bluuebunny/crossref_metadata_2025 huggingface dataset:
Breast cancer patients' willingness to travel to participate in a clinical trial.
Authors: Zdenkowski Nicholas , Lynam James F. , Wall Laura , Brown Scott , Wells Kathryn , Sproule Victoria
Published: September 2018

e14031

Background: The option of clinical trial participation is an important component of high quality care for oncology patients. Despite a recognised need for generalizable research results to guide future practice, and the desire of current oncology patients to participate in trials, only 2-5% of oncology patients in developed nations enroll in a clinical trial. We aimed to determine the willingness of patients to travel, change location and/or clinician to participate in a clinical trial. Methods: Members of a national breast cancer consumer organization were invited by email to respond to an online cross-sectional survey. Questions included demographics, remoteness of residence, prior involvement in clinical trials and location of usual care. This was followed by a Discrete Choice Experiment (DCE) comprising an introduction and 10 hypothetical scenarios to test the effect of variation in travel time, clinician, treating centre, travel cost and type of trial. Results: Between July and August 2016, 288 responses were received, mean age 58. 86% had early stage disease, 51% were currently receiving treatment, 21% had prior clinical trial involvement. Ninety percent were willing to participate in a clinical trial in at least one scenario. Factors that decreased the likelihood of interest in clinical trial participation were increasing travel time, change in oncologist and out of pocket expenses. Type of trial (randomised placebo controlled; randomised open label; single arm) did not influence the decision. If the oncologist remained the same and there were no costs, respondents were willing to travel a mean extra 127 minutes, however if the oncologist changed and there were additional costs, they were willing to travel a mean of 30 minutes. If the oncologist changed and there was no cost, they were willing to travel a mean of 82 minutes. Conclusions: This group of respondents with a past history of breast cancer expressed interest in clinical trial participation, however willingness to travel in the most likely scenario (change oncologist and pay no additional cost) was 82 minutes. To facilitate optimal access to clinical trials, clinicians should consider referral within and between institutions.
A bioequivalence study of proposed bevacizumab biosimilar, MYL-1402O (A) vs EU-Avastin (B) and US-Avastin (C).
Authors: Socinski Mark A. , Hummel Matthew , Bosje Tjerk , Shaw Andrew , Liu Mark Shiyao , Baczkowski Mark , Barve Abhijit , Kothekar Mudgal , Pennella Eduardo J.
Published: September 2018

e14034

Background: MYL-1402O is a proposed bevacizumab biosimilar. The similarity of MYL-1402O to Avastin has been demonstrated in physicochemical analyses, and nonclinical studies. Methods: This single-center, randomized, double blind, three-arm, parallel-group, study was conducted in healthy adult male volunteers. The primary objective of this study was to establish PK similarity of A to B and C, and B to C. Subjects were randomized to receive either A, B or C 1 mg/kg over 90 minutes as an intravenous infusion. Dose was selected based on the lower dose in the linear range of PK and acceptable safety in healthy volunteers. Bioequivalence was to be concluded if the 90% CIs of the ratios (A/B, A/C and B/C) of LS means of the natural log transformed AUC0-inf were within 80% to 125%. AUC0-t, Cmax, tmax, kel and t½ were assessed as secondary PK parameters. Results: A total of 111 subjects (37/treatment) were enrolled and 110 [37 (A), 36 (B), 37(C)] were included in the analysis. Bioequivalence was demonstrated between A and B, A and C and between B and C. LS mean ratios were close to 1, and 90% CIs were within 0.80 to 1.25 for all of the comparisons. The secondary PK parameters were also comparable with the 90% CIs for ratios of AUC0-t and Cmax within 80%-125%. A total of 313 TEAEs were reported, 116 by 33 (89%) subjects who received A, 99 by 29 (78%) subjects who received B and 98 by 28 (76%) subjects who received C. Most TEAEs were consistent with the clinical data of bevacizumab (Avastin). No serious or unexpected TEAEs were reported. TEAEs were grade 1 or grade 2 in severity. The anti-drug antibodies are being evaluated (pending results). Conclusions: These results confirm bioequivalence of Myl-1402O vs. EU-Avastin and US-Avastin. All treatments were well tolerated and no significant safety issues emerged. Clinical trial information: NCT02469987 Clinical trial information: NCT02469987.
A phase Ia/Ib trial of the DNA-dependent protein kinase inhibitor (DNA-PKi) M3814 in combination with radiotherapy in patients with advanced solid tumors.
Authors: Van Triest Baukelien , Damstrup Lars , Falkenius Johan , Budach Volker , Troost Esther , Samuels Michael , Goddemeier Thomas , Geertsen Poul F.
Published: September 2018

e14048

Background: DNA-PK, with its protein subunits, Ku70 and Ku80, regulates one of the major pathways responsible for repair of double-strand breaks in DNA that are induced by radiotherapy (RT) and some chemotherapeutic agents (CT). Therefore, the combined strategy of RT with a DNA-PKi is promising. The purpose of this phase I trial is to explore the safety, tolerability, pharmacokinetic (PK) profile, and clinical activity of M3814 administered together with RT and chemo-RT (CRT). Methods: Patients (pts) with tumors or metastasis in the head and neck region or thorax in need of palliative RT (10 x 3 Gy) are eligible for the dose escalation part Ia, with a starting dose of 100 mg once daily. Dose escalation decisions are aided by the Bayesian logistic regression model with overdose control. Dose-limiting toxicity (DLT) is evaluated up to 3 weeks after RT. Rich PK sampling is taken during treatment. Tumor evaluation is performed every 6 weeks up to 6 months and every third month thereafter. Results: As of January 2017, 7 pts had been enrolled into the part Ia dose escalation arm and treated with 100 mg daily. The most frequent adverse events (AEs) were fatigue, constipation, decreased appetite, dry mouth, dysphagia, headache, oral pain, radiation skin injury, and mucositis in more than 1 pt (20%). No pts discontinued due to AE. Two episodes of grade 3 mucositis lasting > 7 days were reported; one of these was classified as a DLT, and both pts recovered without sequelae. Two of 7 pts enrolled had local tumor control at +300 days. PK analysis demonstrated high exposure variability. Conclusions: M3814 at the 100 mg daily dose was tolerable as palliative treatment and dose escalation is currently at 200 mg. In part Ib of the study, two separate dose escalation arms will enroll pts with either head and neck squamous cell carcinoma (SCCHN; US only) or non-small cell lung cancer (EU and US) to receive CRT 2 Gy x 30-35 over 6-7 weeks with curative intent; the SCCHN cohort is now open for enrollment. For these two cohorts, the DLT window will be 12 weeks. Clinical trial information: NCT02516813.
A first in human study using photodynamic therapy with Redaporfin in advanced head and neck cancer.
Authors: Oliveira Julio , Monteiro Eurico , Santos Juliana , Silva Jose Dinis , Almeida Luis , Santos Lúcio Lara
Published: September 2018

