tbuckley/cabot-search huggingface dataset:
Phase 1 study of NY-ESO-1 vaccine + ipilimumab (IPI) in patients with unresectable or metastatic melanoma.
Authors: Craig L. Slingluff, Hassane M. Zarour, Michael A. Postow, Philip Adam Friedlander, Craig E. Devoe, Kelly Smith, Donna Deacon, Mary J. Macri, Aileen Ryan, Ralph Rudolph Venhaus, Jedd D. Wolchok
Journal: Journal of Clinical Oncology (2018)

e15175 Background: IPI is an approved immunotherapy for advanced melanoma; it has enhanced spontaneous immunity to NY-ESO-1, a cancer-testis antigen expressed by some melanomas. NY-ESO-1 vaccines have been immunogenic when administered with Montanide ISA-51 (MON) and/or Poly-ICLC (pICLC) adjuvants. This trial assessed IPI combined with NY-ESO-1 vaccines (protein or overlapping long peptides [OLP4]). Primary objectives were to assess safety/tolerability and T-cell responses to NY-ESO-1. Secondary objectives included evaluation of tumor response (irRC). Methods: This Phase 1, open-label study (NCT01810016) enrolled patients (pts) with advanced measurable NY-ESO-1-positive melanoma among 3 arms: IPI (IV 3 mg/kg) + NY-ESO-1 protein + pICLC + MON (Arm A); IPI + NY-ESO-1 OLP4 + pICLC + MON (Arm B); and IPI + NY-ESO-1 OLP4 + pICLC (Arm C) every 3 weeks x 4. Circulating T cell responses were assessed by ex vivo IFN-gamma ELIspot assay. Response was defined as a 2-fold increase with vaccination and an increase of ≥10 IFN-gamma-secreting cells per 105 PBMC. Results: Target enrollment was 27. Eight pts (mean age 64, 6M/2F) were enrolled and treated in Arms A (5), B (2) and C (1). The study closed early due to slow enrollment. Seven pts received all 4 doses of IPI + vaccine. All 8 pts had ≥1 treatment emergent adverse event (TEAE); most common were fatigue, injection site reaction, pruritus, diarrhea, rash, skin induration and pyrexia. Three pts had serious TEAEs (SAEs) and Gr3 TEAEs; 1 pt (Arm C) had Gr4 lactic acidosis. Two pts (Arm A) had Gr3 TEAEs related to IPI: diarrhea (SAE), colitis (SAE) and large intestine hemorrhage (n = 1); and hypophysitis (SAE), nausea, vomiting, fatigue, decreased sodium, dehydration and hypotension (n = 1). Best responses were irSD (n = 4) and irPD (n = 4); 3 of these pts discontinued early due to disease progression (1 died). T-cell responses to NY-ESO-1 were detected in 6 of 8 pts (75%), including 4/5 Arm A, 2/2 Arm B, 0/1 Arm C. Conclusions: IPI + NY-ESO-1 vaccines were well tolerated by most pts, and many related TEAEs were attributable to IPI alone. Circulating T cell responses were induced in most pts and were evident ex vivo, suggesting that IPI may have enhanced T cell responses to NY-ESO-1 protein and OLP4. Clinical trial information: NCT01810016.
Clinical pharmacology assessment of PF-06647020 (PF-7020), an antibody-drug conjugate (ADC) targeting protein tyrosine kinase 7 (PTK7), in adult patients (pts) with advanced solid tumors.
Authors: Dawei Xuan, Xiaohua (Robert) Xin, Brenda Gibson, Tenshang Joh, Hequn Yin, Pamela D. Garzone, Jasgit C. Sachdev, Michael L. Maitland, Manish Sharma, Victor Moreno, Emiliano Calvo, Shivaani Kummar, Erica Michelle Stringer-Reasor, Nehal J. Lakhani, Anthony W. Tolcher, Darrin M. Beaupre
Journal: Journal of Clinical Oncology (2018)

