bluuebunny/crossref_metadata_2025 huggingface dataset:
A study of capecitabine metronomic chemotherapy is non-inferior to conventional chemotherapy as maintenance strategy in responders after induction therapy in metastatic colorectal cancer
Authors: Shi Min , Ma Tao , Xi Wenqi , Jiang Jinling , Wu Junwei , Zhou Chenfei , Yang Chen , Zhu Zhenggang , Zhang Jun
Published: March 2020

Background

The aim of this study is to demonstrate that capecitabine metronomic chemotherapy is non-inferior to capecitabine conventional chemotherapy as maintenance treatment, in patients who have responded to 16–18 weeks first-line chemotherapy in metastatic colorectal cancer (mCRC).

Methods

The study design is a prospective, randomized, open label, phase II clinical trial. Those patients with mCRC who respond well after 16–18 weeks of standard doublet chemotherapy as induction may be enrolled into this study, and randomly assigned to the capecitabine metronomic group or standard dosage group. The duration of disease control after randomization and progression-free survival after enrollment are the primary endpoints. Overall survival, safety, and quality of life are the secondary endpoints. The sample size required to achieve the research objectives of this project is 79 patients in each group. The study recently started on 1 January 2018, and will last for 36 months.

Discussion

This project is intended to study the efficacy and safety of capecitabine metronomic chemotherapy in the maintenance treatment of advanced colorectal cancer, and to explore the strategy of “low toxicity, high efficiency, economy, and individualization”, which is suitable for China’s national conditions and pharmacoeconomics. It has great prospects for clinical application and a clear socioeconomic value.

Trial registration

ClinicalTrials.gov: NCT03158610. Registered on 15 May 2017.
Pathway dissection, regulation, engineering and application: lessons learned from biobutanol production by solventogenic clostridia
Authors: Li Shubo , Huang Li , Ke Chengzhu , Pang Zongwen , Liu Liming
Published: March 2020

The global energy crisis and limited supply of petroleum fuels have rekindled the interest in utilizing a sustainable biomass to produce biofuel. Butanol, an advanced biofuel, is a superior renewable resource as it has a high energy content and is less hygroscopic than other candidates. At present, the biobutanol route, employing acetone–butanol–ethanol (ABE) fermentation inClostridiumspecies, is not economically competitive due to the high cost of feedstocks, low butanol titer, and product inhibition. Based on an analysis of the physiological characteristics of solventogenic clostridia, current advances that enhance ABE fermentation from strain improvement to product separation were systematically reviewed, focusing on: (1) elucidating the metabolic pathway and regulation mechanism of butanol synthesis; (2) enhancing cellular performance and robustness through metabolic engineering, and (3) optimizing the process of ABE fermentation. Finally, perspectives on engineering and exploiting clostridia as cell factories to efficiently produce various chemicals and materials are also discussed.
Oral colonisation by antimicrobial-resistant Gram-negative bacteria among long-term care facility residents: prevalence, risk factors, and molecular epidemiology
Authors: Le Mi Nguyen-Tra , Kayama Shizuo , Yoshikawa Mineka , Hara Toshinori , Kashiyama Seiya , Hisatsune Junzo , Tsuruda Keiko , Onodera Makoto , Ohge Hiroki , Tsuga Kazuhiro , Sugai Motoyuki
Published: March 2020

Background

For residents of long-term care facilities (LTCFs), antimicrobial-resistant bacteria (ARB) are a risk factor, yet their oral colonisation, potentially leading to aspiration pneumonia, remains unclear. This study was undertaken to survey the prevalence, phenotypic characteristics, and molecular epidemiology of antimicrobial-resistant Gram-negative bacteria in the oral cavity of LTCF residents, and to analyse the risk factors for such carriers.

Methods

This study involved 98 residents of a LTCF in Hiroshima City, Japan, aged between 55 and 101 years. Oropharyngeal swabs were collected and plated on screening media for ESBL-producing and carbapenem-resistant bacteria; isolates were identified and tested for antibiotic susceptibility; biofilm formation was tested in vitro; identification of epidemic clones were pre-determined by PCR; resistance genes, sequence types, and whole-genome comparison of strains were conducted using draft genome sequences. Demographic data and clinical characterisations were collected and risk factors analysed.

Results

Fifty-four strains from 38% of the residents grew on screening media and comprised predominantly of Acinetobacter spp. (35%), Enterobacteriaceae spp. (22%), and Pseudomonas spp. (19%). All Escherichia coli isolates carried CTX-M-9 group and belonged to the phylogroup B2, O25:H4 ST131 fimH30 lineage. Six Acinetobacter baumannii isolates presented identical molecular characteristics and revealed more biofilm production than the others, strongly suggesting their clonal lineage. One Acinetobacter ursingii isolate displayed extensive resistance to various ß-lactams due to multiple acquired resistance genes. One Pseudomonas aeruginosa isolate showed exceptional resistance to all ß-lactams including carbapenems, aminoglycosides, and a new quinolone, showing a multidrug-resistant Pseudomonas aeruginosa (MDRP) phenotype and remarkable biofilm formation. Genome sequence analysis revealed this isolate was the blaIMP-1-positive clone ST235 in Japan. Strokes (cerebral infarction or cerebral haemorrhage) and percutaneous endoscopic gastrostomy tubes were recognised as risk factors for oral colonisation by ARB in the LTCF residents.

Conclusions

ARB, as defined by growth on screening agar plates, which carried mobile resistance genes or elements or conferred high biofilm formation, were already prevalent in the oral cavity of LTCF residents. Health-care workers involved in oral care should be aware of antimicrobial resistance and pay special attention to transmission prevention and infection control measures to diminish ARB or mobile resistance elements dissemination in LTCFs.
Combinative evaluation of primary tumor and lymph nodes to predict pelvic lymphatic metastasis in cervical cancer: an integrated PET-IVIM MRI study
Authors: Xu Chen , Li Xiaoran , Shi Yanchi , Wang Bo , Sun Hongzan
Published: March 2020

Background

The aim of this study was to evaluate the value of combining pelvic lymph node and tumor characteristics on positron emission tomography-intravoxel incoherent motion magnetic resonance (PET-IVIM MR) imaging for predicting lymph node metastasis in patients with cervical cancer, especially in those with negative lymph nodes on PET.

