bluuebunny/crossref_metadata_2025 huggingface dataset:
A dose finding and PK/PD study of weekly amrubicin in patients with refractory or relapsed lung cancer: Central Japan Lung Study Group (CJLSG) 0601 trial
Authors: Kitagawa C. , Saka H. , Adachi T. , Kajikawa S. , Mori K. , Kogure Y. , Oki M. , Shimokata K.
Published: August 2020

e13517

Background: Amrubicin (AMR) is a potent topoisomerase II inhibitor, and a promising agent for both small cell and non-small cell lung cancer. AMR is usually administered on days 1–3 intravenously. However, it causes severe, occasionally fatal, toxicity of leucopenia and neutropenia. The purpose of this study was to evaluate the safety and tolerability of AMR, to determine the recommended weekly dose, and to conduct a PK/PD study in patients with chemotherapy-refractory or recurrent lung cancer. Methods: Refractory or relapsed non-small cell and small cell lung cancer patients after 1 or 2 regimens, younger than 80 and with adequate main organ functions were eligible. AMR was initiated 45 mg/m2 given weekly (on day 1 and 8 q3wks). The dose level was increased by 5 mg/m2 by modified Fibonacci dose escalation scheme. Dose limiting toxicity (DLT) was assessed on the 1st cycle. Results: 16 patients were enrolled. Patients were 7 small cell lung cancer and 9 non-small cell lung cancer. 54 cycles (median: 3, range: 1–6) were administered in 5 dose levels. In 65 mg/m2 level, 3 patients had DLTs. The maximum tolerated dose was 65 mg/m2. The recommended weekly AMR dose was determined to be 60 mg/m2. Leucocytopenia, neutropenia, thrombocytopenia, and the dose level were correlated (p<0.001, p=0.0012, p=0.043) respectively. Leucocytopenia, neutropenia, and amrubicinol (AMR-OH) Cmax were correlated (p=0.042, p=0.047) respectively. AUC (AUC extrapolated to concentration-zero) of AMR and AMR-OH did not depend on the dose levels. The pharmacokinetic results are shown in the Table.

[Table: see text]

[Table: see text]
Oral metronomic chemotherapy using cyclophosphamide in metastatic patients (pts) after standard treatment: Results of a randomized phase II trial
Authors: Clisant S. , Adenis A. , Dansin E. , Desauw C. , Degardin M. , Mortier L. , Fournier C. , Penel N.
Published: August 2020

e13519

Background: Oral metronomic chemotherapy (OMC) has antiangiogenic properties and megestrol acetate (MA) is an orexigen used to maintain the general condition in critically ill pts. Anecdotal responses have been reported with each treatment. We hypothesized that each treatment offer disease control without significant severe toxicity. Methods: This multi-center-randomized study was aimed to assess the efficacy and tolerance of both treatments. Primary endpoint was stable disease rate at 2 months: 2mSD (RECIST). Main eligibility criteria were as follows: non-breast cancer, pts with progressive disease refractory to standard therapies or without established standard care, ECOG=0–1, neither hypercalcemia nor hypoalbuminemia. Pts were randomized to receive MA 160 mg b.i.d or OMC 50 mg b.i.d until severe toxicity or progression. The sample size calculation was based on Simon Minimax design (α=10%, β =90%, P0=5%, P1=20%). The second stage was allowed because at least 2mSD were seen among 12 first pts. Results: 88 pts were included from 9/2006 to 12/2008 (44 in each arm). Median age was 61 (22–84). Most common primaries were: colorectal cancer (30 pts), soft tissue sarcoma (17), lung cancer (13), head & neck (8) and unknown primaries (4). The median number of previous lines of treatment was 4 (0–10). As of 28 December 2008, 80 pts are assessable for primary endpoint: 6/40 pts (15%) experienced 2mSD in OMC arm whereas 2/40 pts (5%) in MA arm. Three long-lasting SD (6 months +) are currently being observed in 3 pts receiving OMC (2 sarcomas and 1 RCC). No Grade 3 or 4 toxicity was notified. Treatment was discontinued in 1 case because of MA- induced deep venous thrombosis. Conclusions: OMC and MA offer SD in patients with advanced, refractory and progressive tumors, without any significant toxicity. The non-progression rate with OMC (15%) is in a same range of efficacy that was recently reported with new targeted therapy or anti-angiogenic agents administered in such pts. The accrual is now completed, and a longer follow-up is necessary to better analyze the clinical benefit and the prognostic factors.

[Table: see text]
A phase I study of intravenous (IV) milataxel in combination with carboplatin in adult patients with advanced malignant solid tumors
Authors: Flood W. A. , Lewis L. D.
Published: August 2020

e13525

Background: Milataxel (MXL) is a novel taxane with activity in human xenograft models against tumors resistant to paclitaxel. The primary objective of this study was to determine the MTD when MXL was given intravenously in combination with a fixed dose (AUC=6) of carboplatin (C) every 21 days in subjects with advanced malignant solid tumors. Secondary objectives were to (i) assess the safety and tolerability of the combination (ii) define the pharmacokinetics of MXL and C when given in combination (iii) obtain preliminary information on the antitumor activity of MXL+C. Methods: Key subject eligibility criteria included: adult pts with refractory malignant tumors, ECOG PS <3 and adequate hematologic, hepatic and renal function. PK data was obtained on day 1 for MXL and both free and bound platinum. Results: 11 pts (median age 60; 2 F,9 M) were treated. MXL was dose escalated in three cohorts (15, 20 and 25 mg/m2). Three patients were treated at 15 mg/m2 of MXL without a DLT. At the 25 mg/m2 dose of MXL there were two DLT's out of the 4 pts enrolled at this dose (1 pt - grade 3 febrile neutropenia, grade 4 thrombocytopenia; 1 pt - grade 4 ANC, grade 4 thrombocytopenia). At the 20 mg/m2 dose of MXL there were two DLT's out of the 4 pts enrolled at this dose with both pts having grade 4 ANC. The MTD and the recommended Phase II dose of MXL was 15 mg/m2 plus C (AUC= 6). The median number of cycles administered was 3 (range 1–16). The most frequent grade 3 or 4 treatment emergent adverse events were neutropenia (82%), leukopenia (55%), pancytopenia (27%), asthenia (18%), generalized edema (18%), thrombocytopenia (18%), anemia (18%), confusion (18%), and dyspnea (18%). One pt in the MTD cohort with cholangiocarcinoma had a PR. This patient received 16 cycles of therapy and had a response duration of 378 days and a TTP of 406 days. PK data (n=9) showed the elimination half-life of MXL ranged from 26 to 110 h, and that for free and total platinum were as would be predicted for C monotherapy. Conclusions: The MTD of MXL was 15 mg/m2 IV per three week cycle when combined with carboplatin (AUC= 6). One patient with a cholangiocarcinoma had a sustained PR for 378 days.

