bluuebunny/crossref_metadata_2025 huggingface dataset:
Dynamic contrast-enhanced CT (DCE-CT) as an early biomarker of response in metastatic renal cell carcinoma (mRCC) under anti-angiogenic treatment
Authors: Fournier L. , Thiam R. , Cuenod C. , Medioni J. , Trinquart L. , Balvay D. , Banu E. , Balcaceres J. , Frija G. , Oudard S.
Published: March 2020

14003

Background: Evaluation of treatment response for cancer relies on application of criteria based on size such RECIST. However, changes in size are often delayed and small. An accurate and early evaluation of tumor vascular characteristics would allow selection of patients (pts) who would most likely benefit of these therapies and early detection of treatment response to tailor therapy on an individual basis. Changes in tumor vascular parameters were quantified using dynamic contrast-enhanced computed tomography (DCE-CT) as a biomarker for tumor angiogenesis. Methods: A total of 44 mRCC pts were enrolled in an imaging study corollary of two phase III trials evaluating efficacy of anti-angiogenic drugs: sorafenib (N=9) vs. placebo (N=13), or sunitinib (N=17) vs. interferon (N=5). Perfusion CT acquisitions after injection of 80 ml of iodinated contrast agent were performed on a single “functional metastatic target” before treatment and every 6 weeks for follow-up. Microvascular parameters of the functional target were calculated using a dedicated software based on compartmental models: tumor blood flow (TBF) (ml/min/100g), tumor blood volume (TBV) (%), vascular permeability (VP) (ml/min/100g) and mean transit time (MTT) (s). These parameters were correlated to the best treatment response as evaluated by the size variation of the RECIST targets. Results: Among the 26 treated pts, there was a statistically significant drop in TBF and TBV as early as the first cycle of treatment (respectively -50%, p=0.03 and -51%, p<0.01) compared to pre-treatment, showing the biological effect of the drug on tumor vascularity. There was a significantly higher drop in TBF and TBV in pts who would be later classified as responders (N=16) vs. non-responders (N=10) after the first cycle of treatment (-66% vs. -6%, p=0.02; -60% vs. -26.5%, p=0.04). The changes in MTT and VP were not correlated to the best response. Conclusions: The functional imaging biomarkers TBF and TBV quantified by DCE-CT detect the biological effect of anti-angiogenic drugs on tumor vessels. TBF appears as very early predictor of mRCC response to anti-angiogenic drugs supporting the hypothesis that DCE-CT may constitute a surrogate biomarker of angiogenesis inhibition.

No significant financial relationships to disclose.
Correlative study of EGFR mutations or protein expressions of EGFR, phosphorylated EGFR, HER2, phosphorylated HER2 and IGFR-1 with gefitinib sensitivity in patients with non-small cell lung cancer: Results of West Japan Thoracic Oncology Group trial (WJTO)
Authors: Hirashima T. , Nakagawa K. , Kashii T. , Kubo A. , Sasaki J. , Tanaka K. , Sato S. , Kurata T. , Tamura K. , Fukuoka M.
Published: March 2020

14008

Background: Both epidermal growth factor receptor (EGFR) mutation and gene copy number of HER2, a member of EGFR family, are associated with gefitinib sensitivity. We carried out a correlative study to determine the relationships between EGFR mutations, EGFR or HER2 protein expressions, their activation status (pEGFR, pHER2) or insulin-like growth factor receptor 1 (IGFR-1) protein expressions and clinical outcomes after gefitinib treatment in advanced NSCLC. Method: Tumors from patients (pts) were evaluated for EGFR mutations by DNA sequence, and for protein expressions of EGFR, pEGFR, HER2, pHER2 and IGFR-1 by immuno-histochemistry. Time to progression (TTP) was calculated by the Kaplan-Meier method; groups were compared using the log-rank test. Risk factors associated with TTP were evaluated with Cox proportional hazard regression modeling. Correlation between EGFR mutation and response was evaluated by Fisher’s direct method. Relationship between each protein expression and response was tested by two-sided. Primary endpoint was to detect biomarkers to predict gefitinib sensitivity. Results: From Dec. 2003 to Dec. 2005, 103 consecutive pts were enrolled onto the study, and received gefitinib until disease progression. Median age was 68 years, female (58%), adenocarcinoma (83%), never smoker (55%) and no previous chemotherapy (49%). 98 pts were evaluable for efficacies, toxicities and gene analyses. Forty-one pts (42%) had EGFR mutations; 14 pts had deletional mutation in exon 19, 27 pts had missense mutation (L858R) in exon 21. EGFR mutations were significantly related to response (62 vs. 26%; P = 0.001), disease control rate (92 vs. 65%; P = 0.003) and TTP (median, 10.1 vs. 5.1months; hazard ratio = 0.64; P = 0.048). Both pEGFR (0, +1 vs. =+2; P = 0.002,) and pHER2 (0 vs. =+1; P = 0.001) expressions are significantly associated with incidence of EGFR mutation. Conclusions: EGFR mutation was a significant predictive biomarker of response to gefitinib. Phosphorylated EGFR protein expression is a potent replaceable biomarker for EGFR mutation.

