bluuebunny/crossref_metadata_2025 huggingface dataset:
Single domain antibody (SBT-100) crosses the blood brain barrier (BBB) and inhibits human glioblastoma by selectively targeting KRAS and P-STAT3.
Authors: Singh Sunanda , Murillo Genoveva , Singh Avani , Singh Samara , Parihar Meenakshi S , Singh Anjali H , Mehta Rajendra , Parihar Ashutosh S
Published: September 2018

e13547

Background: Glioblastoma is difficult to treat malignancy that has a high incidence of KRAS mutations ( > 90%) and hyper-expression of P-STAT3 ( > 90%). Most chemotherapeutic agents and large biologics (four chain heterotetrameric IgG) cannot cross the BBB. Therefore Singh Biotechnology’s (SBT) propriety technology has developed a novel targeted therapy and engineered SBT-100 a 15 kD single domain antibody (sdAb) that is bispecific for KRAS and STAT3, which can cross the BBB to target gliablastomas. Methods: Human glioblastoma (U87MG) cell line was used and obtained from ATCC. Biacore affinity assay was used to demonstrate SBT-100 binding to KRAS, KRAS (G12D), and STAT3. The glioblastoma cells were incubated with 0µg/ml to 200µg/ml of SBT-100. MTT assay was performed after 3 days of treatment with SBT-100 and the growth inhibition was calculated. Xenograft (athymic nude mouse) with a well established tumor growing for 6 weeks was injected with SBT-100 intraperitoneally (IP). After 15 minutes the brain of this animal was harvested for immunohistochemical staining. Results: Biacore studies showed SBT-100 binds KRAS with affinity constant of 10-9M, KRAS (G12D) at 10-8M, and STAT3 at 10-8M. MTT assay reveals 62% (p < 0.01) growth inhibition of U87MG within 3 days. A xenograft mouse with a well established tumor ( > 150mm3), when injected IP with 5mg/kg of SBT-100 showed localization in the brain within 15 minutes. Therefore SBT-100 (sdAb) crosses the BBB, and shows intracellular localization in the animal’s neurons and glial cells. Conclusions: SBT-100 significantly inhibits the growth of glioblastoma. KRAS mutations and/or over expression of P-STAT3 in glioblastomas are promising targets for sdAbs like SBT-100, which is bispecific for KRAS and STAT3. SBT-100 crosses the BBB and localizes within the neurons and glial cells of the brain. SBT’s proprietary single domain antibody technology platform used to engineer SBT-100 holds promise for targeting primary brain malignancies, metastatic cancers that go to the brain, and for neurologic disease amenable to targeted therapy. Many chemo-resistant and radiation-resistant cancers use STAT3 as an escape mechanism.
Prognosis of leptomeningeal metastases from melanoma: A case series of 28 patients.
Authors: Oinino Sarah , Rodrigues Isabelle , Boulanger Thomas , Andre Charles , Bonneterre Jacques , Zairi Fahed , Mortier Laurent , Desmedt Eve , Templier Carole , Le Rhun Emilie
Published: September 2018

e13550

Background: Leptomeningeal metastasis (LM) are reported in 5-25% of patients with melanoma. However, only very few large contemporary cohorts of melanoma patients with LM have been published. Methods: We report on a case series of 28 consecutive patients with LM from melanoma (BRAF mutated in 14 cases, of 19 tested) diagnosed between April 2007 and April 2016, and treated for LM using a combination of systemic treatment, intra-cerebrospinal fluid (CSF) therapy and radiotherapy according to prior treatments and the presentation of LM. Results: The median age at LM diagnosis was 49.5 years (range 27-73). Median ECOG-performance status was 2 (0-4). Concomitant brain metastases were present in all but 4 patients at LM diagnosis. LM was the first site of metastatic disease for only 2 patients. Median time from melanoma diagnosis to LM diagnosis was 0.33 years in patients with metastatic disease at melanoma diagnosis (4 patients) and 4.5 years in patients without metastatic disease at melanoma diagnosis (24 patients). First line treatment for LM was a combination of intra-CSF (liposomal cytarabine) and systemic treatments in 25 cases, and systemic treatment alone in 3 cases. Systemic treatments include chemotherapy (n = 18), targeted therapy (BRAF inhibitor n = 9; MEK inhibitor, n = 3) and immunotherapy (n = 4). No radiotherapy was performed. Ten patients received more than one line of treatment for LM. Median progression-free survival with first line treatment was 1.75 months. Responses or stabilization (for at least 2 months) were observed in only 7 patients. Median overall survival (OS) for the whole cohort was 3.08 months. Conclusions: The prognosis of patients with LM from melanoma remains poor. The role of new agents such as targeted therapies and immunotherapy for the treatment of LM is still not well defined. Adequate use of intrathecal chemotherapy, targeted therapy and immunotherapy could improve the survival of these patients.
Paradoxical behavior of time to RECIST progression as a metric for treatment effect.
Authors: Bottino Dean , Gomez Axel , Burton Jackson , Williams Katherine , White Douglas , Chakravarty Arijit
Published: September 2018

