bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase I trial of PEGylated glutaminase (PEG-PGA) in combination with 6-diazo-5-oxo-L-norleucine (DON) in advanced, refractory, solid tumors
Authors: Mueller C. , Al-Batran S. , Jaeger E. , Bausch M. , Sethuraman N. , Unger C.
Published: March 2020

14040

Background: Tumor cells are avid glutamine consumers and highly dependent on extracellular glutamine supply. Based on a competitive mechanism, the effectiveness of the glutamine analogue DON is enhanced if the available pool of glutamine is significantly (below 10% of baseline) depleted by PEG-PGA. Methods: The study was designed to determine the maximal tolerable dose (MTD) of DON in combination with PEG-PGA. The patients received intravenous PEG-PGA 120 I.U./m2 in combination with DON twice weekly for six weeks followed by a tumor assessment according to RECIST. DON dose was escalated from 5 to 185 mg/m2 using modified Fibonacci design and traditional 3-patient cohorts. Results: Fifty-eight pts (23f/35m) received at least 1 drug administration and were evaluable for the analysis. Median age was 62 (range 43–79) and median Karnofsky PS was 90% (range 70%-100%). Median treatment duration was 29 days (range 1–106). Nausea and vomiting represented the most common non-hematological grade 3 toxicities, being observed in 6.9% and 10.3% of pts, respectively. Hematological side effects were G4 leuco- and neutropenia (1.7%) and G3 thrombocytopenia (1.7%). The treatment was very well tolerated with all other grade 3 or 4 toxicities affecting less than 5% of patients. Forty-six pts were evaluable for efficacy. Stable disease was observed in 20 (43.5%) pts, including MR (>10%) in 5 (10.8%) pts. The efficacy was dose depended. Conclusions: The combination of PEG-PGA and DON is active and has a favorable toxicity profile. The MTD is now investigated in a Phase IIa trial in patients with refractory colorectal, renal or non small cell lung cancer. The accrual will be finished by January 2007.

No significant financial relationships to disclose.
A phase 1 study of MORAb-009, a monoclonal antibody against mesothelin in pancreatic cancer, mesothelioma and ovarian adenocarcinoma
Authors: Armstrong D. K. , Laheru D. , Ma W. W. , Cohen S. J. , Phillips M. , Brahmer J. , Weil S. C. , Hassan R.
Published: March 2020

14041

Background: MORAb-009 is a monoclonal antibody that targets mesothelin, a cell surface adhesive protein overexpressed in pancreatic, ovarian, non-small cell lung carcinomas and mesothelioma and has minimal expression in normal tissue. The target is over-expressed by tumor cells. It was identified as one of the most prominent, differentially expressed cell surface antigens on pancreatic adenocarcinoma using SAGE of primary tumors vs. normal pancreatic tissue. In vitro studies show MORAb-009 to be effective in mediating cell killing by ADCC and inhibiting cell adhesion.. In xenograft models, MORAb-009 has single agent anti-tumor activity enhanced by the addition of chemotherapy. Toxicology studies show no toxicity in non-human primates and no significant binding to non-tumor tissues. Methods: Sequential cohorts of 3 patients received MORAb-009 intravenously on days 1, 8, 15 and 22 at doses of 12.5, 25, 50 and 100 mg/m2. Major inclusion criteria are the presence of a mesothelin-positive tumor with progression on primary therapy, acceptable organ function, ECOG PS 0–2, and measurable disease by CT. Safety pharmacology studies include chemistry, hematology, urinalysis and EKG. Tumors were re-imaged at day 35. Results: 11 patients have received MORAb-009 at doses up to 100 mg/m2. 6 patients had mesothelioma, 3 had pancreatic cancer and 2 had mesothelin-positive ovarian cancer. 4 patients exhibited grade 1 (3) or 2 (1) infusion reactions; no dose limiting toxicity was observed. A subject in the 50 mg/m2 cohort with pancreatic cancer who progressed on gemcitabine showed stable disease by CT and a drop in CA 19/9. Based on the response, this patient continues on extended MORAb-009 therapy. Enrollment to the final cohort of 200mgs/m2 is ongoing, as are pharmacokinetic and anti-MORAb-009 antibody analysis. Conclusion: MORAb-009, a monoclonal antibody against mesothelin is safe and well tolerated at doses up to 100 mg/m2. One subject with previously progressive pancreatic cancer had disease stabilization. In light of the positive preclinical data and safe clinical profile, this study supports further evaluation of the efficacy of MORAb-009 in mesothelin-positive tumors.

No significant financial relationships to disclose.
Molecular targeting of IGF-I receptor for human pancreatic cancer
Authors: Adachi Y. , Yamamoto H. , Imsumran A. , Wang Y. , Li R. , Min Y. , Arimura Y. , Lee C. , Shinomura Y. , Carbone D. P. , Imai K.
Published: March 2020

14051

Background: Pancreatic cancer is one of the worst prognostic diseases. Continuous tumor growth depends on the altered regulation of the cell cycle that is modulated by signals from growth factors and their receptors, including insulin-like growth factors (IGF) and IGF-I receptor (IGF-Ir). It have been reported that blockade of IGF-Ir can suppress tumorigenicity and induce regression of established tumors. Recently several approaches of targeting IGF-Ir have been reported, including monoclonal antibodies and tyrosine kinase inhibitors. Methods: To study the mechanism of this effect and develop potential targeted therapeutics, we have constructed truncated IGF-Irs that function as dominant negative inhibitor (IGF-Ir/dn) and short hairpin RNA for IGF-Ir (shIGF-Ir). Those were cloned into recombinant adenoviruses (ad-IGF-Ir/dn and ad-shIGF-Ir). The effects of these adenoviruses were studied in human pancreatic cancer cell lines, BxPC3, Panc1, and AsPC1. We assessed efficiency of IGF-Ir signaling blockade, the effect of the adenoviruses on cell growth, steady-state, radiation, and chemotherapy induced apoptosis, and in vivo therapeutic efficacy in xenografts. Results: The blockade for IGF-Ir suppressed tumorigenicity of cancer cells both in vitro and in vivo and increased the amount of steady-state apoptosis in cancer cells. IGF-Ir/dn effectively blocked both IGF-I and IGF-II signaling through Akt-1 and shIGF-Ir reduced both IGF-Ir expression and ligands inducing phosphorylaion. The blockade for IGF-Ir increased chemotherapy and radiation induced apoptosis in vitro and the combination therapy with chemotherapy was very effective against established tumors in mice. Conclusions: These data suggest that the blocking of IGF-Ir signals, by ad-IGF-Ir/dn or ad-shIGF-Ir, may be a useful therapeutic strategy for pancreatic cancers.

