bluuebunny/crossref_metadata_2025 huggingface dataset:
A clinical phase II study of combination Cisplatinum and Vinorelbine followed by Docetaxel as first-line chemotherapy in metastatic breast cancer
Authors: El-Saghir N. S. , Otrock Z. , Abdel Khalik Z. , Yassine H. , Khalifeh M. , Bitar N. , Charafeddine M. , Jalloul R. , Dandashi A. , Shamseddine A.
Published: March 2020

10683

Background: Many chemotherapeutic options exist for metastatic breast cancer (MBC) but there is no standard regimen. We tested a sequential combination regimen using Cisplatinum and Vinorelbine (PVn) followed by Docetaxel as first-line chemotherapy in a phase II clinical trial. This is the first study using a non-anthracycline sequential combination chemotherapy of PVn with Docetaxelin MBC. Methods: Thirty-five patients were enrolled. Cisplatin 80 mg/m2, which was given on day 1 and Vinorelbine 30 mg/m2 on days 1 and 8 q3 weeks for 4 cycles. After the 4th cycle, responding patients received Docetaxel 75 mg/m2 every 21 days for a maximum of 4 cycles. Patients were evaluated every two cycles and those who had no response were offered other therapy. Patients who showed progression after 2 cycles of PVn were offered Docetaxel but were considered off protocol. Three patients were excluded from analysis because of death unrelated to treatment. Results: After a median follow up of 14 months (range 1–36), 32 patients (91.4%) completed the study. Overall response rate was 53.1%. Complete remission was seen in 5 pts (15.6%), partial response in 12 patients (37.5%), stable disease in 6 patients (18.75%), and progressive disease in 9 patients (28.1%). 20 patients (62.5%) were alive at 12 months. Median time to disease progression was 8 months (range 1–24). At 24 months 37.5% (12 patients) were alive. Response rates to PVn were not significantly improved by sequential addition of Docetaxel. A total of 183 cycles were administered with a median of 6 cycles per patient. Delay of chemotherapy because of Grade II neutropenia occurred in 41/183 cycles (22.4%). Febrile neutropenia was observed in 4 patients (2.2%). Grade II anemia was observed in 40/183 cycles (21.8%) and Grade III in 24/183 cycles (13.1%). Grade II nephrotoxicity occurred in 12 cycles (6.5%) and Grade III vomiting was observed in 31/183 cycles (16.9%). No treatment-related mortality has been reported. Conclusions: Sequential PVn-Docetaxel is a feasible and effective non-anthracycline option as first-line chemotherapy in patients with MBC. More effective Docetaxel may be better used upfront and followed by PVn. This regimen has acceptable toxicity as well.

No significant financial relationships to disclose.
Pegfilgrastim in dose-dense, sequential adjuvant chemotherapy for patients with breast cancer (BC)
Authors: Stickeler E. , Földi M. , Kummle A. , Hinke A. , Hartmann P. C. , Woll J. , Watermann D. O. , Gitsch G.
Published: March 2020

10708

Background: Large randomized trials in the US and Europe have recently shown, that increased dose density of adjuvant chemotherapy leads to a relevant and significant prolongation of disease-free and overall survival in breast cancer. Dose density refers to the administration of drugs with a shortened intertreatment interval. G-CSF support is an essential requirement for increasing dose intensity. We explored the feasibility of pegylated filgrastim (Neulasta) in this setting. Methods: Patients (pts) up to the age of 60 with a confirmed histology of breast cancer and lymph node involvement were recruited into the study. A dose-dense chemotherapy, consisting of 3 x 4 sequential single drug cycles of epirubicin 90 mg/m2, paclitaxel 175 mg/m2, and cyclophosphamide 600 mg/m2 was planned on a two-weekly schedule (similar to Citron et al., J Clin Oncol, 21 (2003): 1431–1439). Pegfilgrastim was to be administered on day 2 of each cycle, 24 h after chemotherapy application. Results: Seventeen pts with a mean age of 49 years were enrolled into this feasibility study. 76% of pts had pN2–3 stage, 65% G2 and 35% G3 tumors, 71%/47% a positive estrogen/progesterone receptor status, respectively. All but one pt were HER2-negative. The full number of 12 cytotoxic courses could be administered in all but one patient due to an anaphylactic reaction against paclitaxel. A total of nine weeks of treatment delay was recorded in 6 of the remaining 16 patients (38%), resulting in an overall mean relative dose intensity of 95.9% (range 80– 100%). Pegfilgrastim was given during 85% of the 198 courses. Febrile or grade 4 neutropenia were not recorded, grade 3 neutropenia in one cycle (6%) without G-CSF support. Antibiotic treatment was necessary in only 18% of pts. Median peak WBC count during the complete treatment course was 28,150/μl, no values above 100,000/μl were recorded. Bone pain was reported in 4 patients (24%) and occurred in a total of 6 cycles (3%). Conclusions: Pegfilgrastim can be used safely and seems to achieve the required supportive efficiency in a dose dense sequential chemotherapy schedule for locally advanced BC.

[Table: see text]
Docetaxel and capecitabine as first-line chemotherapy in patients with advanced breast cancer
Authors: Gennatas C. , Michalaki V. , Psychogios J. , Gennatas S. , Kondi-Paphiti A. , Karvounis E. , Kairi E.
Published: March 2020

10734

Background: Capecitabine (C) and Docetaxel (D) have demonstrated synergy in both preclinical and clinical studies in metastatic breast cancer (MBC). The aim of the study was to evaluate the activity and tolerability of the combination of CD as a first -line therapy for patients with advanced breast cancer. Methods: Thirty- five patients have been enrolled in the study. Median age was 54 years (range 35–73). ECOG PS was of 0–2 (PS 0: 6 patients, PS 1: 5 patients, PS 2: 14 patients), All patients were Her-2 neu negative. Patients received Docetaxel 75 mg/m2 on day 1, with routine pre and post-medication with steroids, and Capecitabine 950 mg/m2 p.o. bid on days 1–14, every 3 weeks until disease progression or unacceptable toxicity. Results: A total of 233 cycles were given with a median of 7 (2–12). Of the 35 evaluable patients, 17 patients (48%) achieved partial response (PR) and 6 patients (17%) attained stable disease (SD). The median duration of response was 12 weeks and the median duration of SD was 20 weeks. The median time to progression (TTP) was 28 weeks. The median overall survival was 90 weeks. All patients were evaluable for toxicity. Toxicity was mainly hematological with G3 or 4 neutropenia in 7 patients (20%). Febrile neutropenia was not encountered. There was not significant GI toxicity. Conclusions: Combination chemotherapy with Capecitabine and Docetaxel shows promising efficacy as first- line therapy in advanced breast cancer with an acceptable toxicity profile.