No significant financial relationships to disclose.
Synergistic apoptosis and antitumor activity induced by ST1926, an atypical retinoic acid derivative
Authors: Zanna C. , Pisano C. , Vesci L. , Pace S. , Lucreziotti M. R. , Merlini L. , Zunino F. , McCanna S. , Penco S. , Carminati P.
Published: March 2020

14029

Background: ST1926 is a novel adamantyl retinoid active against a wide panel of human tumor cell lines, including p53-defective cells. Moreover, its cytotoxic activity is not affected by Pgp overexpression or resistance to cisplatin. The drug induces an early G1/S cell cycle arrest associated with a modulation of genes involved in apoptosis and DNA damage. Although the ST1926 molecular targets are still not fully elucidated, some in vitro studies suggest that this drug induces activation of both intrinsic and extrinsic apoptotic pathways. Methods: ST1926 antiproliferative activity was evaluated in vivo by oral route using fractionated daily schedules in CD1 nude mice against different human tumor xenografts, including NSCLC, ovarian carcinoma, H&N, neuroblastoma and melanoma, as well as hematological malignancies. Pharmacokinetic and toxicological studies were conducted in rodents and dogs after single and repeated (5 days and 4 weeks) oral administration. Results: As monotherapy, ST1926, showing a favorable tolerability profile, was effective in inhibiting tumor growth in several tumor models. In particular, ST1926 showed significant tumor inhibition on doxorubicin- and platinum-resistant ovarian carcinomas at 30 mg/kg po given according to different schedules. The most prominent tumor growth inhibitory effects were noted in combination regimens with cisplatin and carboplatin in both sensitive and resistant ovarian carcinoma. The plasma t1/2 was about two hours in all animal species tested. The hemolymphopoietic system and GI tract were identified as the main target organs of toxicity. Toxicology findings indicated the starting dose in humans at 30 mg daily for five consecutive days. Conclusions: ST1926 is a new antitumor proapototic agent acting through particular molecular mechanisms. ST1926 is active by oral administration on both solid tumors, especially ovarian carcinoma, and acute myeloid leukemia. A Phase I clinical program to evaluate safety and tolerability of ST1926 as monotherapy and in combination with platinum compounds is ongoing in women with advanced ovarian cancer.

[Table: see text]
A phase Ib study of telatinib (BAY 57–9352), a VEGFR-2 inhibitor, in combination with docetaxel in patients with advanced solid tumours
Authors: Shaw H. M. , Molife L. R. , Spicer J. , Karavasilis V. , Marriott C. , Ong T. J. , Tate L. , Brendel E. , Christensen O. , de Bono J. S.
Published: March 2020

14035

Background: Telatinib (BAY 57–9352) inhibits VEGFR-2 and VEGFR-3 tyrosine kinases, and PDGFR-β and c-Kit. Preclinical data suggests that targeting VEGFR signaling increases antitumor activity. Methods: This trial investigated the safety, pharmacokinetics (PK), and tumor efficacy of telatinib combined with docetaxel (D). D was administered at a fixed dose of 75mg/m2 on day 1 of 21-day cycles. Telatinib was administered orally, twice daily (bid) from day 3 of Cycle 1 and onwards, thereafter continuously. Dosing of telatinib commenced at 600mg bid (cohort 1, n=6) and increased to 900mg bid (cohort 2, n=7). PK in Cycle 1 were determined on day 1 (D) and day 21 (telatinib). In Cycle 2 comparative PK profiles for both telatinib and D were sampled on days 1–3. Results: Thirteen patients (pts) with advanced solid tumors were enrolled (9M/4F; median age: 56 [range: 34–69]; ECOG PS 0/1: 3/10). A total of 69 cycles have been completed (range,1–10). Treatment-emergent adverse events of CTCAE =3 (NCI-CTC v3.0) were neutropenia (n=11, 79%), fever (n=2, 15%), and fatigue (n=2, 11%). Adverse events of CTC =3 occuring in two pts was febrile neutropenia. Others occurring in only one patient were; hypertension, ALT increase, dehydration, and reversible symptomatic pneumonitis. Study treatment-related adverse events leading to a dose reduction or interruption were neutropenia (n=5, 38%), hypertension (n=1), ALT increase (n=1), and fatigue (n=1). Two pts with prostate ca and 1 with cervical ca had a confirmed partial response. Five pts (1 NSCLC, 1 esophageal ca, 1 renal cell ca and 2 prostate ca) had stable disease for =4 cycles. Mean AUC of D increased by 48% in cohort 1, but only by 16% in cohort 2. Thus, PK data to date do not indicate a clear clinically relevant interaction between telatinib and D. Conclusions: The combination of telatinib and D was tolerated without reaching the toxic dose at telatinib 900mg bid and D 75mg/m2. This combination has demonstrated promising antitumor activity. An extension of the cohort at 900mg bid with 75mg/m2 D is being evaluated to gain further safety and PK data.

No significant financial relationships to disclose.
Nuclear factor kB (NF-kB) may predict efficacy of cetuximab therapy in EGFR-positive colorectal cancer
Authors: Scartozzi M. , Bearzi I. , Pierantoni C. , Mandolesi A. , Loupakis F. , Catalano V. , Berardi R. , Silva R. , Falcone A. , Cascinu S.
Published: March 2020

14036

Background: NF-kB is part of the aberrant activation of the EGFR-downstream signalling pathway in colorectal tumours, which is described to be inhibited by anti-EGFR therapies. Methods: We retrospectively analysed nuclear immunoreactivity for NF-kB with the aim to determine a correlation between NF-kB expression and outcome in terms of response rate and time to progression in EGFR-positive advanced colorectal cancer patients receiving cetuximab and irinotecan. Results: To date 67 patients (40 males and 27 females, median age 62, range 38–78) were analysed. Cetuximab and irinotecan were administered as a second-line in 18 cases (27%) and after = 3 lines of chemotherapy in the remaining 49 patients (63%). Among the 56 patients evaluable for response we observed a partial (PR) or a complete response (CR) in 10 and 1 cases respectively for an overall response rate of 20%. Twenty-seven patients (48%) obtained progressive disease, median time to progression (TTP) was 3,6 months, median overall survival was 16 months. NF-kB was positive in 46 cases (69%). All main clinical characteristics resulted well balanced between NF-kB positive and NF-kB negative patients. Response rate was 6% (2 PR) vs 43% (8 PR and 1 CR) (p= 0.001) in NF-kB positive and NF-kB negative tumours respectively whereas progressive disease was observed in 19 (54%) vs 8 (23%) cases in NF-kB positive and NF-kB negative cases respectively. Median TTP in NF- kB positive patients was 2.9 months versus 6.8 months in the remaining NF-kB negative patients (p= 0.01). Conclusions: Both the difference in median TTP and in response rate seem to confirm that NF-kB may play a crucial role in predicting the efficacy of cetuximab therapy in advanced colorectal tumours. The analysis is ongoing and updated results on an expanded number of cases will be presented.