No significant financial relationships to disclose.
Safety and pharmacokinetics (PK) of AMG 706 in combination with panitumumab and gemcitabine-cisplatin in patients (pts) with advanced cancer
Authors: Crawford J. , Burris H. , Stephenson J. , Otterson G. , Stein M. , McGreivy J. , Sun Y. , Ingram M. , Yang L. , Schwartzberg L. S.
Published: March 2020

14057

Background: AMG 706 is an oral, investigational multikinase (MKI) inhibitor with antiangiogenic and direct antitumor activity that selectively targets VEGF, PDGF and Kit receptors. Methods: This is an ongoing phase 1b, open-label, dose-finding study of AMG 706 plus panitumumab and gemcitabine-cisplatin. Objectives are to establish the maximum tolerated dose and to assess safety, objective response and PK of AMG 706 with this regimen. Pts =18 yrs with advanced cancer, ECOG 0–1, =1 prior chemotherapy for advanced disease and no prior oral VEGFr MKIs or anti EGFR therapy, received panitumumab (9mg/kg IV day 1 of each 3-wk cycle) plus gemcitabine (1250mg/m2 IV days 1 and 8) and cisplatin (75mg/m2 IV day 1), and escalating doses of AMG 706 given continuously from day 1 of cycle 1. Assessments included dose-limiting toxicities (DLT; cycle 1), PK and tumor response (every 6–9 wks from wk 6). Results: As of Nov 2006, 36 pts (NSCLC n=19; pancreatic cancer n=4; other n=10; unknown primary n=3) were enrolled; 42% had prior chemotherapy. There was 1 DLT: pulmonary embolism, grade 5 (50mg QD). Selected treatment-related adverse events in =10% of pts are shown in the table . 39% of pts receiving AMG 706 had thromboembolic events (TE); 25% receiving study therapy without AMG 706 had TEs. There was 1 case of cholecystitis (grade 1), 1 of gallbladder pain (grade 3). Preliminary data showed that AMG 706 PK at 125 mg QD was comparable to data from monotherapy studies at the same dose level. Based on 29 pts with available response data (too early to evaluate/data unavailable n=7), objective tumor responses per RECIST were: CR n=1, 3% (breast cancer); PR n=9, 31% (NSCLC n=6; pancreatic cancer n=2; unknown primary n=1); SD n=17, 59%; PD n=1, 3%. Conclusions: In this study of pts with advanced cancer, AMG 706 was tolerable when combined with panitumumab and gemcitabine-cisplatin, with little effect on AMG 706 PK. Further studies need to determine if the observed TE rate exceeds gemcitabine-cisplatin background rates.

[Table: see text]

No significant financial relationships to disclose.
Brief intravenous infusions of oblimersen (Genasense; Bcl-2 antisense) alone and in combination with multiple agents are highly effective in human tumor xenografts
Authors: Brown B. D. , Paine-Murietta G. D. , Julian T. N. , Warrell R. P.
Published: March 2020

14061

Background: Oblimersen (OBL; Genasense®) is a phosphorothioate-modified antisense oligodeoxynucleotide (ODN) that down-regulates Bcl-2 and may enhance the response to chemotherapy in patients with melanoma and chronic lymphocytic leukemia (CLL). Extensive safety data for Genasense and other systemically administered ODNs have been obtained using low-dose continuous intravenous infusions (CIVI). However, this method is inconvenient and unsuitable for drug combinations that employ frequent or discontinuous dosing. We have now established that OBL can be effectively administered by high-dose, short IV infusions. Methods: We tested multiple treatment schedules of OBL, alone and in combination with paclitaxel, paclitaxel albumin nanoparticles, imatinib, sorafenib, sunitinib, and erlotinib against human tumor xenografts (melanoma A375, NSCLC A549 and H460, colon HT29 and SW620) grown in C.B-17/SCID mice. Results: Periodic OBL monotherapy (high dose IV Q2–3d) yielded consistently superior antitumor efficacy when compared with low- dose daily IV injections. These results have been obtained against all tumor models evaluated to date. This increased efficacy was also observed when OBL was combined with any other therapeutic agent. For combination treatments that included taxanes, efficacy was shown to be schedule dependent. Conclusions: These results, and recent clinical observations, suggest that brief high-dose IV infusions of OBL may significantly increase antitumor activity, and may obviate the need for CIVI. Brief high-dose IV infusions are being incorporated into ongoing clinical trials to evaluate the safety and efficacy of OBL in combination with other agents.

