Potential effective inhibitory compounds against Prostate Specific Membrane Antigen (PSMA): A molecular docking and molecular dynamics study.

One of the most prevalent cancers in men is prostate cancer and could be managed with immunotoxins or antibody treatment. Because of the substantial rise of the Prostate-Specific Antigen and the Prostate-Specific Membrane Antigen (PSMA), cancer vaccination should be rendered with these antigens. Through pharmacodynamic experiments in a library of natural compounds from ZINC database, the current research sought to identify compounds that could suppress PSMA protein. To test the most productive compounds for further research, the Library has been scanned with Pharmacophore and ADMET analysis followed by molecular docking methods in the first phase. After selecting 15 ligands with the best pose related to docking results, to evaluate the stability of the ligand-protein bounds of the compounds, a molecular dynamics simulation considering the effect of the presence of zinc ions on the protein structure was performed. The measurement of ligand binding modes and free energy has shown that four compounds, including Z10, Z06, Z01, and Z03, have formed critical interactions with the active site's residues. Besides, multiple approaches were employed to determine their inhibition rating and describe the variables that facilitate the attachment of ligands to the protein active site. The results are obtained from the MMPBSA/GBSA analysis of four selected small molecules (Z10, Z06, Z01, and Z03), which are very close to the IC50 value of reference ligand (DCIBzl); they are -13.85 kcal/mol, -12.58 kcal/mol, -10.71 kcal/mol and -9.39 kcal/mol respectively. Finally, we evaluate the results obtained from selected ligands using hydrogen bond and decomposition analyzes. We have examined the effective interactions between ligands and S1/S1'pockets in protein. Our computational results illustrate the design of more efficient inhibitors of PSMA.

N-(2-18F-fluoropropionyl)-l-glutamate as a potential oncology tracer for PET imaging of glioma.

N-(2-18F-fluoropropionyl)-l-glutamate (18F-FPGLU), a new N-substituted 18F-labeling l-glutamate, is a potential amino acid tracer for oncology PET imaging with good tumor-to-background contrast in several tumor-bearing mice. Herein, we evaluated the potential value of 18F-FPGLU for PET imaging of glioma in orthotopic glioma-bearing SD rats. A series of competitive inhibition experiments with various types of inhibitors were conducted with C6 cells to investigate the transport mechanism of 18F-FPGLU in glioma. Establishment of orthotopic rat C6 glioma-bearing SD rats models was confirmed by MRI. Then PET imaging of 18F-FPGLU was performed on the orthotopic C6 glioma-bearing SD rats and compared with that of 18F-FDG. After the rats sacrificed, the whole brain was collected and immunofluorescence staining of glial fibrillary acidic protein (GFAP) and matrix metalloproteinase 2 (MMP2) were processed. Na+-dependent system XAG- and Na+-independent system XC- are the mainly transporters of 18F-FPGLU in C6 cells. N-methyl-d-aspartate (NMDA) receptor, which is associated with the invasiveness and proliferation of glioma cells, is also involved in the uptake of 18F-FPGLU. High uptake and retention of 18F-FPGLU was observerd in orthotopic glioma with good visualization and the tumor/background ratio reached 2.35 at 60 min post-injection, which was significantly higher than that of 18F-FDG (1.72) in small-animal PET images. High expression of MMP-2 and GFAP was observed in the immunofluorescence staining of glioma xerography slices. 18F-FPGLU seems to be a better potential PET tracer than 18F-FDG for brain glioma imaging with good visualization and ability to assess the tumor activity.

A Bivalent Inhibitor of Prostate Specific Membrane Antigen Radiolabeled with Copper-64 with High Tumor Uptake and Retention.

Molecules containing lysine-ureido-glutamate functional groups bind to the active site of prostate specific membrane antigen, which is overexpressed in prostate cancer. To prepare copper radiopharmaceuticals for the diagnosis and therapy of prostate cancer, macrobicyclic sarcophagine ligands tethered to either one or two lysine-ureido-glutamate functional groups through an appropriate linker have been prepared. Sarcophagine ligands can be readily radiolabeled with positron-emitting copper-64 at room temperature. The bivalent agent, in which two targeting groups are tethered to a single copper complex, dramatically outperforms the monomeric agent with respect to tumor uptake and retention. The high tumor uptake, low background, and prolonged tumor retention, even at 24 hours post injection, suggest the bivalent agent is a promising diagnostic for prostate cancer and could be used for prospective dosimetry for therapy with a copper-67 variant.