Methods

The medical records of 95 patients with cervical cancer who underwent surgical resection with pelvic lymph node dissection were evaluated. The patients were divided into negative and positive groups according to postoperative pathologic lymph node diagnosis, and comparisons of the PET and IVIM-derived parameters between the two groups were performed. Univariate and multivariate analyses were performed to construct a predictive model of lymph node metastasis.

Results

For all patients, tumor SUVmax, TLG, Dmin, PET and MRI for lymph node diagnosis showed significant differences between patients with and without confirmed lymph node metastasis. Univariate and multivariate logistic analysis showed that the combination of tumor TLG, Dmin and PET for lymph node diagnosis had the strongest predictive value (AUC 0.913, p < 0.001). For patients with PET-negative lymph nodes, SUVmax, SUVmean, MTV, TLG, and Dmin showed significant between-group differences, and univariate and multivariate logistic analysis showed that TLG had the strongest predictive value.

Conclusions

The combination of tumorTLG, Dmin and PET for lymph node diagnosis is a powerful prognostic factor for all patients. TLG has the best predictive performance in patients with PET negative lymph nodes.
Transition towards green banking: role of financial regulators and financial institutions
Authors: Park Hyoungkun , Kim Jong Dae
Published: March 2020

This paper provides an overview of green banking as an emerging area of creating competitive advantages and new business opportunities for private sector banks and expanding the mandate of central banks and supervisors to protect the financial system and manage risks of individual financial institutions. Climate change is expected to accelerate and is no longer considered only as an environmental threat because it affects all economic sectors. Furthermore, climate-related risks are causing physical and transitional risks for the financial sector. To mitigate the negative impacts, central banks, supervisors and policymakers started undertaking various green banking initiatives, although the approach taken so far is slightly different between developed and developing countries. In parallel, both private and public financial institutions, individually and collectively, are trying to address the issues on the horizon especially from a risk management perspective. Particularly, private sector banks have developed climate strategies and rolled out diverse green financial instruments to seize the business opportunities. This paper uses the theory of change conceptual framework at the sectoral, institutional and combined level as a tool to identify barriers in green banking and analyze activities that are needed to mitigate those barriers and to reach desired results and impacts.
A prospective database of 100 patients with locally soft tissue sarcoma (STS) treated by isolated limb perfusion with melphalan and TNFα 1mg
Authors: Bedard V. , Vataire A. , Desouche C. , Le Péchoux C. , Muret J. , Vanel D. , Terrier P. , Le Cesne A. , Bonvalot S.
Published: March 2020

10010

Background: In a prior randomized phase II trial comparing hyperthermic isolated limb perfusion (HILP) with melphalan and 4 different doses of TNFa (0.5 mg; 1 mg; 2mg, 3 mg/4mg superior/ inferior limb), there was no dose effect detected for the tumour response but systemic toxicity was significantly lower with low doses TNF-a (Bonvalot S et al. 2005). The objective of the present study was to confirm these datas on a larger population of locally advanced or recurrent STS of the extremity using low dose TNFa. Methods: Prospective database including 100 HILP (38–40°) with melphalan (10 mg/L) and TNFa 1 mg. Resection of the remnant tumour was performed 2 months after ILP. The main endpoint was complete response on MRI. Secondary endpoints were histological response, rate of amputation and toxicity. Results: Sex ratio was and median age was 43 years. Location/ median size were 30/48 mm and 70/72 mm for upper and lower limbs respectively. There were 26 multifocal tumors, 52 recurrences of which 18 arising in a pre irradiated field. Grade (FNCLCC) were 1 (23 pts), 2 (34 pts), 3 (43 pts). Fifty one pts had pre ILP systemic chemotherapy. A complete radiological response was obtained in 30% of pts while 48%, 9% and 13% of pts exhibited a partial, no change and disease progression. There was no mortality and no systemic toxicity. Local toxicity were (Wieberdink) grade 2 (16 pts), 3 (5 pts) and 4 (1 pt). A limb salvage surgery was achieved in 88% pts. With a median follow-up of 27 months, 3 years overall survival and local recurrence rate were 89% and 15% respectively. Age, gender, tumor size, recurrence, uni/multifocality, grade, pre op chemotherapy, pre irradiated field, were not predictive of the responses rates. Conclusions: This study confirm that 1mg TNFa is as effective as the standard dose without its systemic toxicity. A wide population of pts may benefit from this approach.

No significant financial relationships to disclose.
Safety and efficacy of combined trastuzumab and CMF therapy in women with metastatic breast cancer: EORTC protocol 10995
Authors: Neskovic-Konstantinovic Z. , Nooij M. , Khaled H. , De Valk B. , Vermorken J. , Welnicka-Jaskiewicz M. , Piccart M. , Marreaud S. , Bogaerts J. , Cameron D.
Published: March 2020

