bluuebunny/crossref_metadata_2025 huggingface dataset:
Dose-dense epirubicin with paclitaxel as preoperative treatment in locally advanced breast cancer: Phase II trial
Authors: Bautista Aragón Y. L. , Silva J. , Gonzalez Avila G. , Gutierrez A. , Pluma-Jiménez M.
Published: August 2020

e11633

Background: Treatment of locally advanced breast cancer (LABC) with anthracycline-based regimens have pathological complete response (pCR) of 10–15%, and with anthracyclin-taxane therapy have pCR 18–30%. Combined or sequential are both acceptable with the most important agents. Methods: We use a dose- dense regimen epirubicin and paclitaxel for 12 weeks to determine the effectiveness in the neoadjuvant setting could increase pCR and safety of the regimen. This phase II study investigated women with untreated locally advanced breast cancer assigned to receive epirrubicina 25 mg/m2 and paclitaxel 70 mg/m2 for twelve weeks. Results: 21 patients were enrolled at median follow up of eight months. The median age was 55 years old (28–67). The distribution by TNM was IIB (15%), IIIA (52%), IIIB (24%) y IIIC (9%) and tumor type was lobular (24%) and ductal (76%). The mean tumor size was 8 cm (5 -14 cm). Ninety percent completed twelve cycles of chemotherapy with a two hundred forty five cycles administered. In six patients had dose reduction by 10–20% in subsequent doses and one patient withdrawn from de study because of chemotherapy related toxicity. In 9 percent of patients we use G-SCF. Surgery was performed in 18 patients. Eleven patients (52%) achieved a clinical response (PR o CR) after twelve cycles. Complete pathological response and partial was 11% y 14%. Subset analysis of the effect of Independent predictors included receptor status, Her2 neu, tumor size, and histology was no statistically significant (p.68). Treatment was generally well tolerated. Grade 3/4 non-hematologic adverse events (neurotoxicity, nauseas and palmar plantar dysesthesia) events occurred in 5% of patients. No cardiac toxicity was found. Conclusions: Despite the small sample size, it was representative of our population of LABC. These data indicate that the combined regimen in dose-dense epirubicin and paclitaxel is a regimen with acceptable toxicity. However we have low percent of cPR, maybe we have a high percent of patients with stage IIIA and IIIB with large diameter of tumor size.

No significant financial relationships to disclose.
Pegylated liposomal doxorubicin in combination with gemcitabine in elderly women with locally advanced or metastatic breast cancer: Safety and activity results of our clinical experience
Authors: Adamo B. , Franchina T. , Denaro N. , Garipoli C. , Ferraro G. , Briguglio R. , Ricciardi G. R. , Gambadauro P. , Ferrandina G. , Adamo V.
Published: August 2020

e12005

Background: Elderly breast cancer patients have an increased risk of toxicity from chemotherapy, especially from anthracycline-based regimens. Pegylated liposomal doxorubicin (PLD) has shown a better tolerability profile also in combination with gemcitabine (GEM), as evidenced in several phase II trials. The aim of this study is to retrospectively evaluate the safety and activity of this combination in chemo-naïve or pre-treated elderly patients with advanced breast cancer. Methods: From January 2006 to March 2008, 39 patients (pts) with age ≥ 65 received, at our institution, PLD 25 mg/m2 (day 1, q21) and GEM 800 mg/m2 (days 1 and 8, q21). Median age was 72 (range, 65–79). ECOG PS was 0/1/2 in 14/23/2 pts, respectively. 12 pts (31%) were chemo-naïve, 20 (51%) received prior adjuvant anthracycline-based regimens, and 7 (18%) received other chemotherapies. PLD-GEM combination was administered as first line in 35 pts (90%). Median left ventricular ejection fraction (LVEF) at baseline was 61% (range, 50%-75%). 28 patients (72%) had metastatic disease: 10 in liver, 6 in lung, 2 in skin, and 10 in multiple sites. Estrogen receptor was positive in 32 pts (82%); HER-2+ in 5 pts; 7 pts were triple negative. Results: A total of 206 cycles were administered with a mean number of cycles per patient of 5.2 (range, 3–12). Grade 3–4 neutropenia occurred in 4 (10%) and 3 patients (8%), respectively; grade 3 anemia in two pts (5%). Non-hematological toxicity was mild, with 5 cases (13%) of grade 3 mucositis, and 2 cases (5%) of grade 2 palmar-plantar erythrodysesthesia syndrome. No modifications in LVEF or toxic deaths were documented. We observed 1 CR (2.5%) and 11 PR (28.2%). Eighteen (44%) patients experienced SD for 16 weeks and an overall clinical benefit of 76.8%. Conclusions: The combination of PLD and GEM has a favorable tolerability and a safety profile with an evident clinical benefit and should represent an interesting treatment option in elderly women with advanced breast cancer.

No significant financial relationships to disclose.
Late relapse in triple negative breast cancer
Authors: Tomasevic Z. , Radosevic-jelic L. , Tomasevic Z. M. , Jelic S. , Milovanovic Z.
Published: August 2020

e12022

Background: Approximately 10%-15 % breast cancer (BC) are classified as triple negative. Although triple negative status carries grave prognosis, recent data suggests that it is mostly due to high relapse rate in first 2–3 years following initial diagnosis. Late relapses are less explored. The aim of this paper is to determine the percentage of triple negative BC among patients with late relapses, and to record relapse site in this subgroup of pts. Late relapse is determined as contra-lateral BC, loco-regional relapse, or any distant metastases at least 5 years after initial diagnosis of BC. Methods: Among 2,234 patients with various stages of BC registered during one year at the Institute for Oncology and Radiology of Serbia (March 2005-March 2006), 256 (11, 4%) had late relapse. Median time to relapse was 7 years (range 5–34 yrs). Median follow-up was 9 years. Results: IHC HER-2 status was retrospectively determined on 189 paraffin embedded primary BC specimen. HER-2 3 + is recorded in 17 specimen (8.9%); HER-2 2+/1+ in 86 (45.5%); and HER-2 0+ in 86 (45.5%) Among patients with HER-2 0+ only 10 also had ER score 0 and PGR score 0 (5.3%). Time to late relapse in this subgroup was 7.24 years (range 5–17 yrs). Relapses were resectable in 6 pts with local recurrence (4/10 pts) and contra-lateral BC (2/10). Three pts had bone metastases (3/10) and only 1 pt had pleural relapse (1/10). Median time to resectable relapse was 8.75 yrs (5–17). Median time to non-resectable relapse was 5.75 yrs (5–8 ). Conclusions: According to our results it seems that late relapse of triple negative BC is rare representing only 5.3% of late relapses. None of these pts had liver, lung, or brain metastases. Most relapses (6/10) could be resected, and therefore could potentially be cured.