Preliminary evaluation of prostate-targeted radiotherapy using (131) I-MIP-1095 in combination with radiosensitising chemotherapeutic drugs.

OBJECTIVES: Despite recent advances in the treatment of metastatic prostate cancer, survival rates are low and treatment options are limited to chemotherapy and hormonal therapy. (131) I-MIP-1095 is a recently developed prostate-specific membrane antigen (PSMA)-targeting, small molecular weight radiopharmaceutical which has anti-tumour activity as a single agent. Our purpose was to determine in vitro the potential benefit to be gained by combining (131) I-MIP-1095 with cytotoxic drug treatments. METHODS: Various cytotoxic agents were evaluated in combination with (131) I-MIP-1095 for their capacity to delay the growth of LNCaP cells cultured as multicellular tumour spheroids. Two end-points were used to assess treatment efficacy: (i) the time required for doubling of spheroid volume and (ii) the area under the volume-time growth curves. KEY FINDINGS: The PARP-1 inhibitor olaparib, the topoisomerase I inhibitor topotecan, the proteasome inhibitor bortezomib, the inhibitor of the P53-MDM2 interaction nutlin-3 and the copper-chelated form of the oxidising agent disulfiram (DSF:Cu) all significantly enhanced the inhibition of the growth of spheroids induced by (131) I-MIP-1095. However, the Chk1 inhibitor AZD7762 failed to potentiate the effect of (131) I-MIP-1095. CONCLUSIONS: These results indicate that targeted radiotherapy of prostate cancer may be optimised by combining its administration with chemotherapy.

[Pemetrexed nephrotoxicity]. / Néphrotoxicité du pemetrexed.

Pemetrexed belongs to a new generation of multitargeted antifolate cytotoxic agents. It is increasingly used as first-line treatment in combination with cisplatin, and as second-line treatment or maintenance monotherapy mainly in metastatic non-small cell lung cancer and in malignant mesothelioma. It is increasingly used as first-line treatment in combination with cisplatin in lung adenocarcinoma, and as second-line treatment or maintenance monotherapy in patients mainly controlled by the first-line to progression or poor tolerance. In mesothelioma, pemetrexed is indicated only in first-line with a platinum salt. The main side effect of pemetrexed is myelosuppression, which may be prevented by folinic acid supplementation. This review focuses on the progressive and cumulative emerging renal toxicity of pemetrexed, affecting five to ten percent of "long-term" pemetrexed-treated patients.

Prediction of renal transporter mediated drug-drug interactions for pemetrexed using physiologically based pharmacokinetic modeling.

Pemetrexed, an anionic anticancer drug with a narrow therapeutic index, is eliminated mainly by active renal tubular secretion. The in vitro to in vivo extrapolation approach used in this work was developed to predict possible drug-drug interactions (DDIs) that may occur after coadministration of pemetrexed and nonsteroidal anti-inflammatory drugs (NSAIDs), and it included in vitro assays, risk assessment models, and physiologically based pharmacokinetic (PBPK) models. The pemetrexed transport and its inhibition parameters by several NSAIDs were quantified using HEK-PEAK cells expressing organic anion transporter (OAT) 3 or OAT4. The NSAIDs were ranked according to their DDI index, calculated as the ratio of their maximum unbound concentration in plasma over the concentration inhibiting 50% (IC50) of active pemetrexed transport. A PBPK model for ibuprofen, the NSAID with the highest DDI index, was built incorporating active renal secretion in Simcyp Simulator. The bottom-up model for pemetrexed underpredicted the clearance by 2-fold. The model we built using a scaling factor of 5.3 for the maximal uptake rate (Vmax) of OAT3, which estimated using plasma concentration profiles from patients given a 10-minute infusion of 500 mg/m(2) of pemetrexed supplemented with folic acid and vitamin B12, recovered the clinical data adequately. The observed/predicted increases in Cmax and the area under the plasma-concentration time curve (AUC0-inf) of pemetrexed when ibuprofen was coadministered were 1.1 and 1.0, respectively. The coadministration of all other NSAIDs was predicted to have no significant impact on the AUC0-inf based on their DDI indexes. The PBPK model reasonably reproduced pemetrexed concentration time profiles in cancer patients and its interaction with ibuprofen.