No significant financial relationships to disclose.
Imaging of angiogenesis in metastatic breast cancer by positron emission tomography (PET) using [18F]AH11585, an [18F]- labeled alphaVbeta3 (αvβ3) peptide
Authors: Kenny L. M. , Aboagye E. , Cohen P. S. , Miller M. , Turkheimer F. , Al-Nahhas A. , Blunt D. , Coombes R. C.
Published: March 2020

14067

Background: In vivo imaging of avβ3 expression in tumors and tumor endothelial cells may be a useful biomarker of angiogenesis. [18F]AH11585 is a novel peptide containing an Arginine-Glycine-Aspartic Acid (RGD) motif that binds to avβ3 with high affinity designed for use in PET studies. Methods: 7 patients with metastatic breast cancer (aged 37–68 years) received intravenous injections of [18F]AH11585 and were scanned dynamically by PET over 61.5 mins. Radioactivity concentrations, derived from regions of interest placed on tumour and normal tissues, were analysed mathematically to determine the net irreversible uptake (Ki), fractional retention (FRT) and standardized uptake at 56.5min (SUV) of the radiotracer. Computed tomography (CT) was performed within 4 weeks of the scan. Results: Tumor lesions were clearly visible on PET images in 6/7 patients. In one patient with a palpable supraclavicular lymph node not visible on CT, we were unsure if a hyperintense region visible by PET was tumor. In total 18/19 tumor lesions were identified on both PET and corresponding CT images. Tumors in areas of low background were hyperintense (lung, bone, breast) whereas those in areas of high background were hypointense regions (liver). Tumors with central necrosis showed high uptake of [18F]AH11585 around the periphery only. Mathematical analysis demonstrated irreversible retention of [18F]AH11585 in tumors. [18F]AH11585-PET discriminated between non-liver lesions (n=10) and normal tissues: Ki (p=0.002), FRT (p=0.0039), SUV (p=0.002). Corresponding comparisons for liver lesions (n=8) were significant for FRT (p=0.0078) and SUV (p=0.0078) only. Conclusions: [18F]AH11585 PET is a promisng method for in vivo imaging of avβ3 integrin expression in metastatic breast cancer.

No significant financial relationships to disclose.
A novel K-samII/FGF-R2 autophosphorylation inhibitor is therapeutically useful for scirrhous gastric carcinoma with K-samII amplification
Authors: Yashiro M. , Nakamura K. , Sawada T. , Kawajiri H. , Shimizu T. , Miwa A. , Hirakawa K.
Published: March 2020

14070

Background: Scirrhous gastric carcinoma, a diffusely infiltrating also known as linitis plastica-type carcinoma, carries the highest mortality of all gastric cancers. Scirrhous carcinoma cells with amplification of the activated K-samII gene, which encodes fibroblast growth factor receptor type 2 (FGF-R2), have a growth advantage during tumor progression The poor prognosis carried by scirrhous gastric cancer is closely associated with amplification of the K-samII/FGF-R2, a tyrosine kinase growth factor receptor. Ki23057, a newly developed small molecule acting K-samII/FGF-R2 inhibitor, is a kinase inhibitor that competes with ATP for the binding site in the kinase, thus strongly blocking phosphorylation of FGF-R2. The aim of the current study is to clarify the possibility of molecular target therapy with Ki23057 for treating scirrhous gastric cancer. Methods: Five human gastric cancer cell lines were used. OCUM-2MD3 and OCUM-8 were derived from scirrhous carcinomas. MKN-7, MKN-45 and MKN-74 cells were derived from non-scirrhous carcinomas. In vitro effects of Ki23057 on cell growth were determined by calculating the number of cancer cells. The influences of Ki23057 on the MAP kinase and PI3 kinase signaling pathways and the apoptosis pathway in the gastric cancer cells were also examined. For in vivo experiments, the Ki23057 was administered orally to mouse models of peritoneal dissemination. Results: K-samII amplification was found in OCUM-2MD3 and OCUM-8 cells, but not in MKN-7, MKN-45, or MKN-74 cells. Ki23057 significantly inhibited the proliferation of scirrhous cancer cells, but not non- scirrhous gastric carcinoma cells. Ki23057 decreased phosphorylation of K-samII/FGF-R2, ERK and Akt, and increased apoptosis in scirrhous cancer lines. The oral Ki23057 administration significantly (p<0.001) prolonged survival of mice with peritoneal dissemination following injection of OCUM-2MD3 scirrhous cancer cells. Conclusions: A novel K-samII/FGF-R2 phosphorylation inhibitor, Ki23057, appears therapeutically promising in scirrhous gastric carcinoma with K-samII amplification.

No significant financial relationships to disclose.
A phase I study of therapeutic amplitude-modulated electromagnetic fields (THERABIONIC) in advanced tumors
Authors: Pasche B. , Barbault A. , Bottger B. , Bomholt F. , Kuster N.
Published: March 2020

14072

Background: In vitro studies suggest that low levels of amplitude-modulated electromagnetic fields may modify cell growth. We have identified specific frequencies that may block cancer cell growth. We have developed the THERABIONIC device, a portable and programmable emitter of a 27.12 MHz radiofrequency signal, amplitude-modulated at cancer-specific frequencies ranging from 0.2 to 23,000 Hz with high precision. The device is connected to a spoon-like coupler, which is placed in the patient’s mouth during treatment. The levels of absorbed electromagnetic energy are well below safety limits. Methods: A phase I study consisting of three daily 40 min treatments until disease progression or death. From March 2004 to September 2006, 24 patients with advanced solid tumors were enrolled. The median age was 57.0 ± 12.2 years. 16 patients were female. As of January 2007, 5 patients are still on therapy, 13 patients died of tumor progression, 2 patients are lost to follow-up and one patient withdrew consent. The most common tumor types were breast (7), ovary (5) and pancreas (3). 21 patients had received prior systemic therapy and 16 had documented tumor progression prior to study entry. Results: The median duration of therapy was 15.7 ± 19.9 weeks (range: 0.4–72.0 weeks). There were no NCI grade 2/3/4 toxicities. Three patients experienced grade 1 fatigue during and immediately after treatment. 12 patients reported severe pain prior to study entry. Two of them reported significant pain relief with THERABIONIC treatment. Objective response could be assessed in 13 patients, 6 of whom also had elevated tumor markers. 6 additional patients could only be assessed by tumor markers. Among patients with progressive disease at study entry, one had a partial response for > 14.4 weeks associated with > 50% decrease in CEA, CA 125 and CA 15–3 (previously untreated metastatic breast cancer); one patient had a 50% decrease in CA 19–9 for 12.4 weeks (recurrent and previously systemically-treated pancreatic cancer). Among patients with stable disease at enrollment, four patients maintained stable disease for 17.0, > 19.4, 30.4 and > 63.4 weeks. Conclusions: THERABIONIC is a safe and promising novel treatment modality for advanced cancer.

