bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase I single dose escalation trial of ch806 in patients with advanced tumors expressing the 806 antigen
Authors: Scott A. M. , Gill S. S. , Lee F. , Liu Z. , Skrinos E. , Murone C. , Saunder T. , Chappell B. , Papenfuss A. , Old L. J.
Published: March 2020

13028

Background: Ch806 is a chimeric antibody (mAb) that binds to a unique epitope only exposed on a transitional untethered form of the Epidermal Growth Factor Receptor (EGFR), and the de2–7 EGFR, but not exposed on wtEGFR. Immunohistochemistry (IHC) studies have demonstrated that the 806 antigen is not detected in any normal human tissue, but is highly expressed in a broad range of epithelial cancers, and in gliomas. Preclinial studies have shown that ch806 has potent anti-tumor activity in xenograft models expressing amplified EGFR or de2–7 EGFR, and is internalized into tumor cells. Methods: The primary objective of this first in man study was to determine the toxicity of increasing single doses of c806. The secondary objectives were to characterize the biodistribution, pharmacokinetics (pK) and tumor uptake of In-111 ch806, to determine human antibody responses (HACA), and to document tumour responses to ch806. Patients with advanced or metastatic disease whose tumors expressed the 806 antigen by IHC received a single infusion of 111In-labelled ch806. 111In-ch806 was administered as a single, 1 hour infusion at dose levels of of 5 mg/m2, 10 mg/m2, 20 mg/m2 and 40 mg/m2. Results: 7 patients (1 at 5mg/m2 dose and 2 each at 10, 20 and 40 mg/m2 doses) have been entered into the study: squamous cell lung (2), colorectal (1), squamous cell anus (1), mesothelioma (1), squamous cell larynx (1) and squamous cell skin with lung metastasis (1). Patients had a median age 66 (range 49–75) and median of 1.5 (range 0–4) prior oncological treatment regimens. No significant toxicities were observed. The biodistribution of ch806 showed excellent targeting of tumour sites in all patients. There was no evidence of any normal tissue uptake of ch806. PK analysis showed comparable Cl at all dose levels (mean ± SD: 34.6 ± 5.0 mL/hr), no normal tissue saturable compartment, and dose dependent Cmax and AUC. HACA analysis is ongoing. One patient had a reduction in size of cervical lymphadenopathy on study, and progressive pulmonary disease at study completion. There was 1 patient with SD and 6 with PD at study completion. Conclusion: ch806 was very well tolerated and targeted a wide range of tumour types with no normal tissue uptake, which is markedly different to other mAbs that target wtEGFR.

No significant financial relationships to disclose.
Phase-1 trial of ZIO-101, a novel organic arsenic in patients with advanced cancers
Authors: Camacho L. H. , Hong D. S. , Gutierrez C. , Vertovsek S. , Tannir N. , Parker C. A. , Purdom M. A. , Lewis J. , Gale R. P. , Kurzrock R.
Published: March 2020

13041

Background: Arsenics are potent anti-cancer drugs. Organic arsenics are much less toxic than inorganic arsenics (like arsenic trioxide [As2O3]). We synthesized ZIO-101 (S-dimethylarsino-glutathione) by conjugating dimethylarsenic to glutathione. ZIO-101 is active against multiple cancers in in vitro tests and animals. In mice, the LD50 of ZIO-101 is about 50-fold higher than As2O3. At equimolar extracellular arsenic concentrations of ZIO-101 and As2O3, intracellular arsenic concentrations are about 15-fold higher with ZIO-101 than As2O3. In cancer cells this results in dramatically more mitochondrial damage and more apoptosis induction. Preclinical data suggest ZIO-101 may induce apoptosis by different mechanisms than As2O3 and can kill As2O3-resistant cancer cells. Methods: A phase-1 study evaluating the safety and pharmacokinetic profile of ZIO-101 in pts with advanced cancers. 18 patients enrolled in 5 cohorts. Mean Age 63 (42–79). Starting dose was 78 mg/m2/d IV for 5 days every month with 40% dose increases. Results: Thirty-three courses of ZIO-101 have been delivered. Therapy with ZIO-101 was safe. Toxicities ≥ grade-2 include Fatigue (N = 4), Vomiting (N = 4), and Anorexia (N = 2). One patient with rapidly progressing metastatic renal cell cancer had complete resolution of a brain metastasis and stable disease elsewhere (beyond 6 months). Pharmacokinetic (PK) studies at 214 mg/m2/d showed a tmax = 1 h (no SD), Cmax = 685 μg/mL (SD ± 130 μg/mL), t1/2 = 13.9 h (SD ± 0.3 h) and AUC0-∞ = 14.9 μg.h/mL (SD ± 2.6μg.h/mL). Conclusions: Clinical and PK data show ZIO-101 is safe at doses that result in blood levels that have substantial anti-cancer activity at in vivo concentrations. There is early evidence of clinical activity. Dose-escalation continues. Results on subsequent dose-levels will be presented.

[Table: see text]
Imatinib for hepatocellular cancer (HCC)—Focus on PK/PD modelling and liver function
Authors: Treiber G. , Wex T. , Eberhard S. , Hosius C. , Malfertheiner P.
Published: March 2020