2574 Background: PF-7020, an ADC composed of humanized monoclonal antibody (Ab) against PTK7, auristatin payload, and valine-citrulline linker, is being investigated in the ongoing first in human Phase 1 study in pts with advanced solid tumors resistant to standard therapy. We present preliminary results of clinical pharmacology assessments of PF-7020, including pharmacokinetic (PK) analyses, and exploratory exposure-response analyses for efficacy and safety endpoints. Methods: Non-compartmental PK analyses were conducted on data from dose escalation and expansion studies of once every 3 weeks dosing (Q3W). A semi-mechanistic model that integrates ADC, total Ab (TAb), and unconjugated payload (PL) was built to characterize PK. We explored the relationship between objective response rate (ORR, current 27%) in ovarian cancer pts (OVCA) and PF-7020 exposure (Cmin,C1D21) with logistic regression modeling. A semi-mechanistic PK-pharmacodynamic (PD) model was built to explore the relationship between PL concentrations and absolute neutrophil counts (ANC). Results: As of Oct 24, 2017, 112 pts were treated with PF-7020 at doses of 0.2 – 3.7 mg/kg Q3W. PK exposure increased in a dose related manner, with a terminal half-life for PF-7020 of approximately 3 days at 2.8 mg/kg. Integrated PK model suggests that deconjugation and proteolytic degradation of ADC played major roles in elimination of PF-7020, and PL formation. A significant correlation was identified between ADC Cmin,C1D21 and OVCA ORR based on univariate analysis (P < 0.05); ORR increased with higher Cmin,C1D21, suggesting pts with lower exposures may benefit from increase in dose/dosing intensity. PK/PD analysis suggests higher PL concentrations were associated with lower ANC. Conclusions: The PK exposure increased in a dose related manner, with a terminal half-life for PF-7020 of approximately 3 days at 2.8 mg/kg. Increase in PK exposure correlated with better clinical response in OVCA pts. The PL exposure appeared to correlate with ANC profiles. The preliminary PK/PD analyses support evaluating PF-07020 under once every 2 weeks dosing (Q2W) in the ongoing study.
Outcomes of advanced soft tissue sarcoma from dedicated medical oncology sarcoma clinic in North India and evaluation of the respective model.
Authors: Sameer Rastogi, Atul Sharma, Aditi Aggarwal, Naresh G, Adarsh Barwad, Ekta Dhamija, Rambha Panday
Journal: Journal of Clinical Oncology (2018)

e23561 Background: Data of advanced soft tissue sarcoma (STS) is sparse from developing world in the times of contemporary therapies. We started dedicated sarcoma medical oncology clinic in October 2015, first in North India. Methods: This is retrospective analysis of prospective database from adult sarcoma medical oncology clinic from October 2015 to Feb 2018. Besides treatment, patients were helped through involvement of palliative care team/local NGOs/sarcoma support groups. Indian government provides limited funds for patients who are not affordable for the treatment. Statistical analysis was done through SPSS version 23. Results: Total of 156 patients with 99 males (63%) and median age 41 (17-77 years). Hundred one patients (65%) were metastatic while 35% patients were locally unresectable disease. Majority (79%) of the patients at presentation were PS 1-2 while 21% patients were PS 3-4. Extremity primary site (25.6%) was the most common site followed by retroperitoneum (16%), lung (12.8%), head and neck (14%) and others(31%). Most common sarcomas were synovial sarcoma (22%), MPNST (16%), leiomyosarcoma (11.5%), pleomorphic undifferentiated sarcoma (7%) and others (43.5%). Of patients who were started on first line chemotherapy (n = 123), single agent doxorubicin was given in 34%, ifosfamide and doxorubicin in 18.6%, pazopanib in 13.5% and other regimens in 34%. 51 patients (41%) received targeted therapy during all the lines of treatment. At median follow up of 13 months median OS was 16 months. On univariate analysis for overall survival (OS) the significant factors were performance status ( PS 1 vs PS 2 vs PS3/4-Median OS- NR vs 9months vs 4m) OS, serum albumin(≥3.5g/dl vs < 3.5g/dl) 19m vs 9m, locally advanced disease vs metastatic (18 vs 12months) . On multivariate analysis the statistically significant factors were poor PS and metastatic disease. Conclusions: Performance status and the presence of metastasis are the most powerful prognostic factor in these patients. Good outcomes could be due to dedicated clinic with availability of targeted therapy with government help and local NGOs. This model can be replicated in rare tumors in India and other developing countries.
The effect of patient-to-patient variability in drug response on combination cancer therapies, from 1961 to today.
Authors: Adam Christopher Palmer, Bruce Allan Chabner, Peter Sorger
Journal: Journal of Clinical Oncology (2018)