1040

Background: Safety and efficacy of classical CMF combined with 3-weekly Trastuzumab (T), followed by T alone in metastatic breast cancer (MBC). Methods: Patients (pts) with previously treated MBC were enrolled into a Phase II study of T (4 mg/kg then by 2 mg/kg) IV weekly plus CMF, Bonadonna regimen, for a maximum of 8 cycles (cy), followed by T alone (6 mg/kg) IV 3 weekly. Entry criteria included HER2 overexpression, limited anthracycline (A) exposure, normal baseline LVEF and measurable disease (RECIST). Cardiac endpoints were defined as: symptomatic CHF or LVEF drop by ≥ 15% from baseline or to ≥ 5% below lower limit. Results: The trial was closed to recruitment in January 2006, 12 pts are still on treatment. Seventy one pts were entered with a median age of 54 (range 31–75). Forty-one pts had prior CT (32 A), of which 26 adjuvant, 6 MBC, and 9 both adjuvant and MBC. Median PS was 0, 52 pts had visceral disease with a median interval from diagnosis to first relapse of 33.4 months (mo). Out of 70 pts receiving T+CMF (33 pts with 8 cy), 42 continued with T alone for a median duration of 7 cy. Eleven pts discontinued treatment for toxicity (9 on T+CMF, 2 on T alone). To date, the overall response rate is 55% (31/56 pts): 55% (23/42) 1st line; 57% (8/14) 2nd line. An independent review of responses is on-going. Median time to response was 2 mo, median duration of response was 8.3 mo and the median progression free survival was 9.2 mo. The most common grade 3–4 toxicity was neutropenia (53 %). Fourteen pts had cardiac toxicities, one NYHA grade 2 CHF, 6 pts with a drop in LVEF of 15% from baseline after a median of 3 mo of treatment, 9 pts with a drop in LVEF of 5% below LLN, after a median of 8 mo of treatment. The other toxicities included one grade 3 arrhythmia, two grade 3 hypertension, one grade 2 SVT, one grade 3 thrombosis, and one grade 2 dyspnea. One pt previously exposed to A had NYHA grade 4 CHF one year after treatment discontinuation. Conclusions: Combination of T+CMF regimen is feasible treatment for HER2+ MBC patients. The safety profile was acceptable, with cardiac toxicity and neutropenia within previously reported range. Drops in LVEF were mostly asymptomatic irrespective of previous exposure to A. Preliminary response data confirm good efficacy of CMF+T in MBC patients.

[Table: see text]
HER2 expression and HER2:HER2 dimerization identifies subpopulations of metastatic breast cancer patients with different probabilities of long-term survival following trastuzumab treatment and with different requirements for concomitant chemotherapy
Authors: Bates M. P. , Desmedt C. , Sperinde J. , Huang W. , Larsimont D. , Durbecq V. , Winslow J. , Chappey C. , Piccart M. , Sotiriou C.
Published: March 2020

10557

Background: Selection of patients for treatment with trastuzumab is currently based on the semi-quantitative measurement of HER2 protein expression (IHC) or gene amplification (FISH). We made quantitative measurements of HER2 expression and homodimerization using a novel assay, eTag, and correlated them with overall survival (OS) and time-to-progression (TTP) following trastuzumab treatment in a cohort of patients with metastatic breast cancer (MBC). We also examined the benefit of concomitant chemotherapy (CT) depending on quantitative HER2 expression. Methods: The Jules Bordet cohort (Brussels, Belgium, N=71) had MBC and prior treatment with at least two CT regimens. Patients received trastuzumab alone or combined with predominantly paclitaxel. Independent medical data review and central confirmation of HER2 overexpression by FISH (N=64) or IHC (N=7) were mandatory. The eTag assay was used to quantitate HER2 protein expression and HER2:HER2 dimers in FFPE specimens. eTag measurements were correlated with OS and TTP using Kaplan-Meier and Cox Proportional Hazards regression analyses. Results: Cox analyses identified three independent correlates of OS and TTP: number of metastatic sites (HROS = 2.4/site, 95%CI 1.5–3.9, p = 0.00019), treatment with trastuzumab only (HROS = 2.8, 95%CI 1.1–7.3, p = 0.036), and HER2 expression level (HROS = 0.24/log10(HER2), 95%CI 0.09–0.7, p = 0.0058). Patients with high HER2 (above median expression) experienced better OS than those with low HER2 (HR 0.24, p = 0.0014). Patients with high HER2 expression did not benefit from added CT (HR = 0.95, 95%CI 0.24–3.8, p = 0.94), while patients with low HER2 expression did (trastuzumab alone HR 4.4, 95% CI 1.3–18, p = 0.018). Similar results were observed for HER2:HER2 dimerization. Conclusions: Within a population of patients selected by FISH or IHC to receive trastuzumab, higher HER2 expression or HER2:HER2 dimerization correlated with better outcomes. Patients with high HER2 expression derived no benefit from concomitant CT, while patients with low HER2 expression benefited significantly from the addition of CT to trastuzumab.

No significant financial relationships to disclose.
A multicenter phase II study of epirubicin (E) with low-dose herceptin (LD-H) as a first-line treatment in HER2 overexpressing metastatic breast cancer (MBC)
Authors: Tursi M. De , Carella C. , Ricevuto E. , Gennari A. , Orlandini C. , Frassoldati A. , Conte P. F. , Iacobelli S.
Published: March 2020

1060

Background: The combination of doxorubicin and herceptin (H) has been proven to be an effective regimen in metastatic breast cancer (MBC), although it was associated with an increased risk of cardiotoxicity. Methods: The aim of this study was to evaluate cardiac safety and efficacy of epirubicin (E) in combination with low-dose herceptin (LD-H) as first-line chemotherapy for women with HER-2 positive MBC. Forty-five patients were enrolled in a two-step, multicenter phase II study. In the first step, H was given at 2 mg/Kg loading dose on day 1, followed by 1 mg/Kg weekly; in the second step (≥ 12 objective responses/21pts), H dose was maintained at 1 mg/kg weekly. E was administered at 90 mg/m2 on day 1 every 3 weeks. After 6–8 courses, H was continued as a single agent for a maximum of 52 weeks. To assess cardiotoxicity, patients were evaluated for the left ventricular ejection fraction (LVEF) at baseline, every two cycles during E and LD-H, and every three months during LD-H alone. Cardiotoxicity was defined as signs or symptoms of congestive heart failure in = 10% of patients at an E dose of 720 mg/ m2 or in = 20% of patients at an E dose > 720 < 1,000 mg/m2. Results: Eight episodes of cardiotoxicity were observed (an asymptomatic decrease in LVEF =15% in 6 patients and an asymptomatic decline of LVEF at = 50% in 2 patients). Grade 3–4 neutropenia, alopecia and thrombocytopenia occurred in 25%, 45.5% and 6.8% of patients, respectively. Complete and partial responses were 2.4 and 61.9%, respectively, for an overall response rate of 64.3%. The median time to progression was 8.2 months (95% CI, 5.2–9.2 months) and the median overall survival was 32.8 months (95% CI, 17.1–48.6 months). Conclusions: E plus LD-H is an active treatment regimen for HER-2 positive MBC and demonstrates a very favourable safety profile, with manageable cardiotoxicity.