e14022

Background: RECIST time to progression (RTTP) is the cornerstone of widely used surrogates for patient benefit such as RECIST progression-free survival (RPFS), which in turn is used either for accelerated regulatory approval or to study the effects of factors such as drug exposure and drug target expression levels on RPFS. While one might expect increased antitumor effect to result in longer RTTP and RPFS, we will show that this is often not the case due to a fundamental mathematical property of the RECIST definition of disease progression. Methods:We use a simple mathematical model that treats patient tumor burden dynamics as an evolutionary process consisting of a decreasing drug-sensitive subpopulation of tumor cells and an independently growing drug-resistant subpopulation. This model has successfully described tumor dynamics in NSCLC, melanoma (CPT Pharmacometrics Syst. Pharmacol. (2017) 6, 29–39), and ovarian cancer (internal data). In the presence of drug, we represent the net fitness of the sensitive cells in terms of an exponential decay or “kill” rate k > 0, and the net fitness of the resistant cells as an exponential growth rate g > 0, and the initial fraction of drug-resistant cells by 0 ≤ f ≤ 1. For a given virtual patient (parameter set), we simulate RTTP as the time after start of treatment at which tumor burden V(t) is 20% higher than its lowest value (per RECIST criteria). We then vary the kill rate k and check whether RTTP increases or decreases with increasing k. Results: There is a large set of parameter values for which RTTP is predicted to vary inversely with increasing kill rate k. These parameter values are attained clinically in ovarian cancer patients taking alisertib and paclitaxel (internal data). Conclusions: While RECIST progression criteria may be useful for patient care to identify when a patient is losing her response, care must be taken in interpreting RTTP as a metric of treatment effect due to the real possibility that a stronger treatment effect results in shorter RTTP. We recommend that alternative metrics for patient benefit, such as a generalization of Days Gained (Neal et al PLoS ONE 8(1)e51951), be evaluated. We will present results of these evaluations currently in progress.
Patient-reported outcomes (PRO) in cancer trials submitted to the FDA from 2012-2015.
Authors: Kanapuru Bindu , Singh Harpreet , Kim Janice , Kluetz Paul Gustav ,   U.S. Food and Drug Administration
Published: September 2018

e14024

Background: PRO measures are commonly assessed in cancer trials. We reviewed the PRO strategy, tools and trial designs for new drug applications (NDA) and biologics license applications (BLA) submitted to FDA over a 4 year period. Methods: A review of protocols and clinical study reports for original NDA and BLA applications submitted to the Office of Hematology and Oncology Products between 2012 and 2015 to support initial approval for adult malignant hematology and oncology conditions was done. We reviewed applications for inclusion of PRO data, trial design, type of PRO measure employed and statistical analysis methods. Results: Forty three trials were submitted to support 40 original NDA or BLA approvals targeting adult malignancies between 2012 and 2015. Of these 43 trials, 17/43 (40%) were accelerated approval, 26/43 (60%) were randomized, 17/43 (40%) were single arm and 27/43 (63%) were open label trials. Sponsors documented the incorporation of PRO assessments in 28/43 (65%) trials. For trials that included PRO assessments, 22/28 (79%) were randomized controlled trials, 6/28 (21%) were single arm and 17/28 (61%) were open label studies. The most common PRO instruments used were the EORTC-QLQ-C30 (15/28; 54%), EQ-5D (13/28; 46%) and various FACIT measures (8/28; 29%). Although 20/28 (71%) trials had PRO measures listed as a secondary endpoint, only 1 trial included PRO endpoints in the statistical testing hierarchy. Conclusions: PRO measures are often employed in randomized controlled cancer trials; however accelerated approval is common in oncology and trial designs are increasingly open label and single arm. Patient-focused drug development efforts will need to identify clinical trial objectives and analysis methods for PRO measures to describe symptoms and function that are suitable for these contexts. Descriptive PRO data on the tolerability of an anti-cancer agent may be one objective that is relevant across trial contexts. To support a claim of superiority, PRO endpoints should be adjusted for multiplicity by inclusion in the statistical hierarchy.
Predictive score of early mortality in patients with solid tumors enrolled in phase I clinical trials.
Authors: Ugidos Lisardo , Boni Valentina , Garralda Elena , de Miguel Luken Maria Jose , Alvarez-Gallego Rafael , Rodriguez-Pascual Jesus , Vega Estela , Munoz Cesar , Garcia-Rey Cesar , Cubillo Antonio , Calvo Emiliano
Published: September 2018

e14029

Background: A usual inclusion criterion for phase I trials is life expectancy of more than 3 months. Prediction of early mortality (EM), in the first 90 days after starting treatment, is thus a challenge. Predictive scores may help to select more adequate patients (pts). Our main objective was to generate a predictive score in a training set of phase I pts and to confirm it in a validation score. Secondly, we figured out if our score also predicts overall survival (OS). Methods: Consecutive pts treated in our phase I unit between 2008 and 2013 were retrospectively reviewed. We collected 35 clinical and analytical characteristics at base line. Stepwise regression was used to correlate pts characteristics with EM and generate a predictive score. Log-rank regression and Kaplan Meier curves were used to study survival. Results: We identified 438 pts. Median age was 61 yr (18-87) and 52.7% were male. More frequent tumor types were gastrointestinal (37%), thoracic (17%), and breast (12%). Pts treated with chemotherapy were 32%, targeted therapy 36%, combination 29%, and immunotherapy 3%. Response rate was 12.4%. Median progression free survival (PFS) and OS were 2.6 and 8.5 months respectively. Most common causes of discontinuation were tumor progression (87.2%) and toxicity (5.7%). EM rate was 20.5%. We randomly included 243 pts in the training score. In multivariate stepwise regression, 6 features were related to EM: ECOG PS 2 (vs 0-1), gastrointestinal or thoracic tumors (vs other types), red cell counts below 4*106/ml, LDH above 600 U/L, calcium below 8.6 mg/dL, and ratio neutrophil/lymphocyte above 5. An EM score was generated ranging 0-7 (2 points for ECOG PS and 1 point for each other characteristic). Using cut off value of 0-2 vs 3 or more, we would reduce EM90 rate to half (11%) and avoid inclusion of 60% pts with EM. Our EM score was validated in the second cohort; we reduced EM rate to 10.5% avoiding undesirable inclusion of 59% pts. Applying score to all pts, median OS was 16, 8.4, 4.4, and 3 months for score 0, 1, 2, and 3-7 respectively (p < 0.01). Conclusions: Our score can avoid inclusion of 60% of pts who would die before 90 days, reducing EM rate from 20 to 10%. This score can identify four prognostic groups with different median OS.
Enrollment into molecular selection trials and impact on patient disposition.
Authors: Harvey R Donald , Steuer Conor Ernst , Judson Emma C , Lewis Colleen Margaret , Collins Hannah H , Saba Nabil F. , El-Rayes Bassel F. , Curran Walter John , Ramalingam Suresh S. , Pentz Rebecca D. , Owonikoko Taofeek Kunle
Published: September 2018