A phase I, dose-escalation trial of continuous- and pulsed-dose afatinib combined with pemetrexed in patients with advanced solid tumors.

INTRODUCTION: Afatinib, an irreversible ErbB family blocker, demonstrated synergistic inhibition of epidermal growth factor receptor-mutant cell growth with pemetrexed. This phase I study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, and antitumor activity of afatinib plus pemetrexed in patients with advanced solid tumors. METHODS: In a 3 + 3 dose-escalation design, patients were given intravenous pemetrexed (500 mg/m(2)) on day 1 of a 21-day cycle (maximum 6 cycles), combined with continuous daily oral afatinib (schedule A [SA]; starting dose 30 mg, escalation to 50 mg) or pulsed-dose daily oral afatinib (schedule B [SB]; starting dose 50 mg, escalation to 70 mg) on days 1-6 of each 21-day cycle. Primary endpoint was determination of MTD based on dose-limiting toxicities (DLTs) in cycle 1. RESULTS: Fifty-three patients were treated (SA: n = 23; SB: n = 30). Eight patients had DLTs in SA, 11 patients in SB; diarrhea and fatigue were the most common. MTD of afatinib was 30 mg in SA and 50 mg in SB. Six patients in SA and eight in SB completed 6 treatment cycles. One patient in each schedule had confirmed objective response; 18/53 patients had disease control (SA: n = 7; SB: n = 11). Most frequent drug-related adverse events were diarrhea, rash, fatigue, and stomatitis. No relevant pharmacokinetic interactions were observed. CONCLUSIONS: Continuous- or pulsed-dose afatinib combined with pemetrexed exhibited a manageable safety profile. Pulsed dosing conferred no apparent safety or dose advantage. Continuous-dose afatinib 30 mg/day with pemetrexed is recommended for phase II studies.

Preclinical analyses and phase I evaluation of LY2603618 administered in combination with pemetrexed and cisplatin in patients with advanced cancer.

LY2603618 is an inhibitor of checkpoint kinase 1 (CHK1), an important regulator of the DNA damage checkpoints. Preclinical experiments analyzed NCI-H2122 and NCI-H441 NSCLC cell lines and in vitro/in vivo models treated with pemetrexed and LY2603618 to provide rationale for evaluating this combination in a clinical setting. Combination treatment of LY2603618 with pemetrexed arrested DNA synthesis following initiation of S-phase in cells. Experiments with tumor-bearing mice administered the combination of LY2603618 and pemetrexed demonstrated a significant increase of growth inhibition of NCI-H2122 (H2122) and NCI-H441 (H441) xenograft tumors. These data informed the clinical assessment of LY2603618 in a seamless phase I/II study, which administered pemetrexed (500 mg/m(2)) and cisplatin (75 mg/m(2)) and escalating doses of LY2603618: 130-275 mg. Patients were assessed for safety, toxicity, and pharmacokinetics. In phase I, 14 patients were enrolled, and the most frequently reported adverse events included fatigue, nausea, pyrexia, neutropenia, and vomiting. No DLTs were reported at the tested doses. The systemic exposure of LY2603618 increased in a dose-dependent manner. Pharmacokinetic parameters that correlate with the maximal pharmacodynamic effect in nonclinical xenograft models were achieved at doses ≥240 mg. The pharmacokinetics of LY2603618, pemetrexed, and cisplatin were not altered when used in combination. Two patients achieved a confirmed partial response (both non-small cell lung cancer), and 8 patients had stable disease. LY2603618 administered in combination with pemetrexed and cisplatin demonstrated an acceptable safety profile. The recommended phase II dose of LY2603618 was 275 mg.

Radiation dosimetry and first therapy results with a (124)I/ (131)I-labeled small molecule (MIP-1095) targeting PSMA for prostate cancer therapy.