No significant financial relationships to disclose.
Age-stratified phase I trial of a combination of bortezomib, gemcitabine, and liposomal doxorubicin in patients with advanced malignancies
Authors: Falchook G. S. , Dhillon N. , Moulder S. , Duvic M. , Ng C. , Hong D. , Camacho L. , Lim J. , Wang M. , Fayad L. , Kurzrock R.
Published: March 2020

14087

Background: Bortezomib, a potent proteasome and NF-kB inhibitor, potentiates the activity of chemotherapy in a variety of tumors in vitro and in mouse models, and preclinical data suggest that the combination of bortezomib, gemcitabine, and liposomal doxorubicin is synergistic. Because tolerance to combination therapy may be attenuated in elderly patients, we performed a phase I age- stratified trial to determine the maximum tolerated dose (MTD), toxicity, and antitumor activity of this combination. Methods: Starting doses were bortezomib 0.7 mg/m2 (days 1 and 8), gemcitabine 500 mg/m2 (days 1 and 8), and liposomal doxorubicin 20 mg/m2 (day 1). Two parallel age-stratified arms (< 65 and = 65 years old) were accrued, with at least three patients per dose level per arm. Each treatment cycle was 21 days. Results: 47 patients have enrolled, and the MTD has not yet been reached. For patients < 65 years old, accrual continues at the ninth dose level with bortezomib 1.3 mg/m2 (days 1, 4, 8, 11), gemcitabine 800 mg/m2 (days 1 and 8), and liposomal doxorubicin 40 mg/m2 (day 1). For patients = 65 years old, accrual continues at the fourth dose level with bortezomib 1.0 mg/m2 (days 1, 4, 8, 11), gemcitabine 800 mg/m2 (days 1 and 8) and liposomal doxorubicin 20 mg/m2 (day 1). The most common side effects have been thrombocytopenia and neutropenia, with thrombocytopenia necessitating dose delays and withholding of doses. In the arm with patients = 65 years old, a dose-limiting toxicity of grade 3 fatigue was observed at dose level 4, and that cohort is currently undergoing dose expansion. Seven patients have achieved a partial response, including one patient with small cell lung carcinoma (6 months; 3 prior therapies) and all of six evaluable patients with cutaneous T cell lymphoma (1, 3, 4, 6, 7, and 8 months; median 4 prior therapies). Stable disease = 6 months was observed in 5 patients with various solid tumors (7, 7, 8, 9, and 9 months; median 4 prior therapies). Conclusions: This combination regimen is well tolerated. Dose-limiting toxicity has developed earlier in the elderly cohort, as predicted. Antitumor activity in heavily pretreated patients with advanced malignancies has been observed.

No significant financial relationships to disclose.
Interim results of a phase I trial with a novel orally administered synthetic triterpenoid RTA 402 (CDDO-Me) in patients with solid tumors and lymphoid malignancies
Authors: Dezube B. J. , Kurzrock R. , Eder J. P. , Supko J. G. , Meyer C. J. , Camacho L. H. , Andreeff M. , Konopleva M. , Lescale-Matys L. , Hong D.
Published: March 2020

14101

Background: RTA 402 (CDDO-Me) is a novel synthetic triterpenoid with potent anticancer and anti-inflammatory activity through selective modulation of proteins that respond to changes in oxidative stress, including NF-κB, JNK, and STAT3. Based on preclinical data demonstrating effects on tumors and associated stroma, a Phase 1 dose-finding and pharmacokinetic study was initiated. Methods: RTA 402 is administered orally once a day for the first 21 days of a 28-day cycle. Dose escalation is proceeding according to an accelerated titration design until an MTD is reached. Results: RTA 402 has been administered to 11 patients at 7 dose levels (5 to 300 mg/day). Cycle 1 data are available for 8 patients. No significant drug-related toxicity has been reported and dose escalation continues in 100% increments. The median biological half-life of RTA 402 was 49 h (range, 18–67 h), and all patients receiving doses >20 mg/day were continuously exposed to plasma levels of the drug exceeding 1 ng/mL. Evidence of antitumor and biological activity has been observed in initial patients. A patient with medullary thyroid carcinoma treated at 5 mg/day has received eight cycles of therapy and has had stable disease with a 70% reduction of calcitonin levels. A patient with metastatic melanoma has experienced disease stabilization through four cycles and remains on study. A second melanoma patient has also experienced disease stabilization through two cycles and remains on study. Radiographic evidence of regressing lesions has been observed in both melanoma patients. Additionally, significant reductions in circulating VEGF, MMP-9, TNF, IL-8, and IL-10, up to 65%, 91%, 90%, 73%, and 70%, respectively, have been observed in at least half of patient samples. Cytokine suppression has correlated with improvements in reported pain and fatigue. Conclusions: Orally administered RTA 402 appears well tolerated up to 150 mg/day and with prolonged exposure up to 8 months. Data from initial patients indicate biological activity and suggest clinical benefit, with disease stabilization in several patients who had rapidly progressing disease with high tumor burden. Phase 2 trials are planned.