e14035

Background: Optimal use of molecularly targeted therapies is achieved by pairing agents with driver mutations present in tumor tissue. Enrollment on clinical trials designed to demonstrate this objective requires obtaining informed consent prior to molecular analysis, with potential delays in tissue acquisition, testing results, and treatment initiation. We reviewed our experience and patient disposition with studies where assignment to treatment required mutation data. Methods: We identified trials requiring consent prior to tissue mutational analysis. Review included time intervals between landmark events starting with trial presentation to patient, consent, tissue shipment, mutation analysis results, and if and when treatment was initiated. Demographic data, change in ECOG PS, and subsequent therapy were also collected. Patients were included in the analysis if they signed consent. Results: Experience with 68 patients consented across 4 molecular selection trials was reviewed. Median age: 60 years (32-87); 56% female; self-identified race White (72%), African-American (24%), Asian (4%). Most common cancers were lung (35%), colorectal (18%), parotid (7%) and sarcoma (7%). Nineteen patients required new biopsies; 15 patients (22%) discontinued participation prior to molecular results being available. Common reasons for discontinuation included insufficient archival tissue (5), lost to follow up, initiation of other treatment, and death (2 each). In 53 patients who continued, overall median time from consent to test results received was 41 days (12-149); with median time from consent to obtaining tissue of 22 days (0-121), and tissue sent to results received was 13 days (1-77). In those with advanced disease (n = 36), PS worsening occurred in 28%. Three patients matched to therapy; 1 received more than 1 cycle. In those not matching (n = 50), 46% received approved therapies, 22% were lost to follow-up, 18% enrolled on another trial and 14% died. Conclusions: Molecular selection of patients for clinical trials requires additional time and resources, and many patients do not have driver mutations. Long time intervals between decision points can delay therapies and impair the ability to explore alternative treatment.
The incidence and risks of adverse events in randomized controlled trials (RCTs) of cancer drugs downplaying the harms.
Authors: Gyawali Bishal , Honda Kazunori , Shimokata Tomoya , Ando Yuichi
Published: September 2018

e14036

Background: Proper assessment of harms of cancer treatment is essential to make risk-benefit trade off decisions in oncology clinic. CONSORT guidelines require the authors of RCTs to provide exact data for adverse events (AEs) grade 3 or higher (severe AEs), serious AEs (SAEs) and fatal AEs (FAEs) and avoid using general terms (such as well-tolerated) that downplay the harms. We aimed to assess the incidence and risks of severe AEs, SAEs and FAEs in such RCTs of cancer drugs that downplayed the harms. Methods: We extracted all the phase 2 and 3 RCTs of cancer drugs from the five major journals (NEJM, Lancet, Lancet Oncology, JAMA, JCO) from 2016 January to 2016 December. The abstracts/full texts of the papers were studied to assess if the harms of the experimental arm were downplayed. Use of any of the following terms while describing toxicities or AEs or safety was assumed to downplay the harms: acceptable, feasible, tolerable (or well-tolerated) , favorable, safe, manageable. Data on severe AEs, SAEs and FAEs for both the experimental and control cohorts were extracted from these RCTs and pooled using random-effects model to determine the overall incidence and risk. Results: Of 122 phase 2/3 RCTs of cancer drugs identified, 53 (43.4%) reports used terms downplaying the toxicities of the experimental arm and were included in this analysis. The overall incidence of severe AEs, SAEs and FAEs with these cancer drugs were 50.6% (95% CI: 41.5%-59.7%), 21.9% (95% CI: 16.3%-28.7%) and 1.6% (95% CI: 1.2%-2.2%) respectively. Compared with control, the risk of severe AEs and SAEs were significantly increased with the use of these cancer drugs: severe AEs (RR 1.15, 95% CI: 1.04-1.27, p = 0.005) and SAEs ( RR 1.49, 95% CI: 1.26-1.77, p < 0.001) . However, the risk of FAEs was similar across the experimental and control arms ( RR 0.89, 95% CI: 0.72-1.11, p = 0.306) Conclusions: Our analysis shows that considerable proportions of patients suffer severe AEs, SAEs and FAEs and significantly increased risk of severe AEs and SAEs in the trials that downplay the toxicities of cancer drugs. Terms that falsely downplay the toxicities of cancer drugs should be avoided in the reporting of RCTs to encourage accurate risk-benefit assessment.
Intracellular targeting of the oncogenic MUC1-C protein with a GO-203 nanoparticle formulation overcomes MCL-1- and BFL-1-mediated resistance in human carcinoma cells.
Authors: Hiraki Masayuki , Jin Caining , Alam Maroof , Maeda Takahiro , Murata Masaru , Hiratsuka Masahiro , Doki Yuichiro , Kharbanda Surender , Mori Masaki , Kufe Donald W.
Published: September 2018