No significant financial relationships to disclose.
Electrochemoterapy (ECT) for the treatment of superficial tumor localizations
Authors: Guida M. , Porcelli G. , Ruggieri E. , Zito A. , Mattioli V. , Montemurro S. , Colucci G.
Published: August 2020

e13526

Background: ECT is an effective local treatment for palliation on inoperable superficial neoplastic lesions from any type of tumour. It combines chemotherapy and electric pulses that permeabilize the cell membrane in a transient and reversible manner, allowing low-perrneant drugs to enter the cell, thus magnifying their cytotoxicity. Recent1y, a new device (Clinoporetor, IGEA-Srl, Italy) has been developed to supply electric pulses with appropriate parameters permitting the clinical use of ECT. Methods: We treated 26 pts, M/F 12/14; median age 61 yrs, range 38–87: 7 breast cancer with nodular or infiltrating lesions in thoracic or abdominal wall; 12 melanoma (2 wide infiltration of thoracic wall, 10 in transit metastases or loco-regional recurrences); 2 head-neck cancer with a wide neck-scalp infiltration; 3 lymphomas with cutaneous lesions, 1 soft tissue sarcoma with a subcutaneous recurrence, 1 gastric cancer with 2 cutaneous localizations. The areas treated ranged from 1 to 30 cm on diameter. 12 pts requested a prior surgery debulking and 3 pts received ECT in pre-irradiated area. Intravenous bleomycin (15 mg/m2) were used in all patient; electric pulses were than applied to the tumor areas by needle electrodes in a time window of 20 minutes. In total 32 procedures were performed, 6 as out-patient in local anaesthesia and 26 in general anaesthesia; 6 pts requested a second application. Results: Treatment was safe and well tolerated, particularly when general anaesthesia was used. At the second/third week, all pts showed a regression of almost all lesions with a necrotic, fibro-sclerotic evolution. After 1–2 months from ECT, we obtained a 70% CR and a 10%PR of the lesions. Some pts showed a response after the second procedure. About 50% of lesions remained in remission for a long period (median 8 months, range 1–23+); 11 of 12 pts previously undergone surgical debulking never relapsed in the treated area. Concomitant systemic treatment, no rapid spreading of the disease and surgical debulking were related to a better local control and survival. Conclusions: ECT is a promising and safe treatment for superficial lesions from different malignancies. General anaesthesia and surgical debulking permit to treat very large and deeper lesion with a very good local control.

No significant financial relationships to disclose.
Expression of breast cancer resistance protein (BCRP) in esophageal cancers (EC)
Authors: Bharthuar A. , Khoury T. , Haas K. N. , Mashtare T. , Black J. , Baer M. , Yang G. , Khushalani N. , Iyer R. V.
Published: August 2020

e13529

Background: EC patients face a dismal outcome despite tri-modality management strategy. Median survival remains 15–18 months despite platinum, fluropyrimidine & irinotecan based therapy. BCRP is an ATP-dependent efflux protein associated with chemotherapy (CT) (e.g. irinotecan) resistance. Role of BCRP expression in EC and normal esophageal cells is not known. We examined the expression of this protein and correlate it with survival (OS) in patients receiving irinotecan-based CT. Methods: With IRB approval, 40 cases of EC diagnosed between 2004 and 2008 were stained for BCRP expression by IHC & scored by the pathologist blinded to clinical data. Baseline demographics, therapy given & OS data were collected and correlated with BCRP expression. BCRP score (membrane or cytoplasm) >/= 30 was considered positive (calculated by multiplying BCRP intensity and % staining). Fisher's exact test used to determine association between BCRP expression & demographics. Cox proportional hazards model used for association of BCRP & OS. Results: Baseline patient and tumor characteristics: Gender: M 35, F 5; Histology: 37 Adenoca & 3 SCC; Stage 1-III 27, Stage IV 10, unknown 3; CT: cisplatin+irinotecan (n=16), oxaliplatin+fluoropyrimidine (n=8), other (n=16); IHC: 30 of 40 cancers (75%) expressed BCRP [strong (n=28) & intermediate (n=3); membranous (n=17), cytoplasmic (n=27) & both (n=14)]. Down-regulation of BCRP expression in tumor compared to normal cells seen in 40% of patients. Median OS was 19 months with no difference in OS between BCRP positive and negative patients (p=0.13). Estimated hazard ratio (HR) of death for BCRP positive patients was 2.29 (95% CI 0.79 - 6.64).There was no association between BCRP expression and stage, age, gender or histology. For patients who received cisplatin and irinotecan as first line CT there was no difference in OS (p=0.39) of BCRP negative versus positive patients. Conclusions: BCRP expression is seen in a majority of EC & normal esophageal mucosa. Response rates to irinotecan based therapies are seen in 30–40 % of EC, whether the 40% with low tumor BCRP constitute a majority of the responders needs to be prospectively validated in a larger dataset & should include markers that predict response to 5-FU & platinum based CT to allow individualizing therapy for this cancer.