No significant financial relationships to disclose.
MGMT expression in low-grade gliomas
Authors: Lin Y. , Jiang T. , Li G.
Published: August 2020

e13001

Background: To evaluate the expression of MGMT in low-grade gliomas, and explore the relationship between its expression and the histological type of the tumour and the corresponding MRI characteristics. Methods: We assessed 389 low-grade gliomas (182 astrocytomas, 145 oligoastrocytomas, 61 oligodendrocytomas) with immunohistochemistry staining. We also recorded the preoperational MRI criteria such as tumor volume on T2 image, enhancing volume, tumor location, and relationship with ventricles. Results: The expression of MGMT in astrocytomas, oligoastrocytomas, and oligocytomas were 1.67 ± 0.78, 1.41 ± 0.86,1.44 ± 0.78, respectively. Significant stronger expression of MGMT was observed in astrocytomas than oligoastrocytomas and oligodendrocytomas (t = 3.00, p = 0.03), but no significant difference was observed between the latter two (t = 0.28, p = 0.78). MGMT expression level was significantly correlated with the enhancing volume of the tumor (r = -0.605, p = 0.002), but did not correlate with the total tumor volume (p = 0.504). Conclusions: MGMT is more strongly expressed in tumors of solely astrocyte component, and its expression level is negatively correlated with the extent of blood-brain barrier disruption. This suggest that MGMT may contribute to the tumor resistance to radiotherapy and chemotherapy in low-grade gliomas.

No significant financial relationships to disclose.
Phase Ib study of cediranib in combination with daily temozolomide and radiation in patients with newly diagnosed glioblastoma
Authors: Chi A. S. , Gerstner E. R. , Eichler A. F. , Chea H. K. , Drappatz J. , Wen P. Y. , Ivy S. P. , Loeffler J. S. , Sorensen A. G. , Jain R. K. , Batchelor T. T.
Published: August 2020

e13010

Background: Pre-clinical evidence suggests antiangiogenic therapy combined with radiation therapy (RT) and chemotherapy may improve tumor control in patients with glioblastoma (GBM). We conducted a phase Ib study to evaluate the safety and maximum tolerated dose (MTD) of the combination of cediranib, a potent pan-VEGF receptor tyrosine kinase inhibitor, standard RT, and temozolomide (TMZ) in patients with newly diagnosed GBM who were not taking enzyme-inducing antiepileptic drugs (EIAED). Methods: After undergoing tumor biopsy or resection, six patients with pathologically confirmed GBM were treated with concurrent TMZ (75mg/m2/day), RT (60 Gy) and cediranib (dose level 1 = 20mg/day; dose level 2 = 30mg/day) followed by post-radiation TMZ (150–200 mg/m2 on days 1–5 of each 28 day cycle) and cediranib (45mg/day) for up to 6 monthly cycles. Cediranib was started concurrently with RT and TMZ 14–21 days after surgery. Results: Six patients were treated (cediranib 20mg = 3 patients; cediranib 30mg = 3 patients). No patients experienced a DLT, establishing the MTD for cediranib in combination with RT and TMZ as 30mg/day in this patient population. Expected toxicities of hypertension, fatigue, and palmar/plantar erythema were observed. During combined cediranib and TMZ therapy in the post-radiation setting, one patient discontinued cediranib because of toxicity (grade 3 transaminase elevation) and one patient required dose reduction to 15mg/day due to grade 3 proteinuria. No intratumoral or intracerebral hemorrhages were observed during the course of cediranib treatment. No cases of wound infection or wound dehiscence were observed. All patients are alive with a median follow-up of 156 days. Conclusions: Cediranib given in combination with standard RT and TMZ for newly diagnosed GBM patients not on EIAEDs is well tolerated and the MTD is 30mg/day. The phase II component of this trial is underway and will include correlative biomarker and MRI studies.

[Table: see text]
Addition of continuous low dose temozolomide (T) to bevacizumab (Bev) plus irinotecan (Iri) after bevacizumab plus irinotecan failure in heavily pretreated glioblastoma multiforme (GBM)
Authors: Stankewitz S. , Dresemann G.
Published: August 2020

e13015

Background: In several phase II studies in relapsed GBM, Bev plus Iri showed impressive objective response rates (>50%) with acceptable toxicity rate, duration of response, however, was moderate. Methods: From April 2007 to October 2008, 35 pretreated patients with confirmed GBM with progressive disease (PD) after Bev (4 mg/kg body weight i.v.) plus Iri (80 mg/m2 i.v.) were treated with additional continuous low dose T (20 mg per day p.o.) while Bev plus Iri were continued. ECOG performance status (PF) was 0 - 2 in all pts. MRI scan was required after 4 weeks and every 6 weeks afterwards. MacDonald criteria were used for evaluation of response. If MRI scans could not be performed, patients were considered to have PD. Treatment was given until PD or intolerable toxicity occurred. Results: All 35 patients were eligible for toxicity and efficacy, median follow up was 7 months (2 - 20), 25 patients were male, 10 female, median age was 51 years (29 - 80), 21 patients had primary GBM, 14 patients secondary GBM. All patients had prior irradiation (56 - 60 Gy) 2 patients had 5, 8 patients had 4, 15 patients had 3, and 10 patients 2 prior chemotherapeutic regimen. 1 patient developed grade 3 leucopenia, and 1 patients grade 3 thrombopenia; 3 patients asymptomatic intracerebral bleeds requiring treatment delay, 1 pat. grade 3 sepsis and 2 patients grade 3 fatigue. In 4/35 patients a partial response (PR) was achieved, in 14/35 patients a disease stabilization for at least 2 months, while 17/35 patients showed primary PD. Median duration of PR was 3.5 months (2–5), median duration of SD was 5 months (2–13), Median survival was 5 months (2–13). Data will be updated. Conclusions: The addition of continuous low dose T in combination with Bev plus Iri seems to have activity in GBM patients, after progression on Bev plus Iri treatment, and has an acceptable toxicity profile. Further investigation of the combination Bev plus Iri plus T in GBM patients is necessary.