No significant financial relationships to disclose.
The taxane-enhancer STA-4783 induces Hsp70 expression and apoptosis via an oxidative stress mechanism
Authors: Kirshner J. , Du Z. , Kepros J. , Balasubramanyam V. , He S. , Zhang M. , Yang C. , Barsoum J. , Bertin J.
Published: March 2020

14107

Background: STA-4783 is an inducer of Hsp70 expression and apoptosis that recently completed a successful Phase II clinical trial in melanoma. In a double-blind, randomized, controlled trial in patients with Stage IV disease, STA-4783 plus paclitaxel doubled progression-free survival compared to paclitaxel alone (Perspectives in Melanoma X and the Third International Melanoma Research Congress, 2006). The mechanism by which STA-4783 synergizes with paclitaxel is not fully understood. To identify the major pathway modulated by STA- 4783 in vitro, a transcriptional profiling analysis of drug-treated melanoma cells was performed. Methods: Transcriptional profiling was performed on Hs294T and MDA-MB-435 melanoma cell lines treated with STA-4783. The induction of Hsp70 RNA and other human genes was monitored by Real Time-PCR (RT-PCR) analysis. Measurement of reactive oxygen species (ROS) was performed in human cells using the Carboxy-H2DCFDA probe. Levels of apoptotic cell death were determined by flow cytometry analysis using an Annexin V specific probe. Results: Transcriptional profiling revealed that STA-4783 induced the expression of numerous gene families known to be regulated by oxidative stress, including heat shock proteins and metallothioneins. STA-4783 induced the generation of ROS in cells resulting in the oxidation and activation of the Carboxy-H2DCFDA fluorescent probe. The antioxidants N-Acetyl Cysteine (NAC) and Tiron potently blocked the induction of Hsp70 RNA and apoptotic cell death. Conclusions: STA-4783 induces oxidative stress in cells resulting in Hsp70 induction and apoptotic cell death. Although STA-4783 initially induced a transient protective response, apoptotic cell death occurred due to sustained oxidative stress. Cancer cells produce more ROS than normal cells and are thus more sensitive to insults that induce oxidative stress. The induction of ROS in melanoma cells by STA-4783 may therefore enhance the efficacy of paclitaxel in vivo. STA-4783 belongs to a novel class of anticancer agents that induce cell death by pushing the cancer cell beyond its oxidative stress breaking point.

[Table: see text]
PET FES measures in vivo pharmacodynamics of endocrine therapy
Authors: Linden H. M. , Mankoff D. A. , Krohn K. A. , Link J. M. , Stekhova S. , Livingston R. B. , Gralow J. R. , Ellis G. K. , Kurland B. , Peterson L. , Schubert E. K.
Published: March 2020

14110

Background: Many clinical options are available for management of hormone sensitive breast cancer, including agents which lower estrogen levels such as aromatase inhibitors (AIs) and agents with block ligand binding to receptor such as tamoxifen (TAM) or fulvestrant (FUL). Estrogen receptor (ER) function is essential for sensitivity to hormonal manipulation in breast cancer treatment. We and others have previously shown that functional ER imaging using PET FES predicts response to hormonal therapy using a quantitative threshold of SUV >1.5. Herein we report that FES PET provides a unique insight into in vivo pharmacodynamics of ER therapy. We hypothesized that the impact of therapy on estradiol binding to ER, measured by FES PET, differs between AIs and ER antagonists, and that early changes in receptor expression/occupancy show efficacy of drug at the tumor target. Methods: Patients undergoing treatment with AI, TAM, or FUL underwent baseline PET FDG and FES, and follow-up PET FES imaging at 2–8 weeks post initiation of therapy. Results: We observed the following changes in FES uptake on hormonal therapy: Mean percent change in FES SUV were 54% decline for TAM and FUL vs. 14% decline for AI treated patients (p<.001). Patients on TAM showed complete blockade of tumor FES uptake on therapy (5/5 with residual SUV <1.5), whereas patients on FUL had variable uptake and incomplete blockade at tumor sites in most patients (4/11 with residual SUV <1.5) (p < .05 FUL vs. TAM), despite consistent blockade of uterine FES uptake in patients where the uterus was visualized pre-FUL. Patients on AI therapy (n=14) had variable tumor uptake following treatment initiation. Conclusions: PET FES effectively monitors the in vivo activity of therapy. Estrogen blocking therapies result in a greater change in tumoral estradiol binding than in ligand depletion. TAM effectively blocks uptake of FES as would be predicted by the mechanism of action of this agent. However, FUL (while blocking uterine uptake) incompletely blocks tumor uptake, providing a mechanism to explain reduced activity of this agent in some patients. Ongoing analysis is designed to assess whether early changes in FES predict response or clinical benefit.

No significant financial relationships to disclose.
Actions of a novel therapeutic formulation: Zn, Se and Mn plus Lachesis Muta venom (O-LM) on radiation deleterious immune effects
Authors: Rivera E. , Cremaschi G. , Genaro A. M. , Croci M. , Sambuco L. , Cricco G. , Martin G. , Bergoc R. , Crescenti E.
Published: March 2020