No significant financial relationships to disclose.
A phase I study with exploratory pharmacodynamic endpoints of XL647, a novel spectrum selective kinase inhibitor, administered orally daily to patients (pts) with advanced solid malignancies
Authors: Wakelee H. A. , Molina J. R. , Fehling J. M. , Lensing J. L. , Sikic B. I.
Published: March 2020

14044

Background: XL647 is an orally bioavailable small molecule inhibitor of multiple receptor tyrosine kinases involved in tumorigenesis, angiogenesis, and metastasis, including EGFR/ErbB1, ErbB2/HER2, VEGFR2/KDR, and EphB4. In a previous Phase I study, the MTD was 350 mg when XL647 was dosed orally for 5 consecutive days every 14 days. Of 41 pts treated, one pt with NSCLC achieved a PR and 14 pts had prolonged stable disease (3.5–14+ months). The purpose of the present study is to determine the MTD of XL647 administered orally on a continuous daily schedule. Methods: Pts are enrolled in successive cohorts to receive XL647 daily for repeated 28 day cycles. PK sampling is performed to determine Cmax, and AUC at each dose level. Plasma samples are analyzed by ELISA for mechanism-of-action related molecules. Eyebrow hair bulbs are being evaluated by IHC to monitor effects of XL647 on signal transduction pathways downstream of EGFR. Tumor response is assessed every 8 weeks by RECIST. Pts remain on study until PD or unacceptable AEs. Results: Twelve pts have been enrolled. The starting dose was 75 mg (n=3) and has been escalated to150 mg (n=3), 200 mg (n=3) and 300 mg (n=3). To date, dose escalation continues as no DLTs have occurred and the MTD has not been determined. Ten pts remain on study, including 4 with stable disease for at least 3 months. In cohort 2, eyebrow samples from 3 pts were analyzed. XL647 caused a significant reduction in the phosphorylation of the EGFR downstream signaling kinases AKT (up to 73%) and ERK (up to 78%) in 2/3 and 3/3 pts, respectively. Preliminary analysis of potential plasma protein biomarkers from pts in cohorts 1 and 2 showed a trend towards upregulation of PlGF plasma levels in 4/6 pts during XL647 treatment. Conclusions: XL647 is well-tolerated when administered daily at doses tested to date. Dose escalation will continue until the MTD is defined. Analysis of eyebrow samples demonstrated its feasibility as a potential surrogate epidermal tissue for assessing inhibition of EGFR downstream targets by XL647. Updated safety, PK and pharmacodynamic results will be presented.

[Table: see text]
Epidermal growth factor receptor expression in and targeted therapy for metastatic squamous cell carcinoma of the penis
Authors: Pagliaro L. C. , Osai W. , Tamboli P. , Vakar-Lopez F. , Pettaway C. A.
Published: March 2020

14045

Background: Penile carcinoma is highly fatal when associated with bulky regional or distant metastases, despite chemotherapy and surgery. Epidermal growth factor receptor (EGFR) is a potential target for systemic therapy, but little is known about its expression or significance in penile carcinoma. Methods: The results of EGFR immunohistochemistry in cases of metastatic squamous cell carcinoma of the penis performed in our Department of Pathology over a 2-year period were reviewed retrospectively. The antibody used in the assay was Zymed clone 31G7. To assess the biological significance of EGFR expression, we reviewed the charts of these patients for EGFR-targeted therapies and outcomes. Results: Thirteen cases were assayed for EGFR expression. The tissue was from a lymph node metastasis in 5 patients, inguinal or scrotal skin metastasis in 2 patients, and the primary tumor in six patients. Tumor cells in all cases were positive for EGFR, and 9 were scored as 3+ or strongly positive. The percentage of cells positive for EGFR was >90% in six cases, 40–50% in one case, and not specified in six cases. All of the patients received one or more EGFR-targeted therapies including erlotinib (one patient), cetuximab (three patients), or cetuximab combined with one or more cytotoxic agents (nine patients). Six patients received a second or third EGFR-targeted therapy. Grade 3 or 4 adverse events were limited to cellulitis, thrombocytopenia, and tumor hemorrhage (one patient each). Two patients had disease progression during initial treatment with paclitaxel, ifosfamide, and cisplatin (TIP), then had partial responses to TIP plus cetuximab. Two patients had partial responses to cetuximab and cisplatin, also after having disease progression while receiving TIP. A patient with visceral metastases who had extensive prior chemotherapy received cetuximab and cisplatin as salvage treatment and experienced objective tumor regression lasting 3 months. Conclusions: High levels of EGFR expression are common in metastatic penile carcinoma. Five of 13 patients showed evidence of response to cetuximab in combination with cisplatin or TIP. These results indicate that EGFR plays a clinically important role in metastatic penile carcinoma and is a promising target for therapy.