No significant financial relationships to disclose.
Activity of trastuzumab (t) beyond disease progression in HER2 over-expressing metastatic breast cancer (MBC)
Authors: Metro G. , Mottolese M. , Cosimo S. Di , Papaldo P. , Ferretti G. , Carlini P. , Cianciulli A. M. , Giannarelli D. , Cognetti F. , Fabi A.
Published: March 2020

1066

Background: In HER-2 over-expressing MBC patients (pts), preclinical evidence suggests that T therapy should be continued until disease progression. On the other hand, the activity of T beyond disease progression is unknown. Methods: We retrospectively evaluated HER-2 over-expressing (score 3+ by IHC or 2+ and FISH amplified) unselected MBC pts treated at our institution with successive T-based cytotoxic therapies. Results: From 06/2001 to 06/2006 59 patients (57 female and 2 male) receiving at least 1 T-based regimen for advanced breast carcinoma were identified. Characteristics of patients at initiation of T were as follows: median age 51 years (32–73), pre-menopausal 28/57 (49%), HER-2 IHC 3+ 49/59 (83%), negative hormonal receptor status 34/59 (58%), visceral disease 45/59 (76%), adjuvant chemotherapy 47/59 (80%), chemo-naïve for MBC 30/59 (51%), median number of previous chemotherapy lines for MBC prior to T 1 (0–2). A total of 37, 16 and 9 patients received respectively a 2nd, 3rd and 4th T-based regimen. In the 1st T-based line there was an overall response rate (ORr) of 60% (clinical benefit-CB- 83%) while 2nd T-based line yielded an ORr of 29% (CB 62%). None of the 16 and 9 patients who received respectively a 3rd and 4th T-based line responded to treatment. At a median follow up of 26 months (range 7–78), median time to progression was 9.5 months (95%c.i. 8.2–10.9), 6.7 months (95%c.i. 3.9–9.4), 4.0 months (95%c.i. 2.4–6-0) and 4.5 months (95%c.i. 3.7–8.3) from 1st to 4th T-based line respectively. Overall survival (OS) was 37 months (95%c.i. 22.4–53.4). No significant difference was observed in OS between the 22 patients receiving only 1 T-based line and the 37 patients who underwent at least 2 T-containing regimens (28 months vs 38 months, p=0.85). Conclusions: In HER-2 positive MBC patients T beyond disease progression maintains activity in terms of CB, TTP and OS. Prospective randomized trials are warranted to draw definitive results.

No significant financial relationships to disclose.
Chemotherapy use for hormone receptor-positive, node-negative breast cancer
Authors: Hassett M. J. , Hughes M. E. , Niland J. C. , Edge S. B. , Theriault R. L. , Wong Y. , Wilson J. , Carter B. W. , Blayney D. W. , Weeks J. C.
Published: March 2020

11004

Background: High quality evidence has shown that adjuvant chemotherapy (chemo) improves survival for hormone receptor- positive, node negative breast cancer measuring >1 cm (H+/N-/T>1cm BC). Since 2002 National Comprehensive Cancer Network (NCCN) guidelines have recommended chemo for this group. Because the benefit from chemo in this situation is modest there is debate regarding which women, if any, can forego chemo. We describe trends in chemo use and identify factors associated with not receiving chemo for H+/N-/T>1cm BC. Methods: We identified women less than 70 years old with H+/N-/T>1cm BC diagnosed 1997–2004 and treated at 8 NCCN institutions. We analyzed the frequency of chemo use on a yearly basis (chi square). A multivariable logistic regression model assessed the relationship between likelihood of not receiving chemo and year of diagnosis, institution, tumor size, histologic characteristics and socio- demographic variables. We incorporated interaction terms to explore how chemo use varied over time and between institutions. Results: Of 3190 women with H+/N-/T>1cm BC, 56% received chemo. Chemo use was less common for 1.1–2 cm than for >2 cm tumors (48 vs. 83%; p<.01). There was no significant change in chemo use over time, but there was significant variability among institutions (range 47–65%; p<.01). On multivariable analysis, predictors independently associated with not receiving chemo included lower histologic/nuclear grade, non-ductal/lobular histology, absence of lymphovascular invasion or HER2 overexpression, and older age (p<.01 for all). The interaction between institution and year of diagnosis was also significant (p<.01). Over the 2 years following the NCCN guideline’s definitive recommendation for chemo in 2002, the relative change in institutional chemo use ranged from a 25% decrease to a 28% increase. Conclusions: Many women did not receive chemo despite clinical trial evidence. Providers considered molecular features, tumor size and patient age when deciding who should receive chemo. While overall trends in chemo use did not change, use appeared to increase at some institutions and decreased at others after the 2002 guideline recommendation for chemo. This suggests a lack of consensus at NCCN institutions regarding when to administer chemo for H+/N-/T>1cm BC.