No significant financial relationships to disclose.
Limited impact of tamoxifen following dose-intensive L-FAC multimodality therapy of breast cancer
Authors: Jabboury K. W. , Wong A. , Sexton K. , Rogers L. , King K. , Reilly C. , Thomas S. , Curtis P. , Mangini O. , Behar R.
Published: March 2020

10741

Background: Front-line dose-intensive L-FAC has demonstrated a favorable 5-year relapse free survival pattern (ASCO 2004 #739). Tamoxifen was given for 5 years to ER+ patients after L-FAC completion. We evaluated the impact of adding tamoxifen to L-FAC. By design, this pilot study excluded low-risk patients not candidates for chemotherapy. Methods: 109 breast cancer patients were enrolled (4 excluded due to treatment violations) from 6/1989 to 1/2003: 20 Stage I (S), 52 S-II, 22 S-III, for a total of 94 patients. 11 S-IV patients were excluded from survival analysis. Adverse tumor presentations included: ER- 49, PgR- 60, P53+ 24, non-diploid 39, histological grade III 37, CerbB2+ 33. L-FAC included 72 hour (h) iv infusion 400mg/m2/day (d) 5-fluorouracil (F) modulated by iv bolus 200mg/m2/d X3 leucovorin (L), concomitantly with 24h iv d1 600–1000mg/m2 cyclophosphamide (C), 48h iv d2 + d3 60mg/m2 doxorubicin (A). S-I and S-II were given 6 courses and 8 for S-III. Increasing A + C dose level and/or shortening treatment intervals < 3 weeks with growth factors provided intensification. 40 patients received tamoxifen. Results: At a median follow-up of 74 months (range 9–214), 73 (78%) are alive (1 with relapse). Relapse free survival was: S-I 95%, S-II 81%, S-III 78%. At average course intervals of 18 days, dose intensity A/C mg/m2/wk was 24.2 / 335.4 with evidence of WHO grade III/IV stomatitis in 43%, neutropenia 59%, cumulative thrombocytopenia 50%, hand-foot syndrome 32% of patients. Aside from delayed relapse associated with tamoxifen, relapse-free survival >82 months was similar with and without tamoxifen. No relapse was observed after >53 months in ER- tumors despite showing higher frequency of adverse tumor risk factors. Conclusion: The impact of adding tamoxifen appears quite limited in a patient population with adverse tumor presentation treated with dose-intensive L-FAC.

No significant financial relationships to disclose.
An intraoperative sentinel lymph node identification in breast cancer patients guided by near-infrared fluorescence imaging: Preliminary results
Authors: Tagaya N. , Yamazaki R. , Nakagawa A. , Mori S. , Hamada K. , Kubota K.
Published: March 2020

10776

Background: Recently, radioactive tracer, a vital dye, or a combination of both has been applied to detect intraoperative sentinel lymph nodes (SLN) in early breast cancers. In this study, we present a novel method in SLN identification that provides with high detection and low false-negative rates. Methods: This study enrolled 19 patients with a tumor less than 3 cm in diameter. Their mean age was 49.6 years. Preoperative TNM stage was I in 13 cases, IIa in 4, and IIb in 2, respectively. Initially the combination dye of indocyanine green and indigocarmine was injected subdermally in the areolar. Fluorescence imaging (photodynamic eye: Hamamatsu Photonics Co.) was obtained using a charge coupled device camera with a cut filter as the detector, and light emitting diodes at 760 nm as the light source. Subcutaneous lymphatic channels draining from the areola to the axilla or other directions were visible by fluorescence imagings immediately. After incising the axillary skin on the disappeared point of fluorescence image, SLN was then dissected under the guidance of fluorescence. Results: In all patient, lymphatic channels and SLN were successfully visualized. SLN was observed before skin incision in two patients. The number of fluorescence SLN ranged from 2 to 11 (mean: 5.5) and blue dyed SLN ranged from o to 6 (mean: 2.3). In the latter, SLN was not identified in one patient. Six patients had lymph node metastases pathologically. All of them were recognized by fluorescence imagings, however, in two patients LN with metastasis were not identified by a vital dye. There were no intra- or postoperative complications associated with SLN identification. Conclusions: This method is feasible and safe to detect SLN intraoperatively with less invasive, real-time observation and no requirement of training. We hope that this method will provide with high detection and low false-negative rates in SLN navigation surgery.