e14053

Background: Aberrant expression of MCL-1 and BFL-1, the pro-survival members of the Bcl-2 family, is a major cause of drug resistance in human cancers. Mucin 1 (MUC1) is a heterodimeric oncoprotein that is aberrantly expressed in most human carcinomas. Notably, there is no known relationship between the oncogenic MUC1 C-terminal subunit (MUC1-C) and these anti-apoptotic proteins. Methods: MUC1-C was targeted in breast, lung and colon cancer cells by a stable shRNA, a tetracycline-inducible shRNA, or a pharmacologic peptide inhibitor GO-203. MCL-1 was inhibited by siRNA or the MS-1 peptide. In vitro and in vivo studies were conducted using our polymeric nanoparticles (NPs) for intracellular delivery of peptide cargos. Cells were selected for resistance to ABT-737 or ABT-263, which target BCL-2, BCL-XL and BCL-w, but not MCL-1 and BFL-1. Results: Targeting MCL-1 with MS-1/NPs inhibited the survival of parental cancer cells in vitro and in vivo, and was associated with upregulation of BFL-1 levels. In addition, MS-1/NPs treatment had limited effects on ABT-resistant cells because of increased BFL-1 expression. Importantly, we found that targeting MUC1-C is associated with suppression of both MCL-1 and BFL-1. Mechanistically, MUC1-C (i) stabilizes MCL-1 by activating the MEK→ERK and PI3K→AKT pathways, and (ii) induces BFL-1 through the NF-κB p65 pathway. Treatment with GO-203/NPs suppressed proliferation of parental and ABT-resistant cells. In addition, we show that combining GO-203 with ABT-737 is synergistic in inhibiting survival of parental and ABT-resistant cells. Conclusions: These findings demonstrate that targeting MUC1-C with GO-203/NPs is a potential strategy for abrogating MCL-1- and BFL-1-mediated resistance.
The activity of the HDAC inhibitor HBI-8000 (Chidamide) combined with eribulin on 4T1 spontaneous metastasis development.
Authors: Bissonnette Reid Paul , Rolland Alain , Goodenow Bob , Gillings Mireille
Published: September 2018

e14055

Background: In preclinical studies eribulin has shown significant effects on epithelial-mesenchymal transition (EMT) in human breast cancer cells in vitro and in vivo, inducing a switch from mesenchymal to epithelial states, decreasing migration and invasiveness of human breast cancer cells in vitro, as well as experimental metastases in vivo. HBI-8000 is a novel, orally bioavailable Class I selective HDAC inhibitor (HDACi). In addition to its demonstrated positive effects on antitumor immunity, it also exerts significant effects on EMT pathway components, enhancing CDH1 (e-cadherin) expression and inhibiting TGF-β induced metastasis. Methods: The syngeneic, orthotopic 4T1 model is thought to be a close representation of the clinical situation; similar to human mammary carcinoma, the major cause of morbidity and mortality is development of spontaneous metastases. 4T1-implanted mice treated with combinations of eribulin and HBI-8000 were monitored for primary tumor growth inhibition (TGI), survival, and metastatic lung foci. Tumor samples were analyzed by Q-PCR for expression of genes involved in EMT or in the metastatic process. Results: Eribulin alone had no effect on primary TGI. Eribulin combined with HBI-8000 resulted in significant (P < 0.05) reductions in median tumor volume, tumor volume distribution (TMD) and survival (P < 0.005). Single agent HBI-8000 had a similar effect on TGI, TMD (P < 0.05) and survival (P < 0.005). Whereas single agent HBI-8000 or eribulin failed to significantly reduce metastases, the eribulin-HBI-8000 combination produced significant (P < 0.01) and synergistic inhibition of metastases, decreasing the number of lung foci approximately 10-fold. Gene expression analyzed by Q-PCR revealed correlations between metastasis blockade and increases in E-Cadherin, Occludin and Claudin1. There was a strong correlation with inhibition of HMGA2 (High Mobility Group AT-Hook 2) gene expression. Conclusions: Eribulin combined with HBI-8000 inhibited primary tumor growth and inhibited metastasis development and increased survival. This effect was correlated and consistent with changes in genes relevant to EMT, tumor plasticity and stemness.
Characterization of URST1 as a prognostic biomarker and therapeutic target for lung and oral cancers.
Authors: Takano Atsushi , Yoshitake Yoshihiro , Shinohara Masanori , Miyagi Yohei , Daigo Yataro ,   Research Hospital, Institute of Medical Science, The University of Tokyo
Published: September 2018

e14057

Background:Lung cancer and oral cavity cancer belong to aerodigestive cancers whose clinical outcome after multimodal therapy remains poor. Methods:To identify new biomarkers and therapeutic targets for lung and oral cancers, we screened genes using our original gene expression profile database for various solid cancers, and characterized clinical and oncogenic values of up-regulated in solid tumor 1 (URST1) protein as a candidate. Results: URST1 was highly expressed in the most of lung or oral cancer cell lines and tumor tissues, but was hardly detected in normal lung or oral epithelial cells and tissues as detected by real-time PCR and western blot analyses. Immunocytochemical analysis revealed that URST1 was mainly localized in the nucleus and cytoplasm of lung or oral cancer cell lines. Immunohistochemical analysis using tissue microarray showed that positive staining of URST1 was observed in 231 of 358 (64.5%) lung cancers, but not in normal lung, and it was significantly associated with poor prognosis after curative surgery. In addition, URST1 was expressed in 64 of 96 (66.7%) oral cancers, but not in oral mucosa, and it was significantly correlated with poor clinical outocome after surgery. Multivariate analysis confirmed that URST1 expression was an independent prognostic factor for oral cancer. Suppression of URST1 expression by siRNA or treatment with synthesized inhibitor specific for URST1 activity inhibited mitosis and growth of lung or oral cancer cell lines. Conclusions:URST1 is likely to be a prognostic biomarker and therapeutic target for aerodigestive cancers such as lung and oral cancers.
Targeting of human cancers by miRNAs delivered by mesenchymal stem cell derived microparticles.
Authors: Epenetos Agamemnon A. , Prokopi Marianna , Pitsillides Costas
Published: September 2018