No significant financial relationships to disclose.
Gemcitabine and docetaxel combination regimen in metastatic breast cancer (MBC)
Authors: Karacetin D. , Maral O. , Aksakal O. , Okten B. , Yalçın B. , Incekara O.
Published: March 2020

1107

Background: No standart chemotherapy regimen has been estabilished for the treatment of patients with metastatic breast cancer. The gemcitabine and docetaxel combination has been shown to be synergistic . This study is conducted to verify the clinical efficacy and safety of gemcitabine and docetaxel combination therapy in metastatic breast cancer. Methods: 27 metastatic breast cancer patients were treated with gemcitabine-docetaxel combination . Gemcitabine 1,250 mg/m2 IV infusion, on day 1 and 8, and docetaxel 70 mg/m2 on day 1 in 21 day cycles. 4–6 cycles of chemotherapy were repeated every 3 weeks. The primary endpoint was response rate, and survival. Results: The median age was 50 years (range,32–77). Performans status (ECOG) was 0–1. Hormone receptor status: ER+/ER-; 11/16, PR+/PR-; 14/13. Menopausal status were: 11 premenopausal, 16 postmenopausal. Of the 27 evaluable patients, there were 11 (40.7%) partial responses and no complete response. Overall response rate was 40.7%. Median time to progression was 7 months, and median survival was 14 months. Toxicities included grade 3–4 neutropenia in 9 (30%), thrombocytopenia in 6 (22%), anemia in 3(9%). There were no treatment releated deaths Conclusions: The combination of gemcitabine and docetaxel has shown favorable toxicity profile and promising activity in metastatic breast cancer patients.

No significant financial relationships to disclose.
Bevacizumab plus irinotecan therapy in relapsed, heavily pre-treated malignant glioma: A case series
Authors: Friedland D. M. , Ali S. A. , Ahmad A. , Rahman M. , Bejjani G. , Braffet M.
Published: March 2020

12500

Background: Endothelial proliferation has been recognized as a marker of high grade or aggressive glioma in several grading classifications and it has been demonstrated that the degree of microvascularity as assessed by the endothelial cell/capillary density correlates well with the biologic aggressiveness of these tumors. These features suggest that high grade gliomas are a suitable target for angiogenesis inhibiting therapies. Bevacizumab (B) is a humanized IgG1 monoclonal antibody to VEGF that has been shown to have activity in malignant gliomas when combined with irinotecan (CPT-11), a topoisomerase 1 inhibitor. Methods: We report a case series of 10 patients with recurrent, heavily pre-treated malignant glioma who were treated with the combination of B and CPT-11. Nine patients had WHO grade 4 tumors while one had a grade 3 lesion. All patients had failed standard therapy with primary resection followed by adjuvant chemotherapy and radiation. Most had also failed additional resection, chemotherapy and radiation after their initial relapse. The mean number of failed therapies in addition to adjuvant therapy prior to starting B and CPT-11 was 3 (range 1–6) and the median ECOG performance status was 2 (range 1–3). Nine patients were started on B at a dose of 5 mg/kg every 2 weeks and were given CPT-11 at a dose of 125 mg/m2 every week for 3 weeks with 1 week off. The tenth patient received B at a dose of 10 mg/kg but with CPT-11 at 125 mg/m2 every 2 weeks. Results: This regimen was well tolerated with no CNS hemorrhages or >grade 1 bleeding. One patient had treatment held for repair of an anal fissure but then had it restarted. One patient had a DVT while on therapy. The objective response rate was 80% (8 PR and 2 SD).The median progression- free interval on treatment is 25 weeks with 5 patients still having a response at the time of this report. In patients with progressive disease, the median time to progression is 25 weeks. The median overall survival has not been reached, and exceeds 6 months. There has been one death due to disease progression. Conclusion: The combination of B and CPT-11 is safe and has excellent activity even in this relapsed, heavily pre-treated population of patients with high grade malignant glioma, most of whom would not be candidates for clinical trials.

No significant financial relationships to disclose.
Phase I/II study of enzastaurin plus temozolomide during and following radiation therapy in patients with newly diagnosed glioblastoma multiforme (GBM) or gliosarcoma
Authors: Butowski N. A. , Lamborn K. , Chang S. , Thornton D. , DeBoer R. , Page M. , Rabbitt J. , Parvanateni R. , Kivett V. , Nicol S. , Prados M.
Published: March 2020

12511

Background: Enzastaurin is a potent, selective, oral serine/threonine kinase inhibitor of PKCβ, an enzyme activated by vascular endothelial growth factor (VEGF). VEGF is upregulated in most cases of GBM, producing significant angiogenesis. This study combines the anti-angiogenic properties of enzastaurin with the current standard treatment of radiation therapy (RT) and cytotoxic chemotherapy (temozolomide; TMZ). Methods: A Phase 1/2 study of enzastaurin with TMZ during and following RT is ongoing in patients with newly diagnosed GBM. Two doses of enzastaurin will be evaluated during Phase 1. The first 6 patients will received 250 mg of enzastaurin daily. If no more than one patient experiences a dose-limiting toxicity (DLT) during RT and the first adjuvant cycle, an additional 6 patients will receive an escalated dose of 500 mg daily. The dose established in Phase 1 will be administered to 60 patients in Phase 2. The primary objective of Phase 2 is to determine the efficacy of enzastaurin as measured by overall survival. Multiple pharmacokinetic (PK) and pharmacodynamic (PD) endpoints will be evaluated using perfusion imaging and plasma biomarkers. Relevant growth factors and pathways will be analyzed in primary tumor tissue from each patient. Results: Since September 06, 6 patients have completed RT with concurrent enzastaurin (250 mg) and TMZ. None of these patients has experienced a DLT to date. It is expected that an additional 6 patients will be enrolled in January 07 and Phase 2 will start in May 2007. Conclusions: Enzastaurin with concurrent RT and TMZ appears safe. Final Phase 1 safety results and preliminary PK and PD data will be presented.