INTRODUCTION: Since the prostate-specific membrane antigen (PSMA) is frequently over-expressed in prostate cancer (PCa) several PSMA-targeting molecules are under development to detect and treat metastatic castration resistant prostate cancer (mCRPC). We investigated the tissue kinetics of a small molecule inhibitor of PSMA ((S)-2-(3-((S)-1-carboxy-5-(3-(4-[(124)I]iodophenyl)ureido)pentyl)ureido)pentanedioicacid; MIP-1095) using PET/CT to estimate radiation dosimetry for the potential therapeutic use of (131)I-MIP-1095 in men with mCRPC. We also report preliminary safety and efficacy of the first 28 consecutive patients treated under a compassionate-use protocol with a single cycle of (131)I-MIP-1095. METHODS: Sixteen patients with known prostate cancer underwent PET/CT imaging after i.v. administration of (124)I-MIP-1095 (mean activity: 67.4 MBq). Each patient was scanned using PET/CT up to five times at 1, 4, 24, 48 and 72 h post injection. Volumes of interest were defined for tumor lesions and normal organs at each time point followed by dose calculations using the OLINDA/EXM software. Twenty-eight men with mCRPC were treated with a single cycle of (131)I-MIP-1095 (mean activity: 4.8 GBq, range 2 to 7.2 GBq) and followed for safety and efficacy. Baseline and follow up examinations included a complete blood count, liver and kidney function tests, and measurement of serum PSA. RESULTS: I-124-MIP-1095 PET/CT images showed excellent tumor uptake and moderate uptake in liver, proximal intestine and within a few hours post-injection also in the kidneys. High uptake values were observed only in salivary and lacrimal glands. Dosimetry estimates for I-131-MIP-1095 revealed that the highest absorbed doses were delivered to the salivary glands (3.8 mSv/MBq, liver (1.7 mSv/MBq) and kidneys (1.4 mSv/MBq). The absorbed dose calculated for the red marrow was 0.37 mSv/MBq. PSA values decreased by >50 % in 60.7 % of the men treated. Of men with bone pain, 84.6 % showed complete or moderate reduction in pain. Hematological toxicities were mild. Of men treated, 25 % had a transient slight to moderate dry mouth. No adverse effects on renal function were observed. CONCLUSION: Based on the biodistribution and dose calculations of the PSMA-targeted small molecule (124)I-MIP-1095 therapy with the authentic analog (131)I-MIP-1095 enables a targeted tumor therapy with unprecedented doses delivered to the tumor lesions. Involved lymph node and bone metastases were exposed to estimated absorbed doses upwards of 300 Gy.

Biodistribution and radiation dosimetry in healthy volunteers of a novel tumour-specific probe for PET/CT imaging: BAY 85-8050.

PURPOSE: Novel tracers for the diagnosis of malignant disease with PET and PET/CT are being developed as the most commonly used (18)F deoxyglucose (FDG) tracer shows certain limitations. Employing radioactively labelled glutamate derivatives for specific imaging of the truncated citrate cycle potentially allows more specific tumour imaging. Radiation dosimetry of the novel tracer BAY 85-8050, a glutamate derivative, was calculated and the effective dose (ED) was compared with that of FDG. METHODS: Five healthy volunteers were included in the study. Attenuation-corrected whole-body PET/CT scans were performed from 0 to 90 min, at 120 and at 240 min after injection of 305.0 ± 17.6 MBq of BAY 85-8050. Organs with moderate to high uptake at any of the imaging time points were used as source organs. Total activity in each organ at each time point was measured. Time-activity curves (TAC) were determined for the whole body and all source organs. The resulting TACs were fitted to exponential equations and accumulated activities were determined. OLINDA/EXM software was used to calculate individual organ doses and the whole-body ED from the acquired data. RESULTS: Uptake of the tracer was highest in the kidneys due to renal excretion of the tracer, followed by the pancreas, heart wall and osteogenic cells. The mean organ doses were: kidneys 38.4 ± 11.2 µSv/MBq, pancreas 23.2 ± 3.8 µSv/MBq, heart wall 17.4 ± 4.1 µSv/MBq, and osteogenic cells 13.6 ± 3.5 µSv/MBq. The calculated ED was 8.9 ± 1.5 µSv/MBq. CONCLUSION: Based on the distribution and dose estimates, the calculated radiation dose of BAY 85-8050 is 2.67 ± 0.45 mSv at a patient dose of 300 MBq, which compares favourably with the radiation dose of FDG (5.7 mSv).

Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations.