e14062

Background: Recent data has shown that several oncogenic and tumor suppressor kinases that are deregulated in human cancers can be targeted via specific miRNA sequences. miRNAs can inhibit oncogenic kinase activity as well as upregulate tumor suppressor kinases in cancer cells, leading to inhibition of tumor processes such as invasion, migration and resistance to apoptosis. Examples include the inhibition of PLK1 activity that is overexpressed in breast, ovarian, pancreatic and colorectal cancers by the ectopic expression of miR-10b, miR-100 or miR-593, and the targeting of the increased FAK expression in breast cancer cells by miR-7. Methods: In this study, we have employed preclinical models of cancer disease and have utilized advanced genomics technologies in combination with innovative in vivo imaging techniques to conduct pharmacokinetics and pharmacodynamics studies as well as safety and efficacy studies in order to establish a mechanism of action and demonstrate that miRNA-loaded microparticles can interfere with tumor promoting kinase activity in vivo Results: Our results demonstrate that delivering specific miRNAs targeted against aberrant protein kinase activity may potentially be a novel approach to selectively inhibit cancer cell processes. Conclusions: We report the development of a new microRNA-based approach to target cancer cells by potentially interfering in multiple signaling pathways that are mediated by kinase-dependent mechanisms. We propose that therapeutic miRNA sequences can be delivered to cancer cells via microparticles (MPs) derived from umbilical cord mesenchymal stem cells (MSCs). The engineered MPs home selectively to tumor sites via specific chemokine receptors, fuse with the cell membrane and incorporate miRNA directly into the target cancer cells.
A phase I safety study of topical calcitriol (BPM 31543) for the prevention of chemotherapy-induced alopecia (CIA).
Authors: Lacouture Mario E. , Konner Jason A. , Belum Viswanath Reddy , Stevens Janice , Dion Hedy , Ciccolini Kathryn , Kitts Sarah , Ye Ran , Ravipaty Shobha , Akmaev Viacheslav R , Sarangarajan Rangaprasad , Jimenez Joaquin Juan , Narain Niven R. , Berman Brian , Goldfarb Shari Beth
Published: September 2018

e14064

Background: Chemotherapy-induced alopecia (CIA) may lead to significant psychosocial and quality of life issues. Currently there are no FDA approved oral or topical agents available to prevent CIA. In murine studies, topical calcitriol reduced CIA, likely due to arrest of cell cycle in healthy hair follicles, and reduction in the sensitivity of follicular epithelium to chemotherapy. Methods: A prospective dose escalation study is being performed in up to 31 women with breast cancer, gynecologic cancer and sarcomas. Each patient is applying 1mL of BPM 31543 to her scalp BID, ≥ 5 days prior to initiation of taxane-based chemotherapy for at least 3 months or until the completion of chemotherapy. The study cohorts are: 5/10/20/40/60/80 μg/mL. All 6 cohorts have been completely enrolled. Each patient undergoes PK analysis, adverse event (AE) monitoring, patient self-assessment diaries (1-10 scale), and blinded photographic assessments. Results: Twenty-eight patients have been enrolled (evaluable, n = 21). PK data (n = 21; 5-80 μg/mL) showed inter-individual variability, with increases in serum vitamin D in the 10/20/40/60/80 μg/mL cohorts (range, < 21.3-110 pg/mL). Treatment-related AEs (probably/possibly) were mild/moderate in nature and included scalp pain (n = 1; 5 μg/mL), elevated vitamin D levels in 3 patients (20/40/60 μg/mL) and passage of renal calculus in another (n = 1; 40 μg/mL). A clinical response was observed at each dose level. The study will be complete and final study data will be available and presented at ASCO. Conclusions: Data have shown that the twice daily application of BPM 31543 in patients receiving taxane-based chemotherapy was safe and well-tolerated. The Maximum Tolerated Dose (MTD) was not detected. No Dose Limiting Toxicities (DLTs) or severe treatment-related adverse events occurred in any of the dose cohort. A signal of efficacy was detected at each dose level. Clinical trial information: NCT01588522.
A drug-drug interaction study of capecitabine and celecoxib in patients with advanced solid malignancies.
Authors: Ramirez Jacqueline , House Larry , Karrison Theodore G. , Janisch Linda A. , Turcich Michelle , Salgia Ravi , Ratain Mark J. , Sharma Manish
Published: September 2018

e14066

Background: Warfarin is an anticoagulant and CYP2C9 substrate commonly used in oncology patients. Several studies suggest a drug-drug interaction between capecitabine and warfarin that may be mediated by CYP2C9. Celecoxib is a CYP2C9 substrate that may also have anticancer activity. We aimed to characterize the magnitude and the time course of the capecitabine-celecoxib interaction in cancer patients in order to better understand the effect of capecitabine on CYP2C9. Methods: Patients received 200 mg celecoxib PO twice daily continuously, with capecitabine (1,000 mg/m2 PO twice daily for 14 days every 21 days) starting 7 days later. Celecoxib and celecoxib-OH pharmacokinetics (PK) were collected on days 7, 14 and 21. Thirteen patients were evaluable for PK analysis. Results: Comparison of steady state PK parameters showed an average 31%, 17% and 34% increase in celecoxib’s Cmax (p = 0.036; paired t-test), Cmin (p = 0.043) and AUC (p = 0.006) between day 7 (celecoxib only) and day 14 (celecoxib + capecitabine), respectively. PK comparison of day 7 vs. day 21 (after one week washout of capecitabine) showed a further increase in Cmax (46%, p = 0.011), Cmin (92%, p = 0.002) and AUC (49%, p = 0.006). Conclusions: Coadministration of capecitabine results in higher exposure to celecoxib, and the interaction persists for at least 7 days after discontinuation of capecitabine. Clinical trial information: NCT01705106.
Plasma and cerebrospinal fluid pharmacokinetics of doxil after intravenous administration in adults with primary CNS lymphoma.
Authors: Higham Christine , Murphy Robert F. , Bhaumik Sucharita , Dunleavy Kieron , Wilson Wyndham Hopkins , Widemann Brigitte C.
Published: September 2018