No significant financial relationships to disclose.
A phase I evaluation of intravenous (IV) 131I-chlorotoxin delivery to solid peripheral and intracranial tumors
Authors: Gribbin T. E. , Senzer N. , Raizer J. J. , Shen S. , Nabors L. B. , Wiranowska M. , Fiveash J. B.
Published: August 2020

e14507

Background: Pre-clinical studies demonstrate TM601 binding to glioblastoma, melanoma, and other tumor types in vitro and in vivo (human xenograft tumors in mice). Here we report imaging and safety data from a Phase I clinical trial in patients with recurrent metastatic somatic and/or cerebral solid tumors that received IV 131I-TM601. Methods: Patients received an IV imaging test dose of 10 mCi/0.2mg 131I-TM601. Subjects not showing tumor localization, received a second imaging test dose of 20 mC/0.4mg 131I-TM601. Subjects without localization at either dose were dropped from study; patients showing tumor localization without toxicity then received a 30 mCi/0.6mg 131I-TM601 IV injection. The primary objectives were to: 1) determine whole body localization and dosimetry, 2) estimate the maximum tolerated dose based on normal tissue dosimetry and 3) determine the acute toxicity of IV 131I-TM601. Results: A total of 44 evaluable patients received IV doses of 131I-TM601 without dose-limiting toxicity. 31/44 (70%) showed tumor specific uptake on follow-up gamma camera or SPECT imaging. Tumor-specific uptake was observed in patients with malignant glioma (7/8), metastatic melanoma (7/7), non-small cell lung cancer (3/4), colon cancer (6/7), pancreatic cancer (2/3), prostate cancer (2/2), breast cancer (1/4) and in one evaluable patient each with transitional cell carcinoma, pleomorphic xanthoastrocytoma and metastatic paraganglioma. Notably, all patients with metastatic cerebral disease showed tumor-specific uptake of systemically injected 131I-TM601. No uptake was seen in CNS lymphoma (n=1), ovarian (n=2), small cell lung (n=2), or medulllary thyroid cancers (n=1). Conclusions: Tumor-specific uptake of IV 131I-TM601 in primary and metastatic (including brain) solid tumors suggests that further dose escalation is warranted. Notably, IV injected 131I-TM601 crossed the blood brain barrier. Based on normal tissue dosimetry from this study, future clinical trials will evaluate safety and therapeutic efficacy in patients with recurrent glioma and metastatic melanoma at doses up to 100 mCi 131I-TM601 (maximum single dose).

[Table: see text]
A novel mutant-enriched liquidchip for detection of circulating EGFR mutations in advanced non-small cell lung cancer patients
Authors: Lu S. , Yang H. , Ye X. , Xu X. , Li Z. , Ren L. , Xu Y. , Xu J.
Published: August 2020

e14526

Background: We developed a novel technology, Mutant-enriched liquidchip (MEL), which integrates the sensitive mutant enriched PCR and quantitative high throughput liquidchip (suspension array), to detect circulating EGFR mutations (Exon 19 deletion and exon 21 L858R mutation) in patients with advanced non-small cell lung cancer (NSCLC). Methods: To enrich mutant EGFR, a unique restriction site is introduced into the mutation alleles so that the wild type sequence can be selectively removed by restriction digestion, and the undigested mutated DNA is amplified by PCR. The product is then hybridized to complementary probes (including 15 types of exon 19 deletion and exon 21 L858R mutation) which had been conjugated to beads coding with different fluorescent dye, followed by measuring through Luminex 200 system. Plasmid DNA mixture with different EGFR genotypes was applied to determine the sensitivity and accuracy of MEL. Afterwards, the MEL was validated in 49 patients whose EGFR genotypes of tissue specimen had been tested with direct sequencing The circulating genomic DNA was obtained from serum sample of other 201 Chinese stage IIIB or IV NSCLC patients without EGFR-TKI administration, and the EGFR mutation status was analyzed by using of MEL. Results: The results shows that MEL is capable of detecting as few as 20 copies of mutant EGFR alleles with a sensitivity limit of at least mutant/wild-type ratio of 0.1%. It also shows that MEL can not only confirm EGFR mutations status in tissue specimens already known by direct sequencing (13/49), but also detect mutations in some of those showing wild type by sequencing (16/49). Overall, 54% of patients had circulating EGFR mutation. 34% of patients had an exon 19 deletion and 29.6% had L858R. 63.1% of mutations were found in females and 67.6% in never-smokers. Conclusions: This novel MEL method allows for highly sensitive and reproducible detection of human somatic mutations in heterogeneous specimens, and could be applicable to test EGFR mutations non-invasively in advanced NSCLC patients for predicting response to targeted therapy.

No significant financial relationships to disclose.
A phase I dose-escalation study of 5-day intermittent oral lapatinib therapy with biomarker analysis in patients with HER-2–overexpressing breast cancer
Authors: Chien A. J. , Auerback G. , Rugo H. S. , Melisko M. , Munster P. N. , Khanafshar E. , Ordovas K. G. , Petricoin E. F. , Koch K. M. , Moasser M. M.
Published: August 2020