13088

Background: Imatinib represents standard medical care for treatment of gastrointestinal stroma tumors (GIST) and chronic myeloic leucemia (CML). Indications for other malignancies are evolving, especially in the context of antiangiogenesis, mediated by the inhibition of platelet-derived growth factor (PDGF). Liver metastasis occurs often in GIST patients, usually not affecting liver function. No reliable data about imatinib metabolisation under conditions of true hepatic impairment are available. Methods: Phase-II trial, involving 10 patients with hepatocellular cancer (HCC) as a model disease, we attempted to (1) study short-term changes in serum biomarkers following treatment with octreotide (targeting VEGF) alone or octreotide added by imatinib (400 mg/d, additionally targeting PDGF); (2) to explore a potentially decreased metabolisation of imatinib because of hepatic impairment; and (3) to correlate pharmakokinetic and pharmacodynamic findings (PK/PD modelling). Results: Compared to literature results, PK parameters for imatinib are similiar to patients with normal liver function, however, the main active metabolite N-DMI shows a more prolonged half-life. The AUC of N-DMI depends on liver function as expressed by CPT score (r= −0.67) and serum bilirubine (r= −0.70), p<0.05 each. During short-termed imatinib treatment (4 weeks), plasma PDGF significantly decreased at week 2 compared to controls only receiving octreotide treatment. VEGF secretion was unaffected by imatinib. The AUC of N-DMI could be attributed to the pharmacodynamic effect of PDGF inhibition (r= −0,679 [−0.917 to −0.0868], p = 0.031). Conclusions: In HCC patients with different stages of liver cirrhosis, the metabolisation of N-DMI, but not imatinib, is impaired. PK of imatinib is closely correlated to PDGF inhibition. Whether this translates into antiangiogenesis and tumor regression must be awaited by long term clinical studies.

[Table: see text]

No significant financial relationships to disclose.
A phase 1 study of oral navelbine in patients with advanced solid tumors
Authors: Rajdev L. , Dai Q. , Goldberg G. , Hoschander S. , Baker C. , Miller K. , Sparano J. A.
Published: March 2020

13095

Background: Anti-tubulin agents have potent anti-angiogenic effects (Blood 94: 4143–4155, 1999). Recent evidence suggests that “metronomic” drug schedules employing doses sufficient to inhibit angiogenesis yet low enough to allow more frequent administration may enhance the effectiveness of antiangiogenic therapy (J Clin Invest 105: 1045–7, 2000). We therefore performed a phase I trial to determine feasibility and safety of administering and oral navelbine (ON) preparation that is 40% bioavailable thrice weekly (TIW). Methods: ON was given TIW (eg, Monday-Wednesday-Friday) using the dosing escalation schema outlined below with 3–6 patients/cohort. Dose limiting toxicity (DLT) during cycle 1 was defined as a) neutrophil nadir < 500/uL, b) platelet nadir < 50,000/uL, c) febrile neutropenia, or d) grade 3–4 non-hematologic toxicity. One patient was not evaluable (NE) due to urosepsis unrelated to treatment. No patient had a DLT. The most common toxicities were grade 2 nausea (n = 1), dyspepsia (n = 1) and abdominal cramping (n = 2), and grade 3 neutropenia (N = 1). One patient with renal cell carcinoma had stable disease for 19 months; a second with prostate cancer had a greater than 50% PSA response that lasted 18 weeks. Results and Conclusions: The recommended phase II dose of ON is at least 50 mg TIW. Further dose escalation was not possible due to cessation of the drug supply by the manufacturer. Correlative studies of surrogate angiogenesis markers (urine VEGF and serum VCAM-1 and Tie2in serum by ELISA) are currently being analyzed and will be presented.

[Table: see text]

No significant financial relationships to disclose.
A phase 1 study of flavopiridol in combination with gemcitabine and irinotecan in patients with metastatic cancer
Authors: Rabinowitz I. , Verschraegen C. F. , Lee F. C. , Smith H. O. , Royce M.
Published: March 2020

13099

Background: Flavopiridol is a cyclin-dependent kinase (CDK) inhibitor. The major toxicities are secretory diarrhea and neutropenia for the 72- and 1-hour infusion schedules, respectively, fatigue, and thrombosis. Gemcitabine or irinotecan (SN-38) followed by flavopiridol at concentrations that correlate with CDK inhibition, produce sequence-dependent cytotoxic synergy with increase in apoptosis by 10–15-fold in all the cell lines tested. Both gemcitabine and irinotecan have broad activity in a number of solid tumors and may be synergistic with flavopiridol. Methods: Eligibility criteria included: patients (pts) with any advanced solid tumors; >18 years old; PS ≤ 2; life expectancy > 3 months; and normal kidney, liver, and marrow functions. Treatment consisted in gemcitabine 800 mg/m2 and irinotecan 80 mg/m2 on day 1 and flavopiridol, starting dose of 30 mg/m2 on day 2 with increment of 15 mg/m2 per dose level, repeated on days 8 and 9 for the first 6 patients, then on days 15 and 16 for the other patients (protocol was amended for inability to redose after one week). Results: Fifteen pts (12 women and 3 men) were enrolled. Characteristics were: Median age, 49 (33–77) years; Median PS 1; ethnicities, 6 whites, 3 native americans, 3 hispanics, and 3 others; Median number of prior chemotherapies, 2 (0–9). Six pts were treated on the first schedule at the first dose level, which caused 1 neutropenic sepsis and death, 1 grade 3 diarrhea, and 5 neutropenia preventing retreatment. On the q 2 week schedule, we have reached the second dose level. Side effects at flavopiridol 30 mg/m2 were all grade 1: nausea (3/3), fatigue (2/3), anorexia (1/3), and neuropathy (1/3). At 45 mg/m2 one heavily pretreated pt had DLT of diarrhea and fatigue. The other 5 pts had grade 2 fatigue (2/5), nausea (2/5), diarrhea (1/5), anorexia (1/5). Additional grade 1 side effects include thrombocytopenia, pitting edema, and pain. Response were seen a small cell tumor of the ovary, and a leiomyosarcoma of the uterus. Conclusions: The every two week dosing is well tolerated and the MTD has not yet been reached. Main side effects are consistent with known toxicity profile for irinotecan and gemcitabine. Mild pitting edema and sensory neuropathy have been noted in 2 patients each.