No significant financial relationships to disclose.
Seizures in patients with glioma treated with phenytoin and levetiracetam
Authors: Merrell R. T. , Lachance D. H. , Anderson S. K.
Published: August 2020

e13020

Background: Seizures are common in patients with glioma. Phenytoin, traditionally used for these patients, can be associated with intolerable side effects and potentially alters the metabolism of chemotherapeutic agents. Levetiracetam has more favorable pharmacokinetics facilitating ease of use with fewer side effects and is nonenzyme inducing. We compare seizure outcomes and side effects in patients with glioma treated with phenytoin and levetiracetam monotherapy. Methods: Retrospective analysis of consecutive patients with glioma. Subjects had at least one clinical seizure and had to be followed for 6 months. Seizure outcomes and side effects were compared between cohorts treated with phenytoin or levetiracetam. Seizure outcomes were measured by time to second seizure and seizure frequency. Results: 76 patients (34 female) with pathologically proven glioma and seizures were identified, 25 treated with phenytoin and 51 with levetiracetam. 64% had grade 4 astrocytoma. There was no difference in seizure outcome between the phenytoin and levetiracetam groups when comparing time to second seizure (p = 0.584), second seizure rates (p = 0.462), and average seizures per month (p = 0.776). When adjusting for age, gender, type of seizure, type of glioma, and dosage using univariate and multivariate models there were no differences between the treatment groups and none of these covariates were statistically significant for explaining the second seizure rates between treatment groups (all p values >0.05). The incidence of side effects in the levetiracetam group was 5.9% versus 20% in the phenytoin group (p = 0.106). Additionally, 36.0% of the patients in the phenytoin group had dose adjustments not related to breakthrough seizures compared to only 9.8% in the levetiracetam group (p = 0.010). Conclusions: In this study, glioma patients treated with levetiracetam had similar seizure control as patients treated with phenytoin. Patients treated with levetiracetam experienced fewer side effects and required fewer non seizure related dose adjustments than patients treated with phenytoin. Levetiracetam is a safe, effective, and preferred alternative for seizure management in patients with glioma.

No significant financial relationships to disclose.
A phase I study of sunitinib plus irinotecan in the treatment of patients with recurrent malignant glioma
Authors: Friedman H. S. , Vredenburgh J. J. , Desjardins A. , Janney D. E. , Peters K. B. , Friedman A. H. , Gururangan S. , Reardon D. A.
Published: August 2020

e13024

Background: Malignant glioma (MG), an incurable primary CNS tumor, are highly angiogenic due to overexpression of VEGF/VEGFR. The current study was designed to determine the MTD and DLT of sunitinib (S), a once-daily, oral selective inhibitor of VEGFR when combined with irinotecan (I), a topoisomerase-1 inhibitor among recurrent MG patients. Methods: We employed a ‘3+3‘ dose escalation design to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of S, administered once daily for the first 28 days of each 42 day cycle, with I, administered every 2 weeks. The initial S and I doses were 25 mg/day and 75 mg/m2. Key eligibility criteria included KPS ≥ 70%, adequate organ function and no concurrent CYP3A-inducing anti-epileptics. Pharmacokinetic studies for S are obtained during cycle 1 among 6 additional patients treated at the MTD. Results: Eleven patients (grade 4 MG, n = 6; grade 3 MG, n = 5) have enrolled. No DLTs were observed in cohort 1, but 2 patients experienced hematologic DLT (grade 3 thrombocytopenia, n = 2; grade 4 neutropenia, n = 1) in cohort 2. Therefore the MTD for this regimen is 25 mg of S plus 75 mg/m2 of I. Evidence of therapeutic benefit to date includes 8 patients (73%) with stable disease including 3 who continue on therapy. Conclusions: Combination of sunitinib plus irinotecan is well tolerated in recurrent MG patients at the defined MTD dose level. Accrual to the PK dose expansion cohort continues.

No significant financial relationships to disclose.
Magnetic resonance imaging evaluation of radiation: Cranial radiation therapy-induced diffuse white matter injury
Authors: Mohran T. Z. , Omar M. M. , Hameed M. A. , Elnaggar M. S.
Published: August 2020

e13033

Background: To study the value of MRI in detection and grading of diffuse white matter injury induced by cranial radiation therapy for brain tumors and to evaluate the influence of various risk factors for its development. Methods: This study included 60 patients who had primary brain tumors and received external beam conventionally fractionated radiotherapy. Twenty-three out of 60 patients received chemotherapy after radiotherapy. Post radiotherapy follow-up MRI examination was performed for all patients at 6 weeks, 3, 6, 9, 12 months, and at more than 1 year from completion of radiotherapy. MR imaging was performed with T2-weighted turbo spin echo, fast fluid-attenuated inversion- recovery (FLAIR), T1-weighted spin-echo, and T1-weighted post-contrast spin-echo sequences. Results: Twenty-one of 60 patients (35%) developed diffuse white matter injury at a mean of 15.3 + 7.6 months from the completion of radiotherapy (range, 5–36 months). Radiation-related diffuse white matter changes were characterized as diffuse high signal intensity in the periventricular deep white matter on T2WI and FLAIR sequences. The MRI grading system of these periventricular hyperintensity (PVH) were as follow: 39 patients (65%) had no WMI (grade 0), four had grade 1 changes, three patients had grade 2 changes, nine patients had grade 3, and five patients had grade 4. They were symmetrical in 13 of 21 patients (61.9%), and asymmetrical in eight out of 21 patients (38.1%). The prevalence of diffuse matter injury found to be significantly related to the volume of irradiation (p = 0.02), fraction size (p = 0.008), and concomitant use of chemotherapy (p > 0.02)Conclusions: Diffuse white matter injury is a known consequence of radiation therapy, and the capability of detecting and grading such damage is optimally provided by MRI.