14116

Background: We have previously reported that O-LM inhibits malignant cell proliferation and increases survival in rodent tumor models (Int J Cancer S13:183, 2002). Molecular and immunological basis of O-LM action were reported (J Clin Oncol 24:18S, 2006). As O- LM selectively protects normal tissues from high doses of ionizing radiation (Proc Int Cancer Congress,1495–9, 1998), we here investigated O- LM protective action upon radiation effects on immune cells. Methods: Balb/c mice (n=15 each group) were employed: control (C); 2Gy whole body irradiated (IR); treated with O-LM (Zn, Se, Mn 4μg/ml each; L. Muta 4 ng/ml; 0.1 ml/day, sc) for 15 days and 2Gy irradiated (O-LM+IR). Mice were sacrificed at day 3, 7 or 15 post-irradiation (PI). Proliferation was evaluated in lymphocytes by [3H]- Thymidine incorporation after T- or B selective mitogen stimulation. In cell-free supernatants (SN) from mitogen-stimulated cultures cytokines involved in lymphocyte regulation and/or inflammation were determined by ELISA. Results: Irradiation induced a decrease in T lymphocyte proliferation at 3 and 7 days PI (% of decrease in IR: 47.6±9.0, p<0.05; 42.0±7.2, p<0.02 respectively). Pretreatment with O-LM recovered proliferation to basal values (day 3 PI 93.4±10.2%; day 7 PI 130.9±15.3%, O-LM+IR vs. C; p=NS). No modifications were observed in B cells. At day 3 PI, a marked decrease in IFN? levels was obtained in SN of IR mice that was reverted by O-LM treatment (pg/ml: IR 1653±419; C 10884±2783, p<0.02; O-LM+IR 16924±4284, p<0.05 vs C). Also, at day 7 PI, an important increase in TNFa was observed in IR mice, that were reverted by O-LM (pg/ml: IR: 300.7±62.3 vs O-LM+IR: 28.7±2.3, p<0.02). No differences were found in IL-2 levels. Conclusions: The therapeutic action of O-LM is based on its ability of targeting simultaneously multiple pathways involved in cancer development. Present data demonstrate that O-LM protects animals from irradiation by recovering the immune function, improving T lymphocyte activity and modulating the production of key cytokines as IFN? and TNFa. The reported effect may represent a potential benefit for cancer patients undergoing radiotherapy.

No significant financial relationships to disclose.
Effect of celecoxib, a specific cyclooxygenase 2 inhibitor, on the apoptotic and mitotic indexes of breast cancer in patients with early stage disease
Authors: Tfayli A. H. , Cherry M. , Yang J. , Kojouri K. , Jafari M. , Thor A. , Ozer H.
Published: March 2020

14132

Background: To assess whether the administration of celecoxib, a specific cyclooxegenease-2 (COX-2) inhibitor, to patients with breast cancer alters the proliferative and apoptotic indexes of their tumors. Methods: Women newly diagnosed with non metastatic breast cancer were enrolled into the study after undergoing a diagnostic core needle biopsy. Patients received celecoxib treatment at 400 mg orally twice a day for 14 days, and then underwent surgical excision of their tumor. Core biopsies obtained at the time of initial diagnostic procedure and surgical excision specimens were stained for Ki-67, as well as COX-2 and cleaved poly (ADP-ribose) polymerase (PARP) expression (as an apoptosis marker). Appropriate negative and positive controls were included. We assessed the difference in Ki- 67, COX-2 and cleaved PARP expression levels, before and after treatment using the Wilcoxon’s matched-pair ranks test and the McNemar’s test. Results: 16 patients were enrolled. The median age was 54.6 years. ER and/or PR expression was present in 81% of tumors; Her-2 neu overexpression was present in 25%. No significant change in COX-2 or cleaved PARP expression was noticed in the post intervention specimen compared to the core biopsies. Surprisingly, there was a significant increase in the Ki-67 expression (p < 0.009). Conclusions: we have conducted a short term prospective study to assess the effects of celecoxib, on the proliferative and apoptotic indexes in patients with early stage breast cancer. We have found an increase in the Ki-67 activity, with no significant down regulation of COX-2 or increase in cleaved PARP expression with 14 days of therapy. This could be partly due to the small sample size.

[Table: see text]
A phase I study of 2-cyano-3, 12 dioxoolean-1, 9-dien-28-oic acid (CDDO) in advance solid tumors
Authors: Holkova B. , Kummar S. , Glauber P. , Chen A. , Strong J. M. , Parker R. J. , Collins J. , Murgo A. J. , Doroshow J. H. , Gutierrez M. E.
Published: March 2020

14137

Background: CDDO, a synthetic triterpenoid, induces apoptosis through intrinsic and extrinsic pathways, and as a ligand for the transcription factor PPAR-? that controls cellular differentiation and growth inhibition. Methods: CDDO was given as a 5 day continuous infusion every 28 days; starting dose 0.6 mg/m2/hr. Accelerated titration design used, 1 patient (pt)/cohort entered until a single pt has dose-limiting toxicity (DLT) or 2 pts exhibit grade (gr) = 2 toxicity during the first cycle. The study then converts to a standard 3–6 pt/cohort design. Maximum tolerated dose (MTD): Dose at which no more than 1/6 pts have DLT and the dose below which at least 2/6 patients have DLT. Objectives: Determine toxicity profile, pharmacokinetics (PK), and MTD of CDDO. PK were determined by LC-MS/MS analysis of plasma collected pre, during and post CDDO infusion. Results: 6 pts have been accrued thus far up to dose level 6. (19.2 mg/m2). Diagnoses: colon -3, sarcoma-1, bladder -1 and ovary-1. Median age: 52. DLT and MTD have not yet been achieved. Gr 1–2 toxicities have been acceptable: anemia, thrombocytopenia, decreased Na+, Mg++ and albumin, elevated Ca++, transaminases and bilirubin, and anorexia, fatigue and constipation. Gr 4 pulmonary emboli (unrelated to CDDO) was seen in one pt. PK: Steady state CDDO plasma concentrations (Css) in the first 3 dose levels increased linearly (see table ). Post infusion CDDO plasma concentrations decreased in a bi- exponential manner for the first three dose levels. Data indicate that < 1% of CDDO is excreted in the urine unchanged. No oxidative metabolism has been observed; however, we identified a CDDO glucuronide conjugate in urine and in human liver tissue incubations in vitro. Conclusions: The DLT and MTD have not been reached, and accelerated dose escalation continues. Since the CDDO Css appears to increase linearly with dose, we anticipate achieving 1 μM plasma levels at dose level 5 (9.6mg/m2/hr), the effective concentration in preclinical models. [Table: see text]