[Table: see text]
CVX-045: A novel thrombospondin-1 (TSP-1) mimetic CovX-Body that potentiates chemotherapy in preclinical colon cancer models
Authors: Levin N. J. , Leedom T. A. , Doppalapudi V. R. , Li L. , Lai J. , Johnson K. , Rizzo J. D. , Lappe R. W. , Bradshaw C. W. , Woodnutt G.
Published: March 2020

14011

Background: TSP-1 reduces angiogenesis and tumor growth in vivo, and induces endothelial cell apoptosis in vitro. CVX-045 was produced by fusing a peptide derived from TSP-1, known to have anti-vascular activity, to a proprietary monoclonal antibody. CVX-045 possesses the potency and specificity of the TSP-1 mimetic peptide, along with the advantageous PK of an antibody. Methods: Anti-tumor activity of CVX-045 was evaluated in A549, A431, and HT-29 human adenocarcinoma xenograft models. Cells were implanted SC in female nu/nu mice, and tumors were staged to 300–400 mm3 prior to initiation of weekly treatments: CVX-045 IV 10–30 mg/kg; 5-FU or CPT-11 IP 100 mg/kg. Results: CVX-045 (10 mg/kg) significantly reduced A549 and A431 tumor growth 73% (day 49) and 51% (day 22), respectively, but was not effective in the HT-29 xenograft (10 or 30 mg/kg). CVX-045 demonstrated significant anti-vascular activity, reducing tumor microvessel density 51% in A549, 49% in A431, and 36% in HT-29 xenografts. CVX-045 (30 mg/kg) plus 5- FU significantly decreased HT-29 tumor growth 70% and microvessel density 61.2% on day 30 (both P<0.01), effects significantly greater than either agent alone. Co-treatment with CVX-045 (30 mg/kg) plus CPT-11 decreased HT-29 tumor volume 91% on day 28 (P<0.001), also significantly greater than either agent alone. As a surrogate measurement of survival, mice remained on treatment until tumors reached 2000 mm3. CPT-11 alone extended the time to reach tumor load from day 28 to day 39, while the combination of CPT-11 with CVX-045 extended this further to day 60. Conclusions: CVX-045 exhibits significant anti-angiogenic activity in several tumor models and enhances anti-tumor activity in combination with standard chemotherapies in a highly aggressive colon tumor model.

No significant financial relationships to disclose.
Phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of LBH589, a novel deacetylase (DAC) inhibitor given intravenously on a new once weekly schedule
Authors: Sharma S. , Vogelzang N. J. , Beck J. , Patnaik A. , Mita M. , Dugan M. , Hwang A. , Masson E. , Culver K. W. , Prince H.
Published: March 2020

14019

Background: LBH589 is a novel deacetylase inhibitor that inhibits proliferation of tumor cells at nanomolar levels. This phase I study tested the safety and tolerability of IV LBH589 once each week for 3 of 4 wks in pts with advanced solid tumors or lymphoma. Methods: LBH589 was administered IV over 30 min. on days 1, 8 and 15 of a 28-day cycle. Western blots on peripheral blood lymphocytes were used to study histone acetylation (HA). Plasma PK profiles were analyzed on Days 1 and 8. Results: Thirty five pts (median age: 70 yrs; 23M, 12F) have been treated on 3 dose levels [10 mg/m2 (8pts), 15 mg/m2 (8 pts), 20 mg/m2 (19 pts)] with the following tumor types: Cutaneous and peripheral T cell lymphoma (7 pts), prostate (6 pts), mesothelioma (4 pts), colon (3 pts) and other (15 pts). There was one dose-limiting toxicity (transient grade 4 thrombocytopenia) at 20 mg/m2, none at the lower doses. Other G3/G4 toxicities (all cycles) include: transient thrombocytopenia (G4–5 pts, G3–5 pts), neutropenia (G3–2 pts), anemia (G3–5 pts), G3 hypophosphatemia (1 pt), G3 hypokalemia (1 pt), G3 nausea (1 pt) and G3 pruritus (1 pt). Thrombocytopenia was transient. Of 2,042 ECGs, 1 pt had an increase in QTcF from baseline of > 60 msec another with a QTcF >500 msec, both at 20 mg/m2. There was a dose-dependent increase in HA 7 days after one dose with 43% (10 mg/m2), 50% (15 mg/m2) and 60% (20 mg/m2) of pts with increased acetylation. The LBH589 plasma conc. peaked at the end of the 0.5 hr infusion with a mean terminal half-life of 16 hr. Median Cmax achieved with 20 mg/m2 was 1,000 ng/mL (2.86 μM). The AUC0-inf increased linearly with IV doses of 10–20 mg/m2. One pt with CTCL achieved a complete response (CR) on cycle 3, Day 1; this pt had previously received oral LBH589 at 20 mg MWF, achieving a CR on cycle 6, Day 28 that lasted for 7 months. One peripheral T-Cell lymphoma pt achieved a partial response that has persisted for >7 months. One pt with prostate cancer has had a 26% reduction in nodal disease and > 50% drop in PSA in the first 2 cycles. Conclusions: The maximum tolerated dose of LBH589 given IV wkly on a 3 of 4 wk schedule is 20 mg/m2. This dose produced sustained PD effects and higher systemic exposure compared to oral LBH589. Preliminary evidence of antitumor activity has been observed.

No significant financial relationships to disclose.
AMG 386, a selective angiopoietin 1/2-neutralizing peptibody, in combination with chemotherapy in adult patients with advanced solid tumors
Authors: Mita A. C. , Wang D. , Takimoto C. H. , Malseed E. , Nguyen L. , Rasmussen E. , Storgard C. , LoRusso P.
Published: March 2020