e14056

Background: Photodynamic therapy (PDT) may be an appealing approach when head and neck cancer (HNC) patients (pts) develop locoregional standard treatment failure. Currently available systemic photosensitizers (PST) present several limitations, such as longstanding photosensitivity. Redaporfin is a new PST specifically designed to achieve improved efficacy and safety over existing options. Methods: This phase I/IIa clinical trial had the objective to determined Redaporfin tolerability, anti-tumor effect and pharmacokinetics (PK). “Dose-finding phase”: each patient was submitted to a single-ascending dose of Redaporfin, administered by iv infusion, lasting 10-20 minutes, in ≥ 21 days interval; drug was titrated up to a dose that, in combination with a laser light of 50 J/cm2 at 749±3 nm, was safe and caused tumor necrosis (“effective dose”) in a spot of 1.0 cm of diameter of tumor surface. “Final PDT session”: all accessible tumor was treated with the individual effective dose. Results: Thirteen pts (10 men, 3 women; median age 62 yrs; range 35-80) with advanced HNC in symptomatic treatment were submitted to Redaporfin doses: 0.05 mg/kg (n = 6), 0.1 mg/kg (n = 4), 0.25 mg/kg (n = 2), 0.5 mg/kg (n = 4), 0.75 mg/kg (n = 6) and 1.0 mg (n = 1). Treatment-related adverse events (TRAE): 2 pts had grade (G) 3 photosensitivity reaction (PR) after accidental exposure to intense sun-light (0.75 mg/Kg dose); G≤2 TRAEs in 7 pts (G2 infusion-related reactions in 2 pts and PR in 2 pts). Photodynamic effect was observed in all subjects at doses ≥ 0.5 mg/kg and was dose-dependent; 0.75 mg/kg dose caused necrosis in 1 cm diameter target spot deeper than 5 mm. The patient submitted to final PDT session achieved complete tumor necrosis of treated area. PK showed to be linear; drug was eliminated from the body in a relatively fast manner (half-life of 19 hrs following Redaporfin 0.75mg/Kg). Reported data allowed to conclude phase I part of the trial; next steps of clinical development were authorized. Conclusions: Redaporfin effective dose was established at 0.75 mg/Kg. PDT with Redaporfin revealed anti-tumor effect and was safe in patients with advanced HNC. Further research with this promising compound is ongoing. Clinical trial information: NCT02070432.
Phase Ib pharmacokinetics of non-hormonal SM88 in patients with non-metastatic recurrent prostate cancer.
Authors: Del Priore Giuseppe , Rothman John , Sokol Gerald H. , Hoffman Karen , Retter Avi S. , Hoffman Steve
Published: September 2018

e14061

Background: SM88 is a combination of tyrosine isomers ( TI) and repurposed drugs (modulators of CYP3A4, mTOR, and oxidative stress). This regimen has previously reported non-toxic activity in cancers including prostate (PC) ( J Clin Oncol 2013 31: e22095). We present summary data from a completed Ib trial of non-metastatic recurrent PC (nmPC), an ideal candidate for a well-tolerated, non-androgen based treatment. Methods: This was an open-label safety and PK trial of SM88 in patients with nmPC. Cohort 1 received 230 and cohort 2 - 460 mg/day of TI, along with the lowest available doses of the other 3 agents. Multiple samples were drawn at pre-dose and up to 48 h post dosing from 4 patients after a single TI dose; after a single dose of all 4 components; and after 2 weeks of steady state daily combined dosing (SS). Only cohort 2 results are presented. Results: See table below. Each of the 3 approved drugs had expected PK results that will be provided. There was no evidence that the combination altered the expected PKs at SS. There were no serious drug related adverse events. Favorable biomarker activity was documented at both TI dose levels. Conclusions: Single dose and SS TI results from this completed phase Ib trial are consistent with preclinical predictions (ESMO 2016. Ann Oncol (2016) 27 (suppl_6): 1605P). TI PK results changed transiently with the additional components but returned to desirable levels at SS including a higher Cmax, AUC, and more rapid Tmax, indicating rapid absorption. The PK results (not shown) are consistent with the published data for the approved agents, despite the use of lower than typical label doses. Based on these results, the higher TI dose was chosen for the ongoing phase II expansion cohort in nmPC patients. SM-88 appears to have predictable PK as an effective metabolomic regimen for the treatment of advanced prostate cancer devoid of significant toxicities. [Table: see text]
Hypomagnesemia and exposure to romidepsin: A Research on Adverse Drug events and Reports (RADAR) project.
Authors: Lee Dylan E. , Serrano Linda , Martinez-Escala Estela , Kaplan Jason B. , Pro Barbara , Guitart Joan , Temps William H. , West Dennis P. , Belknap Steven M.
Published: September 2018