No significant financial relationships to disclose.
A phase II study of docetaxel-carboplatin as first line therapy in the patients with visceral metastatic breast cancer: A Bangladesh experience
Authors: Reza M. S. , Chowdhury Q. , Hai M. A. , Rahman M. A.
Published: March 2020

10792

Background: Metastatic breast cancer is heterogeneous and treatment decisions are influenced by multiple factors. Docetaxel remains as the standard chemotherapy agent in the management of metastatic breast cancer. We conducted a phase II study to examine the efficacy and tolerability of docetaxel with carboplatin in the treatment of visceral metastatic breast cancer patients. Methods: From July 2000 to December 2004, 32 patients with; histologically/cytologically proven, bidimensionally measurable visceral (pulmonary & hepatic) metastatic breast cancer, age 18–75 years with ECOG performance status 0–3, no prior chemotherapy, life expectancy > 3 months, adequate bone marrow, renal, hepatic and hematological values were enrolled. It was an open-labeled, non-randomized, single-centered and prospective study. The patients received docetaxel (75 mg/m2) and carboplatin AUC 5 on day 1 at an interval of 3 weeks. Outcome measures were response rates and tolerability was measured by adverse events and laboratory blood values. Results: This study consisted of 30 female and only 2 male patients. Median age was 55 years. 18 patients (56.25%) were presented with pulmonary metastases, where as there were 12 patients (66.67%) with single lung and the remaining 6 patients (33.34%) with bilateral lung metastases.14 patients (43.75%) had hepatic metastases. In total, 168 cycles chemotherapy were administered with a median of 5.25 cycles per patient, and 29/32 patients were evaluable for responses. The overall response was 62.07% with 8 complete responses and 10 partial responses. 6 patients (20.69%) had stable disease and only 5 patients (17.24%) had progressive disease. Grade 3 hematological toxicities were observed as follows: neutropenia (24%) and anemia (15.6%). Some non-hematological toxicities (including nausea, vomiting, fluid retention and peripheral neuropathy) in 15 patients (51.72%) were observed. No severe febrile neutropenia and no fatal events were observed. Conclusions: This phase II study supports the use of docetaxel-carboplatin combination in chemo naïve visceral metastatic breast cancer patients due to its very promising effects with well tolerated toxicities in Bangladeshi population.

No significant financial relationships to disclose.
Phase I analysis of systemic interferon alpha utilized with gliadel in adults with recurrent glioblastoma multiforme (GBM)
Authors: Lawson D. H. , Phuphanich S. , McKenzie E. , Greiner K. , Shires K. , Olson J. J.
Published: March 2020

11508

Background: Local therapy with Gliadel was found to increases median survival at recurrence from 23 to 31 weeks when compared to placebo wafers. Brain tumor specimens have been observed to have a 40–50% rate of deletion of the IFNα interferon a gene. Previous clinical studies have demonstrated response rates to IFN-α in the range of 0–41% in the treatment of recurrent primary malignant glioma, either alone, or in combination with other modalities. This study assess the safety and toxicity of Interferon α-2b (IFN-α) and 3.85% BCNU-permeated wafers (Gliadel®). Methods: This is a phase I dose escalation assessment of the toxicity of IFN-α utilized in conjunction with Gliadel® in patients with recurrent GBM, who failed previous radiation and chemotherapy. Ten patients were enrolled in this dose escalation trial. Three dose levels were studied were with the starting dosage of was IFN-α 3 Mu/m2 (n = 3), 6 Mu/m2 (n = 3) and 9 Mu/m2 (n = 4) subcutaneously injection 3 times a week for a total period of 8 weeks with the first dose being initiated 1 week following craniotomy and Gliadel placement. Results: There were 10 patients, 5 males and 5 females with a median age of 46 yrs (range 35–55). At re-operation, all histology revealed 10 GBM. At dose 3 Mu/m2, 2/3 pts developed grade 2 fatigue, myalgia and depression, but completed treatment with 1 PR (109 + wks) and 1 CR (91 + wks) and 1 PD (6 wks). Another patient was off study because of progressive disease (PD). At dose 6 Mu/m2, all 3 had PD with 2 pts having Grade 2 received a dose reduction because of diarrhea and 1 patient withdrawing early for PD finished only 1 cycle (4 wks). At dose 9 Mu/m2, 2 patients developed grade 3 toxicity fatigue/malaise and one patient completed therapy with dose reduction and but progressed, another patient stopped treatment after first 3 doses due to progression. There were overall response of 20% (1 PR and 1 CR) with duration of 109+ and 91+ wks. Clinical response with IFNα gene is being analyzed. Conclusions: This study defined MTD at 6 Mu/m2 with a DLT at 9 Mu/m2 and recommended a Phase II dose in this population. Since interestingly, the responses occurred at the lowest dose, suggesting a portion of the effect may be anti-angiogenic in nature.

No significant financial relationships to disclose.
Radiosurgery for pituitary adenomas: Evaluation of its efficay and safety
Authors: Salvajoli Sr. J. V. , Castro D. G. , Cecílio S. A. , Canteras M. M.
Published: March 2020

11515

Background: Pituitary adenomas account for approximately 15% of all primary brain tumors. Multimodality treatment is often necessary and options include medical management, microsurgery, radiotherapy and radiosurgery (RS). Recently, RS has gained acceptance as a complementary treatment since it has been associated with a shorter latency for its effects and lesser morbidity than that of radiotherapy. The objective of this study was to assess the effects of RS on the radiological and hormonal control and its toxicity in the treatment of pituitary adenomas. Methods: It was done a retrospective analysis of the first 26 consecutive patients with pituitary adenomas treated with RS at our institution between 1999 and 2004. RS was delivered with a multiheaded cobalt unit (Gamma Knife). The median radiation dose was 20 Gy defined to the 50% isodose line. Almost 20% of tumors were non-secretory. The remaining were prolactinomas (31%), adrenocorticotropic hormone-secreting (34%) and growth hormone-secreting tumors (15%). Hormonal control was defined as hormonal response (decline of more than 50% from the pre-RS levels) and hormonal normalization. Radiological control was defined as stasis and shrinkage of the tumor. Hypopituitarism and visual deficit were the morbidity outcomes. Hypopituitarism was defined as the initiation of any hormone replacement therapy and visual deficit as loss of visual acuity or visual field after RS. Results: The median follow-up was 40,8 months.Tumor growth was controlled in 96% of the cases and tumor shrinkage ocurred in 8% of the cases. Hormonal control was observed in 14 of 20 (70%) and hormonal normalization in 7 of 20 (35%) patients after RS, with a median latency period of 28,2 months. The 3-year actuarial rate of hormonal control and normalization were 51% and 47,6%, respectively, and the 5-year actuarial rate were 74% and 68,6%, respectively. There were no patients with visual deficit or hypopituitarism after RS. Conclusions: RS is an effective and safe therapeutic option in the management of selected patients with pituitary adenomas. The short latency of the radiation response, the highly acceptable radiological and hormonal control and absence of complications at this early follow-up are consistent with literature.