No significant financial relationships to disclose.
Preliminary results of a phase II study of continuous low dose metronomic (LDM) cyclophosphamide (CTX) and celecoxib (CEL) for asymptomatic hormone refractory prostate cancer (HRPC) with assessment of anti-angiogenic biomarkers
Authors: Berry S. R. , Ko Y. , Emmenegger U. , Shaked Y. , Choo R. , Klotz L. , Zhang L. , Lee C. , Kerbel R.
Published: March 2020

14046

Background: LDM CTX is a minimally toxic anti-angiogenic therapy that has demonstrated activity in multiple tumour types including HRPC. Increased Cyclooxygenase 2 (COX 2, a prostaglandin synthase enzyme) expression appears to be a consistent feature of a variety of human tumours, including prostate cancer. COX 2 inhibitors like CEL exhibit anti-tumour activity in pre-clinical studies, at least in part due to their anti-angiogenic activity. Pre-clinical work supports the concept that the combination of selective angiogenesis inhibitors like CEL with metronomic chemotherapy can enhance the effects of these agents on tumour angiogenesis. Methods: Men with asymptomatic HRPC at a single Canadian centre received celecoxib 400 mg po BID and cyclophosphamide 50 mg po daily. The primary efficacy endpoint of this 2 stage phase II study is disease control rate (DCR): 50% PSA response, tumour response or prolonged (=6 mos) PSA or stable measurable disease. This study is also assessing the safety of LDM CTX and CEL as well as potential anti-angiogenic biomarkers in these patients including circulating endothelial cells and their precursors (CEC/P), plasma levels of thrombospondin-1 (TSP-1) and vascular endothelial growth factor (VEGF). Results: Enrollment for the first stage of this study (10 men) has been completed. There were 2 patients with disease control by the a priori criteria: one patient with a partial tumour response (PR) (PR duration 13 mos with PSA stabilization for 12 mos) and one patient that had both prolonged stable PSA (7 mos) and prolonged stable measurable disease (8 mos). In addition, another patient had an unconfirmed PR. The therapy was well tolerated. One patient had angina that responded well to medical therapy but there were no serious arterial-thromboembolic events. One patient developed grade 3 hypertension. All other toxicities were grade 1/2. Data on CEC/P, TSP-1 and VEGF levels will be presented at the meeting. Conclusions: LDM CTX + CEL is a well tolerated therapy in men with asymptomatic HRPC. 2/10 patients achieved disease control in the first stage of the trial, meeting the criteria to proceed to the second stage.

[Table: see text]
Epigenetic regulation of IFN-α2b in multiple myeloma by a hydroxamic acid histone deacetylase (HDAC) inhibitor (SAHA) and a non-hydroxamic acid HDAC inhibitor (A-423378)
Authors: Cheriyath V. , Glaser K. B. , Healan-Greenberg C. , Waring J. F. , Kalaycio M. , Borden E. C.
Published: March 2020

14048

Background: Full clinical potential of IFN-a2b is yet to be achieved in multiple myeloma. Although IFN-a2b leads to the induction of pro-apoptotic interferon stimulated genes (ISGs) (>100 fold) in myeloma cells, <20% of cells underwent apoptosis. Thus, we hypothesized that epigenetic silencing of ISGs may be responsible for the sub-optimal cellular response of myeloma to IFNs. Re-expression of suppressed ISGs by inhibiting HDACs could enhance IFNs effects. Methods: Myeloma cell lines NCI H929, RPMI 8266 and U266 treated for 96 hr with increasing concentrations of SAHA (Suberoyl Anilide Hydroxamic Acid) or A-423378, were assessed with alamar blue to determine IC50, and synergy between IFN-a2b and HDAC inhibitors (HDACi). Microarray analysis was performed to determine the effects on gene expression. Results: Both SAHA and A-423378 inhibited myeloma cell growth (IC50 100–400 ?M). Combinations of IFN-a2b and sub-IC50 concentrations of A-423378 or SAHA synergistically reduced the viability of NCI H929 and RPMI 8266. Treatments at their IC50 did not increase the expression of p21, p27 or p16, known mediators of HDACi. To identify target genes mediating cellular effects, RNA from RPMI 8266 cells treated for 18 or 72 hr with IFN-a2b, A-423378, SAHA or their combinations were hybridized to Affymetrix human genome U133A array. A-423378 had a greater effect on global gene expression (3228 genes) than SAHA (2249 genes) at 18 hr. But, at 72 hr SAHA (1344 genes) had more persistent effect on gene modulation than A-423378 (1091 genes). IFN-a2b altered the expression of 2072 genes at 18 hr and 1374 genes at 72 hr. Combination of IFN-a2b with A-423378 further altered the gene expression (IFN-a2b plus A-423378 3589 genes, IFN-a2b plus SAHA 2017 genes at 18 hr). RARRES3, a tumor suppressor gene was synergistically induced (34 fold) by IFN-a2b and HDACi combinations. Conclusions: A-423378 had a greater effect on global gene expression at early time points whereas SAHA had a more persistent effect. HDACi of different classes enhanced anti-viability effects of IFN- a2b. RARRES3, a tumor suppressor gene, may mediate antiproliferative effects of HDACi and IFN-a2b.

No significant financial relationships to disclose.
Evaluation of statistical designs of phase I/II clinical trials for cancer patients published in 2005
Authors: Houede N. , Kramar A. , Paoletti X.
Published: March 2020

14077

Background: Phase I trials determine the maximal safe dose that could be used in phase II trials. Designs are based on the assumption that efficacy and toxicity increase with dose. Phase I/II trials determine the safety, dosage levels, and response rate. This review addresses statistical issues of phase I/II studies designs. Methods: We reviewed phase I/II clinical trials for cancer patients published in 2005. The main criteria were: type of treatment, statistical design, endpoints, expected efficacy and toxicity, one- or two-steps designs, dose levels, definition of Dose Limiting Toxicity and recommended dose, objective response, survival, patient selection and follow-up. Results: 41 phase I/II trials were found. All but one, targeted a specific type of tumor. 14 studies included combined cytotoxic therapies. 21 studies included a cytotoxic agent combined with a targeted therapy (12) or with radiations (9). Others used monochemotherapy, immunotherapy, vaccine or gene therapy. 23 studies were a two steps design, i.e. a phase I followed by a phase II trial, and used a classical Fibonacci escalation dose model. All others used a one-step design evaluating efficacy and toxicity concomitantly. Among them, 3 had a Fibonacci-like design with a desescalation model and 4 had a randomization to different dose levels. In 1 trial, dose escalation was performed in the same patient. In the 10 remaining studies, 1 evaluated only one dose level and was improperly presented as a phase I/II study, and 9 did not describe any statistical design. DLT was described in only 27 trials. Also, recommended doses for further trials were only provided in 30 studies. Efficacy was evaluated with clinical or radiological response for 34 studies, biological marker was evaluated in 5 cases and time to progression in 2 cases. Conclusion: Most of the phase I/II trials published in 2005 used a classical two steps design with an adapted Fibonacci dose escalation. None of them used new designs such as continual reassessment method (CRM), which have the advantage to incorporate data during the course of the trial, leading to optimization of the study in terms of cost and speed. Methodological progresses are necessary to address issues related to multiple endpoints and to help clinicians to feel comfortable with the CRM.