e14067

Background: Doxil, a pegylated liposomal doxorubicin (PLD) has excellent CNS penetration in rodent brain tumor models and is active in patients with lymphoma. The CNS penetration of doxil in humans is unknown. We evaluated the plasma and cerebrospinal fluid (CSF) pharmacokinetics (PK) of doxil in adults primary CNS lymphoma (PCNSL) as a surrogate for CNS penetration. Methods: Adults with PCNSL enrolled on a NCI phase I study of ibrutinib and multi-agent immune-chemotherapy (NCT02203526) received doxil 50 mg/m2 IV over 1 hour on day 2 of 21-day cycles of chemotherapy. In 4 patients with indwelling Ommaya reservoirs serial blood and CSF samples were obtained prior to infusion and until a median of 345 hours, (range 72-477 hours) after doxil administration. Total doxorubicin concentration (liposome bound + protein bound + free) was quantified with a validated liquid chromatography/tandem mass spectrometry assay (lower limit of quantification plasma=0.29 ng/mL, and CSF=0.06 ng/mL). PK parameters were estimated using non-compartmental methods. CSF penetration was calculated from the AUCCSF:AUCplasma. Results:Total doxorubicin plasma concentration time curves were characterized by sustained drug exposure and a median terminal half-life of 64.5 hours. (range, 61.9-65.1 hours). Doxorubicin was measurable in CSF in all patients, but CSF penetration was low. The terminal half-life of doxorubicin in CSF could not be calculated due to persistently measurable concentrations throughout the sampling times. Conclusions: In patients with PCNSL doxorubicin was measurable in CSF for prolonged time periods after doxil administration, but CSF penetration is low. Clinical trial information: NCT02203526. [Table: see text]
Plasma and cerebrospinal fluid pharmacokinetics of selumetinib in non-human primates (NHP).
Authors: Gross Andrea M. , McCully Cynthia M. , Warren Katherine E. , Widemann Brigitte C.
Published: September 2018

e14070

Background: Selumetinib (AZD6244 hyd sulfate) is an orally bioavailable agent targeting mitogen-activated protein kinase (MEK) 1/2. Selumetinib has shown activity in children with NF1 plexiform neurofibromas and refractory low-grade gliomas. The central nervous system (CNS) penetration of selumetinib in humans is unknown. Methods: We analyzed selumetinib in the cerebrospinal fluid (CSF) of NHP as a surrogate for CNS penetration. Four adult male rhesus macaques were each given a single dose of selumetinib capsules 2.5 mg/kg (human equivalent dose 50 mg/m2) by mouth on an empty stomach. Selumetinib was quantified in serial paired plasma and CSF samples from 0 to 48 hours after administration by Covance Bioanalytical Services (lower limit of quantification 0.5 ng/mL). Free selumetinib was estimated at 2.3% of total based on reported plasma protein binding of 97.7% in NHP. Pharmacokinetic parameters including area under the concentration x time curve (AUC) of selumetinib were calculated using non-compartmental methods and CSF penetration was calculated from the ratio of AUC (CSF): AUC (plasma). Results: Selumetinib was detected in plasma in all four NHPs, but in the CSF of only one NHP (ZH60). The mean (± SD) AUC0-∞ and half-life (t1/2) in plasma were 3350 ± 489 ng•h/mL and 10.8 ± 2.5 hours, respectively. In ZH60, the CSF AUC0-48 hr was 10.6 ng•h/mL. The CSF penetration of total and free selumetinib in this animal was 0.4%, and 14%, respectively. The mean plasma AUC and t1/2 were comparable to that of children (2842 ng•h/mL and 6.9 hours, respectively) at a similar dose in a phase I trial. However, the average peak concentration in children occurred at approximately 1 hour with a Cmax of 841 ng/mL, while the Cmax in NHP plasma ranged from 1 – 4 hours and averaged 198.8 ng/mL. Conclusions: The CSF penetration of oral selumetinib is limited; in one NHP it was 0.4% and 14% when corrected for plasma protein binding of selumetinib. The fact that plasma AUC0-∞ and half-lives in NHP were similar to previously reported human plasma PK indicates that this model may accurately reflect human CSF penetration as well.
Pharmacokinetics (PK) and safety of enzalutamide in healthy Chinese males.
Authors: Chen Qian , Liu Yan-Mei , Zhang Xiaopeng , Fukushi Risa , Asahina Seitaro
Published: September 2018

e14073

Background: Enzalutamide (ENZ), an androgen receptor inhibitor, is approved in over 60 countries except China for use in metastatic castration-resistant prostate cancer. The PK of ENZ have been assessed in healthy Caucasian males (Gibbons 2015). This open-label, single-dose study evaluated the PK of ENZ and its major metabolites, and safety of ENZ, in healthy Chinese male volunteers. Methods: Non-elderly healthy Chinese male volunteers received a single oral dose of ENZ (160 mg) under fasting conditions on day 1 and were followed for 50 days. Full PK profiles were obtained for ENZ and its major metabolites, carboxylic acid metabolite (M1; inactive metabolite) and N-desmethyl enzalutamide (M2; active metabolite), on day 1 up to 1176 hours (49 days). Safety data were collected from screening until the end of study visit. Results: 14 healthy Chinese male volunteers were enrolled and received a single ENZ dose (mean age, 29.0 years; mean BMI, 21.7 kg/m2). All volunteers receiving study drug were included in the PK and safety analyses; two subjects withdrew from the study during the study period. ENZ plasma concentration rapidly increased (median tmax of 1.5 hours) followed by a slow decrease (mean t1/2 of 90.7 hours). Plasma concentrations of M1 and M2 increased gradually with a median tmax of 72.0 and 121 hours, respectively. M1 and M2 mean metabolite to parent ratio was 0.206 and 1.32, respectively. Mean AUC0-inf of the sum of ENZ and M2 was 828 μg·h/mL compared to 368 μg·h/mL for ENZ. Cmax and tmax of the sum of ENZ and M2 were comparable to ENZ. Mean t1/2 of the sum of ENZ and M2 was 155 hours, which was similar to that of M2 (162 hours). Treatment-emergent adverse events (TEAEs) were reported in seven out of 14 males (50.0%). Possible/probable drug-related TEAEs were reported in four males (28.6%); one each of upper respiratory tract infection, chest discomfort, increased bilirubin, and decreased white blood cell count. No deaths, serious TEAEs, or TEAEs of grade ≥3 were observed. Conclusions: The PK profiles of ENZ, M1, M2, and the sum of ENZ and M2 in healthy Chinese males were generally consistent with Caucasian males. No clinically relevant safety concerns were reported. Safety and PK profiles indicate that ENZ 160 mg/day is appropriate in a Chinese population.
Cancer associated thrombosis in patients taking direct oral anticoagulants (DOACs): Retrospective review of a single institutional series.
Authors: Angelov Sophia , Dean Andrew Peter
Published: September 2018