e14530

Background: Although current HER2 targeting agents have made measurable impact on the treatment of HER2overexpressing breast cancer, their effects have been modest. Recent evidence has redefined the target of interest as the HER2-HER3 signaling dimer and identified inherent signal buffering capacity that protects it against partial inhibitors of HER2 function. In preclinical studies, HER2 catalytic function and HER2-HER3 signaling can be suppressed, but this requires higher fully inactivating doses of HER- family tyrosine kinase inhibitors (TKIs) leading to apoptotic tumor cell death. We hypothesize that TKIs may be much more clinically effective if used at much higher and fully inactivating doses. Such high dosing may only be tolerable if given intermittently rather than continuously. Methods: To test this hypothesis clinically, we conducted a phase 1 dose-escalation study of a 5-day course of lapatinib (Lp) in women with advanced HER2-overexpressing breast cancer. Lp was administered on days 1–5 of a 14 day cycle. Starting Lp dose was 1750 mg/day and was escalated in cohorts of 3 until the maximum tolerated dose (MTD) was defined. The first cycle of Lp therapy was bracketed by tumor fine needle aspirations and serologic studies, performed at baseline and on day 5. Functional signaling pathway biomarker analysis was performed on tumor lysates using Reverse Phase Protein Microarrays to assay the inactivation of HER2-HER3 signaling. Plasma Lp concentration was assayed at all dose levels and cardiac function was rigorously monitored. Tumor core biopsies were performed on a subset of patients at the MTD to determine tissue Lp levels. Results: 17 patients have been treated to date. No grade 4 or serious adverse events (AEs) attributable to Lp have been noted. 1 patient experienced dose-limiting toxicity at dose level 6 (7000 mg/day) consisting of grade 3 diarrhea despite maximal anti-diarrheal support. There have been no cardiac AEs. The most common AEs include grade 2 diarrhea, nausea, vomiting, acne. Conclusions: The MTD and systemic exposure of Lp can be considerably increased throsugh intermittent dosing.

[Table: see text]
Pharmacogenomic analysis of the triplet combination of gemcitabine, oxaliplatin, and cetuximab as salvage therapy for metastatic colorectal cancer (mCRC) patients
Authors: Hernandez A. , Bandres E. , Rodriguez J. , Bitarte N. , Ramirez N. , Zarate R. , Abajo A. , Chopitea A. , Viudez A. , Garcia-Foncillas J.
Published: August 2020

e14531

Background: We have previously reported that biweekly gemcitabine-based therapy was active in pretreated mCRC pts (De la Cruz et al, ASCO GI 2008, abstr 377). We aimed to investigate whether germ line polymorphisms may be predictors of clinical outcome in mCRC pts treated with this combination. Methods: We evaluated SNPs of genes involved in gemcitabine metabolism (CDA, dCDK, RRM1, DCTD, SLC28A1), DNA repair (XRCC1, XRCC 3, ERCC1, XPD) and two IgG Fcγ R polymorphisms (Fcγ RIIa- H131R and Fcγ RIIIa-V158F), reported to be predictive of cetuximab-based therapy, even in K-ras mutated pts. Whole blood was collected and DNA extracted from peripheral lymphocytes using a DNA isolation Kit (Qiagen, CA). Polymorphisms were detected using the TaqMan genotyping assays (Applied Biosystems, CA). Clinical response was evaluated according to RECIST criteria. Univariate analysis (Fisher´s exact test for response; log-rank test for TTP and OS) was performed to examine associations between polymorphisms and clinical outcome. Results: Blood samples of 35 out of 39 enrolled pts were tested for genomic analysis. Patient‘s characteristics are as follows; M/F: 26/13, median age: 59 years, median number of prior chemotherapy lines: 2 (1–4), Köhne risk groups; low: 8 pts, intermediate: 18 pts, high: 13 pts. After a median follow-up of 20 months, median progression-free survival (PFS) is 6.7 months (95% CI; 5.2–8.3) and median overall survival 15.4 m (95% CI; 14.7–16.1). Overall response rate (ORR) was 53.8%. RRM1 R284R SNPs (p=0.06), T741T (p=0.02) and RRM1–524CT (p=0.04) were linked to clinical responsiveness. All pts possessing 2 or 3 favourable RRM1 SNPs responded. ORR was 53.3% for pts with no favourable SNPs versus 85% for pts with any favourable SNP (p=0.04). ORR was also significantly higher in pts with any histidine allele in the Fcγ RIIa polymorphism (93% vs. 60%, p=0.034). Median PFS was adversely affected in pts harbouring no favourable RRM1 SNPs (4.2m versus 6.7 months, p=0.019) and in those pts with homozygous Fcγ RIIa-131R allele (4.4 vs. 7.5 months, p=0.007). Conclusions: Polymorphic variants of RRM1 and Fcγ RIIa may play a key role in the efficacy of gemcitabine and cetuximab-based therapy for mCRC pts.

No significant financial relationships to disclose.
A phase I study of daily BIBW 2992, an irreversible EGFR/HER-2 dual kinase inhibitor, in combination with weekly paclitaxel
Authors: Ang J. , Mikropoulos C. , Stavridi F. , Rudman S. , Uttenreuther-Fisher M. , Shahidi M. , Pemberton K. , Wind S. , de Bono J. , Spicer J. F.
Published: August 2020

e14541

Background: BIBW 2992 is an oral, potent and irreversible inhibitor of both EGFR and HER2 receptor tyrosine kinases. The efficacy of cytotoxic agents can be enhanced by erbB inhibition. The primary objective of this Phase I open- label dose-escalation trial was to determine the maximum tolerated dose (MTD) of BIBW 2992 in combination with weekly paclitaxel. Methods: This study evaluated safety, pharmacokinetics (PK), and anti-tumor efficacy of daily BIBW 2992 combined with paclitaxel administered on Days 1, 8 and 15 of a 4-weekly cycle. The dose of paclitaxel was 80 mg/m2, and the BIBW 2992 starting dose was 20 mg, escalated in successive cohorts to 40 then 50 mg. After 6 cycles of combination therapy, patients benefiting and tolerating treatment were eligible to continue single agent BIBW 2992. Results: Sixteen patients with advanced solid tumors expressing erbB receptors and suitable for treatment with a taxane have been enrolled (6 male/10 female; median age: 59 [range: 39–72]; ECOG PS 0/1: 5/11). Two dose-limiting toxicities of fatigue and mucositis occurred at a BIBW 2992 dose of 50 mg. The most frequent adverse events were fatigue, rash, mucositis and diarrhea. Partial responses were seen in patients with non-small cell lung cancer (3), prostate cancer (1), oesophageal cancer (1) and cholangiocarcinoma (1). Eight patients have remained on treatment beyond 4 cycles. The PK data of paclitaxel (with and without BIBW 2992 administration) as well as of BIBW 2992 at steady state (in combination with paclitaxel) will be described. Conclusions: A BIBW 2992 dose of 40 mg daily in combination with weekly paclitaxel 80 mg/m2 is the likely recommended dose for Phase II study. Promising anti-tumor activity was seen with this combination. The addition of bevacizumab to BIBW 2992 with 80 mg/m2 weekly paclitaxel is now being evaluated. Adverse events of BIBW 2992 combined with paclitaxel were generally mild to moderate and manageable.