No significant financial relationships to disclose.
Patterns of management of rash associated with epidermal growth factor receptor inhibitors (EGFRIs): A national practice survey
Authors: Lacouture M. E. , Lai S. , Rademaker A. W. , Liu D. , Pfeiffer C. , Mauro D.
Published: March 2020

14081

Background: Dermatological toxicities are frequent in patients receiving epidermal growth factor inhibitors (EGFRIs), which significantly affect health and quality of life. No current consensus or guidelines exist for the management of these manifestations. In order to gain insight on actual management approaches, a retrospective survey was conducted across oncology practices in the US. Methods: A survey in person was carried out that included 51 questions to 110 practitioners administering EGFRIs in the US, during which time erlotinib, cetuximab and gefitinib were FDA-approved. Open- and closed-ended questions relating to frequency and CTC-graded (G) severity of rash observed, management patterns, and impact on continued EGFRI therapy were evaluated. Statistical testing for correlations was done using Fisher’s exact test. Results: Respondents (resp) included MDs (72%), nurses (23%), NPs (4%), and pharmacists (1%). Majority (>50%) of rash events observed were mild/moderate (G1 in 39% + G2 in 34%). Interventions against rash by resp was based on severity, with G1 treated by 47%, G2 (71%), G3 (87%), G4 (80%). Treatments for G1/2 included only topical agents (TA) by 30% of providers, and combined TA + systemic agents (SA) for G3 (G4) by 48% (30%) of providers. Interestingly, 84% of resp indicated G2 rash improved with TA+SA therapy and only 44% with SA only. Although severe events were reported infrequently (4% and 3% of resp see >50% of G3 and 4 events, respectively), EGFRIs were frequently dose modified (76%) or discontinued (32%) due to rash. Conclusions: Rash is frequent and its management heterogeneous across the US, which increases with rash G. These findings suggest that combined therapy (TA + SA) is more effective than single-agent. Therefore, the high frequency of dose EGFRI modification/discontinuations reported may be minimized by proactive interventions. Trials evaluating proactive and reactive combined TA + SA against rash are currently underway.

No significant financial relationships to disclose.
A novel zinc-chelating small molecule exhibits cancer cell growth inhibition in vitro and in vivo by induction of tumor suppressors early growth response 1 (Egr-1) and Krüppel-Like Factor 4 (KLF4)
Authors: Lock L. , Khine A. , Huesca M. , Lawson V. , Peralta R. , Cammisa E. , Wang M. , Jin H. , Lee Y. , Wright J. , Young A.
Published: March 2020

14084

Background: Lead compound LT-253 was selected from a group of 2-indolyl imidazol [4,5-d] phenanthroline derivatives with anticancer activity. It shows potent and selective anti-proliferative activity against several human cancer types in vitro, and in vivo in xenograft mouse models of human colon carcinoma (HT-29) and non-small cell lung carcinoma (H460). Methods: The mechanism of cell growth inhibition of LT-253 was investigated in HT-29 colon cancer cells using the XTT cell proliferation assay, flow cytometry and apoptosis assays. In vitro and in vivo zinc chelation was determined by competition assays using fluorescent and chromophoric chelators. Gene expression studies were performed by human genome microarray analysis and confirmed by quantitative real- time PCR. The transcription factor activity profile of LT-253-treated cells was determined by a multiplex transcription factor array and electrophoretic mobility shift assays. The functional role of specific genes was evaluated by siRNA gene knock-down. Results: LT-253 functions as chelator of zinc in vitro, and of intracellular labile zinc in HT-29 cells. Moreover, LT-253-mediated HT-29 cell growth inhibition was reversed by zinc supplementation. Gene expression profiling confirmed sustained changes in zinc-sensitive genes such as metallothionine and several zinc transporters, but not copper-sensitive or iron-sensitive genes. LT-253 induces cancer cell growth inhibition primarily through G1/S phase cell cycle arrest. Gene expression and transcription factor activities of both Egr-1 and KLF4 are induced within 4 hr post LT-253 treatment. Moreover, increased expression of both Egr-1 and KLF4 is observed in LT-253-sensitive cancer cell lines of various origins. Importantly, Egr-1 and KLF4 gene knock-down by siRNA reversed the LT-253-mediated cell growth inhibition of HT-29 cells. Conclusion: Selective chelation of intracellular labile zinc pool by LT-253 triggers immediate induction of stress-responsive tumor suppressor Egr-1 and sustained induction of zinc-responsive tumor suppressor KLF4, leading to G1/S phase cell cycle arrest and inhibition of tumor growth.