No significant financial relationships to disclose.
Effect of combination inhibition of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGF-R) on ovarian cancer cell lines
Authors: Kehoe S. M. , Ma C. , Rosales N. , Rao T. , Dupont J. , Spriggs D. R.
Published: March 2020

13112

Background: Bevacizumab, a VEGF inhibitor, and cetuximab, an EGF-R inhibitor, have shown promising results in the treatment of solid tumors. The combination of these two antibodies and combinations with platinum chemotherapy is of interest for the treatment of ovarian cancer. Our objective is evaluate the mechanism of action and to determine the direct effect on tumor proliferation, the role of antibody dependent cell cytotoxicity (ADCC) with immune effector cells and the outcome in nude mouse xenografts with antibody treatment combinations. Methods: Five ovarian cancer cell lines were studied; SKOV3, SKOV8, OVCAR3, A2780, and CaOV3. VEGF secretion levels were determined for each cell line by standard ELISA. EGF-R, VEGF-R and VEGF surface expression was determined by flow cytometry. Cytotoxicity alamar blue 96-well plate assays were performed and cells were plated and exposed to bevacizumab or cetuximab alone, in combination and with cisplatin. Standard 51chromium release assays were performed to determine if bevacizumab and cetuximab have a role in ADCC when combined with peripheral blood mononuclear cells (PBMC). Results: All ovarian cancer cell lines secreted VEGF ranging from 210 to 1,849 pg/ml. Flow cytometry studies demonstrated varying degrees of expression of VEGF-R and minimal surface expression of VEGF ligand. EGF-R was present on all cell lines. Five day alamar blue cytotoxicity assays using varying concentrations of single agent bevacizumab (0.1–10 μM) or single agent cetuximab (0.01–1.0 μM) had minimal to no cytotoxic effect on ovarian cancer cell lines. The IC50 for cisplatin in these cell lines was obtained and ranged from 1–5 μM and was not altered by the addition of antibodies. In 51chromium release assays, the combination of bevacizumab and cetuximab caused a trend toward increased SKOV3 cell lysis by PBMC. Conclusion: Bevacizumab or cetuximab alone or in combination with each other in vitro had minimal direct cytotoxic effect. ADCC may be a mechanism of cell lysis when these antibodies are combined with effector cells (PBMC) and further studies are underway. In vivo studies with nude mouse SKOV3 xenografts are being performed to evaluate the effect on combination antibody therapy on established tumors.

No significant financial relationships to disclose.
Pharmacokinetic study of paclitaxel and gefitinib in combination
Authors: Locatelli A. , Viganã L. , Cresta S. , Perotti A. , Capri G. , Grasselli G. , Gianni L.
Published: March 2020

13123

Background: Both gefitinib and paclitaxel are metabolized by CYP3A4, thus co-administration may result in a pharmacokinetic interaction (Miller V.A. et al. JCO 2003, 21:2094–2100). Paclitaxel is formulated in Cremophor EL (crEL), which also has the potential for pharmacokinetic interactions by either altering protein binding or inhibition of P-glycoprotein transporter systems (Gelderblom H. et al. EJC 2001, 37:1590–1598). Gefitinib is a high extraction ratio drug so changes in protein binding are not a concern, but inhibition of P-glycoprotein transporter systems could change gefitinib’s absorption profile. Methods: In a Phase II study, 17 patients (pts) with metastatic breast cancer received paclitaxel (100 mg/m2 on days 8, 15 q21) with gefitinib (250 mg daily, from day 1 to day 15). Blood samples were collected to measure plasma concentrations of gefitinib on days 7, 8, and 15 from six pts at pre-dose and at 3, 7 and 25 hours after gefitinib administration. The AUC at steady-state (AUCss) was calculated by the linear trapezoidal rule using WinNonlin and the minimum concentration at steady-state (Css, min) was taken directly from the data. Results: The effect of paclitaxel or crEL on the exposure to gefitinib was assessed by comparing the AUCss and Css,min on days 8 and 15 in the presence of paclitaxel to those on day 7 when gefitinib was alone. The geometric mean AUCss increased by 30 to 42% and Css,min by 28 to 58% in the presence of paclitaxel. Individual ratios of days 8 and 15 to day 7 also showed a trend to be greater than 1.0, further indicating an increase in exposure to gefitinib in the presence of paclitaxel. Conclusions: Steady state exposure to gefitinib increased by about 30 to 40% in the presence of paclitaxel. As the increase on day 15 was similar to that on day 8, the effect of paclitaxel appears to be transient, and would be unlikely to affect the safety profile of 250 mg gefitinib when in combination with paclitaxel compared to gefitinib monotherapy.

[Table: see text]
Survival outcome of metastatic adenocarcinoma patients after patient-tailored outpatient chemotherapy guided by fusion imaging
Authors: Uckun F. , Morar S. , Larson J. , Qazi S.
Published: March 2020

13145

Background: We treated 173 patients with metastatic Stage IV adenocarcinoma, including 65 patients with metastatic colorectal cancer (MCRC), 22 patients with metastatic pancreas cancer (MPC), and 86 patients with metastatic breast cancer (MBC) in an outpatient setting. The metastatic sites included liver (49% of patients), bone (39%), lung (36%), brain (16%), peritoneum (16%), lymph node (14%) and chest wall (8%). Methods: MCRC patients received multiple cycles of Xeloda-based empirical chemotherapy regimens: alone or in combination with Irinotecan, Oxaliplatin or Mitomycin. MPC patients were given cycles of Gemcitabine-based empirical chemotherapy regimens: alone or with Cisplatin, 5-FU or Xeloda. MBC patients received cycles of Taxol-based chemotherapy: alone or with Adriamycin, Carboplatin or Gemcitabine; Xeloda plus Taxotere or Vinorelbine; Gemcitabine plus Taxotere or Vinorelbine; and Adriamycin plus Taxotere. Anatomic imaging/fusion technology with combined anatomic and functional imaging (CT/MRI fused with whole body PET scans) plus serial cancer marker level measurements monitored response to therapy and in patients showing evidence of progression on a given regimen were switched to a different treatment regimen. Results: Kaplan Meier calculated median survival time for all 173 metastatic adenocarcinoma patients was 17 mo (95% CI 13–19 mo); for subgroups medians were 12 mo (9–16 mo), 16 (8–22 mo) and 22 mo (18–42 mo) for MCRC, MPC and MBC patients respectively. The probability of living at 1 yr after initiation of therapy was 61 ± 6% for all patients, 47 ± 6% for MCRC, 59 ± 10% for MPC and 72 ± 5% for MBC patients. Our results indicate that a significant portion of previously treated patients with MCRC, MPC and MBC with liver, lung, and/or brain metastases can achieve objective responses and long-term progression-free survival with an excellent quality of life on patient tailored outpatient treatments guided by fusion imaging. Conclusions: Fusion technology provides a powerful diagnostic tool for timely termination or modification of ineffective treatments. Empirical patient-tailored chemotherapy should be offered to metastatic adenocarcinoma patients as an alternative to the clinical trial and hospice options.