e14072

Background: Romidepsin (R) is indicated for cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma. Hypomagnesemia (HM) is common in these patients and is also listed in the Full Prescribing Information (FPI) for R. Moreover, since cardiac arrhythmias are associated with HM, patients exposed to R may be at higher risk. This study assessed whether HM was causally related to R exposure and to what extent magnesium (M) supplementation was undertaken in those with HM. Methods: We searched a large, U.S. patient data repository to detect all patients (aged 20-94 years) exposed to R (10/2010-01/2017). For these patients, serum M, as well as M supplementation data, was collected. Baseline M was assessed at initial R exposure, and HM was defined as either, a decline in M to < 1.8 mg/dL after R exposure or, in those with baseline M < 1.8 mg/dL, a decline in M by ≥0.1 mg/dL after R exposure. For each patient with HM after R exposure, the validated Naranjo Adverse Drug Reaction Probability Scale (NADRPS) was used to determine the probability that HM was caused by R. Results: Of 51 R-exposed CTCL (or other lymphoma) patients, 25 (49.0%) had HM. Of these 25, NADRPS scores yielded: 1 doubtful, 16 possible, 8 probable and 0 definite. Additionally, 24 of 25 patients with HM had documentation for presence or absence of M supplementation: 9 (37.5%) had supplementation with M agents considered to be bioavailable, 12 (50%) received M agents considered to have low bioavailability, and 3 (12.5%) had no M supplementation. Conclusions: In this study population, 25 of 51 (49.0%) patients had HM after R exposure, which appears to nearly double the percentage of patients described in the FPI. Moreover, 8 of 25 (32%) patients with HM had causality attributed to R exposure. In addition, 15 of 24 (63%) patients with HM received M supplementation with agents considered to have low bioavailability or received no M supplementation. These findings support the need for ongoing monitoring of R-exposed patients with low M, as well as the importance of repleting M with agents considered to be adequately bioavailable. Also, given that HM appears to be more frequent in this study population compared to pre-marketing data in the FPI, further studies are warranted.
Combination of WEE1 and AURKA inhibition in HPV negative head and neck squamous cell carcinoma.
Authors: Parameswaran Janaki , Lee Jong Woo , Sandoval-Schaefer Teresa , Koo Jaseok P. , Burtness Barbara
Published: September 2018

e14105

Background: Aurora Kinase A (AURKA) is overexpressed in HNSCC, and correlates with poor prognosis. It has been identified as a potential therapeutic target, yet the response rate for the AURKA inhibitor MLN8237 is only 9% in treatment refractory HNSCC. We hypothesized that although AURKA inhibitors lead to defective spindle assembly, they may also reduce mitotic entry, undermining cytotoxic effect. We predicted that adding a WEE1 inhibitor to an AURKA inhibitor would mitigate this effect and enhance cell death Methods: Cell viability assays were performed on FaDu ( p53 mut.), Detroit562 ( p53 mut.), and UNC7 ( p53 WT) HPV negative HNSCC cell lines treated with AZD1775 (AZD), MLN8237 (MLN), and combination of AZD+MLN. Oncosphere formation assays were used to confirm findings of cell death, and western blot analysis and confocal microscopy were used to investigate mechanism of synergy. The above drugs were also given at varying doses via oral gavage to FaDu xenografted nude mice. Results: There was clear synergy of AZD and MLN in-vitro. Combination Indices were determined by the Chou-Talalay method: FaDu 0.4, Detroit562 0.5, and UNC7 0.6 (synergy = < 0.8). Oncopshere assays showed inability of AZD+MLN treated cells to re-differentiate. FaDu cells treated with MLN had increased p-CDK1 and reduced phospho-histone H3 (pHH3), suggesting reduced mitotic entry. AZD+MLN treated cells had reduced p-CDK1 and increased pHH3, similar to AZD treated cells; they also had spindle disarray with poor chromatin organization on confocal microscopy indicating mitotic catastrophe. In mice, the combination of AZD+MLN inhibited tumor growth, with no apparent toxicity. Mice treated with either drug alone had tumor volumes over 1000mm3 and were sacrificed at day 21; those treated with AZD 90mg/kg and MLN 30mg/kg had tumors volumes around 300mm3 on day 28. Conclusions: AZD and MLN synergistically enhance cell death in HNSCC cell lines and significantly inhibit tumor growth in mouse xenograft models. The ability of AZD to overcome intrinsic resistance to MLN may underlie mechanism of synergy. We recommend further investigation of AURKA and WEE1 inhibition in other cancers with high AURKA expression, and in patients with HNSCC.
Immunomodulatory effects of tyrosine kinase inhibitors (TKIs) in renal cell carcinoma (RCC) patients.
Authors: Nuti Marianna , Zizzari Ilaria , Napoletano Chiara , Botticelli Andrea , Calabro Fabio , Gelibter Alain , Rughetti Aurelia , Ugolini Alessio , Ruscito Ilary , Mazzuca Federica , Rahimi Hassan , Onesti Concetta Elisa , Cortesi Enrico , Marchetti Paolo
Published: September 2018