e14080

Background: Venous thromboembolism (VTE) is a common and often serious complication for patients with malignancy. Even though low molecular weight heparin (LMWH) is recommended as first line therapy for initial and long term anticoagulation, patient choice may demand oral anticoagulants. This retrospective review illustrates the repeated observation of recurrent thromboembolic disease in patients taking the new class of oral anticoagulant, DOAC. Methods: The pharmacy database at our institution was searched to identify oncology patients who had received a prescription for a DOAC (rivaroxaban or apixiban). Sixtyfive patients were identified and case records were then examined for evidence of venous thromboembolism. Results: Five seperate episodes of recurrent venous thromboembolism were identified in four patients in our cohort., one patient having two seperate episodes of pulmonary embolus. All were on recommended therapeutic doses of DOAC at the time of thromboembolic event. Two patients experienced proven pulmonary embolus on CT pulmonary angiography (1 twice), one lower limb deep vein thrombosis and one upper limb deep vein thrombosis. Conclusions: This retrosepctive review reinforces the clinical guidelines stated by the Cochrane review and ASCO that LMWH should always be first line for the initial and continuation treatment of a VTE. The guidelines did not focus on the suboptimal anticoagulation aspect of the newer oral anticoagulants but more on the safety issues. Research has been mainly focused on comparing LMWH with unfractionated heparin (UFH) or oral warfarin. Comparisons between DOAC versus Warfarin as an oral form of therapy have also been made. In the available published literature, there is a paucity of research comparing DOACs to LMWH. We have identified four patients out of sixtyfive treated with therapeutic doses of DOAC who developed subsequent thromboembolism. This is additional supportive evidence that newer oral anticoagulant agents may not be efficacious in malignancy driven VTE and that LMWH should remain the standard of care. Patients specifically requesting DOAC for cancer associated VTE should be made aware of this data.
IRX4204 in combination with erlotinib to target distinct pathways in lung cancer cells.
Authors: Liu Xi , Roszik Jason , Karakami Masanori , Sanders Martin , Chandraratna Rosh , Dmitrovsky Ethan , Dragnev Konstantin H.
Published: September 2018

e14095

Background: IRX4204 is a Retinoid X Receptor (RXR) specific agonist (rexinoid). IRX4204 has high potency as a RXR agonist with low binding affinity to Retinoic Acid Receptors (RARs), PPAR, FXR or LXR. Our prior work with the less specific rexinoid bexarotene and erlotinib showed clinical activity in patients with lung cancer cases that harbored KRAS mutations. IRX4204 inhibits lung cancer cell proliferation and can chemoprevent carcinogen-induced lung cancers in mice. We sought to explore the underlying mechanisms engaged by the combination of IRX4204 and erlotinib. Materials and Methods: Human (H1703 and HOP62) and murine (ED1 and LKR13) lung cancer cell lines were treated with IRX4204, erlotinib, IRX4204 plus erlotinib, or vehicle. Reverse phase protein array (RPPA) and mRNA microarray analyses were performed to analyze comprehensively for differentially expressed growth regulatory proteins. Results: Combination of IRX4204 and erlotinib suppressed proliferation of both KRAS mutant (HOP62 and LKR13) and wild-type (H1703 and ED1) lung cancer cell lines. Additive effect was observed as compared to IRX4204 or erlotinib treatment alone. Combining IRX4204 with erlotinib markedly increased inhibition of specific therapeutic targets including Src, phosphorylated Akt and ribosomal S6 proteins. At the mRNA level, Ingenuity Pathway Analysis of species significantly increased or decreased by the combination treatment revealed multiple pathways related to oncogenic signaling. Specifically, we found in H1703 cell line regulation of Granzyme A and AMPK signaling and in HOP62 cell line inhibition of angiogenesis was implicated by altering TSP1 expression. Notably, in ED1 cell line PPARα/RXRα activation, PTEN signaling, PI3K/AKT signaling, TGF-β signaling, and AMPK signaling were each associated with effects of IRX4204 combined with erlotinib. Conclusions: Taken together, these data highlight specific mechanisms and candidate pharmacodynamic biomarkers of response to the combination of this rexinoid and EGFR-TKI in lung cancer. Based on these findings, a clinical trial (NCT02991651) with IRX4204 in combination with erlotinib is underway to treat patients with chemotherapy-refractory non-small cell lung cancer.
Targeting anti-PD1-resistant tumors via indoleamine 2,3-dioxygenase 1 (IDO1) inhibition.
Authors: Li Ailin , Schoenhals Jonathan E. , Barsoumian Hampartsoum B. , Wang Xiaohong , Valdecanas David R. , Niknam Sharareh , Klopp Ann , Younes Ahmed I. A. , Gomez Daniel Richard , Chang Joe Y. , Komaki Ritsuko , Li Guang , Cortez Maria Angelica , Welsh James William
Published: September 2018