No significant financial relationships to disclose.
Nevirapine restores hormone sensitivity in undifferentiated androgen-refractory prostate carcinoma cells
Authors: Landriscina M. , Bagalà C. , Piscazzi A. , Quirino M. , Maiorano N. , Schinzari G. , Fabiano A. , Cassano A. , Barone C.
Published: March 2020

13149

Background: The majority of prostate carcinomas are hormone-dependent tumors and androgen deprivation is the mainstay of therapy for advanced prostate cancer. However, androgen deprivation is ineffective on intermediate androgen-independent cells that are responsible for the hormone-refractory prostate cancer progression. Furthermore, other signaling pathways - i.e. EGF - can provide additional molecular mechanisms contributing to androgen-independent tumor progression. Reverse transcriptase (RT) inhibitors represent differentiating agents able to induce a reprogramming of gene expression in several human tumor cell models. Indeed, nevirapine and efavirenz, two widely used RT inhibitors, block the activity of endogenous RT, a gene highly expressed in tumor cells. Methods: We evaluated the ability of nevirapine to antagonize tumor growth and induce hormone sensitivity in androgen-independent human prostate tumor PC-3 cells either in vitro or in vivo. Results: Nevirapine induced the expression of several molecular markers of an androgen-dependent phenotype, such androgen receptor (AR), PSA and K18 and a reduced expression of K5, a marker of the intermediate-cell phenotype. Indeed, nevirapine enhanced the ability of prostate tumor cells to up-regulate AR in response to dihidrotestosterone. Moreover, the pharmacological inhibition of RT resulted in a significant reprogramming of gene expression, characterized by down-regulation of the notch family receptors, the EGFR1, the VEGF receptor KDR, the FGF family receptors, as well as the angiogenic factors VEGF and FGF1. Interestingly, this exocrine differentiated phenotype correlated with a reversible inhibition of cell proliferation and migration in response to nevirapine. Furthermore, the treatment of mice xenografts of prostate carcinoma cells with efavirenz and nevirapine resulted in the inhibition of tumor growth and in a reduced tumorigenic potential of cells. Conclusions: These findings suggest that RT inhibition is able to convert the androgen-independent intermediate-cell phenotype into an androgen-dependent exocrine luminal phenotype and support the need for clinical trials to test the ability of RT inhibitors and LH-RH analogs in androgen-independent prostate tumors.

No significant financial relationships to disclose.
Fulvestrant in heavily pre-treated breast cancer patients—Single institution experience
Authors: Schornagel J. H. , Helgason H. H. , Rodenhuis S. , Schellens J. H.
Published: March 2020

13157

Background: Fulvestrant is a selective estrogen and progesterone receptor down regulator with equivalent efficacy, i.e. RR, TTP and OS, in comparison to anastrozole in the 1st and 2nd line of hormonal treatment in women with advanced breast cancer. Methods: We retrospectively evaluated all patients with advanced breast cancer who were treated with fulvestrant between 06/2003 and 08/2005 in our institution. Response was evaluated according to the RECIST criteria in case of measurable disease but with bone scintigraphy (new bone metastasis) and/or change in CA 15.3 in case of evaluable disease. Results: In total 32 patients (20 with measurable and 12 with evaluable disease) with advanced breast cancer were identified. Median age was 50 (range: 24 - 72) years, 25 (78%) patients had bone/soft tissue involvement, 17 (53%) had visceral metastases and 1 had CNS metastases. All had received prior hormonal treatments; fulvestrant was the 3rd, 4th or higher line of hormonal treatment in 26 (81%) and 20 (63%) patients, respectively. The preceding hormonal treatments mostly included tamoxifen, non-steroidal aromatase inhibitors, steroidal aromatase inhibitors and megestrole acetate, but also ovarian ablation and aminoglutethimide. In total 20 (63%) patients had received prior adjuvant or palliative chemotherapy, 13 (41%) had received 2≥ and 5 patients (16%) had received 4≥ lines of chemotherapy. The chemotherapy contained an anthracycline, a taxane or capecitabine, but also vinorelbine, gemcitabine or high dose chemotherapy. In total 139 administrations of fulvestrant (mean: 4.3; range 1 - 18) were given. Most patients received 3 - 6 administrations except two who received 17 and 18 administrations respectively. In this cohort of 32 patients no objective tumor response or clinical benefit was seen, except in 1 patient, previously treated with tamoxifen, who had stable disease for > 18 months. The patient receiving fulvestrant for 17 months was slowly progressive during treatment. Fulvestrant was well tolerated without treatment discontinuation because of toxicity. Conclusion: Fulvestrant was not effective in our small cohort of heavily pre-treated breast cancer patients and may not be a good treatment option after 3rd or higher line of hormonal treatment or chemotherapy.