e14552 Background: Combination cancer therapy is an important means to increase rates and durability of drug response. Superior responses to combination therapies are commonly interpreted as evidence that individual tumors respond more strongly to a combination than to a monotherapy, and combinations are often developed based on pre-clinical observations of drug additivity or synergy. Here we explore an alternative and historical hypothesis described by the Acute Leukemia Group B (E. Frei III et al, Blood, 1961), that combination therapy can confer benefit by providing multiple chances of a response to monotherapy. Methods: Frei (op cit) proposed that if drugs A and B act independently, their combination is expected to have Complete Reponse Rate of CRRAB = CRRA + (100 – CRRA)×CRRB. This model was adapted for progression free survival, PFS(t), and to consider cross-resistance between drugs, quantified by correlation in response ρ. Under the null-hypothesis that response in each patient equals the better of two potential responses to drugs given individually, PFSAB(t) = PFSA(t) + (100 – PFSA(t))× PFSB(t)×(1 – ρ). This model was compared to data derived from retrospective analysis of clinical trials of single drugs and drug combinations in advanced solid cancers. Cross-resistance ρ was estimated from ~4500 drug response measurements in patient-derived tumor xenografts. Results: A majority of the combination cancer therapies analyzed confer benefits consistent with independent drug action. This benefit arises from high inter-subject variability, and low cross-resistance between drugs. In a minority of cases responses exceed this expectation and are likely to represent true drug interaction. Conclusions: Independent drug action, without invoking additive or synergistic effects, provides a sufficient and parsimonious explanation for the superiority of many clinically approved combination cancer therapies and changes how trial data are interpreted mechanistically. Even when drug combinations exhibit additivity or synergy in pre-clinical models, patient-to-patient variability often makes independent action the dominant mechanism in clinical populations.
Relations between clinical outcomes and pharmacokinetics of irinotecan, oxaliplatin, and 5-fluorouracil during hepatic artery chronomodulated delivery of intravenous cetuximab in patients with extensive liver metastases from colorectal cancer: A translational study in European trial OPTILIV.
Authors: Francis Levi, Abdoulaye KarabouÃ©, Marie-Christine Etienne-Grimaldi, Gilles Paintaud, C. N. J. Focan, Pasquale F. Innominato, Mohamed Bouchahda, Gerard Milano, Etienne Chatelut
Journal: Journal of Clinical Oncology (2016)

e15006 Background: The combination of hepatic artery infusion (HAI) of irinotecan, 5-fluorouracil and oxaliplatin (IFO) with iv cetuximab (Cet) achieved prolonged survival in colorectal cancer patients (pts) with extensive liver metastases (LM-CRC) despite prior chemotherapy (Lévi et al. Ann Oncol 2016). Systemic drug and metabolite exposure is unknown during the HAI delivery of combination chemotherapy in patients with extensive liver metastases. Methods: We estimated the plasma pharmacokinetics of IFO and their main metabolites during the first course of chronomodulated triplet HAI, and related them to toxicity (CTC-AE grades) and efficacy. Results: 11 patients, 7 males, 4 females, aged 33 to 72 years, had PS = 0, one to three prior intravenous chemotherapy protocols, a median number of 7 liver metastases, involving a median number of 7 liver segments. Maximal concentration (Cmax) and area under the curve (AUC) for all drugs and metabolites were not related to response, progression-free survival and overall survival. In contrast, consistent associations were found between the AUC of irinotecan, SN38, total oxaliplatin and platinum ultrafiltrate (P-UF), and leukopenia grade after first course (Spearman test, |r| > 0.50; 0.05 < p < 0.08).Moreover, P-UF Cmax and AUC significantly predicted for the grades of diarrhea (|r| = 0.82, p = 0.004 and |r| = 0.73, p = 0.017, respectively), and anemia (|r| = 0.87, p = 0.001 and |r| = 0.78, p = 0.008, respectively). AUCs and/or Cmax of the HAI drugs and/or their main metabolites displayed consistent relations with leukopenia, anemia, diarrhea, but also fatigue and anorexia over the initial 3 courses as well. Conclusions: Hematologic and intestinal toxicities of this new highly effective protocol mostly related to the systemic exposure of the three HAI drugs. In contrast, the high antitumor efficacy involves the direct drug exposure of liver metastases. Mathematical modelling will help personalize HAI combination chronotherapy for jointly enhancing efficacy and reducing toxicity. Clinical trial information: NCT00852228.
Prospective evaluation of circulating cell-free DNA sequencing in patients with metastatic renal cell carcinoma treated with pazopanib plus abexinostat.
Authors: Jim Leng, Armand Harb, Kamran Abri, Ilaria Mastroserio, Anne Reinert, Jennifer A. Grabowsky, Charles J. Ryan, Terence W. Friedlander, Amy M. Lin, Richard Burnham Lanman, Kimberly C. Banks, Rahul Raj Aggarwal, Pamela N. Munster
Journal: Journal of Clinical Oncology (2016)