e14506

Background: RCC is considered a highly immunogenic tumor responding to anti-angiogenetic TKI and immunotherapy. A better understanding of the functions of immune cells in RCC, the immune-modulatory effects of TKIs treatment as well as defining patients most likely to benefit to the different therapies will be crucial to optimize combined or sequential immunotherapeutic approaches in RCC patients. Methods: Monocyte derived Dendritic Cells (DCs) from 10 healthy donors were differentiated in presence of Pazopanib and Sunitinib used at plasmatic equivalent concentration (Sigma-Aldricht). At the end of the culture, DCs were characterized for marker expression, endocytosis, signal transduction and microvesicle release. Similarly, DCs derived from RCC patients were analyzed together with circulating T cells before and during TKI treatments. Results: Pazopanib and Sunitinib differently affect DC differentiation. Pazopanib, but not Sunitinib, strongly improves DC performance as antigen-presenting cells, promoting the upregulation of the maturation markers HLA-DR (+1,5 fold increase compared to Sunitinib-treated DCs), CD40 (+3 fold increase) and CCR7 (+2 fold increase) a decrease in phagocytosis and the inhibition of pERK1/2 signaling. 99% of Sunitinib-DCs expressed PD-L1 vs 80% Pazopanib-DCs , with a higher expression of the receptor as indicated by mean fluoresce intensity (MFI fold increase of +2,1). Similar results were obtained analyzing shedded microvesicles. Results were confirmed in DCs differentiated from RCC patients during Pazopanib treatment (before and at 30 and 60 days) and suggest a reverse of the tumor induced immunosuppression. Moreover, only Pazopanib treatment appears to induce in these patients a defined circulating CD4+ T cell population highly expressing CD137 molecule (%CD4+CD137+: T0:0,3; T30: 4,7; T60:29,4). Conclusions: TKIs can affect immunity in RCC patients. In particular, Pazopanib appears to function as a potent activator of DCs in vitro and in vivo associated with the neo-activation of a CD137+ T cell population. These results can guide for designing novel protocols to combine TKIs with immunoregulatory receptors targeting in RCC.
Radiomic biomarkers for the prediction of immunotherapy outcome in patients with metastatic non-small cell lung cancer.
Authors: Trebeschi Stefano , Kurilova Ieva , Călin Adriana M. , Lambregts Doenja M. J. , Smit Egbert F. , Aerts Hugo , Beets-Tan Regina GH
Published: September 2018

e14520

Background: PD-1 checkpoint inhibitors have recently been approved for the treatment of patients with metastatic NSCLC. Predicting to what extent patients will benefit from these treatments is challenging. Research on predictive biomarkers focus on genetic and histological markers from biopsies, necessarily limited to parts of the tumor. Radiomics is a novel approach to quantify characteristics of the tumor on medical imaging, which may have potential value as non-invasive biomarkers. In this study, we explored the value of radiomic data from primary tumors to predict overall survival (OS) in patients with metastatic NSCLC treated with Nivolumab Methods: We retrospectively selected 64 metastatic NSCLC patients treated in 2ndline setting with Nivolumab (240 mg q 2 weeks until progression). Inclusion criteria were: primary tumor in situ with contrast enhanced CT scan (thorax abdomen; slice thickness ≤3mm) within 6 weeks before the start of the treatment. Exclusion criteria were: presence of atelectasis or fusion with other structures and presence of multiple lung lesions at first scan. A certified radiologist delineated the tumors on CT from which we extracted 1696 Radiomic features. Unsupervised feature selection was performed. Multivariate Cox Regression was used to model the OS based on the selected features, as well as, histopathological type (adeno vs squamous), age at the start of the treatment, and extent of metastatic disease ( < 5, 5–10, or > 10 metastasis) Results: The selection resulted in three textural features derived from a Laplacian of Gaussian (LoG): regions dissimilarity (GLRLM_rlnun), entropy (GLSZM_ze), and uniformity. The resulting model was significant (p = 0.005). Both regions dissimilarity (HR = 0.11, 95% CI 0.03–0.46, p = 0.002) and entropy (HR = 0.20, 95% CI 0.06–0.67, p = 0.009) were significant predictors of OS. Subtype and disease extent were close to significance (p = 0.099) Conclusions: Results indicate that more heterogeneous tumors with irregular patterns of intensities showed better OS. The availability of CT scans makes Radiomics a potentially valuable adjunct to other clinical biomarkers. Further validation of our findings in larger cohorts are warranted
Combination of biomarker and clinicopathologic characters to circle out beneficiaries through second-line immunotherapy: A meta analyse.
Authors: Zhang C , Zhong Wenzhao , Dong Zhong yi , Wu Yi-Long
Published: September 2018

e14535

Background: Programmed cell death ligand 1 (PD-L1) expression had been proposed as predictive biomarker to immune-checkpoint inhibitors. Yet treatment responses are not always consistent with this single agent in the second-line therapy of non-small cell lung cancer (NSCLC). Whether combination of PD-L1 and clinicopathologic characters could circle out optimal beneficiaries are still unknown. Methods: We performed a meta-analysis of randomized control trials that compared immune-checkpoint inhibitors against chemotherapy in second-line therapy. Data including smoking status, EGFR status, KRAS status and histology were extracted as subgroup analyse to estimate the potential predictor of efficacy for anti PD-1/L1. Results: Five clinical trials that compared immune-checkpoint inhibitors against chemotherapy for second-line therapy were included. Both PD-L1 positive (HR = 0.64, 95%CI = 0.56-0.73, P < 0.00001) and PD-L1 negative (HR = 0.88, 95%CI = 0.78-1.00, P = 0.05) favored anti PD-1/L1. Subgroup analyse indicated that adenocarcinoma (ADC) as well as squamous cell carcinoma (SCC) preferred anti PD-1/L1. Never smokers may not benefit from anti PD-1/L1 but current/ever smokers did (HR = 0.70, 95%CI = 0.63-0.79, P < 0.00001). Patients with EGFR mutation could not gain benefit from anti PD-1/L1 while the EGFR wild type could (HR = 0.67, 95%CI = 0.60-0.76, P < 0.00001). Both KRAS mutation (HR = 0.60, 95%CI = 0.39-0.92, P = 0.02) and wild type/unknown (HR = 0.81, 95%CI = 0.67-0.97, P = 0.02) were apt to anti PD-1/L1. Conclusions: Regardless of PD-L1 status, immune-checkpoint inhibitors could achieve better efficacy than chemotherapy in second-line therapy. Current/ever smokers without EGFR mutations may benefit more from anti PD-1/L1. Combination of PD-L1 and strongly relevant clinicopathologic characters should be considered to tailor optimal patients for anti PD-1/L1.
Utilizing IL-7 to generate melanoma antigen T cell receptor-modified cells for adoptive transfer in the absence of activation.
Authors: Wang Siao-Yi , Scurti Gina , Dalheim Annika , Moore Tamson , Nishimura Michael
Published: September 2018