14033

Introduction: AMG 386 is a selective angiopoietin 1 /2-neutralizing peptibody that inhibits angiogenesis by preventing interaction between angiopoietins and Tie2 receptors. This open-label study evaluated the safety, pharmacokinetics (PK), and antitumor activity of AMG 386 in combination with FOLFOX-4 (F), carboplatin + paclitaxel (CP), or docetaxel (D) in adult patients (pts) with advanced solid tumors. Methods: Three cohorts of 6–9 pts received 1 full cycle of chemotherapy (2 weeks of F or 3 weeks of D 75 mg/m2 or CP). Administration of AMG 386 10 mg/kg IV weekly was started on day 1 of cycle 2 for patients who did not experience a dose-limiting toxicity (DLT) to chemotherapy during cycle 1, and continued until disease progression or intolerance. Safety and tolerability, tumor response (RECIST every 8 weeks), PK profiles of AMG 386 and chemotherapy agents, and formation of antibodies to AMG 386 were assessed. Results: As of October 2, 2006, 16 pts have received AMG 386: 6 pts in the F cohort, 5 in CP, and 5 in D; 7 pts were men, median age 59.5 years (range, 44- 75 years). No AMG 386-related serious AEs or DLTs were reported. AEs related to chemotherapy + AMG 386 in = 2 pts were neutropenia (n = 3), thrombocytopenia (n=2), diarrhea (n=2), and vomiting (n=2). No neutralizing antibodies were observed. F, CP, and D coadministered with AMG 386 did not appear to affect the PK profile of AMG 386, and AMG 386 had no apparent effect on the PK profile of 5 FU, leucovorin, C, P, or D. Tumor response data are available for 6 pts. One pt receiving CP+ AMG 386 for bladder cancer refractory to gemcitabine/cisplatin had a complete response (CR) at week 8, confirmed at week 16. Stable disease in 4 pts and progressive disease in 1 pt were also observed. Conclusions: Weekly administration of AMG 386 in combination with F, CP, or D appears to be safe and well tolerated. A CR in bladder cancer suggests promising antitumor activity of AMG 386 in combination with chemotherapy. Further clinical studies of AMG 386 in combination with chemotherapy and other targeted agents are warranted.

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A phase I study of oral belinostat (PXD101) in patients with advanced solid tumors
Authors: Kelly W. K. , Yap T. , Lee J. , Lassen U. , Crowley E. , Clarke A. , Hawthorne T. , Buhl-Jensen P. , de Bono J.
Published: March 2020

14092

Background: Belinostat (PXD101) is a hydroxamate HDAC inhibitor which demonstrates broad anti-neoplastic activity in vitro and in vivo. In Phase I studies in patients (pts) with advanced cancer, IV belinostat is well-tolerated up to 1000 mg/m2 daily x5. Preliminary results of an oral formulation of belinostat showed that the oral bioavailability was 20 - 50%. This Phase I trial of oral belinostat will determine the maximal tolerated dose (MTD) of once and twice daily dosing, tolerability and pharmacokinetics (PK) in pts with advanced solid tumors. Methods: Sequential cohorts of 3–6 pts with advanced solid tumors refractory to standard therapy or for which no standard therapy exists were administered belinostat 250–500mg once or twice daily in 4 week cycles. Fasting (day 1) and non-fasting (day 7) pharmacokinetic studies were performed on all patients along with serial ECGs to evaluate any potential effects on QTc prolongation. Patients were evaluated with routine blood work weekly and tumor imaging at the end of cycle 1 then every other cycle. Results: Sixteen pts have been treated in 3 dose levels at 250mg QD (6 pts), 500mg QD (6 pts) and 250mg BID (4 pts). The median number of cycles of therapy is 1 (range 1–5), nine pts continue to be treated. The most common reasons for discontinuation were adverse event (3 pts) and PD (3 pts). No DLTs were identified at 250mg QD or 250mg BID. DLTs of grade 3 dehydration and grade 3 fatigue were reported at 500mg QD. In pts from the first 3 dose cohorts, there were no grade 4/5 events reported. Other Grade 3 toxicities were fatigue (2 pts), abdominal pain (1 pt), ataxia (1 pt), prolonged INR (1 pt), prolonged PTT (1 pt) and confusion (1 pt). Symptoms were transient and usually resolved after drug was held. In > 500 ECG’s collected, there were no QTcF > 500 ms, and no QTcF increase > 60 ms above baseline. To date, the best clinical response observed has been SD in 7 patients. Conclusions: Oral belinostat at doses of 250mg QD and 250mg BID given on a continuous schedule appears to be well tolerated. Alternative dosing schedules are being explored to further dose escalate the belinostat. Updated safety, activity and pharmacokinetic data will be presented on these and alternate dose schedules.

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The Hsp32/HO-1-targeted drug SMA-ZnPP counteracts the proliferation and viability of neoplastic cells in solid tumors and hematologic neoplasms
Authors: Gleixner K. V. , Mayerhofer M. , Vales A. , Gruze A. , Pickl W. F. , Lackner E. , Sillaber C. , Zielinski C. C. , Maeda H. , Valent P.
Published: March 2020

14122

Background: Heat shock protein 32 (Hsp32) is a stress-related survival factor that is overexpressed in various neoplastic cells. Recently, specific Hsp32- targeting drugs such as styrene maleic acid encapsulated zinc protoporphyrin (SMA-ZnPP) have been developed. Methods: We examined the effects of SMA-ZnPP on proliferation and survival of various tumor cell-lines, including U97MG (glioblastoma), A549 (lung cancer), MDA-MB-231 (breast cancer), BxPC-3 (pancreatic), HepG2 (hepatocellular), Colo201, Colo320DM, DLD-1 (colon), OvCar3 (ovarian carcinoma), KG1, U937, HL60, K562 (myeloid leukemias), RAJI, NALM-6 (lymphatic leukemias), RPMI 8226, U266 (multiple myeloma) as well as on primary neoplastic cells. Moreover, Ba/F3 cells with doxycycline-inducible expression of oncoproteins (RAS-G12V, BCR/ABL, KIT-D816V) were analyzed. Expression of Hsp32 mRNA was examined by RT-PCR and Northern blotting, and expression of the Hsp32 protein by Western blotting. To silence Hsp32 in neoplastic cells, we used specific siRNA as well as SMA-ZnPP. Proliferation was analyzed by 3H-thymidine uptake and apoptosis by light microscopy. Results: All neoplastic cells tested were found to express Hsp32 mRNA and the Hsp32 protein in a constitutive manner. In Ba/F3 cells, induction of RAS-G12V, BCR/ABL, or KIT D816V enhanced the expression of Hsp32. The Hsp32 siRNA was found to lead to a reduced viability and induction of apoptosis. Treatment of malignant cells with SMA-ZnPP resulted in a significant decrease in proliferation and induction of apoptosis. The effects of SMA- ZnPP on primary neoplastic cells and cell lines were dose-dependent and occurred at pharmacologic concentrations (IC50 1–30 μM). Moreover, SMA-ZnPP was found to synergize with various anti-neoplastic drugs (cisplatin, cytarabine, tyrosine kinase inhibitors, bortezomib) in producing growth-inhibition in neoplastic cells. Conclusions: The Hsp32-targeting drug SMA-ZnPP counteracts malignant cell growth and sensitizes neoplastic cells against various other targeted or conventional antineoplastic drugs. Hsp32-targeting drugs may represent an interesting new aproach to inhibit malignant cell growth in solid tumors and leukemias.