[Table: see text]
Vascular endothelial growth factor receptor-2 (VEGFr-2) genetic polymorphisms as predictors to antiangiogenic therapy
Authors: Jurado J. , Ortega J. A. , Iglesias P. , García-Puche J. L. , Belon J.
Published: August 2020

e14561

Background: Vascular endothelial growth factor (VEGF) and its receptors (VEGFr-2) have important roles in angiogenesis, predicting risk and prognosis in several solids tumor. VEGFr-2 located on chromosome 4 (4q11-q12) is organized into 30 exons separated by 29 introns. Recently the VEGF-2578 AA and VEGF-1154 AA genotypes were associated with a superior median overall survival when using bevacizumab in metastatic breast cancer. We investigated the association of VEGFr-2 polymorphisms to efficacy and toxicity in patients with antiangiogenic therapy. Methods: We performed genotype for selected VEGFr-2 polymorphisms in promoter regions 5’UTR, 3’UTR; in exons 7, 8, 9, 11, 16, 17, 18, 21, 27, 30 and introns 9, 17, 20. DNA was extracted from venous blood of 44 patients with non-curable solid tumors who have received treatment with bevacizumab (B) N=20 (45%) or raf kinase inhibitors 55%; vatalanib (PTK-787) N=3, sunitinib (SU011248) N=6, sorafenib (BAY 43–9006) N= 13, ZD6474 N=1 and AMG706 N= 1. Kaplan-Meier survival analysis was used to assess the association between VEGFr-2 staining and either progression-free survival (PFS) or overall survival (OS). Results: 44 patients have received a median of 6 (1–19) cycles of treatment, 72% was used simultaneously with QT. According to the criteria of NCI-CTC the severe toxicity G3–4 occurred in 47%, 9% with a definite suspension of the drug. The toxicity was not associated with VEGFr-2 genotypes. Efficacy; 5/44 patients (11%) had complete response and 11/ 44 (22%) partial responses by RECIST criteria. With a median follow up of 12 months, the ILP was 8.5 months dt (5.8). The analysis of VEGFr-2 polymorphisms identifies the variant AA of the intron-20 rs2219471 with a significant difference in PFS and OS regarding their ancestral variant AG. Conclusions: Our data suggest that VEGFR polymorphism can be a predictor of clinical outcomes in antiangiogenic therapy.

No significant financial relationships to disclose.
Sorafenib monotherapy in patients with treatment-naïve metastatic renal cell cancer: preliminary results of a phase II intra-patient dose-escalation study
Authors: Srinivas S. , Harshman L. , Hauke R. J.
Published: August 2020

e14564

Background: In a phase I dose finding study, the maximum tolerated dose of sorafenib was determined to be 400 mg bid. In subsequent practice, these doses of sorafenib have been associated with minimal or reversible toxicity, which presented an opportunity to explore more intensive dosing. A single institution trial of 44 patients demonstrated complete responses in 26% and partial responses in 36%. 93% of patients were able to be dose escalated. The objective of our study was to confirm these findings. The primary endpoints for this study were safety, feasibility, and toxicity. Secondary endpoints included overall response rate (ORR) and progression- free survival (PFS). Methods: Patients with treatment-naïve metastatic renal cell with clear cell histology were enrolled at Stanford University and the University of Nebraska Medical Center. Cycles consisted of 28 days. Dose limiting toxicity (DLT) was defined as grade 3/ 4 toxicity. Patients received sorafenib 400mg bid for 28 days. If no DLT's were reported after the first cycle, patients were dose escalated to sorafenib 600 mg bid for cycle 2. Patients without DLTs at the end of the second cycle were dose escalated to the highest dose, sorafenib 800 mg bid. Patients continued on therapy until progression or unacceptable toxicity. Results: To date, thirteen patients have been treated. Median age was 63 (47–84) years. The majority (84%) were men. Ten patients had nephrectomy prior to trial initiation. Sites of metastases included lung, nodes, liver, adrenal glands, and bone. Dose escalation was possible in 70% of the patients. Median number of cycles was 7 (3–12). Hand-foot syndrome (skin toxicity) limited escalation in the other 30% of patients. One pathologic complete response was obtained after a patient underwent metastectomy of adrenal gland after 4 cycles. One patient achieved a partial response and seven experienced disease stabilization. Conclusions: This dose-escalation trial is ongoing. Dose escalation has been feasible in 70% of patients. The main toxicity limiting escalation was hand-foot syndrome. Thus far, dose escalation did not result in an increased number of responses as compared to the standard 800mg/d dosing. PFS data will be presented as data matures.

