 at European sites and US sites will shortly participate; up to date the first dose cohort level has been achieved. Clinical trial information: NCT03767335.
VIOLETTE: A randomized phase II study to assess the DNA damage response inhibitors AZD6738 or AZD1775 in combination with olaparib (Ola) versus Ola monotherapy in patients (pts) with metastatic, triple-negative breast cancer (TNBC).
Authors: Tutt Andrew , Stephens Christine , Frewer Paul , Pierce Andrew , Rhee Joon , Edgington Sarah , Ottesen Lone , Ah-See Mei-Lin , Hollingsworth Simon J. , Dean Emma
Published: May 2019

TPS1112

Background: TNBC comprises ≈15% of invasive breast cancer cases and alterations in BRCA1/ 2 are associated with ≈5% of all BCs. Ola (a poly ADP-ribose polymerase inhibitor [PARPi]) is approved for treating pts with HER2-negative metastatic BC with a germline BRCA mutation (g BRCAm), demonstrating an improvement in progression-free survival (PFS). Alterations in other non- BRCA1/2 homologous recombination repair (HRR)-related genes (non- BRCA HRRm) may also confer sensitivity to Ola therapy in pts with TNBC. Ola, AZD1775 (a WEE1 checkpoint inhibitor) and AZD6738 (an ataxia telangiectasia and Rad3-related protein inhibitor) target DNA damage repair and cell cycle regulation. Preclinical studies in TNBC models show synergistic antitumor effects of Ola+AZD1775 and Ola+AZD6738, vs Ola monotherapy supporting the clinical evaluation of these combinations. Methods: VIOLETTE is a global, multicenter, open-label, phase II study (NCT03330847) randomising 1:1:1 450 pts with advanced TNBC to 3 treatment arms: 1) Ola 200 mg bid daily + AZD1775 150 mg bid D1-3, D8-10 q21, 2) Ola 300 mg bid daily + AZD6738 160 mg qd D1-7 q28, or 3) Ola 300 mg bid daily q28. All pts will be stratified by prior platinum exposure. Each treatment arm of ≈150 pts will be comprised of 3 biomarker strata of ≈50 pts each (A: BRCAm; B: non- BRCA HRRm; C: non-HRRm). Centralized tumor molecular testing will be deployed to detect mutation(s) in 15 HRR genes. Eligible pts will have received 1-2 prior lines of chemotherapy for metastatic disease, including an anthracycline or taxane. Exclusion criteria include prior PARPi therapy. The primary endpoint is PFS (each combination vs Ola alone) assessed by blinded, independent central review (RECIST v1.1). Secondary endpoints are objective response rate, duration of response, change in tumor size, and overall survival for comparisons between combinations and for each combination vs Ola alone; drug exposure; and safety and tolerability. The first prespecified futility analysis in Stratum C has met the recruitment target and will be assessed by unblinded review April 2019. Clinical trial information: NCT03330847.
A randomized phase II study of nab-paclitaxel + durvalumab + neoantigen vaccine versus nab-paclitaxel + durvalumab in metastatic triple-negative breast cancer (mTNBC).
Authors: Hernandez-Aya Leonel Fernando , Gao Feng , Goedegebuure Peter S. , Ma Cynthia X. , Ademuyiwa Foluso Olabisi , Park Haeseong , Peterson Lindsay Leuthen , Bagegni Nusayba Ali , Bose Ron , Gillanders William E.
Published: May 2019