No significant financial relationships to disclose.
The influence of rest primary brain tumours on disease free and overall survival
Authors: Scepanovic D. D. , Bajic N. D.
Published: March 2020

11529

Background: We analysed the influence of rest primary brain tumours on disease free survival (DFS) and overall survival (OS). Methods: From 1998 till 2004, 80 patients (pts) with primary brain tumours were treated with postoperative radiotherapy (RT). The male–female ratio was 44 versus (vs) 36 pts (55% vs 45%). The median age was 50 years (yrs) (min 17, max 79 yrs). Performance status was 90–100% in 30 pts, 80–90% in 39 pts and 70–80% in 11 pts. Low grade astrocytoma was reported in 13 pts, anaplastic astrocytoma and glioblastoma in 49 pts, low grade oligodendroglioma in 2 pts, meningeoma in 9 pts and others in 7 pts. The postoperative RT dose was 50 Gy in 20 pts while 60 pts was treated with dose above 50 Gy, 2 Gy per day, 5 fractions per week, linear accelerator X rays, 6 MeV energy. We analysed two groups of pts (50 pts had rest tumours after surgery and RT within 6 months (mo) of operation and 30 pts without rest tumours). We analysed the influence of age, pts ambulatory, corticosteroids therapy during RT, pathohystological diagnoses (PH), RT doses and chemotherapy (CT) application (carmustine, 80 mg/m2, i.v. 1–3 days after 6 weeks of RT completion) on DFS and OS. Results: The median follow up time was 16 mo (min 6, max 96 mo). Thirty pts (37.5%) is still alive while 50 pts (62.5%) died. Cox regression model gave us data of influence on DFS in this way: cortocosteroids therapy during RT, CT application, RT dose and furthermore on OS: age, pts ambulatory, PH report and RT dose. Logistic regression model gave us data for rest tumours group of pts (50 pts) to be the greatest influence on survival patients ambulatory and corticosteroids therapy during RT. Between two groups of pts there is statistically significant difference on DFS and OS (p < 0.001). 1 yrs DFS was 30% and 2 yrs DFS was found in 26% of pts while 1 yrs OS was 44% and 2 yrs OS was 42% of pts. Conclusions: Pts with rest tumours especially anaplastic astrocytoma and glioblastoma have a shorter life span. However, RT dose does influence DFS and OS in pts with good performance status.

No significant financial relationships to disclose.
Potent cytotoxicity and inhibition of pan-cell cycle progression by Alchemix, a novel alkylating anthraquinone
Authors: Epenetos A. A. , Pors K. , Smith P. J. , Patterson L. H.
Published: March 2020

12030

Introduction: DNA topoisomerase II (topo II) is crucial to the maintenance of cancer cells in a proliferative state. DNA intercalation is a crucial part of topo II inhibition by DNA affinic anthraquinones. Potent cytotoxicity of anthraquinones, is related to their slow rate of dissociation from DNA, the kinetics of which favours long-term trapping of the topo-DNA complexes. Currently available DNA interacting agents at best promote a transient inhibition of topo II, since the topo-drug-DNA ternary complex is reversed by removal of the intracellular drug pool. Results: Alchemix cell cycle events: DNA content and Cyclin B1 expression were measured using flow cytometry and a p53 functional human osteosarcoma cell line (U2-OS) The results indicate: (ii) slow pan-cell cycle progression and mitotic commitment with a limited expression of G2 arrest, (iii) B1 cyclin tracking reveals that escape from Alchemix-induced cell cycle arrest in G2 is forcing some cells to enter polyploidy via an aberrant mitosis in keeping with topoisomerase II inhibition. Alchemix in vitro activity against the NCI human cell line panel including several drug resistant cancer cell lines had a mean IG50 = 49 nM. 11 of the 24 cell lines tested have an IG50 of <10 nM. Alchemix retains potent activity against chemotherapy resistant tumors including drug resistant ones. Conclusions: Alchemix possesses potent activity across a variety of different human tumors and significantly shows potent activity in cisplatin and anthracyline resistant human tumors Alchemix has pan-cell cycle effects. Multilevel targeting by Alchemix reduces the probability of evasion of cell cycle related pharmacodynamic responses. Results help explain the activity of Alchemix in both cisplatin and anthracycline resistant tumors in vitro and in vivo.

[Table: see text]
Study of brain and whole blood PK/PD of bortezomib in rat models
Authors: Yu L. J. , Riordan B. , Hatsis P. , Brockman A. , Daniels S. , Stagliano N. , Finklestein S. , Ren J. , Milton M. , Miwa G.
Published: March 2020