No significant financial relationships to disclose.
Growth suppression of human pancreatic cells by a novel PKCβ inhibitor, enzastaurin
Authors: Cheng H. , Yan J. G. , Jiang Y.
Published: March 2020

14141

Background: Human pancreatic cancer is a devastating disease. Standard therapy, gemcitabine, is not able to alter the natural history of the disease. Targeting intracellular signaling molecules has proven to be a powerful approach in cancer therapy. Protein kinase C (PKC) family has been implicated in many human cancers including pancreatic cancer. Methods: In this pre-clinical study, we evaluated the effect of a novel small molecule inhibitor, enzastaurin, for PKCβ on human pancreatic cancer cells. We utilized MTT assay to assess cell proliferation and viability. To evaluate cell transforming activity, soft agar colony forming assay was used. Results: We showed that with addition of 20μM enzastaurin into the culture, the proliferative growth of two pancreatic cancer cell lines, Panc1 and L3.6p1, was significantly attenuated, as measured by the MTT assay. In addition, the combination of enzastaurin and a low dose of gemcitabine (25 nM) resulted in a synergistic cytotoxic effect in L3.6p1 cells. Further, the in vitro tumorogenicity assay demonstrated that the L3.6p1 cells treated with enzastaurin (20μM) formed much smaller colonies than the control parental cells in 0.4% soft-agar. Consistent with the in vitro cell proliferation results, the combination of enzastaurin and the low concentration of gemcitabine (25nM) further reduced the numbers and sizes of colonies in the soft-agar. Conclusions: Collectively, our data indicate that enzastaurin can effectively suppress the proliferation and in vitro transforming activity of the pancreatic cells, and more effectively when applied in combination with the low dose of gemcitabine.

No significant financial relationships to disclose.
The Biomarkers Consortium: A public-private partnership of the Foundation for NIH
Authors: Lee D. , Altar T.
Published: March 2020

14142

Background: In October 2006, the Foundation for the National Institutes of Health (FNIH) announced the launch of a major public-private biomedical research partnership, The Biomarkers Consortium, to search for and validate new biological markers-biomarkers- to accelerate dramatically the delivery of successful new technologies, medicines, and therapies for prevention, early detection, diagnosis, and treatment of disease. The Foundation for NIH is managing The Biomarkers Consortium under direction of the consortium executive committee, with guidance from leading scientists within and outside the member organizations, plus input from a public representative and private industry and non-profit funding partners. FNIH, CMS, FDA, NIH, and the pharmaceutical, biotechnology, diagnostics, and medical device industries recognize the critical need for a coordinated cross-sector partnership effort to more rapidly identify and qualify biomarkers to support basic and translational research, guide clinical practice and, ultimately, support the development of safe and effective medicines and treatments for a wide range of diseases. The Biomarkers Consortium will harmonize approaches to identifying viable biomarkers, verifying their individual value, and formalizing their use in research and regulatory approval. Information and results from consortium projects will be used broadly by researchers to promote the appropriate use of biomarkers to improve the public health worldwide. Methods: N/A Results: Promising project concepts that have been approved in principle for further development by The Biomarkers Consortium include the Fluorodeoxyglucose-Positron Emission Tomography (FDG-PET) Lung Cancer and Non-Hodgkin’s Lymphoma Projects and projects in metabolic disorders and neuroscience. Steering Committees in cancer, metabolic disorders, and neuroscience have been created to evaluate and develop project concepts approved for further development. Conclusions: The Biomarkers Consortium is an important avenue to facilitate the search and validation of a variety of biomarkers projects.

No significant financial relationships to disclose.
Induction of gemcitabine (GCB)-related genes by pemetrexed (MTA): Assessment of the best time interval between MTA and GCB administration
Authors: De Pas T. M. , Danesi R. , Toffalorio F. , Milani A. , Giovannetti E. , Mey V. , Nannizzi S. , Pelosi G. , Manzotti M. , de Braud F.
Published: March 2020

14145

Background: Both MTA and GCB are active drugs in non-small cell lung cancer (NSCLC). Many molecular events induced by MTA support the synergic interaction between the two drugs and explain why the sequence MTA ? GCB is more active than GCB ? MTA. Of major interest, MTA induces the expression of deoxycytidine kinase (dCK), the rate-limiting enzyme of GCB activation, and of the human equilibrative nucleoside transporter-1 (hENT1), the key transporter for the intracellular penetration of GCB. Even if the optimal sequence is well established, no information on the best administration time between the two drugs is available. Methods: To evaluate if there is a reproducible timing of maximum dCK and hENT1 expression by MTA, we measured these targets in patients with advanced NSCLC after administration of MTA 500 mg/m2 q2wks. All patients were not pre-treated with MTA or GCB. Gene-expression was measured in normal lymphocytes by quantitative real-time PCR (qRT-PCR), at various interval (up to 48 hrs) at each of the first 3 chemotherapy cycles. Results: Between September and December 2006, 8 out of the 19 planned patients were enrolled in the present study. At the time of this analysis, dosages from 63 samples / 9 cycles of chemotherapy are available. In all treatment cycles, qRT-PCR analysis revealed an increase of hENT1 and/or dCK genes at least in one time-point. With respect to gene expression levels at basal time, dCK increased both early (+1h: 3 out of 9 valuable cycles; + 4–6 hrs: 4 out of 9 cycles) and late (+ 24–48 hrs: 5 out of 9 cycles); hENT1 increased poorly at +1h (1 out of 6 valuable cycles) but consistently at + 4–6 hrs (5 out of 6 cycles) and late (+24–48 hrs: 6 out of 6 cycles). The increase of dCK and hENT1 gene expression was from + 15% to 285% and from 21% to + 380%, respectively. Conclusions: MTA induces GCB- related genes both at early and late time points with an inter-patients variability. The most rationale time interval between the two drugs administration will be valuated at the completion of the study.