No significant financial relationships to disclose.
Liposomal doxorubicin and cisplatin as first-line chemotherapy in unresectable malignant pleural mesothelioma: A phase II study
Authors: Arrieta O. , Medina L. A. , Guzmán E. , Rios Trejo M. A. , Mendoza D. , Astorga Ramos A. , Martinez Barrera L. , Hernández Pedro N. , Arechaga Ocampo E. , De la Garza J.
Published: August 2020

e13507

Background: Malignant pleural mesothelioma (MPM) is a poor prognosis neoplasm. Its worldwide incidence is rising but until recently chemotherapy has not been shown to be effective in its treatment. The combination of cisplatin and pemetrexed is the approved “standard” treatment in unresectable MPM. Liposomal doxorubicin (LD) consists of pegylated phospholipid- vesicles that encapsulate doxorubicin conferring minimal capture from the reticulo-endothelial system resulting in a greater serum half- life, an enhanced liposome deposition in the tumor and a lower degree of toxicity. We evaluated the combination of LD and Cisplatin (Cis) in chemonaive patients with unresectable MPM. Methods: From September 2006 to October 2008, consecutive patients with stage III / IV MPM were included to receive LD 40 mg/m2 and Cis 60 mg/m2 every 21 days for a maximum of 4 cycles. Imaging studies were performed prior and after 2 cycles to assess response. Gamma camera images (GCI) of Tc-99m-labeled LD were acquired to evaluate LD accumulation in measurable tumor tissue. Patients gave written informed consent. Results: Twenty seven patients were included, 81.5% were stage III and 18.5% were IV. According to EORTC prognostic factors, 33.3% and 66.7% had poor and good prognosis, respectively. Median age was 59.2 years (33–80). Median follow-up was of 5.2 ± 0.8 months. Median survival has not been reached. The 2-year overall survival was 52.5% ± 14.2. Median time to progression was 5.0 ± 1.1 months (CI 95%, 2.7–7.3). Overall response was 45.5%, stable disease 36.4% and progression of 18.2%. GCI showed good accumulation and retention (60%) of the labeled LD in tumor tissue at 4 h after the initial injection. There were no toxic deaths. Conclusions: Cis+LD is a highly active regimen in MPM with comparable results to the most active regimens so far reported. A phase III trial is warranted to confirm these findings.

No significant financial relationships to disclose.
Trabectedin phase II clinical trials: Pooled analysis of safety in patients with solid tumors
Authors: Cioffi A. , LeCesne A. , Blay J. , Delaloge S. , Yovine A. , Maki R. , Nieto A. , Jiao J. J. , Demetri G. D.
Published: August 2020

e13510

Background: Trabectedin is an originally marine-derived antineoplastic agent. Its unique antitumor properties, attributed to specific binding to the small groove of DNA, have been demonstrated activity against soft-tissue sarcoma (STS), ovarian, breast and prostate cancer. Trabectedin treatment has been authorized by EMEA for STS after failure of standard treatment and shows efficacy in relapsed ovarian cancer in a phase III study. This retrospective report on safety includes single-agent trabectedin phase II studies in patients (pts) with solid tumors. Methods: A total of 1,132 pts were treated with trabectedin in 19 international trials (Feb’99 - Apr’08). Three schedules were analyzed: 24-hour infusion every 3 weeks (wk) (570 pts), 3-h every 3 wk (258 pts), and 3-h for 3 out of 4 wk (304 pts). Safety analyses included pts who received at least part of 1 infusion. MedDRA and NCI-CTC v1.0/2.0 were used to code and grade treatment-emergent adverse events (AEs). Results: Median pt age was 54 years with ECOG 0–1 (>99%). Diagnosis included sarcoma (56%), ovary (26%) and breast (7%) cancer, for which 90% of pts had received chemotherapy, 37.5% radiotherapy, and 96.0% surgery. Trabectedin lasted for a median of 3 cy (9.4 wks) and 28% of pts received ≥ 6 cycles, with a median dose intensity of 0.4 (0.1–0.6) mg/m2/wk. The overall rate of discontinuations due to toxicity was 10.3%, similar between all three dose schedules. Most common trabectedin-related AEs (≥ 20% of pts) were nausea, fatigue and vomiting. Most common lab abnormalities were reversible myelosuppression, mainly neutropenia (37% grade3–4) though G-CSF was given to less than 10% of pts; and transient transaminase increases (grade3–4: ALT, 45%; AST, 30%). Of note, only 3.7% and 5.7% of pts had alopecia or mucositis/stomatitis, respectively. Fifteen drug-related deaths (1.3%) occurred. Conclusions: Single-agent trabectedin was reasonably well tolerated, with low rates of drug-related discontinuations and deaths. Sustained clinical benefit in the absence of relevant cumulative toxicities allows its administration to patients for prolonged periods of time.

[Table: see text]
Administration of 24-hour intravenous infusions of trabectedin every 3 weeks in ambulatory patients with mesenchymal tumors via disposable elastomeric pumps
Authors: Schoeffski P. , Cerbone L. , Wolter P. , Stas M. , Dumez H. , Clement P. , Wildiers H. , Paridaens R. , van Oosterom A. T.
Published: August 2020