12036

Background: Bortezomib (Btz) is the first in class proteasome inhibitor and has been approved for treatment of multiple myeloma patients who have received at least 1 prior therapy. The potential for Btz to penetrate the CNS was examined in the rat under two conditions: intact blood brain barrier (BBB) and compromised BBB induced by middle cerebral artery occlusion (MCAO). Methods: Intact BBB: healthy rats received an iv bolus followed by a constant infusion of Btz to steady-state (SS). The blood and brain samples were collected for determination of concentration (Conc) of Btz (PK) and of 20S proteasome activity (PD). The brain samples were collected after a perfusion with saline. Inulin was included in the study in order to determine blood contamination in brain tissues. Compromised BBB: rats underwent MCAO surgery and 1 h later were administered Btz via an iv bolus of 0, 0.1, 0.2 or 0.35 mg/kg. The blood and brain samples were collected through 24 h postdose. Conc of Btz was determined by an LC/MS/MS method. The 20S proteasome activity was measured using an ex vivo assay. Results: 1) Intact BBB: at SS the mean blood Conc of Btz was 140 ng/mL, and proteasome activity in the blood was inhibited by ∼80% compared to the vehicle group (p < 0.0001). In contrast, the brain Conc of Btz was extremely low (∼3 ng/g) with the brain-to-blood ratio of ∼0.02. No difference was observed in brain proteasome activity between the vehicle and Btz-treated groups. 2)The MCAO rat: the PK/PD relationship in the blood was best described by a sigmoid Emax model with an EC50 of 110 ng/mL and gamma factor of 3.8. The model also suggests that there is no proteasome inhibition (PI) when the blood Conc is <40 ng/mL (no effective blood Conc, NOEBC). In the brain, the Cmax of Btz was 22.0 ng/g from the highest dose group, in contrast to the blood Cmax of 164 ng/mL. The increased exposure in the brain of a MCAO rat relative to a normal rat was anticipated as its BBB is impaired. However, the brain Concs were all below the NOEBC. No significant PI was observed in all brain tissues (P>0.1). Conclusion: Very poor brain penetration was observed for Btz in rats. Btz showed PI in whole blood but not in the brain either of normal or MCAO rats following administration of Btz.

[Table: see text]
Combining tumor destruction by electrochemotherapy and innate immunity by CpG-ODN: Toward a new combination treatment for melanoma with skin metastases
Authors: Roux S. , Al Sakere B. , Bernat C. , Opolon P. , Garbay J. , Billard V. , Zitvogel L. , Carpentier A. , Mir L. , Robert C.
Published: March 2020

12507

Background: Electrochemotherapy (ECT), consisting of electroporating cytotoxic agents (bleomycin or cisplatinum) in tumors, is effective in inducing destruction of cutaneous or subcutaneous tumors and can be used as a palliative treatment for patients with skin melanoma metastases. Our objective was to combine the antigen release induced by ECT with a potent and adapted stimulation of the innate immune system in order to induce a systemic anti-tumor response. Methods: The preclinical work was performed on murine models of skin tumors: fibrosarcoma (LPB) and melanoma (B16F10). We found that electrochemotherapy induced the recruitment of immune cells expressing CD11-c and Mac-1 in the first 48h after the treatment. By quantitative RT-PCR, we showed that this immune cell infiltrate was associated with an increase of TLR9 RNA expression. Therefore, we decided to combine ECT with intra-tumoral injection of TLR9 ligands: unmethylated CpG oligodeoxynucleotides (CpG-ODN). The distant and local antitumoral effect of this association (ECT + CpG-ODN) were tested in mice bearing a tumour on the two flanks (fibrosarcoma or melanoma). Animals were treated on the left flank only by a unique ECT course followed by intratumoral injection of CpG-ODN. Tumor growth rates were monitored on both treated (left) and non-treated (right) sides in order to assess direct and systemic antitumor effects of the association respectively. Experiments were also performed on nude mice, in order to investigate the role of lymphocytes in the systemic antitumor effect. Results: Compared to the separated treatments alone we found an increased local efficacy of the ECT-CpG-ODN, but, more importantly, we demonstrated a clear systemic effect of the combination on the controlateral tumors. In nude mice, no effect was observed in controlateral tumors suggesting a mechanism mediated by T lymphocytes.

No significant financial relationships to disclose.
Analysis of dosimetric and radiation safety results of seventeen patients treated with radioimmuno therapy using Iodine 131—Tositumomab for non-Hodgkin’s lymphoma
Authors: Nair M. , Mark R. , Anderson P. J. , Neumann T.
Published: March 2020

12513

Background: Radioimmunotherapy using radioactive Iodine -131 labeled radioimmuno conjugate called Tositumomab has been used in the treatment of non-Hodgkin’s lymphoma. Radiation dosimetry and safety aspects of this treatment modality are very critical for successful implementation of this treatment. Methods: Since year 2001, we have treated 17 patients using I-131-tositumomab. There were 11 female and 6 male patients at age range of 40 to 82 years. Patient specific dosimetry was performed on all the patents using a tracer dose of I-131. The whole body counts were performed after infusion of 5.0 mCi of I-131-tositumomab and whole body counts were taken at 0, 48 and 178 hours. The total body residence time (TBRT) for 37% of the activity to stay in the body was determined by graphical method. The activity in mCi, for delivering 65 cGy or 75 cGy whole body dose, was calculated based on the TBRT and patient’s weight. Based on the measured exposure rate, we have calculated the total effective dose equivalent (TEDE) to the public. The patients were released to home with radiation safety instructions if TEDE delivered to the public was less than 5.0 mGy. We have studied the platelet count recovery time for all the patients, following treatment. Results: The calculated TBRT ranged from 85 to 175 hours and the the mCi/Kgm varied from 1.4 to 0.6, related inverse proportion with TBRT. For both group of patients, treated with total body dose of 65 cGy and 75 cGy, the mCi/Kgm was the same, for TBRT values exceeding 100 hours. The TEDE to public varied from 1.02 to 3.22 mGy, while the exposure rate measured on the patient at 1 meter was less than the permissible value reported in the literature for safe release. Conclusion: The above results show that the patients can be treated as outpatient using I-131 -tositumomab with radiation safety restrictions lasted for one week. The radiation exposure to the public was less than the maximum permissible dose equivalent.