TPS1114

Background: mTNBC is associated with poor outcomes and lacks targeted therapies. Immune modulation with PD-1/L1 inhibitors are emerging as effective anticancer therapies. In mTNBC, atezolizumab (anti-PD-L1) plus nab-paclitaxel demonstrated an improvement in PFS compared to nab-paclitaxel alone. Cancer vaccines targeting neoantigens may enhance the activity of immune checkpoint inhibition (ICI). Neoantigens are targets for CD8 T-cells following ICI. T-cell responses to neoantigens are high in affinity and are not limited by central mechanisms of self-tolerance. Next-generation sequencing and epitope prediction algorithms are used to identify/prioritize neoantigens for vaccine design and development. Preclinical studies have shown that neoantigen vaccines are well tolerated and may be synergistic with anti-PD-1/L1 therapy. Methods: Eligible mTNBC patients are randomized to either Arm-1 ( nab-paclitaxel + durvalumab + neoantigen vaccine) or Arm-2 ( nab-paclitaxel + durvalumab). Initially, all participants are treated with a run-in of gemcitabine + carboplatin (18-weeks; Part A). During this time sequencing and neoantigen vaccine production is performed. Subsequently, patients are treated with nab-paclitaxel + durvalumab + neoantigen vaccine vs. nab-paclitaxel + durvalumab (Part B). The neoantigen vaccine is given subcutaneously. Participants in Arm-1 receive vaccinations on Days 1, 4, 8, 15, 22, 50 and 78. Durvalumab is administered at 1500 mg IV every 4 weeks. Nab-paclitaxel is administered at 100 mg/m2 IV on Days 1, 8, and 15 of each 28-day cycle. Key eligibility criteria include patients with newly diagnosed mTNBC; measurable disease; and tumor accessible for biopsy. The primary endpoint is PFS defined as time from the initiation of Part B to progression or death. Secondary endpoints include safety, objective response rate, clinical benefit rate and OS. The exploratory endpoints include evaluating the immune response induced by the neoantigen vaccine, investigating biomarkers of response including TILs, PD-L1, and immune signature by gene expression, and mutational landscape. This trial is currently recruiting patients (NCT03606967).
Phase I trial of endoxifen gel versus placebo gel in women undergoing breast surgery.
Authors: Alber Katrina , Benante Kelly A. , Xu Yanfei , Tull Mary Beth , Segura Adrian J. , Kalinichenko Kiril , Hou Lifang , Jovanovic Borko , Perloff Marjorie , Heckman-Stoddard Brandy M. , Dimond Eileen P. , Khan Seema Ahsan
Published: May 2019

TPS1588

Background: Despite large Phase III clinical trials that have established the success of selective estrogen receptor modulators (SERMs) for breast cancer prevention and therapy of duct carcinoma in situ (DCIS), acceptance by women likely to benefit has been low, primarily because of toxicity related to systemic exposure. Local drug delivery to the breast in gel form is an attractive alternative since low systemic levels could minimize toxicity. Endoxifen (ENX) is an active metabolite of tamoxifen, that has unique activity compared with 4-hydroxytamoxifen (4-OHT). It is smaller and more polar than 4-OHT making it potentially more suitable for transdermal delivery. The NCI PREVENT program has developed ENX transdermal alcoholic gel products. Methods: We are conducting a randomized, double-blinded, placebo-controlled, Phase I trial to establish the dermal tolerability and safety of endoxifen (ENX) gel. 38 women planning unilateral or bilateral mastectomy will be enrolled across 3 institutions in 3 cohorts: (a) ENX gel 10mg (N = 8) vs. placebo gel (N = 4) daily; (b) ENX gel 20mg (N = 8) vs. placebo gel (N = 4) daily; (c) the maximum tolerated dose (N = 8) with last dose 72 hours prior to surgery. Treatment duration will be 4 ± 1 weeks. All participants will be evaluated for toxicity and skin tolerability. Secondary endpoints include TAM metabolite measurements in breast tissue and plasma; serum hormone concentrations, serum estrogenic response, changes in coagulation parameters, gene expression changes reflective of therapeutic effects, and experienced symptoms. 65 potential participants have been pre-screened for eligibility. 33 were ineligible prior to contact, most commonly due to the use of neoadjuvant chemotherapy. Of 32 potential participants who have been eligible to be contacted, 21 did not consent for screening, most commonly because they were too overwhelmed with their recent diagnosis. 7 have consented, 4 are pending consent, and 6 have started study intervention. No adverse events have been reported to date. This pre-surgical trial testing transdermal ENX for breast cancer prevention is accruing as projected. The results will establish the skin safety of this agent, provide data on skin permeability, and the duration of drug retention in the breast. Clinical trial information: NCT03317405.
The IRX-2 regimen combined with nivolumab in recurrent/metastatic solid tumors: A phase 1b study to evaluate the safety, determine recommended phase 2 dose (RP2D), and investigate the biologic and clinical activity.
Authors: Jain Rohit K. , Zhang Jingsong , Eroglu Zeynep , Creelan Ben C. , Brohl Andrew Scott , Shafique Michael Rahman , Gray Jhanelle Elaine , Muzaffar Jameel , Ida Julia , Lacevic Mensura , Kim Youngchul , Chung Christine H. , Sahebjam Solmaz
Published: May 2019