e13530

Background: Patients (pts) with sarcoma whose disease progresses after standard chemotherapy have poor outcome. In this setting, DNA- transcription-interacting cytotoxic agent trabectedin (TRA) is efficacious and marketed in Europe. It is administered as 24-h i.v. infusion q3w with steroid co-medication. To overcome the inconvenience of hospitalization for drug delivery TRA is now given in Leuven via disposable elastomeric pumps, which facilitate ambulatory treatment and are compatible with the drug. Material and Methods: Heavily pre-treated pts with sarcoma were offered chemotherapy with TRA 1.5 mg/m2 as 24-h i.v. infusion via port catheter, either during hospitalization using electronic pumps or as outpatients using the Baxter LV10 disposable pump (drug dissolved in 267 ml NaCl 0.9%). Co-medication consisted of antiemetics and dexamethasone 2x4 mg days -1,1,2,3. Results: Between 09/07–12/08 28 pts were treated, and 21 (75%) elected outpatient therapy (9 F, 12 M, med. age 49 yrs, range 19–68). Common diagnoses included leiomyo- (5), lipo- (4), synovial (2) and myxofibrosarcomas. Pts had previous primary surgery (17), adjuvant RT (4) and surgery for relapse/metastasis (7). They had local relapse (2), distant metastasis (12) or both (7) when starting TRA, 19 had received previous chemotherapy with a med. number of 2 prior lines (range, 0–5). We administered 130 cycles of TRA in 21 pts, with a med. number of 3 cycles/patient (range, 1–24). Dose reductions were done in 60 cycles, mainly due to laborabory events. Best response (RECIST) was 3 confirmed PR, 1 PR pending confirmation, 6 SD, 11 PD. Grade 3/4 (CTC) AEs were limited to one case each of hemorrhage and lung embolism, other AEs were in line with published TRA experience. One port catheter contamination required replacement, one catheter tip thrombosis occurred and one extravasation due to needle dislocation was observed. Conclusions: Outpatient administration of TRA as 24-h infusion via port catheter using Baxter LV10 pumps is preferred by 3/4 pts, is feasible, safe, effective, cost-efficient and should be considered routine practice in this clinical setting.

[Table: see text]
A PET imaging study of the vascular disruptive agent OXi4503 to confirm in vivo mechanism of action in a phase I trial
Authors: Price P. M. , Asselin M. , Koetz B. , Dickinson C. , Charnley N. , Lorigan P. , Valle J. , Stratford M. , Rustin G. , Saleem A.
Published: August 2020

e14510

Background: OXi4500, the active product of OXi4503, reversibly binds at the colchicine binding site on the ß subunit of tubulin. This study investigated its mechanism of action using PET molecular imaging Methods: OXi4503 was administered by 3 weekly IV infusions in a phase 1 trial (32 pts). Between 1.6 & 15.4 mg/m2 dose levels, PET imaging was performed with 15O-labelled water (measuring blood perfusion) pretreatment & at 90min & 24hr after first infusion (8pts) & at 28days (1 pt). [18F]fluorodeoxyglucose (FDG) (measuring proliferative activity) was performed pretreatment & at 28 days (9pts) Results: 9 pts (mean age 48.5yrs) were studied: CRC (2), pancreatic (1), MM (6). 2 pts with MM (3.8 & 6.5 mg/m2) achieved stable disease. Toxicity included pyrexia, lethargy & hypertension. There was a dose-dependent linear increase in peak plasma concentrations & AUC of OXi4503 & OXi4500. Sustained tumour blood perfusion reduction (50% at 90min & 24hr) was seen in all metastases in the CRC pt treated at 15.4 mg/m2 after just one dose & resulted in FDG reduction (23% in all 5 mets) & tumor marker response. Doses between 1.9 & 11.0 mg/m2 produced dose independent reductions in tumour perfusion which were more variable & less marked with 3/8 pts showing a reduction in tumour FDG uptake. The 1pt studied at 28 days (8.5 g/m2) showed further sustained reduction in tumour blood flow (40%). Variable dose independent changes in normal tissue perfusion were seen at all dose levels eg in 3/4 pt splenic perfusion showed a dose-independent decrease (20–30%) at 90min with recovery at 24hr Conclusions: OXi4503 shows significant activity at 15.4 mg/m2 in line with its proposed mechanism of action. Characterisation of the mixed tumour perfusion response at lower doses will aid planning & assessing combination studies. The MTD is now being identified. Sponsored by CRUK.

[Table: see text]
Optimal patient selection for CPT-11 chemotherapy in colorectal cancer: Quantitative prediction of tumor response and overall survival using expression data of novel marker genes
Authors: Takemoto H. , Tomita N. , Murata K. , Fukunaga M. , Okamura S. , Ohue M. , Ishida H. , Tanimoto K. , Hiyama K. , Nishiyama M.
Published: August 2020

e14529

Background: Unlike the toxicity, none of the critical prediction markers of CPT-11 efficacy has been validated to date. With a hypothesis that expression analysis of a set of the key drug sensitivity genes could allow us to predict the therapeutic response, we identified potent marker genes for CPT-11 in in vitro, conducted this prospective study attempting to develop a prediction formula of efficacy using the expression data (2006 ASCO, 2006 ESMO), and demonstrated the latest prediction formula of the best tumor response (BTR), time to treatment failure (TTP), and the overall survival after CPT-11 chemotherapy (OS). Methods: Seven genes identified as possible marker genes for CPT-11 (SN-38)- AMD1, CTSC, EIF1AX, FLJ13089 , DDX54, PTPN2, and TBX3-, and 5 other possible marker genes (ABCG2, CYP3A4, MGMT, POR, and TOP2A) that had already been known as drug sensitivity determinants and selected by our in vitro screening process, were studied. CPT-11 was intravenously administered on Days 1, 8, and 15, every 4 weeks in chemo-naive patients with stage IV colorectal cancer after palliative operation. Tumor samples were collected at surgery and tumor response was evaluated by RECIST. Results: All of the 44 enrolled patients were assessable for BTR (% of initial tumor size), TTP (day), and OS (day) in the clinical study, and we successfully developed the best linear model for each, which converted the quantified expression data of the 7 selected genes into objective BTR, TTP, and OS. We used 20, 16, and 15 tumor specimens and constructed potent prediction formulae for BTR (r=0.9420), TTP (r=0.7103), and OS (r=0.8406), respectively. Utility-confirmation analyses using another 16, 10, 13 clinical samples appeared to show that the formulae could predict BTR (r=0.6491, p=0.007) and OS (r=0.7947, p=0.011). We also fixed the best linear models using 5 other known marker genes, but they had less advantage in prediction. Conclusions: Despite limited data, our developed formulae using the 7 novel genes would provide advantages in prediction of individual response to CPT-11. Based on the positive results of this study, we have initiated a large scale validation study of the formula.