No significant financial relationships to disclose.
Molecular and immunologycal basis of a novel therapeutic formulation: Oligoelements Zn, Se and Mn plus Lachesis Muta venom (O-LM)
Authors: Crescenti E. J. , Croci M. , Cremaschi G. , Genaro A. , Mohamad N. , Sambuco L. , Medina V. , Bergoc R. , Rivera E. S.
Published: March 2020

13158

Background: We have previously reported that O-LM inhibited malignant cell proliferation in vitro and in vivo, increasing survival in rodent tumor models. We also demonstrated a protective action of O-LM against undesirable effects of chemotherapy and ionizing radiation, enhancing their therapeutic action. Furthermore, O-LM applied to patients with advanced breast, colon and pancreatic cancer resulted in increased survival and better quality of life with no side effects. In this work we further investigated the mechanisms involved in O-LM therapeutic effect. Methods: Two groups of Nude mice, control and O-LM (Zn, Se, Mn 4μ g/ml each; L. Muta 4 ng/ml) treated (0.1 ml/day, sc) were inoculated with PANC-1 cells to evaluate tumor development. PCNA, P53, antioxidant enzymes, apoptosis, microvessels and immune cell markers were studied by immunohistochemistry. In control and O-LM treated BALB/c mice we determined in vitro responses to T and B selective mitogens. Results: O-LM treated tumors showed significant lower growing rate, smaller mass (3,77±0,95 vs 9,75±2,30 cm3) and an important peritumoral lymphoid infiltrate. Apoptotic cells and P53 expression were increased while PCNA was negative and microvessels counts were lower than controls. O-LM produced a 3-fold increase in Superoxide Dismutase activity. The infiltrates showed an important number of CD11 bearing cells and B220 positive but CD3 and CD19 negative cells, suggesting the presence of NK cells. In BALB/c mice T selective mitogen Con A, but not B selective mitogens responses were enhanced, with a maximum after 60 days of O-LM treatment. A 4-fold increase in IFNγ release was observed in cell-free supernatants from lymph node culture stimulated with Con A obtained from 60-days treated mice. Conclusions: Present data demonstrate the capacity of O-LM to modulate free radical production, the expression of tumor markers and suggest an important up-regulation of innate and T-cell mediated immunity induced by in vivo treatment with O-LM. These results reinforce the hypothesis that the effective therapeutic action of O-LM is based on its ability of targeting simultaneously multiple pathways involved in cancer development with the additional advantage of the total absence of adverse effects.

No significant financial relationships to disclose.
Activity of trastuzumab-based therapy beyond disease progression in heavily pretreated metastatic breast cancer patients—Single institution experience
Authors: Tokajuk P. , Czartoryska-Arlukowicz B. , Wojtukiewicz M. Z.
Published: March 2020

13159

Background: Benefits from continuing trastuzumab-based (TZB) therapy beyond disease progression in HER-2-overexpressing metastatic breast cancer (MBC) patients (pts) remain obscure. Methods: A retrospective analysis was undertaken to assess activity of TZB therapy for MBC pts treated in our institution from 2002 to 2005 outside clinical trials. Results: 27 pts were evaluated. Median age: 52 years (range, 33–62). 9 pts (33.3%) were premenopausal. Hormonal receptors status: 9 pts ER(+), 4 pts PgR (+), 2 unknown. HER-2 overexpression was determined by IHC staining (3+ score) in all pts. Metastases location: 18 pts soft tissues/bone, 18 pts visceral disease. Median number of metastatic sites: 2 (range: 1–4). 9 pts (33.3%) had metastases in < 2 locations. 16 pts (59.2%) received neo/adjuvant chemotherapy: 11 pts doxorubicin, 8 pts CMF, 2 pts docetaxel, 4 pts other. Median previous chemotherapy lines for advanced disease: 2 (range: 0–6). 16 pts received doxorubicin/epirubicin, 14 pts docetaxel, 13 pts vinorelbine as a part of advanced disease chemotherapy regimen. Trastuzumab was administered at standard doses and combined with docetaxel, vinorelbine, cisplatin, capecitabine, etoposide, gemcitabine or administered as monotherapy. Response for the first-line TZB therapy was as follows: CR 5/27 pts (18.5%); PR 10/27 pts (37%). Median TTP was 5.8 months (range: 0–22). 14/27 pts (51.8%) received a second-line TZB therapy beyond disease progression. Response for the second-line therapy: CR 2/14 pts (14.3%); PR 5/14 pts (35.7%). Median TTP was 5.1 months (range: 0–24). 6/14 pts received a third-line and subsequent lines (up to five lines) of TZB therapy. PR for subsequent lines of therapy was observed in 4 pts. Median survival has not been reached. Pts who received ≥2 of TZB regimens survived significantly longer than pts who had received only 1 regimen (P = 0,02 logrank). Pts with metastasis in 1 location survived significantly longer than pts with metastasis in ≥2 sites (P = 0,01 logrank). Conclusions: Trastuzumab-based therapy seems to be active in MBC pts beyond disease progression even in heavily pretreated population. Durable responses were observed in some cases.

No significant financial relationships to disclose.
Detection of seven polymorphisms associated with colorectal cancer therapeutic response and toxicity
Authors: Qu K. Z. , Ren Y. , Liu J. , Sferrozza A. , Bender R. A.
Published: March 2020

13160

Background: First-line therapy for metastatic colorectal cancer (CRC) is 5-fluorouracil/leucovorin in combination with oxaliplatin (ie, FOLFOX™) or irinotecan (ie, FOLFIRI). Optimizing this therapy for an individual patient, however, is complicated due to wide variability in drug response and potential for toxicity. Such variability may be due to functional genomic polymorphisms in the drug target gene or in the metabolizing or DNA repair enzyme genes. We report, herein, development and validation of 2 new assays that, together, detect 7 polymorphisms associated with CRC drug response and toxicity. Methods: The first assay (SNaPshot) simultaneously detects 4 polymorphisms by using primers targeting the ERCC1, XPD, GST-P1, and XRCC-1 genes, single nucleotide primer extension of PCR products, electrophoresis and fluorescent detection on an ABI PRISM® 3100 Genetic Analyzer, and data analysis using GeneMapper® software (Applied Biosystems, Inc.). The second assay (F-PCR) simultaneously detects 3 polymorphisms using paired primers targeting the TS and UGT1A1 genes. One primer per pair is labeled with a fluorescent tag, and electrophoresis, detection, and data analysis are performed as described for the SNaPshot assay. Results: Based on fragment size and color, the intra- and interassay precision for SnaPshot ranged from 0.04%-0.51% and 0.14%-0.59%, respectively, and for F-PCR from 0.02%-0.16% and 0.09%-0.29%, respectively. There was 100% concordance in the genotypes determined in 3 separate SNaPshot (n=44 samples) and F-PCR (n=32 samples) assays. Furthermore, there was 100% agreement between genotypes determined by the SNaPshot method and those determined by RFLP (n=10) and between genotypes determined by the F-PCR method and those determined by pyrosequencing (n=17). Conclusions: Our multiplex SNaPshot and F-PCR methods can accurately detect 7 polymorphisms associated with CRC drug response and toxicity. These multiplex PCRs should lead to improved precision and ease of interpretation relative to that of single PCR methods. These methods may help the clinician optimize CRC therapy for individual patients.