TPS2662

Background: IRX-2 is a biologic immunotherapeutic containing a mixture of cytokines including IL-2, IL-1β IL-6, IL-8, TNFα, GM-CSF, and IFN-γ. It is derived from stimulating human PBMCs with phytohemagglutinin. Preclinical studies have shown that IRX-2 enhances dendritic cell maturation, T cell activation, and NK cell stimulation. In a Phase 2 trial of head and neck squamous cell carcinoma (HNSCC) patients, IRX-2 increased immune activation in the tumor microenvironment and was correlated with greater progression free survival and overall survival. Moreover, it has been shown that the degree of lymphocyte infiltration is an important prognostic factor for treatment with anti- programmed cell death protein 1 (PD-1) monoclonal antibodies. These data provide a compelling rationale for incorporating IRX-2 regimen into anti-PD-1 treatment strategies to increase the level of lymphocyte infiltration in the TME and improve immune response. Methods: This is a phase Ib trial exploring safety and tolerability of IRX-2 regimen in combination with nivolumab. Patients with recurrent or metastatic renal cell carcinoma, urothelial carcinoma, non-small cell lung cancer, HNSCC and melanoma are eligible. Patients who have received prior anti-PD-1/PD-L1 antibodies are eligible. IRX-2 regimen consists of cyclophosphamide 300mg/m2 (Day 1) and subcutaneous IRX-2 injections in 2 or 4 lymph node-bearing regions (based on dose level) for 10 days every 3 months. Two dose levels of IRX-2 regimen will be studied. Nivolumab is administered at 240 mg Q2W. Once the RP2D is determined, an additional 88 pts will be enrolled in an expansion phase, for a planned total enrollment of approximately 100 pts. Dose expansion phase will include cohorts of the 5 different diseases. Each cohort will include two groups: 1) anti-PD-1/PD-L1 antibody naïve tumors, and 2) progressed during or after anti-PD-1/PD-L1 antibodies. The primary study objective is to determine safety and tolerability of combination therapy. Secondary objectives are to evaluate the objective response rate, progression-free survival, and overall survival. Study Progress: Study is actively accruing. Clinical trial information: NCT03758781.
A phase Ib/IIa study of rucaparib (PARP inhibitor) combined with nivolumab in metastatic castrate-resistant prostate cancer and advanced/recurrent endometrial cancer.
Authors: Alter Raanan , Fleming Gini F. , Stadler Walter Michael , Patnaik Akash
Published: May 2019

TPS2663

Background: Immune checkpoint blockade (ICB) antibodies have made a major impact in a wide range of cancers. However, only subsets of patients across all malignancies benefit from ICB. In particular, metastatic castrate-resistant prostate cancer (mCRPC) and advanced endometrial cancers (EC) have shown very limited responses to ICB. The central hypothesis of this trial is that the combination of PARP inhibitor (rucaparib) with PD-1 inhibitor (nivolumab) will enhance ICB efficacy in mCRPC and mEC patients. Given that PTEN loss has also been associated with poor response to ICB, a secondary hypothesis of this study is that the combination therapy will have differing efficacy based on the PTEN mutation status of the tumor. Methods: This is an investigator-initiated Phase 1b/IIa clinical trial of rucaparib and nivolumab singly and in combination, in mCRPC and mEC patients. Patients are randomized to one of three arms – rucaparib, nivolumab, or both drugs in combination for 4 weeks. Metastatic biopsy samples are collected at baseline and after 4 weeks on treatment, after which all arms will switch to combination therapy. The primary objective is to assess feasibility of the combination, and to elucidate changes in immune infiltrates by Nanostring RNA sequencing, multiplex immunofluorescence, 3D mapping, IHC, and flow cytometry. Secondary objectives are to assess clinical response, and correlate changes in TME with PTEN status. We have currently enrolled 4 patients to the study, and collected pre- and 4 week on-treatment biopsies. This study presents an opportunity for in-depth TME analysis that will enable the delineation of the effects of PARP inhibition singly and in combination with PD-1 blockade, on immune subsets within the TME. The correlative analyses will also lead to the discovery of novel biomarkers of response/resistance, and suggest additional immunooncology combinations for specific molecular subsets of prostate and endometrial cancers. Clinical trial information: NCT03572478.
Trial in progress abstract phase I trial of 5-aza-4’-thio-2’-deoxycytidine (Aza-TdC) in patients with advanced solid tumors.
Authors: Monge B. M. Cecilia , O'Sullivan Coyne Geraldine Helen , Piekarz Richard , Takebe Naoko , Bruns Ashley , Mittra Arjun , Khan Sabrina Sharmin , Collins Jerry M. , Anderson Larry , Juwara Lamin , Miller Brandon , Kinders Robert J. , Rubinstein Larry , Chen Alice P. , Doroshow James H.
Published: May 2019