[Table: see text]
Evaluation of early sequential 18F-FDG PET imaging as a prognostic indicator and predictor of response to platinum and pemetrexed chemotherapy in malignant pleural mesothelioma (MPM)
Authors: O’Flaherty J. D. , Farrelly C. , Knox M. , Power D. , Lucey J. , O’Byrne K.
Published: August 2020

e14534

Background: Recent evidence has suggested that baseline SUV and metabolic response measured on sequential PET scans early in the course of chemotherapy may predict for survival and response to chemotherapy. Methods: Patients with MPM suitable for platinum/pemetrexed chemotherapy were studied. Baseline pre-chemotherapy PET and CT scans were performed with a further PET scan before cycle 2. CT scans were repeated mid-treatment and at the end of 6 cycles. PET response was determined by measuring the change in the maximum and mean SUV, PET Vol (volume of tumor above SUV threshold of 3.5) and Total Lesion Glycolysis (TLG, calculated as PET Vol x SUV Max). Metabolic response (MR), as measured by a 25% drop in SUV Max, SUV Mean, PET Vol and TLG was compared to overall survival (OS) and to subsequent response to chemotherapy on CT. CT scans were read using Modified RECIST criteria and CT response was compared to OS. Results: 21 patients had baseline PET scans of whom 17 had a further PET before cycle 2. 19 patients had CT scans evaluable by Modified RECIST criteria. Baseline SUV Max and SUV Mean were found to predict for OS. Median survival was 17.2 months for patients with SUV Max less than 15 versus 6 months for those with SUV Max greater than 15 (p=0.0193). Median survival was 14.1 months for patients with SUV Mean less than 5 versus 6.5 months for those with SUV Mean greater than 5 (p=0.0681). MR defined by SUV Max, SUV Mean, PET Vol or TLG did not predict for OS. MR on PET correlated poorly with CT response with Kappa values of 0.01, 0.05, 0.15 and 0.31 for MR defined by SUV Max, PET Vol, SUV Mean and TLG respectively. CT response using Modified RECIST criteria correlated significantly with OS. Patients with partial response (PR), stable disease (SD) and progressive disease (PD) had median survivals of 25.6 months, 8.6 months and 4.6 months respectively (p=0.0072) Conclusions: MR measured by SUV Max, SUV Mean, PET Volume and TLG on early sequential PET scans did not correlate with CT assessed response to chemotherapy or OS. Baseline SUV Max >15 and SUV Mean >5 were indicative of poor prognosis. CT response as measured by Modified RECIST criteria correlated significantly with OS.

No significant financial relationships to disclose.
Target identification by phosphoproteomics: RIN1 modulation of sorafenib-induced cytotoxicity in renal cell carcinoma
Authors: Grozav A. G. , Willard B. , Kinter M. , Vaziri S. A. , Bukowski R. M. , Rini B. I. , Ganapathi M. K. , Ganapathi R.
Published: August 2020

e14543

Background: Sorafenib (SFB) is a multi-tyrosine kinase inhibitor clinically useful in treatment of metastatic renal cancer. While the inhibition of angiogenesis is considered a major mechanism of action, identification of targets regulating growth inhibitory effects of SFB is necessary to further improve its efficacy and reduce toxicity. Methods: In this study we used targeted phosphoproteomics to identify tyrosine phosphorylated proteins that are differentially affected in control and SFB-treated human CAKI-1 renal cell carcinoma cells. The strategy involved immunoaffinity isolation of phosphotyrosine containing proteins and liquid chromatography - tandem mass spectrometry (MS) for identification of candidate proteins. Results: Among identified proteins, signal transducer and activator of transcription 1 (STAT1) and Ras and Rab interactor 1 (RIN1) were found to be hypophosphorylated in SFB-treated compared to untreated CAKI-1 cells based on quantitative MS analysis, by peptide counts and native peptide reference method. A ∼4-fold decrease in expression and phosphorylation of STAT1 was observed in cells treated with 10 μM SFB for 48h. Up to 8-fold SFB dose-dependent (5–15 μM) decrease in phosphorylation of RIN1 at tyrosine 36, but not in total RIN1 expression, was observed. Similar effects on decreased phosphorylation of STAT1 and RIN1 were also observed in 786-O renal cell carcinoma treated with SFB. Hypophosphorylation of RIN1 at tyrosine 36 was observed in CAKI-1 cells treated with 5 μM sunitinib but not with imatinib (≤ 10 μM). Treatment of CAKI-1 cells with RIN1 targeted, but not control si-RNA led to down-regulation of RIN1 expression and attenuation of antiproliferative effects of SFB. Notably, ∼2-fold higher expression of RIN1 protein (total and phosphorylated) was observed in CAKI-1 cells selected for resistance following continuous exposure to 7.5 μM SFB. However, unlike parent CAKI-1 cells, prolonged exposure of these SFB-resistant CAKI-1 cells to 7.5 μM SFB did not completely abrogate phosphorylation of RIN1 at tyrosine 36. Conclusions: These results demonstrate that RIN1, a Ras effector protein with multiple biochemical functions, is a target for the anti-tumor effects of SFB in kidney cancer cells.