e14552

Background: Metastatic melanoma remains a fatal disease as many patients fail to respond to novel therapies. Presently, we have an ongoing trial utilizing T cell receptor (TCR)-modified cells reactive to the melanoma antigen, tyrosinase, for treatment of metastatic melanoma (NCT01586403). Current protocols using viral vectors to generate cells for adoptive transfer require activation in the presence of IL-2. While IL-2 stimulates proliferation and production of mature effector cells, it also induces T cell exhaustion. We hypothesize that tyrosinase-reactive TCR-modified cells generated in the absence of activation have an increased potential for expansion, persistence, and anti-melanoma activity. In these studies, we investigate whether IL-7, a homeostatic regulator, facilitates the transfer of a tyrosinase-reactive TCR to lymphocytes without activation. Methods: Gene-modified cells were generated using a lentiviral vector including alpha and beta chains of a TCR reactive to tyrosinase and a truncated CD34 molecule as a transduction marker. Peripheral lymphocytes from normal human donors were transduced with lentivirus following no treatment, treatment with IL-7, or activation in the presence of IL-2. Transduced CD34 positive cells were isolated using magnetic activated cell sorting (MACS) and injected intravenously into NOD scid gamma (NSG) mice. Results: We found that IL-7 treatment improved transduction in non-activated cells and resulted in expression levels of CD34 and TCR variable beta chain 12 (vbeta12) comparable to cells activated in the presence of IL-2. When non-activated tyrosinase-reactive TCR-modified human T cells were adoptively transferred into NOD NSG mice, the cells were detectable in the peripheral blood of mice up to 7 days after transfer. Conclusions: These findings suggest that generating melanoma antigen TCR-modified cells in the absence of activation for adoptive transfer is feasible with IL-7 treatment. Ongoing studies in NSG mice transplanted with melanoma will help determine whether non-activated gene-modified cells will improve the efficacy and longevity of cell therapy for melanoma and other malignancies.
Autophagy (A) inhibition to enhance combined immunotherapy (I) and anti-EGFR treatment (E) in colorectal cancer (CRC).
Authors: Karamouzis Michalis , Koustas Evangelos , Mihailidou Chrysovalantou , Schizas Dimitrios , Papavassiliou Athanasios G.
Published: September 2018

e14554

Background: Resistance to E impairs survival of metastatic CRC (mCRC) patients. The aim of this study is to assess the preclinical activity of triple inhibition of E, I and A in CRC. Methods: RKO and Colo-205 cell lines were treated with E [cetuximab (C) / panitamumab (P)] and/or I [pembrolizumab (PE) or nivolumab (NI) with/without ipilimumab (IPI)] and/or autophagy inhibitor 3-Methyladenine (3-MA). Phosphorylated EGFR (pEGFR), p62 (SQSTM1), MAP1LC3 (LC3B) and PARP protein levels were detected by Western blotting. Cell viability was determined by MTT Assay. Tumor volumes were determined from 3D cell culture on Corning Matrigel Matrix as well as the apoptotic cell death. Results: E+I combination compared to E alone decreased pEGFR and increased A activation through p62 downregulation and LC3II activation. Similar results were shown for cell viability/apoptosis. Cells were also treated with C or P combined with I plus 3-MA. Triple inhibition suppresses EGFR and blocks A. Compared to E+I, triple inhibition reduced more cell growth/viability. Caspase-3 activity was increased as well as proportion of apoptotic cells (Table). Conclusions: Τhese results indicate that the combinatorial inhibition of A, E and I represents a promising treatment strategy in mCRC that needs further testing. [Table: see text]
In silico analysis of non-synonymous SNPs (nsSNPs) and outcomes in non-small cell lung cancer (NSCLC) patients (pts) treated with immunotherapy (IT).
Authors: Patel Kruti , Stein Matthew K , Morris Lindsay Kaye , Byrd Kenneth P , Weksler Benny , Schwartzberg Lee Steven , Fenton Moon Jung , Vanderwalde Ari M. , Martin Michael Gary
Published: September 2018

e14563

Background: Role of biomarkers in predicting benefit from IT in NSCLC is still evolving. These drugs are expensive and benefit less than 50% who receive them, despite PD-L1 status. We hypothesized cancers with increased pathogenic mutations would generate a more robust immune response resulting in increased benefit. Methods: We retrospectively identified NSCLC pts who received next-generation sequencing (NGS) from 2013-2015 by Caris. Pts were divided into those who received IT (IT+) during any line of therapy and those who only received conventional chemotherapy (IT-). PDL-1 status was determined by IHC. In silico analysis with PolyPhen-2 (Harvard) was utilized to predict the significance of nsSNPs. The total pathogenic coding changes (SUM) were defined as the sum of the known pathogenic mutations (MUTp) and pathogenic nsSNPs (pnsSNPs). Outcomes were compared for those with a SUM above (SA) and at or below (SB) the median. All p-values were two-sided: survival outcomes were compared by the log-rank test. Results: 149 NSCLC pts were identified, 99 IT- and 50 IT+. Of 99 IT- and 50 IT+, median age was 65 vs 64; 47% vs 40% females; 57% vs 74% white, 39% vs 18% black; 66% vs 60% adenocarcinoma, 21% vs 30% squamous; 13% vs 6% nonsmokers; 15% vs 6% received a TKI. Median nsSNPs for both were 4. In both groups the mutational burden (MB)- MUTp plus nonsynonymous changes without in silico prediction - did not predict survival (p = 0.27 and p = 0.50). 51% and 52% nsSNPs were predicted-damaging in IT+ and IT-. The median SUM in IT+ was 2 (0-7) and IT- was 2 (0-11). SUM did not predict OS in all comers (p = 0.17). SUM did not predict OS in IT- (p = 0.10) nor in IT+ (p = 0.19), though strong trend in opposite directions were seen. In SB pts, IT+ compared with IT- had no impact on OS (p = 0.38). In SA pts, IT+ had superior outcomes compared to IT- (OS 423d v 244, p = 0.01). PDL1 status did not predict OS in pts that received IT. Conclusions: While MB and PDL1 did not predict outcomes with IT, SA predicted improved OS with IT+ over IT- suggesting the combination of pnsSNPs and known pathogenic lesions may predict benefit from IT. These results need to be validated in a prospective trial but may help select pts that should receive IT.
Defining adverse events of anti-programmed-death-1 (Anti-PD1) agents using FDA adverse event reporting system (FAERS).
Authors: Xiao Kun , Lian Zhesi , Collins Robert , Dimou Anastasios , Garrett-Mayer Elizabeth , Drabkin Harry A.
Published: September 2018