No significant financial relationships to disclose.
Cetuximab and irinotecan-based chemotherapy as an active and safe treatment option for elderly patients with extensively pre-treated metastatic colorectal cancer
Authors: Bouchahda M. , Macarulla T. , Spano J. P. , Bachet J. B. , Liedo G. , Andre T. , Landi B. , Tabernero J. , Levi F. , Rougier P.
Published: March 2020

14528

Background: Cetuximab ( C ) has demonstrated activity both as a single agent and in combination with irinotecan (CPT11) in patients (pts) with metastatic colorectal cancer (mCRC) expressing epidermal growth factor receptor (EGFR) refractory to CPT 11 and oxaliplatin based chemotherapy. This European retrospective study explored the tolerability and activity of C combined with CPT 11 in an unselected population of elderly pts with CPT11- refractory mCRC Methods: 67 pts with mCRC aged = 70 yrs were treated with C (400 mg/m2 loading dose over 2 hours, then 250 mg/m2 over 1 hour weekly). C was given alone (2 pts), combined with CPT11 (56 pts) or CPT11 + 5FU-LV as conventional (4 pts) or chronomodulated delivery (5 pts). Treatment was administered as 2nd to 6th line. Primary endpoint was time to tumor progression (TTP). Secondary endpoints were toxicity, objective response rate (RR) (with RECIST Criteria) and overall survival (OS). Results: Median age was 77 yrs (70–84); M/F: 44/23; WHO performance status 0/1/2/unknown: 12/40/11/4; EGFR expression: + in 55 pts, - in 2 pts and unknown in 10 pts; colon/rectum/unknown: 49/14 /4. More frequent toxicities included acneiform skin rash, which occurred in 33 pts (Grade (G) 2: 24 pts, 35%; G3: 9 pts, 13%), diarrhea (G3, 11 pts, 16%; G4, 2 pts, 3%) and neutropenia (G3: 4 pts, 6%; G4: 5 pts, 7%). RR was 23% including 1 complete and 14 partial responses. Disease control rate (RR + stable disease) was 53%. No correlation was found between skin rash and response. Median TTP (intent-to treat) was 4.5 months [95% CI: 3.2 - 5.7]. Median OS was 15 months [12.0–17.9]. Conclusions: The combination of C with CPT11-based chemotherapy resulted in good activity and acceptable tolerability in elderly patients with heavily pre-treated mCRC, comparable to that of the younger patients. This treatment option can be reasonably proposed to the elderly population.

No significant financial relationships to disclose.
FDG PET predicts prognosis of patients with resectable metastatic colorectal cancer (CRC) treated with preoperative chemotherapy
Authors: Flamen P. , Huberty V. , Garcia C. , Vanderlinden B. , Muylle K. , Legendre H. , Paesmans M. , Van Den Eynde M. , Hendlisz A.
Published: March 2020

14540

Background: Standard evaluation of response to chemotherapy in metastatic CRC is unsatisfactory. Metabolism based imaging using positron emission tomography and fluorodeoxyglucose (FDG-PET) is increasingly used to assess treatment efficacy. Aim: To evaluate the prognostic value of FDG-PET metabolic response to chemotherapy in resectable metastatic CRC. Methods: We reviewed retrospectively 382 patients with metastatic CRC between 7/2002 and 8/2006. Patients curatively operated from CRC metastases treated with preoperative chemotherapy and evaluated by FDG PET at baseline and before surgery were considered eligible for the study. Time to progression (TTP) was defined as the time between surgery and the first proof of recurrence of disease. Total Lesion Glycolysis (TLG) was used as the metabolic parameter. It represents the product of the mean standardised FDG uptake (SUV) of each lesion and its volume. The change of the sum of the TLG of all lesions was calculated. A cut-off of 30% was used to differentiate responders and non- responders. Results: 18 patients (median age 65 yrs) were included. 16 patients were operated from liver mets, and 2 from lung mets. Chemotherapy regimen was FOLFOX 4 in 10 patients, FOLFIRI in 7, and FOLFIRI-bevacizumab in 1 patient. Median number of lesions was 3 (1 to 10) before and 1 after chemotherapy. Median baseline TLG was 115.8 (6.8–841.8). Median post chemo TLG was 12.8 (0–1608.9). The distribution of the metabolic responses was CR 5, PR 9, SD 1, PD 3, with a response rate of 14/18 (78%, 95% CI : 52%-94%). Baseline TLG was not different between responders and non responders (p=0.88). Median follow-up was 422 days: 6 patients died, 15 had recurrent disease. Median TTP was 31 days for non responders, and 197 days for responders (p value not calculated because of the small number of non responding patients). After dichotomization of TLG values using their median as threshold, the post chemo TLG influenced significantly TTP (p=0.001, median TTP 86 days vs 263 days) along with the change of TLG (p=0.002, 107 days vs 263 days). Conclusions: Metabolic response assessment using PET allows a prognostic stratification after preoperative chemotherapy in resectable metastatic CRC.

No significant financial relationships to disclose.