[Table: see text]
Evaluation of two different schedules of bevacizumab (BEV) with oxaliplatin (OXA), raltitrexed (TOM), levo-folinic acid (LFA), and 5-fluorouracil (5-FU) during preoperative (preop) pelvic RT in high-risk locally advanced rectal cancer (HR-LARC) patients (pts)
Authors: Avallone A. , Delrio P. , Di Gennaro E. , Pecori B. , Aloi L. , Tatangelo F. , Petrillo A. , Budillon A. , Caracò C. , Sandomenico C. , Comella P.
Published: August 2020

e14546

Background: OXA, RTX, 5FU, and LFA during preop pelvic RT produced a high rate of complete (TRG1) or subtotal (TRG2) tumor regression in HR-LARC. BEV might enhance response to chemoradiotherapy (CH-RT), but scheduling of BEV could be critical. Therefore, we added BEV to CH-RT in two different schedules to evaluate their feasibility and activity. According to the Simon's two-stage design, assuming a hypothesis of a 50% TRG1 (α=0.05, β=0.20), at least 6/16 TRG1 should be obtained to continue pts accrual in every schedule. Methods: Inclusion criteria were: cT4, cN+, cT3(<5 cm from the anal verge and/or +ve CRM), resectable M1. Pts received 3 biweekly courses(c) of OXA (100 mg/m2)/TOM (2.5 mg/m2) on day 1, and 5FU (800 mg/m2)/LFA(250 mg/m2) on day 2 during pelvic RT (45 Gy). BEV (5 mg/kg) was given biweekly from day -14 for 4 c in schedule A, and from day -4 for 2 c in schedule B. Toxicity was graded with NCI-CTCv3. Changes of circulating endothelial cells (CECs)assessed by flow cytometry in 17 (7 A; 10 B) pts, and glucose metabolism evaluated by FDG-PET in 27 (15 A; 12 B) pts after 1st c of CT were used as surrogate markers of tumor response. The Mann-Whitney test assessed the differences in CECs and FDG-PET related to schedules. TME was planned 8 wks after CH- RT. Results: Until now, 28 pts (16 A; 12 B) were treated: M/F=19/9; median age 57 (range, 43–74) yrs. All but one pt (A) completed the planned CH-RT. Grade 3/4 neutropenia was the most common toxicity with schedule A (7 pts, 44%), while it never occurred with schedule B. No treatment-related or postop death occurred. CECs were more decreased by schedule B than by schedule A (median, -78% vs -29%, p< 0.05). Glucose metabolism was also more reduced by schedule B (median, -78% vs -50%, p < 0.05). All but one pt (refusal) of schedule A, and 7 pts of schedule B proceeded to TME. With schedule A, 2 pts obtained a TRG1, 8 pts a TRG2, 3 pts a TRG3 and 2 pts a TRG4. With schedule B, 4 pts obtained a TRG1 and 3 pts a TRG2. Conclusions: These data suggest the relevance of BEV scheduling during preop CT-RT to optimize safety and efficacy of the combination treatment. Updated results on the whole study population will be presented.

No significant financial relationships to disclose.
A pharmacokinetic (PK) and safety study of sorafenib plus capecitabine in advanced solid tumors
Authors: McKay C. E. , Infante J. , Jones S. , Bendell J. , Greco F. A. , Markus T. M. , Spigel D. R. , Yardley D. A. , Woudenberg J. , Lathia C. D. , Burris H. A.
Published: August 2020

e14548

Background: The addition of a multi-targeted kinase inhibitor such as sorafenib (S) to standard chemotherapy holds promise for improving therapeutic efficacy in multiple advanced solid tumors. This study is designed to evaluate the PK and overall safety of S in combination with capecitabine (C). Methods: Eligibility included patients (pts) with refractory solid tumors, 0–1 ECOG, adequate organ function, and no prior anti-VEGF tyrosine kinase inhibitors. This single institution study enrolled two simultaneous cohorts of 6 pts each followed by an expansion: Cohort A received S 400 mg bid for 21 days and C 750 mg/m2 bid for 14 days of a 21-day cycle. Cohort B received S 400 mg bid for 21 days and C 1,000 mg/m2 bid for 14 days of a 21-day cycle. Intensive PK collections (pre, 30 min, 1, 2, 4, 6, 8, and 12 hr) were obtained following a week of exposure to S alone, C alone (both C and 5FU levels measured), and both S and C in combination. Results: 17 pts dosed since 2/1/08: median age 66 years (range 36–87); ECOG 0 14(82%); and white 15(88%). Tumor types include colon (4), pancreas (2), prostate (2), and other (11). No treatment-related deaths occurred. Target toxicities are outlined in table below. Despite early and aggressive clinical management, hand foot skin reaction (HFS) necessitated dose reductions in 1 pt in cohort A and 4 pts in cohort B. In total, only 1(14%) pt in cohort A required a dose reduction, as opposed to 5(63%) pts in cohort B. The median # of cycles was 2 (range 1–10), and 5 pts (29%) remain on study. Of the 13 pts evaluable for response, 8 (47%) had stable disease following first restaging scans. PK samples are being analyzed to compare Cohort A vs. B. Conclusions: The results of this trial will help guide future trials of S plus C. The 1,000 mg/m2 bid dose of C in combination with full dose S required frequent dose modifications in our pt population secondary to overlapping toxicity (primarily HFS). Alternate schedules should be considered. PK analysis will be presented.

[Table: see text]

[Table: see text]
Ad-ISF35-transduced autologous cells promote in vitro and in vivo chemosensitization in patients with 17p-/P53-defective chronic lymphocytic leukemia
Authors: Melo-Cardenas J. , Castro J. E. , Cox B. , Sandoval-Sus J. D. , Darrah D. , Urquiza M. , Prussak C. E. , Kipps T. J.
Published: August 2020