e14568

Background: Anti-PD1 inhibitors are a promising therapeutic option in oncology. They have received FDA-approval in treating metastatic and relapsed non-small cell lung cancer, kidney cancer, head-and-neck cancer, and melanoma. Yet its adverse event profile is still being defined. The FAERS database contains information on adverse events and medication error reports submitted to the FDA and serves to support the post-marketing safety surveillance program for drug and therapeutic biologic products. Methods: We searched the FAERS database from January 1, 2015 to June 30, 2016. Only initial cases reported by an MD or pharmacist for treatment of cancers of the lung, kidney, head and neck, or melanoma were included. Cases with incomplete starting, ending or event dates were excluded. The primary outcome was time from drug initiation to onset of the event. Cox proportional hazard model was used to evaluate the association between time to AE and age, gender, disease, and time of report. Results: A total of 105 adverse events (AEs) were identified. Of those AEs, 68 were related to nivolumab, 35 to pembrolizumab, and 2 to atezolizumab. Fifty-six AEs were seen in lung cancer patients, whereas 46 were in melanoma, 2 in kidney cancer and 1 in a head and neck cancer patient. Thirty-three AEs involved pulmonary complications, 30 gastrointestinal systems, 17 endocrine, and 9 were constitutional in nature. The median onset of AEs from the start of therapy was 31 days (range: 2 - 459 days). Using a Cox regression analysis, pembrolizumab was associated with a longer time to AEs compared to nivolumab (HR 0.48, 95%CI: 0.26 - 0.89). Also age between 60 and 70 was associated with a longer time to the onset of AEs compared to age < 60 (HR 0.61, 95%CI: 0.37-0.99). Conclusions: FAERS is a vigilance system to monitor AEs from anti-PD1 inhibitors. Pembrolizumab and age between 60 and 70 were associated with less AEs. Ongoing data accrual will increase the statistical power and analysis of AEs from anti-PD1 inhibitors in greater detail.
Nonconventional responses and survival benefit of immunotherapy in advanced lung cancer.
Authors: Yogarajah Meera , Kuszyk Brian S , Stroud Chipman Robert Geoffrey , Cherry Cynthia R. , Walker Paul R.
Published: September 2018

e14572

Background: Objective response rates (ORR) utilizing RECIST or WHO criteria have been traditionally used as clinical endpoints to assess efficacy of cytotoxic chemotherapy. However in the era of immunotherapeutic agents, response rate assessment can be misleading due to nonconventional responses resulting in premature discontinuation of treatment. Wolchok et al proposed immune-related response criteria (irRC) to assess immune responses in melanoma. He also noted that stable disease which is not indicative of antitumor activity could be a potential surrogate marker of better clinical outcome. Brahmer et al reported nonconventional pattern of responses with Nivolumab in lung cancer. Methods: A retrospective chart review was done to assess differences in responses utilizing both RECIST v1.1 and irRC criteria in lung cancer patients treated with Nivolumab. Patients who received minimum of 4 cycles of Nivolumab were included in the study. The CT scans were reviewed by a senior radiologist. We reviewed 64 patients treated with Nivolumab between 4/30/2015 to 6/21/2016 and 30 patients were found eligible. Results: Patient characteristics. Male 53%; median age 61 years; squamous 47%; adeno 40%; small cell 13%; Median cycles of Nivolumab 6. Response rates utilizing both criteria was essentially similar with only 2 patients showing dis-concordant responses (6.6%). We utilized RECIST responses criteria for further analysis. Partial response (PR) 2/30; stable disease (SD) 12/30; progressive disease (PD) 15/30 and not evaluable (NE) 1/30. ORR 6.6%. Kaplan–Meier curve was used to analyze difference in survival between patients with PR+SD and PD. The median survival for PD was 9 months and PR+SD was not reached at median follow up of 1 year. Overall survival at 1 year for PD 33% and PR+SD 60% (p = 0.048). Hazard ratio for PD was 3.060 (p = 0.60). Conclusions: Patients with stable disease had a better survival and should be considered as responders though traditionally not included in the ORR. However irRC did not help in differentiating nonconventional immune responses in lung cancer patients. [Table: see text]
Toxicities associated with checkpoint inhibitor immunotherapy: The Karmanos Cancer Center experience.
Authors: Nagasaka Misako , Alhasan Roba S , Crosby Marcus , Thummala Nithin , Kim Seongho , Abrams Judith , Sukari Ammar
Published: September 2018