No significant financial relationships to disclose.
A phase 1 dynamic accelerated titration dose escalation study of the vascular disrupting agent NPI-2358
Authors: Spear M. A. , LoRusso P. , Tolcher A. W. , Lin C. , Wang D. , Heath E. , Lloyd G. K. , Cropp G. , Papadopoulos K. P.
Published: March 2020

14097

Background: NPI-2358 is a novel tumor vascular disrupting agent acting on β-tubulin that destabilizes tumor vascular endothelial cells with an additional direct cytotoxic activity. NPI-2358 selectively induces tumor vascular collapse and tumor regression in multiple murine tumor models and also potentiates the effects of chemotherapeutic agents. Preclinical data indicate NPI-2358 may have advantages in terms of safety profile and activity (tumor blood flow remains markedly reduced after 24 hours). Methods: A Phase 1 study of NPI-2358 is being conducted in patients with solid tumors and lymphomas. Patients in this study were treated with NPI-2358 administered as a weekly IV infusion for 3 weeks in 4-week cycles. Eight subjects have been enrolled. The dose of NPI-2358 was escalated in cohorts of 1–3 patients dependent on observed adverse events (any cohort may consist of 1 patient provided no =Grade 2 AE is reported in the prior cohort). A cohort is expanded to 6 patients if a DLT is reported. Escalation was conducted in 100% intervals, and decreased to 50% intervals once a Grade 2 adverse event was reported. In addition to weekly safety monitoring (including ECGs, Troponin I, and blood pressure), echocardiography and pharmacokinetics were performed on Days 1 and 15 (D1 & D15), and a DCE-MRI obtained 4 hours after the first dose was compared to baseline. Results: The dose has been escalated from 2 mg/m2 to 9 mg/m2 (predicted minimum efficacious dose = 7.5 mg/m2) without evidence of dose-limiting toxicity or other significant toxicities including cardiovascular or neurotoxicity. Intrapatient values for Ktrans from DCE-MRIs appear highly reproducible. No responses have been reported, however, one patient with pancreatic adenocarcinoma has had stable disease (SD) for 3 cycles and continues to receive NPI-2358. Average Cmax and AUClast have increased from 16.2 ng/ml to 147 ng/ml, and from 101 to 360 ng/ml*hr respectively. No drug accumulation was observed; T1/2 was 4.2 ±1.9 h, clearance was 45 ±12 L/h and distributive volume was 251±57 L. Conclusions: NPI-2358 is well tolerated at doses above the minimum predicted efficacious dose. PK data show increasing Cmax and AUC with dose escalation and no drug accumulation on a weekly schedule.

No significant financial relationships to disclose.
Long-term administration of oblimersen (OBL) plus chemotherapy: An analysis of safety in patients with solid tumors and hematologic cancers
Authors: Baron N. A. , Gilles E. , Novick S. , Ehlert J. , Wu J.
Published: March 2020

14098

Background: Oblimersen (OBL; Genasense®) is designed to increase the efficacy of cancer therapy by reducing Bcl-2 protein. The agent has been studied in several randomized clinical trials, which prompted an evaluation of safety after extended administration in combination with various anticancer agents. Methods: We evaluated safety data from more than 900 patients (pts) with solid tumors or hematologic cancers who received OBL alone or in combination with chemotherapy in phase I-III studies. A total of 84 pts (65 with solid tumors, 19 multiple myeloma) who received OBL for = 6 months of on-cycle and between-cycle days were identified. We then compared the incidence of adverse events (AEs) in the Day (D) 1 to D180-period with the > D180 day period. Pts with solid tumors received OBL (0.6 to 12 mg/kg/d) in combination with dacarbazine, docetaxel, or mitoxantrone; pts with myeloma received OBL (7 mg/kg/d) combined with high-dose dexamethasone. Results: Among pts with solid tumors, the mean (± SD) number of 21 to 28-day cycles initiated was 12.3 (± 3.7; range, 7–25); the mean number of OBL treatment days was 65.6 (± 24.0; range, 45–156). In pts with myeloma, the mean number of 21 to 28-day cycles initiated was 13.3 (± 3.3; range, 9–20); the mean number of OBL treatment days was 105.3 (± 23.2; range, 77–148). Across both data sets, the incidence of AEs was lower or comparable in most system-organ classes (SOCs) in the > 180-day period compared with the D1 to D180-period. Events were consistent with those reported with short-term administration in multiple studies, and common AEs (including fatigue, fever, nausea, and vomiting) were similar in both periods. Conclusions: Oblimersen can be safely combined with multiple types of anticancer therapy. Prolonged treatment with these combinations for > 180 days has not been associated with the emergence of AEs qualitatively different from those reported with treatment for shorter periods.

No significant financial relationships to disclose.
Phase I dose escalation study of E7080, a novel anti-angiogenic multikinase inhibitor, in Japanese patients with advanced solid tumors
Authors: Yamada K. , Fujiwara Y. , Yamamoto N. , Yamada Y. , Suzuki S. , Kobayashi N. , Koizumi F. , Nishio K. , Tamura T.
Published: March 2020

14099

Background: E7080 selectively inhibits receptor phosphorylation of vascular endothelial growth factor (VEGF), platelet- derived growth factor (PDGF), fibroblast growth factor (FGF) and suppresses tumor angiogenesis and growth in preclinical studies. Methods: E7080 was orally administered to Japanese patients with advanced solid tumors twice daily by a 2 week-on 1 week-off schedule. The primary objectives were to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and the recommended dose for further study. The secondary objectives were to evaluate pharmacokinetics (PK), pharmacogenomics, and efficacy. Results: Twelve patients have been enrolled into cohorts of 1, 2, 4 or 8 mg/day. Major toxicities were hypertension and hyperlipidemia. Thus far, no DLTs or severe toxicities were reported. PK analysis in cohorts of 1, 2 and 4 mg/day showed the dose-proportional increase of Cmax and AUC. Three patients in cohorts of 1 and 2 mg/day experienced long stable disease (SD) for 18 weeks or longer. One patient with colorectal cancer in 4 mg/day cohort showed significant tumor shrinkage of multiple pulmonary metastasis. Biomarkers such as plasma angiogenic proteins and cytokines, circulating endothelial cells and circulating endothelial progenitor cells are exploratively evaluated. Conclusions: E7080 is well tolerated at doses up to 8 mg/day by a 2 week-on 1 week-off schedule. Some patients experienced clinical benefit without severe toxicity. MTD has not been reached and enrollment is ongoing.