No significant financial relationships to disclose.
Predictive and prognostic impact of plasma vascular endothelial growth factor levels in non-small-cell lung cancer patients treated with gefitinib
Authors: Sone T. , Kasahara K. , Tanbo Y. , Tamori S. , Araya T. , Kimura H. , Yoshimoto A. , Fujimura M. , Nakao S. , Shibata K.
Published: March 2020

13030

Background: In non-small cell lung cancer (NSCLC), sensitivity to gefitinib is associated with activating mutations of the epidermal growth factor receptor (EGFR). Tumor samples obtained for diagnosis of NSCLC are limited and often unsuitable for analysis of mutations. Other biomarkers are thus needed. We previously reported that serum vascular endothelial growth factor (VEGF) levels were significantly lower in responders to gefitinib than non-responders. To assess levels of circulating VEGF as a predictive and prognostic marker of gefitinib treatment in NSCLC patients, we examined the associations between plasma VEGF levels before gefitinib treatment and clinical outcome. Methods: Eighty four NSCLC patients treated with gefitinib were enrolled into this investigation. Plasma VEGF levels were measured in blood samples before gefitinib administration. Patients were grouped according to VEGF level around a cut-off of 80.7 pg/ml, based on results from normal controls. Response to gefitinib was judged using RECIST guidelines. Time to progression (TTP) and overall survival (OS) following gefitinib treatment were calculated using Kaplan-Meier methods. Groups were compared using log-rank test. We evaluated the immunohistochemical expression of VEGF and EGFR mutations in tumor samples from 37 patients. Results: Response rate was significantly higher with low VEGF level than with high VEGF level (p = 0.0010). Multivariate analysis for response to gefitinib including sex, histology, smoking status, performance status and plasma VEGF level identified only low VEGF level as predictive of response to gefitinib. Low VEGF level was also correlated with prolonged median TTP (4.1 months vs. 1.1 months, p = 0.0081) and OS (11.1 months vs. 5.4 months, p = 0.0290). Multivariate analysis for survival revealed low VEGF level as associated with prolonged TTP (p = 0.0081) and OS (p = 0.0708). Plasma VEGF level was not associated with either VEGF expression or EGFR mutations of tumor tissue. Conclusions: Our results suggest that plasma VEGF levels before gefitinib treatment are predictive of response to gefitinib and prognostic of patients who receive gefitinib.

[Table: see text]
Phase I study of lenalidomide, a novel thalidomide analog, in patients with refractory metastatic cancer
Authors: Tohnya T. M. , Gulley J. , Arlen P. M. , Sparreboom A. , Venitz J. , Parker C. , Fedenko K. , Parnes H. , Figg W. D. , Dahut W. L.
Published: March 2020

13038

Background: Lenalidomide (L), CC5013, is a thalidomide (T) analog that has shown activity in multiple myeloma and myelodysplastic syndromes (MDS); including activity in pts refractory to T. Preclinical studies suggest L has more potent immunomodulatory and antiangiogenic activity than T. We have conducted a phase I clinical trial of L to determine the maximum-tolerated dose (MTD), characterize the side-effects, characterize pharmacokinetics (PK) in pts with solid tumors. Methods: Pts with refractory metastatic cancer were treated on a modified Fibonacci dose-escalation scheme with an oral daily dose of L. Therapy was continued until MTD or disease progression. Results: Forty-five pts have been enrolled (M/F: 37/8). Median age 68 yrs (range, 25–89 yrs). Tumor types include prostate cancer (36 pts), adrenal carcinoma (3 pt), renal cell carcinoma (1 pt), choleangiocarcinoma (1 pt), small intestine cancer (1 pt), colon cancer (2 pt), and melanoma (1 pt). Dose levels were: 5 mg (n = 3), 10 mg (n = 6), 15 mg (n = 3), 20 mg (n = 3 + 7), 25 mg (n = 6), 30 mg (n = 8), 35 mg (n = 6) and 40 mg (n = 3). Due to side effects the dosing schedule was modified from daily dosing to daily dosing for 21 out of 28 days. Therapy has been well tolerated with most frequent gr 1 and gr 2 toxicities include nausea (43%), myalgia (38%), pruritis/rash (54%), and fatigue (38%), neutropenia (30%) with gr 3 diarrhea (n = 1), hypotension (n = 1), pulmonary effusions (n = 1), thromboses (n = 2) and gr 4 neutropenia (n = 2), arrhythmias (n = 1), hemolysis (n = 1). Dose escalation continues. There were no differences observed between dose levels for either oral clearance values (p = 0.47) or the apparent volume of distribution (Vz) values (p = 0.23). Dose-normalized AUC(0-∞), dose-normalized peak concentrations (Cmax), or half-life (t1/2) did not vary between dose levels (p > 0.12). Conclusion: L has been well tolerated up to 35 mg/d (21 days on; 7 days off), doses higher than the recently FDA-approved doses of 5 and 10 mg/d. In this dose range L exhibits linear PK. Tolerability to myelosuppression the dose-limiting toxicity in pts with MDS may therefore be improved in pts without hematological malignancies.

No significant financial relationships to disclose.
A phase I study of the humanized anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) TheraCIM-h-R3 (nimotuzumab) in patients with advanced solid tumors
Authors: Brade A. M. , Siu L. , Oza A. M. , Southwood B. , De Borja M. , Pond G. R. , Sherman I. A. , Chen E.
Published: March 2020

13054

Background: Nimotuzumab is a humanized mAb against the extracellular ligand binding domain of EGFR. Although well tolerated when combined with radiotherapy in previous studies, the pharmacodynamics (PD) of nimotuzumab has not been elucidated. This phase I study was designed to evaluate the safety, tolerability and PD of nimotuzumab. Methods: Eligibility criteria included advanced solid tumors refractory to standard therapy and performance status of ECOG 0–2. Nimotuzumab was administered intravenously weekly × 6 and then every other week (6 weeks = 1 treatment cycle). Tumor and skin biopsies were obtained at baseline and after 2 weeks of treatment. Results: To date, 9 patients (7 m/2 f, median age 60, 7 colorectal cancer, ECOG 0:1:2 = 5:3:1, prior therapy 1:2:3+ = 1:3:5) have been treated on the first 2 dose levels (100 mg and 200 mg) for a total of 13 treatment cycles. The most common toxicities, mainly grade 1- 2, were lymphopenia (n = 8 patients), fatigue (n = 8), abnormal liver function tests (n = 7) and anemia (n = 6). Observed grade 3 toxicities include: pain (n = 3), hyponatremia (n = 2), elevated ALP (n = 2), fatigue (n = 1), hyperglycemia (n = 1) and hyperkalemia (n = 1). One patient at the first dose level experienced grade 3 fatigue, at least possibly attributable to nimotuzumab, and thus considered as a dose-limiting toxicity (DLT). No DLT were observed in the expanded cohort and dose level 2. No skin toxicities were observed. Stable disease was seen in 3 patients with colorectal cancer. PD from tumor and skin biopsies will be presented, and may clarify the reason for the lack of skin toxicity. Conclusions: Overall nimotuzumab was well tolerated, with disease stabilization observed in heavily pretreated patients. Accrual continues at dose level 3 (400 mg) with one further planned dose level (800 mg).