e14575

Background: PD-1 inhibitors work by re-instating the natural anti-cancer immune-mediated cytotoxicity. Although this new class of therapy offers hope for many advanced stage cancer patients (pts), data on pts who are more likely to experience adverse events (AE) are not available. Methods: Data from pts who received at least one dose of PD-1 inhibitors before August 31, 2016, were captured from our institution’s pharmacy database. AE of anemia, neutropenia, thrombocytopenia, acute kidney injury, hypothyroidism, transaminitis, pneumonitis, colitis and fatigue were recorded and graded based on CTCAEv4. Baseline pt characteristics were statistically compared between subjects who received PD-1 inhibitors on a clinical trial vs as part of standard of care (on vs. off-study) by Fisher’s exact test for categorical variables and Kruskal-Wallis test for continuous variables. Univariable and multivariable logistic regression models were fit to assess associations between toxicities (Grade0-1 vs. Grade2+) and predictors (age, agent, primary tumor, and trial status). Results: 231 pts received at least one dose of PD-1 inhibitors prior to data cut-off. Median age was 65 (24-92) off trial (n = 125) and 59. 5 (25-79) on trial (n = 106). There were 117 (51%) non-small cell lung cancer (NSCLC), 41 (18%) renal cell carcinoma (RCC) and 73 (32%) others. 24 (10%) melanoma, 18 (8%) Hodgkin’s lymphoma (HL), 9 (4%) head and neck squamous cell carcinoma (HNSCC), 8 (4%) small cell lung cancer (SCLC) were included in others. 129 (56%) had nivolumab alone, 50 (22%) had pembrolizumab alone and the rest 52 (23%) received combination treatment. Pts participating in a clinical trial had higher odds to experience grade 2 or more pneumonitis than those not on a trial (unadjusted p = 0.038). On trial pts had lower odds to experience grade 2 or more fatigue than those receiving the agent as standard of care (unadjusted p = 0.026) which remained significant after adjusting age, agent (single agent vs combination) and primary tumor (adjusted p = 0.004). Conclusions: In our observation, pneumonitis was seen more on clinical trials whereas fatigue was seen less.
A phase 1 trial of JS001, a monoclonal antibody targeting programmed death-1 (PD-1) in patients with advanced or recurrent malignancies.
Authors: Yang Sheng , Yang Jianliang , Han Ying , Qin Yan , Han Xiaohong , Dong Lihou , Feng Hui , Song Haifeng , Sun Yan , Shi Yuankai
Published: September 2018

e14581

Background: JS001, a humanized IgG4 anti-PD-1 antibody, showed potent anti-cancer activity in preclinical models. Notably, in vivo study suggests it promotes the proliferation of CD62L-CD45RA- effector memory cell effectively. A phase 1 dose escalation study was conducted to assess its safety, tolerability, pharmacokinetic (PK) profile and preliminary efficacy. Methods: This trial used a 3+3 design across 3 dose levels: 1, 3, 10 mg/kg/dose. At each level, two schedules were assessed: single dose and repeated doses every 2 weeks (up to 6 doses). JS-001 was administered as a 60-minute i.v. infusion. A dose limiting toxicity (DLT) was defined as a Grade≥3 drug-related adverse event (AE) occurring within 28 days of last dosing. Results: At the time of analysis, among 19 patients (pts) enrolled (single dose: 9 pts; multiple doses: 10 pts), no DLT was reported. Most treatment-related AEs were grade 1-2, including fever, diarrhea, rash, influenza-like symptoms, fatigue, mucositis, elevated transaminase and decreased lymphocyte count. One patient experienced grade 3 pneumonia. Although the cause of pneumonia is difficult to determine, and further assessment is ongoing, it resolved after prompt management. No treatment-related death occurred. The preliminary PK profile supports a biweekly schedule, and results in detail are under analyzing. 15 pts with evaluable lesions received response evaluation. Best responses were 1 CR (Hodgkin lymphoma, HL), 5 PR (HL: 3; soft tissue sarcoma, STS: 1; diffuse large B-cell lymphoma: 1) and 5 SD (non-small cell lung cancer: 3; head and neck cancer: 2), yielding a disease control rate of 11/15. Remarkably, a patient with STS achieved dramatic tumor shrinkage after a single injection of JS001. Biomarker analysis is in progress. Conclusions: JS001 is well tolerated and the preliminary efficacy results are promising. Updated data on the expansion cohorts at 3mg/kg and 10mg/kg will be presented. Clinical trial information: NCT02836834. Clinical trial information: NCT02836834.
HDAC and PD-1 inhibition in humanized triple-negative breast cancer xenografts.
Authors: Capasso Anna , Lang Julie , Pitts Todd M. , Francoeur Paul , Davis Sarah Lindsey , Lieu Christopher Hanyoung , Bagby Stacey M , Tentler John J. , Piscopio Anthony d , Diamond Jennifer Robinson , Pelanda Roberta , Eckhardt S. Gail
Published: September 2018