4551 Background: Renal cell carcinoma (RCC) exhibits somatic alterations in genes controlling hypoxia and chromatin states including VHL. Analysis of circulating cell-free DNA (cfDNA) as a means to detect these and other potentially actionable mutations in RCC across histologic subtypes has not been previously fully characterized. Methods: cfDNA was isolated from pretreatment and post-progression plasma samples of sixteen patients with metastatic RCC (N = 12 clear cell; N = 4 papillary) enrolled on a clinical trial of pazopanib and abexinostat (NCT01543763) and analyzed using a cfDNA next-generation sequencing (NGS) panel of 68 genes (Guardant Health). The lower limit of detection was 0.1% mutant allele frequency (MAF) at each nucleotide position. Results: 16 pretreatment and 5 post-progression samples were evaluable. 49 somatic mutations were reported across the entire cohort (mean = 3.06 mutations per patient; range: 0-7). Somatic alterations were detected in 94% (n = 15) of pretreatment samples and 4 of 5 post-progression samples with mean cfDNA MAFs of 0.70% (range = 0.1% - 5.6%) and 1.65% (range 0.10-5.5%) respectively. The most frequently mutated genes were VHL (44% of patients), TP53 (38%), FGFR2 (38%), and KRAS (19%). Evidence of PI3K pathway activation was detected in 25% of pts (N = 2 with activating PIK3CA mutations; N = 2 with PTEN loss-of-function). Activating mutations in MET and IDH1 were identified in two of the four pts with papillary RCC. 2 of 5 pts analyzed to date had novel somatic mutations detected at the time of progression. Conclusions: Analysis of cfDNA in metastatic renal cell carcinoma yields similar frequency of VHL mutations compared to TCGA, as well as potentially actionable mutations across both clear cell and papillary RCC subtypes. PI3K pathway alterations are common and suggest the potential to select patients for combination PI3K/VEGF targeting approach. Detection of novel, actionable mutations using cfDNA at the time of progression is feasible and may provide insights into mechanisms of resistance by non-invasive methods. Longitudinal analysis of the entire study cohort and correlations with radiographic response are ongoing. Clinical trial information: NCT01543763.
Regularizing firing patterns of rat subthalamic neurons ameliorates parkinsonian motor deficits
Authors: Qian-Xing Zhuang, Guang-Ying Li, Bin Li, Chang-Zheng Zhang, Xiao-Yang Zhang, Kang Xi, Hong-Zhao Li, Jian-Jun Wang, Jing-Ning Zhu
Journal: Journal of Clinical Investigation (2018)

The subthalamic nucleus (STN) is an effective therapeutic target for deep brain stimulation (DBS) for Parkinson's disease (PD), and histamine levels are elevated in the basal ganglia in PD patients. However, the effect of endogenous histaminergic modulation on STN neuronal activities and the neuronal mechanism underlying STN-DBS are unknown. Here, we report that STN neuronal firing patterns are more crucial than firing rates for motor control. Histamine excited STN neurons, but paradoxically ameliorated parkinsonian motor deficits, which we attributed to regularizing firing patterns of STN neurons via the hyperpolarization-activated cyclic nucleotide–gated channel 2 (HCN2) channel coupled to the H2 receptor. Intriguingly, DBS increased histamine release in the STN and regularized STN neuronal firing patterns under parkinsonian conditions. HCN2 contributed to the DBS-induced regularization of neuronal firing patterns, suppression of excessive β oscillations, and alleviation of motor deficits in PD. The results reveal an indispensable role for regularizing STN neuronal firing patterns in amelioration of parkinsonian motor dysfunction and a functional compensation for histamine in parkinsonian basal ganglia circuitry. The findings provide insights into mechanisms of STN-DBS as well as potential therapeutic targets and STN-DBS strategies for PD.
Potential Benefits and Risks of High-Nicotine e-Cigarettes
Authors: Robin Koval, Jeffrey Willett, Jodie Briggs
Journal: JAMA (2018)