[Table: see text]
A novel, selective, orally active, potent small molecule inhibitor of Hsp90
Authors: Steed P. M. , Fadden P. , Hall S.
Published: March 2020

13067

Background: The preclinical and clinical data evaluating derivatives of the natural product geldanamycin, including 17-AAG and 17-DMAG, reveal that inhibition of the molecular chaperone HSP90 results in multiple anti-tumor effects. SNX-5422 and SNX-5542 are potent, novel, highly specific, water soluble and orally active small molecule inhibitors of Hsp90. Here we describe the preclinical efficacy and toxicity evaluation of these compounds. Methods: The PK profile of SNX-5422 and SNX-5542 was determined following oral and iv dosing in mice and rats. HT29 xenografts were performed oral doses of SNX-5542 on a schedule of Q2DX3,2 for 2 weeks or 17-DMAG on the previously reported regimen of bid×5,2 for 2 weeks, with tumor progression and body weight monitored. Plasma, tumor and other tissues were harvested for evaluation of HSP70 induction and levels of HSP90 client proteins. Rats were treated with varying oral doses on a schedule of Q2DX3,2 for two weeks. Clinical observations were noted and standard hematology and clinical chemistry parameters were monitored. Results: SNX-5542 exhibited 37% oral BA in rats and >75% in mice, with t½ >7h in each species. SNX-5542 was well tolerated in normal and tumor-bearing mice at 300 mg/m2 Q2DX3,2 for 2 weeks, 0.9% weight gain. 17-DMAG at 30 mg/m2 bid×5,2 for 2 weeks caused 3.3% body weight loss. At these doses, SNX-5542 exhibited 78% median tumor growth inhibition of HT29 tumors while 17-DMAG exhibited 23% inhibition. Mechanistic indicators of HSP90 inhibition correlated with efficacy across multiple dosing levels. At 120 mg/m2 Q2DX3,2 for 2 weeks SNX-5422 was well tolerated in rats, with no significant effect on any clinical, hematology or clinical chemistry parameter with the exception of a slight increase in blood urea nitrogen levels. Histopathological evaluation of liver, thymus, spleen and kidneys revealed no significant treatment-related effects. At 120 mg/m2 Q2DX3,2 for 13 days SNX-5422 does not exhibit any of the toxicities reported for 17-DMAG (bidX5,2 for 8 days at 24 mg/m2). Conclusions: SNX small-molecule HSP90 inhibitors have favorable pharmacokinetic profiles, oral bioavailability, tolerability and superior anti-tumor activity compared to the natural product derivative 17-DMAG.

[Table: see text]
Dose-finding study of fixed dose rate (FDR) infusion of gemcitabine in combination with bevacizumab and escalating doses of irinotecan in patients with advanced gastrointestinal (GI) tumors
Authors: Chopitea A. , Rodríguez J. , Viúdez A. , Viteri S. , De La Cámara J. , Reyna C. , Olier C. , Aramendía J. M. , García-Foncillas J.
Published: March 2020

13068

Background: Gemcitabine (GMB), Bevacizumab and Irinotecan (CPT-11) are active agents in GI tumors with preclinical evidence of synergism. The purpose of this study was to assess the maximum tolerated dose (MTD) of FDR GMB, Bevacizumab and CPT-11 in patients (pts) with advanced GI malignancies. Preliminary evidence of antitumor activity was also evaluated. Methods: A biweekly schedule of FDR GMB at a dose of 1000 mg/m2, Bevacizumab 5 mg/kg and CPT-11 (100–160 mg/m2 with a 10 mg/m2 increase in each cohort level) was analysed. The dose of CPT-11 was escalated in cohorts of three pts until the MTD was defined. Results: Thirty eligible pts with GI tumors were included (oesophagus: 2; gastroesophagic junction: 1; gastric: 2; pancreas: 2; colon: 17; rectum: 6) The median age was 60 years. ECOG status was 0–1 in 70% of pts. Male/female ratio was 21/9. Twenty-nine pts had received prior chemotherapy. The median number of cycles administered was six. Two of three pts at a CPT-11 dose of 160mg/m2 had grade 3 asthenia that required hospitalization. Recommended dose was thus established at CPT-11 dose of 150 mg/m2. Nine additional pts were included in this cohort and no further toxicity was observed. Antitumor activity was seen in 13 pts, with 3 complete responses and 10 partial responses. Conclusions: The recommended dose for phase II studies is CPT-11 150 mg/m2, GMB 1000 mg/m2 in FDR infusion and Bevacizumab 5 mg/kg on a biweekly schedule. Overall, this is a feasible regimen with a promising activity.