e14103

Background: Anti-PD1 inhibitors are effective in only a subset of lung cancers, and many that respond later develop resistance. We recently found in a mouse model of anti-PD1 resistance that tumor-infiltrating lymphocytes (TILs) overexpressed indoleamine 2,3-dioxygenase 1 (IDO1), a rate-limiting step in the catabolism of tryptophan (Trp) to kynurenine (Kyn) often implicated in immunosuppression. We tested whether inhibiting IDO would affect anti-PD1 mediated resistance. Methods: We used our anti-PD1-resistant lung cancer model (344SQ_R), which involved treating the parental 344SQ cells (344SQ_P) with anti-PD1 antibody followed by passage in 129SV/ev mice. We treated 344SQ_P and 344SQ_R mice with or without a selective IDO1 inhibitor (INCB023843) and measured tumor growth and lung metastasis. Plasma Trp and Kyn levels were tested by liquid chromatography–tandem mass spectrometry. TILs from blood and tumor-draining lymph nodes were isolated, analyzed by flow cytometry, and RNA was extracted for qPCR. Plasma C-C motif chemokine 22 (CCL22) levels were tested by ELISA. Data were analyzed with Prism 5.0 (GraphPad Software) and Flowjo V-10. Results: In untreated mice, IDO1 expression was 12 times higher in TILs from 344SQ_R mice than 344SQ_P mice, and mean plasma Kyn and Kyn/Trp levels were 3 times higher in 344SQ_R than in 344SQ_P. IDO inhibition was effective only in the PD1-resistant mice, reducing both tumor growth and lung metastasis. A subpopulation of myeloid-derived suppressor cells (Gr1int/lo CD11b+F4/80+) showed the greatest increase in IDO1 expression when comparing 344SQ_R to 344SQ_P and decreased after INCB023843 treatment only in 344SQ_R. INCB023843 also increased infiltrating CD8+ T cells, decreased CCL22 and regulatory T cells only in 344SQ_R tumors. Conclusions: Our results suggest that IDO1 is overexpressed in TILs from tumors resistant to anti-PD1 therapy; that a high plasma Kyn/Try ratio may be a marker of anti-PD1 resistance; and that IDO1 inhibition could be a promising approach for treating lung cancer that does not respond to anti-PD1 therapy.
Assessment of heterogeneity of PD-L1 expression in NSCLC, HNSCC, and UC with Ventana SP263 assay.
Authors: Scott Marietta L. , Scorer Paul , Lawson Nicola , Ratcliffe Marianne J , Barker Craig , Rebelatto Marlon , Walker Jill
Published: September 2018

e14502

Background: Clinical assessment of PD-L1 status relies on the result of testing 1 FFPE section per patient (pt). Heterogeneity of PD-L1 expression within a single tissue block and between paired blocks from the same pt could impact pt classification. This study characterizes the intra-block and intra-case heterogeneity using the VENTANA PD-L1 (SP263) Assay in non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC) and urothelial carcinoma (UC) for tumor cell (TC) and immune cell (IC) staining. Methods: Two blocks from the same tumor for 5 cases of each of 3 indications (30 unique blocks) representing a range of PD-L1 staining were commercially acquired and sectioned serially at 4 μm. Tumor continuity throughout the blocks was confirmed by staining sections 1 and 51 with H&E. Sections 2, 25 and 50 were stained with VENTANA SP263 and scored by a single trained pathologist, using the SP263 scoring algorithm and interpretation guide. Total percentages of PD-L1+ TCs and ICs were determined. Multiple diagnostic cutoffs were applied to TC and IC scores from multiple sections within each block and pair of blocks to establish overall percentage agreement (OPA) within and between blocks at each cutoff. Additional data were available in NSCLC for 200 cases with repeat SP263 staining (minimum separation 70 μm). Results: TC PD-L1 status at all cutoffs showed no intra-block (sections ~100 μm apart) or intra-case heterogeneity (Table). IC PD-L1 status showed limited intra-block and intra-case heterogeneity, with IC % staining in discordant sections varying by no more than 5%. Results are supported by the 200 NSCLC cases, with a minimum TC OPA across cutoffs of 91% (78.5% for ICs). Conclusions: Intra-block and intra-case concordance of TC PD-L1 status is high, and IC PD-L1 agreement is good across cutoffs. This supports the reproducibility of pt PD-L1 status in NSCLC, HNSCC and UC, within and between blocks. [Table: see text]
Total number of circulating tumor DNA (ctDNA) genomic alterations and outcome after checkpoint inhibitor-based immunotherapy.
Authors: Khagi Yulian , Goodman Aaron , Daniels Gregory A. , Patel Sandip Pravin , Bazhenova Lyudmila , Kurzrock Razelle
Published: September 2018

e14504

Background: High tumor mutational burden on tissue biopsy correlates with efficacy of checkpoint immunotherapy in cancers, such as non-small cell lung cancer and melanoma. However, the relationship between mutational burden detected in non-invasive surrogates, such as blood-derived ctDNA genomic alterations, and outcome after immunotherapy, has not been evaluated. Methods: We analyzed 69 patients with diverse malignancies whose plasma-derived ctDNA had undergone next generation sequencing (NGS) (54 to 70 genes: Guardant Health) and who had received checkpoint inhibitor-based immunotherapy. Data was assessed to correlate total number of alterations (characterized alterations and variants of unknown significance, VUS) in ctDNA and outcome: stable disease (SD) >6 months, complete or partial remission (CR or PR), progression-free and overall survival (PFS and OS), from date of immunotherapy initiation. Results: The69 patients had 23 different diagnoses. All individuals received checkpoint inhibitor-based immunotherapy, with the majority receiving anti-PD1/PD-L1 monotherapy. Evaluable patients with ≥6 vs. <6 total ctDNA alterations had significantly higher rates of SD≥6 months/CR/PR: 40.9% (9/22) vs. 15.9% (7/44) (p=0.035) (Table). Median PFS was 2.85 months vs. 2.1 months (p=0.046). OS was not statistically different. A landmark analysis at 2 months showed that median PFS in the ≥6 alterations group was 23.2 months for responders (CR/PR) vs. 2.3 months for non-responders (p=0.0006); for the group with <6 alterations, the median PFS was 12.6 vs. 3.3 months (p = 0.0006). Conclusions: Total number of ctDNA genomic alterations merits further exploration as a potential predictive biomarker for outcome with checkpoint inhibitor-based immunotherapy. Achieving response to checkpoint-based immunotherapy strongly predicts PFS from the 2-month mark. [Table: see text]