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Expression of podocalyxin-like protein and epidermal growth factor receptor in metastatic colorectal cancer: Prognostic impact and relationship with response to cetuximab.
Authors: Anna H Larsson, Emelie Karnevi, Bjorn Nodin, Halfdan Sorbye, Anca Dragomir, Per Pfeiffer, Camilla Qvortrup, Bengt Glimelius, Fredrik Ponten
Journal: Journal of Clinical Oncology (2018)

e15587 Background: Podocalyxin-like 1 (PODXL) is an anti-adhesive transmembrane protein associated with an aggressive tumor phenotype and poor prognosis in numerous malignancies, including colorectal cancer (CRC). An intercorrelation and synergistic adverse prognostic impact of PODXL and epidermal growth factor receptor (EGFR) expression has previously been demonstrated in CRC. The aim was to investigate the prognostic role of PODXL and EGFR in metastatic CRC (mCRC), and the potential functional link between the two proteins. Methods: PODXL and EGFR expression was analyzed by immunohistochemistry in tissue microarrays with tumors from a prospective cohort including 454 mCRC patients from three Scandinavian countries diagnosed 2003-2006, before implementation of routine RAS testing to preclude anti-EGFR treatment. Cox regression analyzes were applied to demonstrate the impact of PODXL and EGFR expression on overall survival (OS). The effects of small interfering RNA (siRNA)-mediated downregulation of PODXL and EGFR were examined in CRC cells in vitro. Results: There was a strong correlation between high expression of PODXL and EGFR (p < 0.001). Both high expression of PODXL and EGFR was significantly associated with a reduced OS (HR = 1.86; 95% CI 1.29-2.69, and HR = 1.39; 95% CI 1.06-1.84, respectively). High expression of both proteins signified the shortest OS (HR = 2.56; 95% CI 1.18-5.59), and there was a significant prognostic interaction between EGFR and PODXL (p = 0.018). In the entire cohort, 68 (15.0%) patients received anti-EGFR treatment in any line. Median OS for patients with PODXL positive tumors was 33 vs 3 months in the anti-EGFR treated vs untreated group (p = 0.001). Interestingly, a majority of PODXL high tumors in the treated group had RAS mutations. Knockdown of PODXL resulted in downregulation of EGFR, whereas PODXL was not affected by silencing of EGFR. Conclusions: The results from this study demonstrate a functional link between PODXL and EGFR, and a synergistic adverse prognostic effect in mCRC. The potential value of PODXL as a predictive biomarker for anti-EGFR therapy merits further investigation.
Relationship between tumor infiltrating lymphocytes (Tils) and neutrophil-lymphocyte ratio (NLR) as a prognostic factor in patients with advanced non-small cell lung cancer.
Authors: Eduardo Richardet, Patricia Andrea Hernandez, Martin Eduardo Richardet, Matias Nicolas Cortes, Matias Molina, Luciana Paola Acosta, Luciano Dicalbo, Rocio Villavicencio, Evelin Pets, Martin Paradelo
Journal: Journal of Clinical Oncology (2016)

e20617 Background: Association between cancer and inflammation is extensively studied. There is a greater probability that a tumor arises at sites of chronic inflammation. In a recent study in our institution, we demonstrated the role of tumor infiltrating lymphocytes (TILs) as a prognostic factor in non-small cell lung cancer (NSCLC). Our study showed that patients with present TILs had a higher OS and PFS compared to those with no TILs. The relation between cancer and systemic inflammation has been less studied. We primarily aim to investigate the NLR pre-treatment and its relation to overall survival (OS) and progression-free survival (PFS). Our secondary endpoint is to establish the relationship between the state of lymphocyte infiltration and NLR and its association to survival. Methods: Retrospective and analytical study of patients of Instituto Oncológico de Córdoba. 165 patients with stage IIIB and IV NSCLC were analyzed. Patients were split into two groups according to the value of the NLR (pre established as low: < 3.44 and high: ≥ 3.44). TILs were classified as present or absent. Survival curves were calculated using the Kaplan-Meier method. Results: 88 patients had NLR < 3.44, with a median OS of 12.8 months and a median PFS of 7.7 months. The remaining 77 patients had pre-treatment NLR > 3.44. Among them the median OS was 8.8 months and the median PFS was 5.3 months. These differences were statistically significant (p: 0.001 for OS and p: 0.001 for PFS). 52 patients (out of the 88 patients with low NLR) had TILs in their tumor samples with an OS of 11 months; the 36 patients who did not have TILs had an OS of 10 months (p = 0.15). 40 patients with present TILs (out of the 77 patients with high NLR) had an OS of 10.4 months and the remaining 37 with no TILs, had an OS of 7 months (p = 0.16). Conclusions: NLR pre-treatment measurements can provide important prognostic outcomes in patients with NSCLC. In this study, we found that OS and PFS were significantly associated with the value of NLR, with significantly lower outcomes in patients who showed an NLR > 3.44. But when we try to relate the NLR with the presence or absence of TILs, the results are not statistically significant.