No significant financial relationships to disclose.
Phase I/II study of capecitabine plus irinotecan (XELIRI) in combination with bevacizumab as first-line therapy in metastatic colorectal cancer
Authors: Kocakova I. , Spelda S. , Kocak I. , Demlova R. , Simickova M. , Vyzula R.
Published: March 2020

13504

Background: First-line treatment of metastatic colorectal cancer (MCRC) is based on regimens combining oxaliplatin or irinotecan with intravenous 5-fluorouracil (5-FU) and leucovorin (FOLFOX or FOLFIRI/IFL). A few phase II studies of capecitabine with irinotecan (XELIRI) proved to be comparable to FOLFIRI. Methods: A phase I/II study was conducted to assess the efficacy and tolerability of XELIRI + bevacizumab in MCRC. Indication for the therapy: histologically confirmed colorectal adenocarcinoma, metastatic inoperable disease, no prior systematic therapy for metastases, performance status 0–1, normal hematological, biochemical parameters, no other malignity. Therapy consisted of capecitabine 1000mg/m2 bid on days 2–15 and intravenous irinotecan 250mg/m2 on day 1, bevacizumab 7.5mg/kg on day 1, q 21 days. The response was evaluated after 2 or 3 cycles by RECIST criteria. Results: From March 2005 to December 2005 14 patients (pts) 9 males, 5 females with median age 53 years (range 39–67) have been included. 9 pts were initially disseminated, 5 pts relapsed after adjuvant therapy. Liver metastases were in 12 pts, number of metastatic sites was from 1 to 4, median 2. The overall number of cycles was 96, range 2–13, median 7 cycles. 13 pts have been evaluable for response. The CR occurred in 1 (7%) patient, PR in 10 (77%) pts, SD in 2 pts. During therapy CEA and Ca19–9 declined in all pts. Pretreatment level of CEA: median 32 μg/l, range: 2.4 - 9 265 μg/l. CEA at the response evaluation: median 5.3 μg/l, range: 1.2 - 573 μg/l. Pretreatment level of Ca19–9: median 119,7 kU/l, range: 0 - 4 692. kU/l. Ca19–9 at the response evaluation: median 17.4 kU/l, range: 0–666 kU/l. The toxicity: epistaxis in 1 patient, proteinuria < 1 gram / day in 2 pts and granulocytopenia G3 in 1 patient. No other hematologic toxicity > G2 has occurred. The therapy has been continued in all pts so far with median time of therapy 6 months. The time to disease progression and overall survival has not been reached yet. Conclusions: Irinotecan / capecitabine + bevacizumab has shown high efficacy with response rate 84% and low toxicity. The regimen seems to be appropriate for using in further phase II studies.

No significant financial relationships to disclose.
Concurrent radiotherapy (RT) and chemotherapy (CT) with oxaliplatin as primary treatment of advanced rectal cancer: a phase II study
Authors: Alberti A. , Tomei F. , Miele E. , Pizzardi N. , Ramponi S. , De Paula U. , Gentile P. , Proietti F. , Marmiroli L. , De Quarto A.
Published: March 2020

13507

Background: Combined pre-operative RT and CT increase the possibility for conservative surgery in locally advanced rectal cancer. Most clinical trials show that responding patients could obtain a reduction of local relapse and an improvement of overall survival, especially when a complete pathological response is obtained (pCR 9–29%). The aim of our study was to determine the activity of RT concomitant to oxaliplatin (OHP) in combination with c.i. 5-fluorouracil (5FU). Methods: Primary endpoint was pCR. Sample size was defined according to Simon Two-Stage phase II design (planned sample size: 29 evaluable patients). From May 2002 to November 2005, 33 patients (15 males, 18 females) were enrolled: median age was 64 years (range 21–74); clinical stage was cT3/cT4 cN0 or cTany cN+ M0. In 24 patients rectal cancer was ≤ 5 cm from anal verge. Weekly OHP 60 mg/m2 was administered in combination with c.i. 5FU 225 mg/ m2 for 5 days per week. Twelve patients received conventional RT (CRT): 25 fractions with 1.8 Gy, total dose 50.4 Gy on the pelvis and a boost on tumor bed with 3 fractions of 1.8 Gy. 21 patients received hyperfractionated RT (HRT): 1.2 Gy b.i.d. for 5 days per week for 4 weeks and a concomitant boost on tumor bed with daily 3 Gy (total dose 54–56 Gy on tumor bed, 48–50 Gy on the pelvis). Patients underwent surgery after 6–8 weeks from the end of treatment. Results: All patients were evaluable for pathological response. Sphincter preservation was obtained in 30 patients (=90.9%), a clinical down-staging in 30 patients (=90.9%). Overall, 12 patients (=36.4%) experienced a pCR: 9 of 21 patients (=42.8%) who received HRT obtained a pCR; 3 of 12 patients (=25%) who received CRT showed a pCR. Treatment was well tolerated. No G3–4 toxicity was observed. Conclusions: The results of our study are promising in terms of sphincter preservation, clinical down-staging and pCR. Moreover in this trial patients who received HRT obtained an encouraging outcome.