No significant financial relationships to disclose.
Non-oncogenic deletion mutants of adenoviral E1A enhance paclitaxel induced apoptosis of ovarian cancer cells
Authors: Kurzeder C. , Hanselmann C. , DeGregorio N. , Sauer G. , Opalka B. , Kreienberg R. , Deissler H.
Published: March 2020

14102

Background: The phenotypical characteristics and spread of ovarian cancer cells, suggest intraperitoneal gene therapy of this disease. Phase I trials have been conducted to investigate the potential clinical benefits of adenoviral E1A-based gene therapy. Further gene therapeutic approaches which aim to enhance the efficacy of E1A-induced apoptosis in a multimodal approach including conventional chemotherapy are planned. However, besides tumor-suppressive effects, E1A is also known to transform rodent cells in conjunction with other factors, e.g. an activated ras oncogene. In an effort to eliminate elements favouring malignant conversion, the potential therapeutic effect of the E1AdelCR2 deletion mutant on ovarian cancer cells was studied. Methods: To avoid any selection bias, a doxycyclin-regulated system was used to express E1A wildtype protein and the mutant E1AdelCR2 lacking the p105RB-binding motif. The effects of the E1A proteins on proliferation and induction of apoptosis in ovarian carcinoma cell lines was studied with a WST-1 assay and fluorcytometric analysis of FITC labelled AnnexinV. Results: As confirmed by Western blot analyses, expression of the mutant proteins was almost completely suppressed in the presence of doxycyclin. Substantial reduction in proliferation was achieved by expression of both wildtype E1A and E1AdelCR2. Expression of E1AdelCR2 was sufficient by itself to induce apoptosis in 8,7% of ovarian carcinoma cells as shown by an increase of the fraction of Annexin binding OVMZ-8 cells. A strong synergistic effect with an increase of the fraction of apoptotoc cells by 16.7% was found when the cells were treated with paclitaxel. Conclusion: Deletion of the CR2 sequence should increase the safety of therapeutic applications of E1A without affecting tumor suppression. A doxycyclin-regulated expression system was established allowing the elucidation of the mechanisms underlying the therapeutic effects of E1A in ovarian cancer cells in the future by means of expression profiling and quantification of activated components of signal transduction pathways.

No significant financial relationships to disclose.
High throughput, highly multiplexed transcriptional profiling of cytologic preparations from buccal mucosa
Authors: Everson R. B. , Bangsi D. , Darga L. L. , Bell M. R. , Pidlaoan V. P. , Kanakapalli D.
Published: March 2020

14104

Background: Alterations in gene expression can be sensitive and informative indicators that a biologically effective exposure occurred. For example, serial specimens could provide evidence that a dose with a biological effect was reached in Phase I testing. Sampling buccal mucosal can provide epithelial cell specimens rapidly with little discomfort. However, ribonucleases in saliva rapidly degrade epithelial cell RNA, prohibiting analysis by standard array techniques. Using buccal cells, we conducted a pilot study to optimize procedures for RNA isolation and analysis and determined influences of gender, race, and cigarette smoking on gene expression. Methods: Buccal cells were collected by scraping the inner cheek with a previously described standardized plastic tool (BioTechniques. 2004;36:484–487) made available Avrum Spira of Boston University. Preliminary experiments compared RNA extraction procedures, including methods based on trizol (Invitrogen, Carlsbad, CA), RNeasy columns (Qiagen, Valencia, CA), and the High Pure RNA Paraffin Kit (Roche, Indiana, USA). After standardization of the method, specimens were obtained from 64 subjects using a blocked design sampling equal numbers of subjects by gender, African American and white race, and smoking status. Gene expression levels were determined using the cDNA-mediated annealing, selection, extension, and ligation assay (Illumina, Inc.), which measures expression of over 500 genes per analysis. Results: The Roche extraction method provided the highest yield of RNA and was used for subsequent assays. Technical replicates were highly reproducible. Preliminary analyses revealed that using P=0.05, 38 genes were expressed differentially by gender, 20 by race, and 10 by smoking status. The genes most differentially expressed by gender included IRF1, MET, STAT1, RAP1GDS1; race CD9, CCNA2, CEACAM1, FVT1; smoking CD44, NQO1, SKI, SRC. Conclusions: Highly multiplexed gene expression analysis of buccal cells are feasible. Demographic characteristics of study subjects can be important, but they do not heavily influence levels for many genes. Results indicate the assays could be provide useful information in cross-sectional or serial studies of the impact of molecular therapeutics.

No significant financial relationships to disclose.
Growth inhibitory effect of ceramide-incorporated nanoliposomes in human pancreatic cancer cells
Authors: Jiang Y. , Kaiser J. , Heakal Y. , Cheng H. , Loughran T. , Kester M.
Published: March 2020