TPS3148

Background: The nucleoside analog 5-aza-4’-thio-2’-deoxycytidine (Aza-TdC) inhibits DNA methyltransferase 1 (DNMT1), a methyltransferase involved in methylation-mediated silencing of tumor suppressor genes. Attenuation of DNA methylation via DNMT1 inhibitors results in reactivation of silenced tumor suppressor genes and can lead to tumor growth arrest and apoptosis. The DNMT1 inhibitors decitabine and 5-azacytdine are currently FDA-approved for use in myelodysplastic syndromes and are also used in patients with acute myeloid leukemia. Relative to these compounds, Aza-TdC exhibits enhanced stability and incorporation into DNA and has shown improved preclinical antitumor activity in both leukemia and solid tumor xenograft models. This study seeks to evaluate the safety and maximum tolerated dose (MTD) of oral Aza-TdC in patients with advanced solid tumors. Secondary study objectives include assessing objective response by RECIST 1.1, pharmacokinetic (PK) analysis, and examining re-expression of tumor suppressor genes inhibited by methylation in circulating tumor cells (CTCs). Methods: Patients are treated with Aza-TdC on days 1-5 and 8-12 of each 21-day cycle. The study follows Simon accelerated titration design 3, with 100% dose increments and 1 patient per dose level. Accelerated titration will continue until 1 patient experiences a dose-limiting toxicity (DLT) or 2 patients experience drug-related grade 2 toxicity at any dose level, after which, a 3 + 3 dose escalation design will be used. Blood samples are collected for PK and CTC analyses. An MTD expansion cohort is planned, in which tumor biopsies will be collected for further pharmacodynamic assessments. Patients included in this study must be ≥18 years old and have histologically documented solid tumors that have progressed on standard therapy and for which there is no other standard therapy available. Dose level 3 has been completed without any DLTs; enrollment to dose level 4 began in February 2019. Funded by NCI Contract No. HHSN261200800001E. Clinical trial information: NCT03366116.
Update on the Drug Rediscovery Protocol: Expanded use of existing anticancer drugs in patients with a known molecular profile.
Authors: van Berge Henegouwen Jade Maxime , Hoes Louisa Rose , van der Wijngaart Hanneke , Van Der Velden Daphne Liselotte , Huitema Alwin , Cuppen Edwin P.J.G. , Lugtenburg Elly J. , De Vos Filip Yves Francine Leon , Bloemendal Haiko , Grunberg Katrien , Verheul Henk M.W. , Gelderblom Hans , Voest Emile E.
Published: May 2019