[Table: see text]
XPA and XRCC3 gene polymorphisms and survival in esophageal cancer patients receiving neoadjuvant radiochemotherapy with cisplatin (CDDP), docetaxel (DTX), and 5-fluorouracil (FU)
Authors: Gusella M. , De Manzoni G. , Marinelli R. , Bruscagin S. , Bononi A. , Stievano L. , Ferrazzi E. , Zanoni A. , Cordiano C. , Pasini F.
Published: August 2020

e14571

Background: The aim of the study was to evaluate if genetic polymorphism of DNA repair genes may predict pathological response and survival in patients affected by locally advanced esophageal cancer, treated with a neoadjuvant schedule including weekly DTX (35 mg/mq) and CDDP (25mg/mq), protracted venous infusion of FU (150 mg/mq/die) and concomitant radiotherapy for 8 weeks followed by surgery. Methods: Fifty-seven patients were enrolled, aged 60±7 years old. Median follow-up was 27 months. Genomic DNA was extracted from peripheral blood lymphocytes and XPA, XPD, XRCC1, ERCC1 and XRCC3 were genotyped through RFLP analysis. Associations between gene polymorphisms and pathological response and survival were analysed through Chi square test and Log rank test respectively. Results: Thirty-two patients presented complete remission (pCR) and 10 patients microfocal residual disease (pMRD); the remaining 15 patients were considered stable or non-responders (pS-NR). The event free(EFS) and overall (OS) median survival times have not yet reached; significantly better 3-year survival rates were observed after pCR than in case of pMRD and pS-NR (EFS: 87% vs 42.8%, p=0.0004; OS: 86% vs 56%, p=0.02, respectively). No association was found between pathological response or survival with XRCC1, ERCC1 and XPD polymorphisms. On the contrary, the XPA 23AA genotype showed an increased risk of recurrence (HR=3.5; 95% CI 1.3 to 43.7, p=0.02) and death (HR=4.4, 95% CI 1.9 to 78.2, p=0.009); there was a trend for reduced risk of negative pathological response with decreasing number of allele 23A : MRD and S-NR were found in 71%, 45% and 35% cases for AA, AG and GG genotypes, respectively. The XRCC3 241MetMet variant was significantly associated with increased risk of death (HR= 6.0, 95% CI 3.0 to 40.0, p=0.008); a trend toward a higher recurrence (p=0.07) and worse response (60% vs 43%) was found. Conclusions: XPA and XRCC3 gene defective variants were significantly associated with worse outcome and could predict OS in esophageal cancer patients treated with a neo-adjuvant intensive radio-chemotherapy protocol. Founded by CARIPARO, Italy

No significant financial relationships to disclose.
HSP90 inhibition in HER2-positive breast cancer cells
Authors: Qadir Z. , Crown J. , Jensen M. R. , Clynes M. , Slamon D. , O'Donovan N.
Published: August 2020

e14573

Background: HSP90 is required for the stability and activity of HER2 and downstream proteins, such as Akt, which play a key role in survival. We aimed to assess the anti-tumor effect of the HSP90 inhibitor NVP-AUY922 in HER-2 positive breast cancer cell lines. Methods: HER2 positive breast cancer cell lines with varied sensitivity to trastuzumab (Sensitive: BT474, SKBR3; acquired resistance: BT474Res, SKBR3Res; innate resistance: HCC1419, HCC1954, MDA-MB-453) were treated with the HSP90 inhibitor NVP-AUY922 (Novartis) and trastuzumab. IC50s were determined using the acid phosphatase assay. HER2, Akt and HSP90 levels were determined by immunoblotting after treatment with NVP-AUY922. Combinations of NVP-AUY922 with docetaxel, cisplatin and 5'-deoxy-5-fluorouridine (5-DFUR) were tested in BT474 and SKBR3 cells. Results: All of the HER2 positive cells were sensitive to NVP-AUY922, with IC50s ranging from 5.5 to 16.4 nM. Combined treatment with NVP-AUY922 (10 nM) and trastuzumab (10 nM) showed significantly greater inhibition of growth than either trastuzumab or NVP-AUY922 alone in BT474 and BT474Res cell lines (p<0.005). In SKBR3 and SKBR3Res cells, dual treatment with NVP-AUY922 and trastuzumab did not significantly increase response compared to NVP-AUY922 alone ( Table 1 ). Treatment with NVP-AUY922 resulted in a dose-dependent decrease in HER2 and Akt levels in trastuzumab-sensitive and -resistant cells. Combinations of docetaxel, cisplatin or 5-DFUR with NVP- AUY922 were antagonistic in both BT474 and SKBR3 cells (CI values >1). Conclusions: This study demonstrates that NVP-AUY922 has anti-tumor activity in trastuzumab-sensitive, and in both innate and acquired trastuzumab-resistant HER2 positive breast cancer cells. The antagonistic interactions observed for combinations of NVP-AUY922 with chemotherapy do not favour clinical evaluation of such combinations. However, combinations with other targeted therapies, such as trastuzumab, warrant further investigation.

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Advanced epithelial ovarian cancer (EOC): Is there a place for maintenance therapy in patients with sub-optimal debulking?
Authors: Hariprasad R. , Kumar L. , Kumar S. , Bhatla N. , Thulkar S. , Das P.
Published: August 2020

e14580

Background: Survival of patients with advanced epithelial ovarian cancer (EOC) with initial suboptimal debulking surgery (residual disease (>1 cm) and those with recurrent EOC is poor. We used EGFR inhibitor gefitinib for maintenance and analyzed data on safety and toxicity. Methods: Between Nov. 2004 and Dec. 2008, Patients who achieved complete response (CR) following six cycles of paclitaxel and carboplatin received gefitinib as (Group I). Similarly, patients with recurrent EOC who achieved CR following six cycles of salvage CT received gefitinib (Group II). Both groups received gefitinib 250 mg once daily till evidence of relapse. Patients were examined every month and toxicity (CTC version II) was recorded. Serum CA-125 was done once in 2 months and CAT scan of abdomen & pelvis every 6 month. The study was approved by Institute Ethics Committee and informed written consent was obtained from each patient. Results: A total of 48 patients (median age 47 years, range 23 to 63) have been recruited. Group I: 17 subjects and Group II 31 patients (1st relapse- 13, 2nd- 9, 3rd -6 & 4th relapse in 3 patients). The mean duration of gefitinib treatment is 8.77 months (Gp-I: 14.4 months, Gp-II: 5.68 months). Toxicity was mainly in the form of skin rash & diarrhea. Skin rash: 16 patients (33.3%); Group I - 8 (grade I-2, II-4, III-3,) & Group II - 8 patients (grade I-3,II-4,III-1). Diarrhea: 12 patients (25%); Group I-3, group II- 9) all grade I. Two patients had both skin rashes and diarrhea. No pulmonary or hematological toxicity was observed. Currently, 13 patients are on gefitinib (mean duration of treatment 12.6 months); in 34 patients gefitinib has been discontinued due to relapse and in 1 patient due to grade III skin rashes over face. Among 18 patients with skin toxicity, 8 continue to be disease-free compared to 6 of 30 without skin toxicity (p=0.07). Conclusions: Gefitinib was tolerated well with mild toxicities limited to skin and GIT. Correlations between EGFR expressions vs. response may help to identify patients likely to benefit from gefitinib therapy.