e14604

Background: There is great interest in investigating immune checkpoint inhibition in combination with novel agents, however, preclinical studies are limited by the lack of immune-competent human cancer cell line xenograft models. We developed a “hematopoietic” humanized mouse model to address this unmet need. HDAC inhibitors (HDACi) induce T-cell chemokine expression and enhance response to PD1 inhibitors in lung cancer models. We evaluated the combination of OKI-179, a novel Class I HDACi and nivolumab in our humanized mouse model. Methods: BRGS newborn pups were transplanted with CD34+ cells purified from umbilical cord blood. At 16 weeks, MDA-MB-231 cells were implanted in the flanks of the mice. When the average tumor size reached ~150-300 mm3, the mice were randomized into vehicle, nivolumab, OKI-179, or the combination treatment according to % chimerism. At the end of the treatment, mice were euthanized and tissues were collected for further analysis. Results: We observed a statistically significant improvement in tumor growth inhibition with the combination of OKI-179 and nivolumab (%TGI = 77%) as compared to single agent nivolumab (45%TGI). Nivolumab treatment led to a significant decrease in PD-1 expression on T cells. We also observed an increased number of TILs (CD8+ T cells) and T cells in the lymph nodes of treated mice suggesting T cell expansion. All mice were highly chimeric and responding tumors exhibited an increase in CD44 high IFN+ T cells. We observed a higher CD8% and a higher effector memory % (HLADR+, CD45RO+) in these mice. Conclusions: We successfully established a humanized TNBC human cancer cell line xenograft model, with tumor engraftment occurred in all humanized mice. Mice treated with nivolumab demonstrating the development of lymph nodes that were populated by activated T cells. The combo resulted in superior tumor growth inhibition. These preliminary results demonstrate that human immunity and PD-1 expressing T cells exist in these models and provide the basis for planned immunotherapy combination studies.
RECIST 1.1 versus immune-related RECIST and immune-related response criteria in assessing response to nivolumab in patients with lung, renal, and head and neck cancers.
Authors: Pathak Surabhi , Messinger Marina , Mullane Michael Russell
Published: September 2018

e14609

Background: Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 is reported to underestimate response to immunotherapeutic drugs. Therefore, immune related RECIST (iRECIST) based on RECIST 1.1 and immune related response criteria (IRRC) based on WHO response criteria have been studied, mainly in patients with melanoma. Whether RECIST 1.1 underestimates responses in other cancers is not well known. Aim of the present study is to assess response rates to PDL-1 inhibitor Nivolumab in lung, renal and head and neck (H&N) cancers using RECIST 1.1, iRECIST and IRRC. Methods: We reviewed patients from 2012 to present with lung, renal, H&N cancers treated with Nivolumab at John h Stroger Jr. Hospital of Cook County. Incomplete charts and those treated for less than 4 cycles of Nivolumab were excluded. Data was analyzed using descriptive statistics and Fisher exact test. Results: 47 charts were reviewed, 27 met the inclusion criteria. 17 lung (14 adeno, 3 squamous), 7 renal (5 clear cell) and 3 H&N cancer patients were included. Average age was 58.2yrs, 20(74%) were male. Average treatment was for 13 cycles. Response was assessed after at least 4 cycles. Disease control rate for lung, renal, head and neck cancer was 70%,58%, 33% respectively with RECIST 1.1 criteria compared to 77%, 71% and 66% respectively using immune RECIST or IRRC (P > 0.05). No patient developed pseudoprogression. Two had progressive disease per RECIST 1.1 but stable disease with iRECIST and IRRC. 26 of the 27 patients showed concordance between iRECIST and IRRC. One patient had stable disease per iRECIST but partial response per IRRC. Average survival after treatment initiation was 8.3 months for lung, 9.1 months for renal and 5.6 months for H&N cancer. Treatment was discontinued in 2 patients based on progression per RECIST 1.1, both patients had stable disease per iRECIST& IRRC. Conclusions: Trend towards underestimation of treatment response using RECIST 1.1 criteria compared to iRECIST or IRRC was observed. Strong concordance was observed between iRECIST and IRRC. Given relative ease of use, iRECIST might be favored over IRRC in response evaluation for immunotherapeutic drugs.
Association between baseline absolute neutrophil count (ANC), derived neutrophil-to-lymphocyte ratio (dNLR), and platelet-to-lymphocyte ratio (PLR) and response to nivolumab (Nivo) in non-small cell lung cancer (NSCLC): A preliminary analysis.
Authors: Russo Alessandro , Scimone Antonino , Picciotto Maria , Toscano Giuseppe , Raiti Fabio , Sava Serena , Battaglia Alessandra , Adamo Vincenzo
Published: September 2018

e14617

Background: Nivo is a novel therapeutic option in 2nd line NSCLC. However, predictive biomarkers are lacking. The presence of systemic inflammation correlated with poor outcome in many cancer types, including NSCLC. We aimed to evaluate whether there is a correlation between some indicators of inflammation and response in patients (pts) treated with Nivo or Docetaxel (D). Methods: 23 consecutive pts with NSCLC receiving Nivo were analyzed. Baseline white cell count (WBC) and ANC were collected and correlated with tumor response. 27 NSCLC pts treated with D were used as controls. An ANC ≥ 7500 cell/µl was defined neutrophilia. dNLR was calculated as: ANC/(WBC-ANC). Platelet count (PLT) ≥ 450 × 103/μL was defined as thrombocytosis. PLR ratio was defined as PLT/lymphocyte count. dNLR ≥3 and PLR ≥160 were defined high. Results: Baseline characteristics: median age 66 years (range 45-82); sex M 74%; histology squamous 42%, adenocarcinoma 48%, and 10% mixed histology/NOS. Smoking status: 90% smokers/former smokers. Among non-squamous pts, 13,7% were EGFR mutated and 10,3% were KRAS-mutated, with an equal distribution in both treatment groups. Lines of therapies: range 2-8 in Nivo group and 2-3 in D group. Overall response rate (ORR): 13.6% with Nivo vs. 7.7% with D; 9% of pts with Nivo experienced unconventional responses. Baseline neutrophilia (17.4% with Nivo and 27% with D) and thrombocytosis (4.3% and 3.8%, respectively) were not associated with response (ORR 0%). High dNLR (13% and 38% with Nivo and D) correlated with no response (0% ORR), whereas high PLR correlated with no responses to D and reduced ORR to Nivo (10%). Conclusions: The results of this preliminary study suggest that baseline neutrophilia, thrombocytosis and high dNLR are associated with no response to both D and Nivo, whereas high PLR is associated with no response to D and reduced activity with Nivo. Given their relative easy estimation, baseline evaluation of these indicators of inflammation should be included before 2nd line therapy start, especially for highly expensive treatments, such as immunotherapy.