TPS3149

Background: With the emergence of large-scale genetic tumor profiling and the increasing availability of approved targeted therapies, precision medicine has become crucial in cancer treatment. However, for many cancers the relative contribution of either tumor type or genetic aberration to drug sensitivity often remains unknown. Since drug access is generally limited to the on-label indication and outcome of off-label use is not systematically collected in clinical practice, innovative trials facilitating drug access, whilst systematically analyzing treatment outcomes, are urgently needed. Methods: The Drug Rediscovery Protocol (DRUP) is an ongoing, prospective, non-randomized, multi-drug, and pan-cancer trial, in which patients with advanced cancer, who have exhausted all standard of care treatment options, are treated with either targeted or immunotherapy matched to their genetic tumor profile. All submitted patients are reviewed and enrolled in multiple parallel cohorts, preceded by a baseline tumor biopsy for whole genome sequencing to confirm previously identified variants and for exploratory biomarker analyses. Each cohort is defined by a study drug, histologic tumor type, and molecular tumor profile. Efficacy is analyzed per cohort: 8 patients in stage I and 16 more in stage II if ≥ 1 response is observed in the first stage. Primary endpoints include objective response rate, stable disease at 16 weeks, and grade ≥3 adverse events. Since the start of recruitment in September 2016, 870 patients have been submitted for review and 365 patients (42%) have started treatment in one of 101 opened cohorts. Eight cohorts have graduated to the second stage, two cohorts completed accrual in either their first or second stage, and one cohort was closed due to a registered indication. Twenty-two different study treatments (i.e. immunotherapy, monoclonal antibodies, and PARP/small molecule inhibitors), provided by 11 different pharmaceutical companies, are currently available in DRUP. Data sharing with similar trials such as TAPUR and CAPTUR enables to achieve completion of slow accruing cohorts and affirm conclusions. Clinical trial information: NCT02925234.
Basket of baskets (BoB): A modular, open label, phase II, multicenter study to evaluate targeted agents in molecularly selected populations with advanced solid tumors.
Authors: Brana Irene , Massard Christophe , Baird Richard D. , Opdam Frans , Schlenk Richard F. , De Petris Luigi , Vernieri Claudio , Chavarria Elena , Garralda Elena , van der Noll Ruud , Vivancos Ana , Wessels Lodewyk F. A. , Martin Jose-Ezequiel , Tamborero David , Dienstmann Rodrigo , Meijer Gerrit A. , Muñoz Susana , Piris-Giménez Alejandro , Calvo Fabien , Rodon Jordi ,   Cancer Core Europe
Published: May 2019

TPS3151

Background: Basket trials with targeted agents can show high response rates for tumors with specific molecular profiles, granting extension of the label of some drugs. In other cases, study results were disappointing, likely due to the rarity of molecular alterations, limits in trial design and the difficulties in applying molecular tumor profiling in the clinical setting. Methods: Basket of Baskets (BoB), NCT03767075, aims to bridge the gap between Academic Genomics and clinical applications (ready-to market multi-marker Companion Diagnostics) by providing a sustainable and adaptable (to new technologies, markers, and therapeutic agents) platform for co-development of drug/companion diagnostic. BoB is a novel platform trial from Cancer Core Europe, a recently established sustainable European network for innovative cancer research. This protocol has two parts: (1) Part A includes a molecular profiling program for subjects with advanced solid tumors (iPROFILER), a variant annotation tool, and a molecular tumor board to select the most appropriate treatment. It also enables testing/developing companion diagnostics linked with the therapeutic part (part B). (2) Part B includes iBASKET, a modular multi-arm basket trial for subjects with tumors harboing selected molecular alterations. Each module is focused on a certain molecular pathway or on certain molecular alterations that may confer sensitivity to the study drug or study drug combination evaluated in that module/arm. The current version of iBASKET (Module 1- Atezolizumab in genomically-selected patients) is open for enrollment for patients with advanced neoplasms bearing one of the following alterations: Arm 1A: BRCA1 or BRCA2; Arm 1B: MLH1, MSH2, MSH6, PMS2; Arm 1C: POLE, POLD1 mutations; Arm 1D: hypermutated tumors; Arm 1E: other mutations in DNA-repair genes; Arm 1F: PDL1 gene amplification. All patients enrolled in Module 1 will receive single-agent atezolizumab. New Modules for genomically selected populations can be added through amendments. Our final aim is to achieve drug repurposing of treatments, co-develop multi-marker companion diagnostics and a large database of knowledge in Precision Medicine. Clinical trial information: NCT03767075.