No significant financial relationships to disclose.
Phase II study of S-1 plus irinotecan (SIR) in patients with advanced colorectal cancer
Authors: Goto A. , Yamada Y. , Shimada Y. , Shirao K. , Hamaguchi T. , Muro K. , Yasui H. , Kato K.
Published: March 2020

13508

Background: Infusional fluorouracil and leucovorin (5-FU/LV) plus irinotecan is one of the standard regimens for the treatment of metastatic colorectal cancer (MCRC). S-1, a combination of tegafur, 5-chloro-2,4-dihydroxypyridine, and oxonic acid, is an oral DPD inhibitory fluoropyrimidine shown to be very effective as first-line treatment for MCRC. The response rate with S-1 was 35–40% in patients with chemo-naïve MCRC. This study evaluated the efficacy and toxicity of S-1 plus irinotecan (SIR). Methods: Eligible patients had untreated MCRC as confirmed histologically, PS 0–1, adequate organ function, and provided written informed consent. First-line SIR was given in 3-week treatment cycles: intravenous irinotecan 150 mg/m2 (day 1) and oral S-1 40 mg/m2 twice daily for 14 days followed by 7 days of rest. Results: Forty-one patients were enrolled; 40 fulfilled all eligibility criteria, and 1 had double cancers. There were 28 men; median age 60 years (range, 23–74); ECOG PS 0/1, 35/6. The overall response rate was 63% (95%CI, 48–78%). Five patients had a CR, 20 a PR, 11 SD, and 2 PD. Median TTP was 8.0 months (range, 1.4–13.8 months); MST was not reached. The most frequent grade 3/4 toxicities included: neutropenia (17%), diarrhea (15%), and anorexia (12%). One patient had Grade 4 constipation. The relative dose intensity of irinotecan was 84%, and that of S-1 was 79%. Dose reduction of irinotecan was required in 41 of 327 administered cycles, and that of S-1 was required in 15 of 327. Conclusions: SIR is a highly active and convenient first-line therapy for MCRC, with an acceptable toxicity profile. S-1 has the potential to replace infusional 5-FU/LV plus irinotecan for MCRC.

No significant financial relationships to disclose.
Non-coding microRNA hsa-let-7g as a novel chemoresponse biomarker for S-1 in colon cancer
Authors: Nakajima G. , Uchida K. , Hayashi K. , Xi Y. , Takasaki K. , Ju J.
Published: March 2020

13513

Background: MicroRNAs (miRNAs) are small non-cording RNAs (∼ 22 nucleotide) that regulate gene expression by suppressing their target mRNAs at post-transcriptional level. Previous studies from our group have identified a number of dis-regulated miRNAs due to the loss of p53 tumor suppressor in cancer cell lines. As part of the efforts to further investigate the in vivo biological significance of these miRNAs, the expression of both hsa-let-7g and hsa-miR-200c were investigated using formalin-fixed paraffin embedded (FFPE) colon cancer specimens to evaluate the potential correlation with chemosensitivity and tumorigenesis. Methods: Forty-six patients with recurrent or residual colon cancer lesion assessable were treated with 5-FU based antimetabolite S-1. This includes twenty-one pair of tumor and normal samples. Total RNAs were isolated from these samples FFPE specimens (contains either > 90% normal or > 90% tumor tissue). cDNAs were synthesized using primers specific for hsa-let-7g, hsa-miR-200c and internal control 5S. The expression levels of each particular miRNAs were quantified using real time qRT-PCR analysis. The expression level of each miRNAs was quantified by measuring the difference of threshold cycle (CT) of candidate miRNAs and internal control 5S (Δ-CT). Results: The expression level of hsa-let-7g was significantly higher in tumor tissues compare to normal tissues (p=0.0026; Wilcoxon test). In the forty-six tumor tissues, the expression level of hsa-let-7g in disease response group (patients group of complete response, partial response and no change after chemotherapy) was significantly lower than the disease progression group (p=0.03; Mann-Whitney test). The expression of hsa-miR-200c was significantly over-expressed in tumor tissues compare to normal tissues (p=0.0001; Wilcoxon test). Although hsa-let-7g is strongly associated with patient’s response to S-1 treatment, it is not a prognostic factor for predicting survival. Conclusion: hsa-let-7g and hsa-miR-200c may be associated with tumorigenesis in colon cancer. In addition, hsa-let-7g may be a significant indicator for chemoresponse to S-1 based chemotherapy.

No significant financial relationships to disclose.
Combined modality therapy of locally advanced adenocarcinoma of the rectum: Update of a phase I trial of preoperative radiation (RT) with concurrent capecitabine (Cap) and irinotecan (Ir)
Authors: Mitchell E. P. , Anne P. , Goldstein S. , Isenberg G. , Fitzgerald J. , Palazzo J. , Hauck W. , Lavarino J. , Sanson J. , Curran W. J.
Published: March 2020

13547

Background: We previously reported the combination of preoperative radiation (RT) with concurrent Irinotecan and 5-FU in locally advanced rectal cancer, was well tolerated and had an excellent pathologic complete response rate (CR) of 25%, but with catheter related infections and thromboses as major toxicities (Proc Am Soc Clin Onc 22: 2003). With the potential benefits of capecitabine (Cap) and no need for an implanted catheter, a phase I study was initiated to determine the toxicity and maximum tolerated dose (MTD) of Cap with concurrent Ir and RT. Methods: Eligible patients (pts) had primary or recurrent Stage II or III rectal adenocarcinoma, without a history of prior RT or chemotherapy. The treatment regimen was as follows: external beam RT at 1.8Gy daily M-F, to a total dose of 50.4 or 54 Gy; Ir 50 mg/m2 IV, d 1, 8, 15, 22; dose escalating Cap starting at 825 mg/m2 PO divided in 2 doses, Q 12h. Surgical resection occurred at 6–10 weeks. Dose limiting toxicity is defined as Gr4 heme or non-heme Gr3. Results: A total of 16 pts have enrolled on the study, 10 male and 6 female;the median age was 57 (range 44–77). All are evaluable for toxicity. The Table reviews the maximum toxicities. Grade three diarrhea is the only dose-limiting toxicity to date. There has also been 3 pts with Gr 3 hematologic toxicity. There has been no Gr 4 toxicity. Patients are currently accruing on the 4th dose level of capecitabine. A total of 13 pts have completed the preoperative phase and three are currently on treatment. Eleven pts have had surgical resection. One pt refused surgery due to a biopsy proven CR to chemoradiation. One pt refused surgery and died of disease. Of the 11 pts undergoing surgical resection, there have been 3 pathologic CR. Conclusions: The preoperative combination of capecitabine, irinotecan and radiation in locally advanced rectal cancer pts is feasible and well tolerated. The study continues to accrue, and the MTD has not been achieved. [Table: see text]