No significant financial relationships to disclose.
TNF-a, retinoid acid and STAT4 pathways are differentially regulated by the HDAC inhibitors, SAHA, TSA and Sirtinol in Waldenstrom's Macroglobulinemia
Authors: Hunter Z. , Sun J. , Tseng H. , Hatjiharissi E. , Maghsoudi K. , Xu L. , Manning R. , Munshi N. , Anderson K. , Treon S.
Published: August 2020

e14582

Background: HDAC inhibitors (HDAC-I) have emerged as a promising class of therapeutics for the treatment of lymphoplasmacytic malignancies, particularly in combination strategies. The basic mechanisms by which these agents modulate malignant cell growth remain to be clarified. In recent studies, we showed that SAHA, TSA, and Sirtinol have significant preclinical activity in Waldenstrom's macroglobulinemia (WM). As part of our effort to identify potential molecular targets for these agents, we performed gene expression profiling (GEP) using WM cells treated with these agents. Methods: We implemented the Bootstrap re-sampling technique on five BCWM1 GEP datasets to characterize the range of gene expression observed. Individual BCWM1 cells were treated with SAHA, TSA and Sirtinol at their established IC50 dosages for 6 and 24 hours prior to gene expression profiling. The genes which changed by two-fold, and fell outside of the 90% range of expression after drug treatment were identified. Results: SAHA upregulated TNF-α and downstream proteins including HSP70, TNFSF9, SERPINB2, as well as STAT4- dependent genes. Sirtinol upregulated metalloproteinase (MMP) and phosphodiesterase (PDE) family members through retinoic acid signaling. We also observed that SAHA, TSA and Sirtinol differentially upregulate elements of the MAP kinase pathways, including signaling through Erk, JNK, and p38 MAPK, indicating a global stress response to HDAC inhibition. Conclusions: The above studies suggest that HDAC inhibitors differentially effect growth of WM cells through both global as well as pathway specific alterations in signaling. Importantly, this data provides a platform for studying the mechanistic role of HDACs in WM, and provide a framework for the use of HDAC-I as single and combination.

No significant financial relationships to disclose.
Dihydropyrimidine dehydrogenase gene (DPYD) polymorphism among Caucasian patients (pts) with 5-FU and capecitabine (CAP)-related toxicity
Authors: Podoltsev N. A. , Saif M. W.
Published: August 2020

e14588

Background: As many as 1 in 3 pts receiving 5-FU/CAP experience dose-limiting toxicity including diarrhea, hand-foot syndrome (HFS), mucositis and myelosupression. Deficiency of DPD, a rate limiting enzyme in 5-FU catabolism can lead to life- threatening complications. DPD deficiency was found to be related to > 40 sequence variations in DPYD. Known deleterious mutations explain only a limited proportion of 5-FU's adverse events. Full sequence analysis of DPYD gene increases sensitivity by 20% vs. simple identification of two most common deleterious mutations (IVS14 +1 G>A, D949V). Pretreatment detection could prevent serious, potentially lethal side effects. We present analysis of DPYD genotyping in untreated Caucasian pts (control group) and Caucasian pts with 5-FU/CAP-related grade 3/4 toxicities (toxicity group) who underwent TheraGuide 5-FU testing. Methods: Full sequencing of DPYD was performed by Myriad Genetic Laboratories, Inc. as part of TheraGuide 5-FU test. DNA was extracted and purified from white blood cells. Genetic variants within pt's DPYD were detected by comparison with a consensus wild-type DPYD sequence. Results: Among 227 pts from toxicity group 27 (12%) had deleterious mutations in DPYD: 12 (5%) had IVS14 +1 G>A, 11 (5%) had D949V and 4 (2%) other mutations. Only 7/192 (4%) pts from control group had DPYD genotype abnormalities: 2 (1%) had IVS14 +1 G>A, 4 (2%) had D949V and 1 (1%) other mutation. Genotype abnormalities were seen more frequently in toxicity group (p=0.001). Among 49 pts with HFS 9/49 (18%) had mutated DPYD. 9/46 (20%) pts with myelosupression were found to have a deleterious mutation. Mutations were more frequent in both subgroups when compared to control group: p=0.001 and 0.0007 respectively. Among 65 pts with toxicities due to CAP 9 (14%) had mutated DPYD which was more frequent than in control group (p=0.006). Conclusions: Mutated DPYD is frequently observed in Caucasian pts who experience toxicities while receiving 5-FU/CAP. Screening pts for DPYD mutations prior to administration of 5-FU/CAP using new pharmacogenetic testing methods may help to identify those pts who are at greatest risk for adverse effects, allowing a more individualized approach to their chemotherapy management.