No significant financial relationships to disclose.
1249G>A polymorphism of ABCC2 (MRP2) is associated with altered gene expression in human liver
Authors: Kroetz D. L. , Liu W. , Nguyen T. D. , Zwecker B. M. , Ramirez J. , Innocenti F. , Ratain M. J.
Published: March 2020

13072

Background: MRP2, encoded by ABCC2, is an ATP-binding cassette transporter that plays a critical role in the biliary elimination of various drugs and xenobiotics. Although SNPs in this gene have been identified and reported, their functions are not fully understood. T he purpose of this study was to evaluate the effect of polymorphisms/haplotypes of the ABCC2 gene on its mRNA expression in human liver. Methods: Two hundred human liver samples were genotyped for the following polymorphisms: −1549G>A, −1019A>G, −24C>T, 1249G>A (V417I), −34T>C (intron 27) and 3972C>T. Haplotypes and diplotypes were predicted and assigned to each individual. Haplotype-specific expression was then tested using 3972C>T and 1249G>A as markers. Heterozygous Caucasian samples for 3972C>T and 1249G>A were selected and the two SNPs were genotyped in the PCR and/or RT-PCR products from both DNA and the corresponding mRNA. The minisequencing-based SNaPshot method was used to genotype and quantify the expression level of each allele. The relative expression of both alleles in the mRNA was normalized to that in the DNA. Results: There is no haplotype-specific expression discriminated by the 3972C>T polymorphism. However, when using 1249G>A as a marker, the haplotypes containing the 1249A allele had significantly higher mRNA levels when compared with haplotypes containing the 1249G allele (one sample t test, p < 0.001, n = 37). Conclusions: The 1249G>A substitution in the ABCC2 gene may be associated with gene expression in human liver. Significant variability of the relative expression of ABCC2 in the population suggests that other functional polymorphisms and environmental factors may also be involved in the regulation of ABCC2 expression.

No significant financial relationships to disclose.
A dose finding study with erlotinib in combination to irinotecan and capecitabine in metastatic colorectal cancer (mCRC) patients
Authors: Di Bartolomeo M. , Bajetta E. , Buzzoni R. , Ferrario E. , Mariani L. , Gevorgyan A. , Dotti K. , Longarini R. , Platania M. , Canova S.
Published: March 2020

13075

Background: Erlotinib is an oral selective and reversible small molecule inhibitor with specificy for the EGFR/HER1. This study evaluated the maximum tolerated dose and the dose limiting toxicity (DLT) of erlotinib when combined to irinotecan and capecitabine. Secondary objectives included the safety profile and the response rate of the combination. Methods: Twenty-two pts (median age 57 yrs, range: 39–69; M/F:12/10) with mCRC refractory to first-line therapy (oxaliplatin-combinations) were accrued. Five dose level combinations with irinotecan (from 180 to 240 mg/m2, day 1, q21), capecitabine (1500 to 2400 mg/m2/d, days 2–15 q21) and erlotinib (50 to 150 mg/d., continuously until progression) were planned. Cycles were repeated every 3 weeks, maximum of 6–8 cycles. Tumor assessments (RECIST criteria) performed every 3 cycles. Maximum tolerated dose was defined as the highest dose where the toxicity rate does not exceed the 30% target level. Patients were enrolled in cohorts of three, and evaluated for first cycle acute toxicity. Results: Three pts entered the first dose group (no DLT), six the second (1 DLT; G4 neutropenic fever), six the third dose group (2 DLT; G3 diarrhea, G4 neutropenic fever), and one (protocol deviation in the dose escalation scheme) the fourth dose group (1 DLT; G3 diarrhea and vomiting). Cutaneous rash and mucositis G3 (no DLT), were documented in one pt (dose group 2). To confirm these results, six pts were additionally accrued in dose groups 2 and 3 showing no DLT. Among twenty evaluable pts, two had an objective response, 15 showed disease stabilization and completed the 6-cycle treatment, 3 had disease progression. Conclusions: Erlotinib at a dose of 100 mg/d, combined with irinotecan 240 mg/m2 and capecitabine 1500 mg/m2/d, (as correspond to dose group 3) has an acceptable safety profile and appears suitable for further investigation. Editorial Assistance by the Scientific Service of the I.T.M.O. group.

No significant financial relationships to disclose.
A phase II, multi-center study of a new non-cytotoxic A3 adenosine receptor agonist CF101, dose-finding (randomized blinded) in patients (pts) with refractory metastatic colorectal cancer
Authors: Stemmer S. , Shani A. , Klein B. , Silverman M. , Lorber I. , Farbstein M. , Shmueli E. , Figer A.
Published: March 2020

13082

Background: The A3 adenosine Gi protein-coupled receptor is highly expressed in malignant compared to normal cells. Activating the A3 adenosine receptor (A3AR) with the highly selective non-cytotoxic agonist, CF101 (IB-MECA), inhibit of colon, prostate, melanoma, pancreatic and hepatocellular cancer growth in experimental animal models, via down-regulation of the Wnt and NF-κB signal transduction pathways. Oral CF101 has been shown to inhibit colon, prostate, melanoma, pancreatic and hepatocellular cancer growth in experimental animal models. Methods: A phase II dose-finding, randomized, blinded study of oral CF101 (0.1, 1& 4 mg PO BID), was conducted to define activity and safety in heavily pre-treated metastatic colorectal cancer pts. From 6/1/2003–7/4/2004, 70 pts, median age 62 with measurable colorectal cancer, PS ≤2 were enrolled, 21 pts progressed after irinotecan and 49 pts after both irinotecan and oxaliplatin-based regimens. Results: The median time on treatment was 10.3 weeks. No objective response was observed; however, SD for 8 wks duration was achieved in 24 pts (34%), for 16 weeks in 8 pts (11%) and 2 pts were treated for more than 24 weeks. The median time to treatment progression was 72 days and for overall survival was 254 days without any significant difference among the 3 trial doses [8 survivors till today]. There were no obvious treatment related serious adverse events. Conclusions: The final results of the study show that CF101 is well tolerated and may stabilize disease for at least 2 months in 35% of the pts. The median survival time (8 months) compared with other targeted therapy investigated lately is encouraging. Combining CF101 with chemotherapy may be beneficial in the treatment of metastatic colorectal cancer.

No significant financial relationships to disclose.