[Table: see text]
A study for establishment of individualized chemotherapy for colorectal cancer using the area under the concentration curve (AUC) based on the collagen gel droplet embedded culture-drug sensitivity test (CD-DST)
Authors: Ochiai T. , Nishimura K. , Noguchi H. , Kitajima M. , Tsukada A. , Watanabe M. , Futagawa S. , Nagaoka I.
Published: March 2020

13560

Background: The drug sensitivity of tumor cells is one of the key issues to explore for individualized chemotherapy for cancer patients. We reported the 5-fluorouracil (5-FU) sensitivity of cancer cells from colorectal cancer (CRC) patients using the collagen gel droplet embedded culture-drug sensitivity test (CD-DST) under multiple drug concentrations and contact duration. We also reported that growth inhibition rate (IR) and area under the concentration curve (AUC) approximated to logarithmic curve in ASCO 2003 (#1283). The aim of this study was to evaluate the individual 50% inhibitory AUC (AUCIR50) and research the usefulness of individual AUCIR50 for establishment of individualized chemotherapy. Methods: Surgical specimen was obtained from resectable 53 CRC patients without any preoperative chemotherapy during 2002 to 2005. CD-DST was performed under nine different conditions: concentration of 5-FU tested: 0.2, 1 and 10μg/ml; duration of exposure: 3, 24 and 120 hours. After converting drug concentration and contact time to AUC and plotting against growth IR, individual correlation between AUC and growth IR was evaluated. The histogram of individual AUCIR50 was also evaluated. Results: The curve between AUC and growth IR approximated to logarithmic curve in all of the patients (R2=0.69–0.96). We could calculate the individual AUCIR50 in all of the patients (AUCIR50= 23.7–98796298.1μg*hr/ml). The histogram of the individual AUCIR50 (AUCIR50<2500μg*hr/ml) indicated CURT(X) pattern (SK=0.0076). Conclusions: We could obtain a position for each patient on the histogram of AUCIR50. We could also indicate the potential for 5-FU sensitivity to each patient. Some patients demonstrating low 5-FU sensitivity could not be recommended for 5-FU based chemotherapy, and non-5-FU chemotherapy should be explored for them. This study demonstrated that the individual AUCIR50 is useful to distinguish the individualized chemotherapy of colorectal cancer patients. Utilization of CD-DST will facilitate establishment of individualized chemotherapy for colorectal cancer.

No significant financial relationships to disclose.
Activity and tolerability of mitomycin-C (MMC) and chronomodulated capecitabine (C) in advanced colorecatal cancer (ACC) patients
Authors: Campanella C. , Vanni B. , Garufi C. , Torsello A. , Di Lauro L. , Pellicciotta M. , Terzoli E.
Published: March 2020

13563

Background: MMC plus continuous infusion (CI) 5-fluorouracil (5-FU) showed activity with acceptable toxicity profile in ACC patients (pts). Nocturnal infusion of 5-FU was shown to reduce hematological and gastrointestinal toxicity. Capecitabine (C) is an oral pro-drug converted to 5-FU which mimics 5-FU CI activity. C is effective as single drug and in combination, providing equivalent activity and efficacy. Aim of the study was to evaluate activity and tolerability of MMC plus C in ACC patients. Methods: fifty-one pts received MMC 7 mg/mq i.v on day 1 followed by C 2000 mg/mq /die for 14 days out of 21 days; 20% of C dose was given at 8:00 while 80% was given at 20:00; each course (c)was repeated q 6 weeks. Pts data: M/F 33/18; median age: 64 (41–88); WHO PS0: 36, 1: 11, ≥2 :2; metastatic sites: liver (35), lung (17), lymphonodes (9), peritoneum (8), other (14); no measurable disease 1; site: colon/rectum 40/11; previuos lines: 0 (17), 1(18), ≥2(16); 43% and 29% of patients had been previously treated by 5-FU with oxaliplatin or irinotecan. Results: Toxicity was evaluated in 45 out of 51 pts and in 94 courses. Grade 2–3 neutropenia occurred in 5 pts/8 c (10/6%), G2-G3 thrombocitopenia in 4 pts/8 c (8/6%). One pt (2%) experienced G3 anemia. G2–3 nausea and vomiting occurred in 5 pts/5 (10/5%), G2–3 diarrhea in 8 pts/12 c (15/13%) and only 1 pt experienced G4 diarrehea. Mucositis of grade 2 was observed in 3 pts/ (6%). G2–3 hand foot syndrome and G2–3 asthenia both occurred in 5 pts (10%). No differences in toxicity were observed between pre-treated and untreated pts. At this time of the study 45 out of 51 pts were evaluated for response: stable disease was observed in 16 pts (31%), partial response in 5, untreated, patients (10%), progression in 23 (45%). Median time to progression (TTP) was 6,0 months (3,0- 8,5 mo) for both groups. Conclusions: Chronomodulated administration of C plus MMC seems to have an excellent toxicity profile even in pre-treated population, with a TTP similar to more expensive treatments.

No significant financial relationships to disclose.