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Small molecule pan-bcl-2 inhibitor AT-101 induces apoptosis in NSCLC by up-regulating noxa and enhances antitumor activity of docetaxel or targeted kinase inhibitors
Authors: Min P. , Zhang Y. , Ni X. , Wang H. , Wang J. , Wang G. , Leopold L. , Sorensen M. , Yang D.
Published: August 2020

e14591

Background: AT-101 is an orally active pan Bcl-2 inhibitor currently under clinical development in Phase II trials. We investigated the effect of AT-101 alone or in combination with chemotherapies or targeted kinase inhibitors in NSCLC both in vitro and in vivo. Methods: Growth inhibition was measured by WST assays. The CalculSyn method was used to assess drug interaction by calculating the Combination Index (CI) value. The ability of AT-101 to potentiate the anti-cancer effect of chemotherapies or kinase inhibitors was evaluated in xenograft models. Results: A panel of 11 NSCLC cell lines with overexpression of Bcl-2, Bcl- XL or Mcl-1 proteins was treated with AT-101, docetaxel, pemetrexed, erlotinib, sorafenib, sunitinib, rapamycin, as a single agent and in combination. AT-101 inhibited the growth with IC50 at 3–9 uM. When treating cells simultaneously with both agents, AT-101 demonstrated strong synergy with those agents in A549 or H460 cells with CI values < 1.0. Protein analysis results indicated that AT-101 caused apoptosis by a time- and dose-dependent induction of Noxa expression in those cells. The expression of Bcl- XL was not influenced by AT-101. Pro-Caspase-3 was reduced with increasing doses of AT-101. In vivo, combined treatment of AT-101 with docetaxel, erlotinib, or sorafenib synergistically suppressed subcutaneous NSCLC A549 cells tumor growth compared with treatment with either agent alone. The synergist effects with the ErbB1 inhibitor Erlotinib is associated with the overexpression of the target protein ErbB1 in those cells. Only combination therapy resulted in significant tumor growth delay and no significant toxicities were observed. Conclusions: Our results demonstrate that AT-101significantly enhances the anti-tumor activity of chemotherapy and targeted agents and may represent a promising new anticancer agent with a novel molecular mechanism. Molecular targeted therapy with AT-101 may improve the outcome of current chemotherapy for NSCLC with Bcl-2, Bcl-xL and/or Mcl-1 overexpression.

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Effect of GM-CSF on tumor-specific immune response and antitumoral efficacy when combined with suicide gene therapy
Authors: Akbulut H. , Coleri A. , Acikgoz N. , Sahin G. , Ozkal P. , Tang Y. , Icli F. , Deisseroth A.
Published: August 2020

e14610

Background: Suicide gene therapy is one of the promising treatment modalities in cancer treatment. Combination of an immunotherapy modality with suicide gene therapy would increase the tumor eradciating efficacy of either treatment strategy used alone. Methods: In the current study, we constructed adenoviral vectors carying ytosine deaminase (CD), granulocyte macrophage-colony stimulating factor (GM-CSF) vectors. We tested the in vitro efficacy of the vectors in both human and mouse tumor cell lines and in a syngeneic mouse model of colon cancer with tumor explants of CRL 2638 cells. Results: Our results show that the vectors carrying CD/GM-CSF transcription units are effective in terms of killing of tumor cells when 5-FC added. Addition of GM-CSF transgene induced a significant amount of GM-CSF secretion (250 pg/ml/105 cells) of infected cells. In the syngeneic colon cancer model, addition of GM-CSF significantly increased tumor-specific cellular immune response when compared to suicide gene therapy alone. (p<0.01). Likewise, GM-CSF addition caused a 8 times reduction in the ratio of Tregs infiltrating the tumor nodules (p<0.001). Accordingly, GM-CSF decreased the tumor growth by 2 times an d increased the median survival time by 50% (p<0.01). Conclusions: These impressive results of in-vitro cytotoxicity and encouraging results of in-vivo testing of the our newly constructed GM-CSF carrying vector suggest a potential for the use of the vector for the treament of established tumors by inducing tumor specific immune response.

No significant financial relationships to disclose.
Inhibition by lenalidomide of growth factor and hypoxia-induced signaling in endothelial and epithelial tumor cells, and effects within the tumor cell microenvironment
Authors: Lu L. , Schafer P. , Bartlett J. B.
Published: August 2020

e14620

Background: Lenalidomide, an immunomodulatory and anti-angiogenic agent, has activity in many hematological malignancies. It has direct anti-proliferative activity in hematological cells but there is no evidence of direct activity in solid tumor cells. In solid tumors, lenalidomide is being advanced in combination with other agents to take advantage of its immune-enhancing properties in combination with direct anti-tumor agents. Lenalidomide studies in CLL and MM suggest that it may also attenuate pro-survival signals generated by interaction of stroma with the malignant cell itself. Lysophosphatidic acid (LPA) is a key pro-survival factor present at high levels within the ascites of ovarian cancer patients which confers increased tumor invasiveness and reduced survival. Hypoxia-induced factor (HIF)-1α is the key initiator of angiogenesis and tumor invasiveness. Methods: The effect of lenalidomide on growth factor-induced Akt phosphorylation was investigated in endothelial cells, NHL cells, and ovarian cancer cells in vitro. Ovarian cancer cell lines SKOV-3 and OVCAR-3 were treated with LPA and the effect of lenalidomide on invasiveness via enhanced p-Akt was investigated. The effect of lenalidomide on HIF-1α expression by endothelial cells and epithelial cells was also investigated. Results: Lenalidomide inhibited growth factor-induced Akt phosphorylation. Treatment of ovarian tumor cells with LPA increased tumor cell invasiveness via enhanced p-Akt. Lenalidomide strongly inhibited invasion and p-Akt (at S308 but not T473) in a dose-dependent manner. Hypoxic endothelial cells and epithelial tumor cells showed enhanced HIF-1α expression. Lenalidomide inhibited hypoxia-induced HIF-1α expression by endothelial cells and by epithelial tumor cells, including prostate, breast, pancreatic, renal and ovarian tumor cells. Conclusions: Lenalidomide may act within the tumor microenvironment to inhibit key signals of tumor cells survival, growth, and invasiveness. These studies support the potential utility of lenalidomide in combination with other agents in the treatment of patients with solid tumors.

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