e14552

Background: Transduction of chronic lymphocytic leukemia (CLL) cells with a replication-defective adenovirus (Ad) encoding recombinant CD154 (Ad-ISF35) induces expression of death receptors and Bid via a P53-independent pathway involving induction of P73. Induction of P73 significantly enhances the sensitivity of P53-defective CLL cells to “P53-dependent” drugs, such as Fludarabine (F-ara-A). Patients with P53-defective CLL who received iv infusions of autologous Ad-ISF35-transduced CLL cells were observed to achieve complete remissions (CR) with subsequent treatment using F-ara-A based treatment regimens, suggesting Ad-ISF35 could sensitize P53-defective CLL to chemotherapy. Methods: We examined patients with drug-resistant and/or P53-defective CLL before and after iv infusions of autologous Ad-ISF35-transduced CLL cells who were enrolled in a phase I study examining whether such treatment could sensitize patients to a truncated fludarabine, cyclophosphamide and rituximab (FCR) regimen. We examined CLL cells for sensitivity to F-ara-A in vitro, expression of CD95, DR5, Bid, and P73 and correlated these with the response to treatment in vivo. Results: P53-defective CLL cells were resistant to F-ara-A induced apoptosis with IC50 > 10μM prior to treatment. CLL cells collected from patients≥24 hours after IV infusion of autologous Ad-ISF35-trasduced CLL cells became sensitive to the cytotoxic effects of F-ara-A, with IC50 0.3–1 μM. Enhanced sensitivity to F-ara-A was associated with induced expression of Bid, DR5, CD95, and P73 by circulating CLL cells, an effect lasting≥2 weeks following iv infusion. Consistent with this, we observed complete resolution in lymphocytosis, lymphadenopathy and splenomegaly following 1 cycle of FCR administered 2 weeks after 3 biweekly infusions of Ad-ISF35- transduced CLL cells. Conclusions: IV infusion of autologous Ad-ISF35-transduced CLL cells can induce de novo, systemic expression of death receptors and Bid on bystander CLL cells, which is associated with enhanced sensitivity of P53-defective CLL to the cytotoxic effects of standard chemotherapy

[Table: see text]
Safety and efficacy of neratinib (HKI-272) in combination with vinorelbine in patients with solid tumors
Authors: Limentani S. A. , Awada A. , Dirix L. , Beck J. , Dieras V. , Binlich F. , Germa C. , Agrapart V. , Powell C. , Hershman D.
Published: August 2020

e14554

Background: Neratinib (HKI-272) is a potent irreversible pan-ErbB tyrosine kinase inhibitor. Preclinical studies have shown synergistic antitumor activity with the combination of trastuzumab plus vinorelbine in metastatic breast cancer.The recommended dose of neratinib in monotherapy is 240 mg. In this phase 1 study, a combination dose of neratinib plus vinorelbine that is tolerable was determined in patients (pts) with solid tumors. Methods: This is an open-label, 2-part study of ascending multiple daily oral doses of neratinib (160 mg, 240 mg) in combination with 25 mg/m2 IV vinorelbine (administered on days 1, 8 every 3 wks). Tumor measurements were made every 6 wks by modified RECIST criteria. Results: 6 pts have been treated at each dose level. Data for 12 pts (5 pts still ongoing) as of 30 Oct 2008 are presented (median age [range] of 53.5 [38–75] yrs; 83% female). The median duration of treatment [range] was 1.9 [1.5–2.7] m. There was only 1 dose limiting toxicity (DLT) of grade 3 neuropathy (pt had preexisting grade 1 neuropathy) at 160 mg neratinib-25 mg/m2 vinorelbine, so the dose was escalated to 240 mg neratinib- 25 mg/m2 vinorelbine. In this cohort, there were no DLTs, and since the neratinib and vinorelbine doses reached full standard doses there was no need for further dose escalation. AEs, any causality, all grades in ≥ 15% of pts included diarrhea (92%), nausea (67%), constipation (50%), fatigue (42%), vomiting and anthralgia (33% each), abdominal pain and anorexia, (25% each), anemia and neutropenia (17% each). Grade ≥3 AEs that occurred in ≥1 pt included neutropenia (2 pts), pneumonia (1 pt) and peripheral neuropathy (2 pts). Preliminary efficacy data show that 1 pt with stomach cancer had stable disease, lasting ≥21 weeks. Conclusions: The combination of 240 mg neratinib and 25 mg/m2 vinorelbine was found to be tolerable and to demonstrate early evidence of clinical benefit in pts with solid tumors, to be assessed further in pts with metastatic ErbB-2+ breast cancer in part 2.

[Table: see text]
Selective killing of human cancer cells by targeting a fusion mRNA between CYCLIN D1 and TROP2
Authors: Alberti S. , Trerotola M. , Dell’ Arciprete R. , Vacca G. , Veronica B. , Cosmo R. , Rossana L. , Lattanzio R. , Piantelli M. , Guerra E.
Published: August 2020

e14569

Background: Trop-2 is a calcium signal transducer and a stem cell marker. Trop-2 is widely overexpressed by human cancers and stimulates their growth. A TROP2 mRNA was isolated as post-transcriptionally joined to CYCLIN D1 transcripts, suggesting this as one of the transforming mechanisms of TROP2. Methods: In vitro cell growth assays were utilized to assess the cell growth stimulatory capacity of the chimeric mRNA. Colony assays for growth in soft agarose and tumorigenicity assays in nude mice were utilized to assess for the transforming capacity of the fusion transcript. siRNA constructs were utilized for the stably shut-down of the expression of the CYCLIN D1-TROP2 mRNA. Results: The chimeric mRNA transforms primary cells in vitro and induces aggressive tumor growth in vivo in cooperation with activated RAS. The CYCLIN D1-TROP2 mRNA is expressed by a large fraction of human ovarian, endometrial and gastro-intestinal tumors. The chimera is coexpressed with activated RAS in a subset of tumors, consistent with a cooperative transforming activity. The chimeric mRNA is a bicistronic transcript that independently translates wild type Cyclin D1 and Trop-2 proteins, i.e. it does not generate chimeric, oncogenic proteins. On the other hand, joining to the stable TROP2 mRNA leads to a higher CYCLIN D1 mRNA stability, with inappropriate persistence during the cell cycle and acquisition of transforming capacity. As essentially no normal tissues express the chimeric mRNA, we targeted it for destruction in cancer cells with stably expressed siRNA constructs. Specific targeting led to essential annnihilation of the CYCLIN D1-TROP2 mRNA, in the absence of off-target effects. Silencing of the chimeric mRNA blocked the growth of expressing breast cancer cells. Conclusions: Our findings demonstrate a novel, widespread oncogenic mechanism in human cancers, and open novel avenues for mRNA-targeted anti-cancer therapies. Acknowledgments This work was supported by the the Fondazione of the Cassa di Risparmio della Provincia di Chieti, the Association for the Application of Biotechnology in Oncology (ABO and ABO Project S.p.A., grant no. VE01D0019) and the Marie Curie Transfer of Knowledge Fellowship, contract number 014541.

No significant financial relationships to disclose.