No significant financial relationships to disclose.
Preliminary phase II study results of capecitabine (X) + irinotecan (I) + bevacizumab (A) as first-line therapy for patients (pts) with metastatic colorectal cancer (MCRC)
Authors: Beslija S. , Banjin M. , Jungic S. , Obralic N. , Kecman-Malcic G. , Rakita I. , Salkic B. , Pasic A. , Tinjic L. , Ajanovic E.
Published: March 2020

14502

Background: The oral fluoropyrimidine X (Xeloda®) has improved efficacy, safety and convenience compared with 5-FU/LV in MCRC [Van Cutsem et al. Br J Cancer 2004] and early-stage colon cancer [Twelves et al. NEJM 2005]. A recent study showed that I + X q2w is active and well tolerated [Garcia-Alfonso et al. ESMO 2006]. The humanized monoclonal antibody A (Avastin®) targets VEGF and limits tumor angiogenesis. The addition of A to 5-FU/LV/I (IFL regimen) results in significant improvements in survival among pts with MCRC [Hurwitz et al. NEJM 2004]. Replacing 5-FU/LV with X in this combination is a logical step forward. Here we report data from an open-label phase II trial of XIA in MCRC. Methods: Pts with untreated, histologically confirmed MCRC received I 175 mg/m2 i.v. d1, X 1000 mg/m2 orally bid d2–8, and A 5 mg/m2 d1. Treatment was repeated q2w x12 cycles in the absence of disease progression or unacceptable toxicity. Pts without progressive disease after 12 cycles of XIA continued on the same dose of A + X 1500 mg/m2 bid d2–8, q2w. The primary endpoint was progression-free survival (PFS); secondary endpoints were response rate (RECIST), overall survival (OS), safety, and quality of life. Results: 24 out of a planned total of 32 pts have been enrolled. Baseline characteristics are: M/F 50%/50%; median age 53 years (range 30–70); disease stage at initial diagnosis IIIA/IIIB/IV 29%/21%/50%; no. of metastatic sites 1/>1 50%/50%; most common metastatic site liver; prior adjuvant therapy 33% (Mayo 5-FU/LV). Pts received a median of 12 cycles (range 1–18) of XIA. All 24 pts are evaluable for safety and 22 for efficacy. The overall response rate is 77% (4 CR, 13 PR); 2 pts (9%) have stable disease and 3 have progressed. One pt has died. Median PFS and median OS have not yet been reached. The only grade 3 adverse events are diarrhea (13%), fatigue (4%), mucositis (4%), enteritis (4%), ileus (4%); there is one report of grade 4 leucopenia. All other adverse events are mild-to-moderate. Conclusions: The XIA combination appears to be highly active and well tolerated as first-line treatment for MCRC, providing support for further evaluation of this combination.

No significant financial relationships to disclose.
UGT1As polymorphisms predict toxicity in colorectal cancer patients treated with different recommended doses of irinotecan oriented by UGT1A1*28 polymorphism based on previous phase I study
Authors: Hazama S. , Koudo H. , Yoshida S. , Shimizu R. , Ozasa H. , Yamamoto T. , Araki A. , Yoshino S. , Okayama N. , Hinoda Y. , Oka M.
Published: March 2020

14511

Background: We have presented at 2006 ASCO annual meeting about a genetic UGT1A1 polymorphism oriented phase (P) I study of Irinotecan and 5’-DFUR for metastatic colorectal cancer (MCRC) to determine the maximum tolerated dose (MTD) and the recommend doses (RD) for each UGT1A1 *1/*1 and *1/*28 genotypes. The RD of biweekly Irinotecan administration was 150 mg/m2 for patients (pts) with wild *1/*1 genotype and 70 mg/m2 of Irinotecan for mutated *1/*28. Now we are carrying out a *28 oriented P II study based on this RD. Here we report the profiles of toxicities in the P II study of irinotecan and 5’-DFUR to analyze other kinds of UGT1As polymorphisms in relation to irinotecan toxicities. Patients & Methods: Eligibility criteria were as follows; histologically proven CRC with unresectable metastatic lesions, PS 0–1, age<76, adequate organ functions, and written informed consent. Twenty one pts with wild type genotype and 9 pts with mutated genotype were enrolled. Irinotecan was infused 150 mg/m2 for pts with *1/*1 genotype and 70 mg/m2 for *1/*28. Hematological and non-hematological toxicities were graded, and UGT1As polymorphisms (UGT1A1*6 and *7, UGT1A7*1*2*3*4, UGT1A9*22) were analyzed. Results: Grade (G)3 & 4 toxicities were observed in 6 of 22 (27%) wild type pts and in 3 of 9 (33%) mutated pts, and in 9 of 31 (29%) all pts. There was no significant difference on the profiles of toxicities between the pts with wild genotype and mutated genotype, irrespective of the difference of the quantity of irinotecan. So, the RD was thought to be adequate. In pts with UGT1A1*6 allele, G3 & 4 toxicities were observed 6/11 (55%), on the other hand 3/20 (15%) in pts without *6 allele (p=0.038). G3 & 4 toxicities were also more frequent in pts with UGT1A7*3 alleles than pts without *3 allele (p<0.10). Conclusions: The profiles of toxicities of pts with *1/*1 or *1/*28 genotypes were similar irrespective of the difference of the quantity of irinotecan. The result indicated that the RD of latest PI for each group was adequate, and this P II study is suitable to analyze other kinds of polymorphisms that have correlation to irinotecan toxicities. UGT1A1*6 and UGT1A7*3 allele will be a novel predictor for toxicity of irinotecan.

No significant financial relationships to disclose.