14105

Background: In cancer therapy, it is a challenging task to develop an optimal therapeutic regimen with an improved drug delivery vehicle and a cancer targeting strategy. Liposome-based drug delivery vehicles have been proven feasible and effective in clinical applications. We have recently developed a novel 80 nanometer diameter liposomal formulation that incorporates 30 molar percent C6-ceramide, a lipid-derived second messenger that is proapoptotic to cancer cells, but not to normal cells. Methods: MTT assay was used to evaluate cell proliferation and viability. In vitro soft agar colony forming assay was utilized to assess the transforming activity of pancreatic cancer cell lines. For apoptosis, caspase 3/7 assay was applied. Results: We assessed the biological effect of C6-ceramide nanoliposomes (C6 liposome) in two human pancreatic cancer cell lines, L3.6p1 and Panc1 cells. We demonstrated in L3.6p1 cells as well as Panc1 cells that C6 liposomes, but not control liposomes, increased cytotoxicity, as measured by MTT assay. Moreover, the C6 liposome synergized with low dose gemcitabine, a first line pancreatic cancer neoplastic agent, to dramatically enhance apoptosis, as measured by caspase 3/7 activities. Further, in vitro transforming assays (soft agar colony forming assay) indicated that L3.6p1 cells treated with C6 liposome formed much smaller colonies than that of control cells, suggesting that the C6 liposome alone can inhibit the in vitro transforming ability of the L3.6p1 cells. Conclusions: Collectively, we have developed a novel nanotechnology-based liposomal drug delivery system for pancreatic tumors. Our data suggest that the C6 liposomal formulation is able to enhance the efficacy of gemcitabine to suppress the proliferation and in vitro transforming activity of pancreatic tumor cells. Acknowlegements: Penn State Research Foundation has licensed ceramide liposomes to Tracon Pharmaceutical, Inc. San Diego, CA.

No significant financial relationships to disclose.
A phase I trial of lapatinib in combination with carboplatin in patients with platinum sensitive recurrent epithelial ovarian cancer
Authors: Kimball K. J. , Numnum T. M. , Estes J. M. , Kirby T. O. , Barnes M. N. , Alvarez R. D.
Published: March 2020

14106

Objective: Lapatinib is an inhibitor of EGFR and ErBb-2 tyrosine kinase. It has demonstrated anti-tumor activity in preclinical trials. Early trials evaluated toxicities and doses in several tumors types, however very few ovarian cancer patients have been included in lapatanib trials. The primary objective of this study was to determine the nature and degree of toxicity as well as the maximum tolerated dose (MTD) of Lapatinib in combination with carboplatin when used as second line therapy for platinum sensitive, recurrent ovarian or primary peritoneal carcinoma. The secondary outcome includes preliminary evaluation of response to therapy. Methods: After obtaining IRB approval, patients with measurable, recurrent, platinum sensitive epithelial ovarian or primary peritoneal carcinoma were eligible for enrollment. Patient cohorts were treated with intravenous (IV) carboplatin (AUC 6) every 21 days in combination with escalating dosages of daily oral lapatinib for 6 planned cycles. Toxicity was assessed using NCI Common Terminology Criteria for Adverse Events. Response and time to documented progression were also monitored. Results: Nine patients have been enrolled in 2 cohorts to date. Six women with recurrent cancer were administered eighteen cumulative cycles of IV carboplatin and 750 mg of oral lapatinib and were evaluable for toxicity data. The most common toxicity was hematologic with 8 (44%) cycles effected by grade 3 or 4 neutropenia or thrombocytopenia. Two patients were taken off the study secondary to excessive delay for hematologic depression. The dose of carboplatin was reduced to an AUC 5 in the second cohort due to excessive hematologic toxicity and treatment delay. Grade 3 nonhematologic toxicities consisted of abdominal pain (38%), indigestion (6%), fatigue (6%), and urinary frequency (11%). One patient withdrew due to abdominal pain not related to the study drug. Two subjects were evaluable for response. As indicated by biochemical and radiographic examination, both had a complete response and have no evidence of disease. Conclusions: Lapatinib, in combination with IV carboplatin at an AUC 5, portrays an acceptable toxicity profile and antitumor activity. Accrual to cohorts of escalating lapatinib doses is ongoing.

No significant financial relationships to disclose.
Dynamic contrast enhanced MRI (DCE MRI) for assessment of effects of anti-angiogenic therapy: Comparison of the transfer constant (Ktrans) to blood flow and permeability derived by a distributed parameters model
Authors: Thng C. H. , Koh T. S. , Rumpel H. , Khoo J. B. , Ong A. B. , Sukri N. , Tai B. C. , Soo R. A. , Humerickhouse R. , Goh B. C.
Published: March 2020

14109

Background: Transfer constant (Ktrans) and IAUC60 normalized with arterial input function are commonly used dynamic contrast enhanced magnetic resonance imaging (DCE MRI) parameters. The distributed parameters model (DP) is a DCE MRI model that enables derivation of blood flow and capillary permeability-surface area product (PS). We aim to study the distributed parameters model as an alternative method of angiogenesis assessment and correlate the above parameters to drug exposure and patient outcome in a Phase I anti- angiogenic trial. Methods: Fifteen evaluable patients from an on-going Phase I trial (ABT 869) with 3 dose escalations formed the study population. Pharmacokinetic study was performed on Day 1 and the area under the concentration time curve extrapolated to infinity (AUCinfinity) was used as an indicator of drug exposure. All patients underwent DCE MRI at baseline, Day 3 and Day 15 with temporal resolution of 4 seconds. Gadolinium concentrations were estimated using a dual flip angle method. Patients demonstrating progressive disease in first 2 evaluation scans (cycle 2 or 4) based on RECIST criteria were considered progressors and all other patients non-progressors. Receiver operating curve (ROC) analysis was performed. Correlation with AUCinfinity was analyzed. Results: There is good correlation (Spearman’s coefficient -0.67, p = 0.008) between AUCinfinity and DP derived PS and less strong correlation with normalized IAUC60 (Spearman’s coefficient -0.57, p = 0.03). There is no correlation for Ktrans (Spearman’s coefficient 0.04). ROC analysis for predicting progressors versus non-progressors showed a higher ROC area for PS compared to Ktrans (0.83 versus 0.47, p = 0.037). Normalized IAUC60 showed a slightly lower area compared to PS (0.77 versus 0.83) but the difference is not significant (p = 0.58). Conclusions: PS derived from DP model shows better correlation with drug exposure and may predict patient outcome better than Ktrans.

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