PURPOSE: The LUX-Lung 3 study investigated the efficacy of chemotherapy compared with afatinib, a selective, orally bioavailable ErbB family blocker that irreversibly blocks signaling from epidermal growth factor receptor (EGFR/ErbB1), human epidermal growth factor receptor 2 (HER2/ErbB2), and ErbB4 and has wide-spectrum preclinical activity against EGFR mutations. A phase II study of afatinib in EGFR mutation-positive lung adenocarcinoma demonstrated high response rates and progression-free survival (PFS). PATIENTS AND METHODS: In this phase III study, eligible patients with stage IIIB/IV lung adenocarcinoma were screened for EGFR mutations. Mutation-positive patients were stratified by mutation type (exon 19 deletion, L858R, or other) and race (Asian or non-Asian) before two-to-one random assignment to 40 mg afatinib per day or up to six cycles of cisplatin plus pemetrexed chemotherapy at standard doses every 21 days. The primary end point was PFS by independent review. Secondary end points included tumor response, overall survival, adverse events, and patient-reported outcomes (PROs). RESULTS: A total of 1,269 patients were screened, and 345 were randomly assigned to treatment. Median PFS was 11.1 months for afatinib and 6.9 months for chemotherapy (hazard ratio [HR], 0.58; 95% CI, 0.43 to 0.78; P = .001). Median PFS among those with exon 19 deletions and L858R EGFR mutations (n = 308) was 13.6 months for afatinib and 6.9 months for chemotherapy (HR, 0.47; 95% CI, 0.34 to 0.65; P = .001). The most common treatment-related adverse events were diarrhea, rash/acne, and stomatitis for afatinib and nausea, fatigue, and decreased appetite for chemotherapy. PROs favored afatinib, with better control of cough, dyspnea, and pain. CONCLUSION: Afatinib is associated with prolongation of PFS when compared with standard doublet chemotherapy in patients with advanced lung adenocarcinoma and EGFR mutations.

Maintenance therapy with pemetrexed versus docetaxel after induction therapy with carboplatin and pemetrexed in chemotherapy-naïve patients with advanced non-squamous non-small-cell lung cancer: a randomized, phase II study.

PURPOSE: The optimal strategy for maintenance chemotherapy is controversial. We evaluated the efficacy and safety of continuation maintenance with pemetrexed and switch maintenance with docetaxel in advanced non-squamous non-small-cell lung cancer (NSCLC). METHODS: Chemotherapy-naïve patients with non-squamous NSCLC were enrolled in this randomized phase II study. Patients who achieved disease control after four cycles of induction therapy with carboplatin (AUC 6) and pemetrexed (500 mg/m(2)) were randomized to maintenance therapy with pemetrexed (500 mg/m(2)) or docetaxel (60 mg/m(2)). The primary endpoint was survival without toxicity, defined as the time from the initiation of maintenance therapy to the first date of any grade 3/4 toxicity or death due to any cause. RESULTS: A total of eighty-five patients were enrolled in the induction phase, and 26 patients were assigned to the pemetrexed maintenance therapy and 25 patients were assigned to the docetaxel maintenance therapy. Survival without toxicity was significantly longer in the pemetrexed group (median 20.8 months, 95 % confidence interval (CI) 0.7-not estimable) than in the docetaxel group (median 0.5 months, 95 % CI 0.2-2.0, hazard ratio 0.36, 95 % CI 0.17-0.74). CONCLUSIONS: Continuation maintenance with pemetrexed may be a feasible treatment option for patients with non-squamous NSCLC who have achieved disease control after induction therapy with carboplatin and pemetrexed. Switch maintenance with docetaxel may also be efficacious but frequently causes severe hematologic toxicity.

Brain efflux index to investigate the influence of active efflux on brain distribution of pemetrexed and methotrexate.

Antifolates, in particular methotrexate (MTX), have been widely used in the treatment of primary and secondary tumors of the central nervous system (CNS). Pemetrexed (PMX) is a novel antifolate that also exhibits potent antitumor activity against CNS malignancies. Studies have shown that brain distribution of both antifolates is significantly restricted, possible due to active efflux transport at the blood-brain barrier (BBB). This study characterizes the brain-to-blood transport of PMX and MTX and examines the role of several efflux transporters in brain distribution of the antifolates by use of the intracerebral microinjection technique (brain efflux index). The results from this study show that both PMX and MTX undergo saturable efflux transport across the BBB, with elimination half-lives of approximately 39 minutes and 29 minutes, respectively. Of the various efflux transporters this study investigated, multidrug resistance-associated protein 2 (Mrp2) does not play an important role in the brain distribution of the two antifolate drugs. Interestingly, breast-cancer resistance protein (Bcrp) makes a significant contribution to the brain elimination of MTX but not PMX. In addition, the brain-to-blood transport of both antifolates was inhibited by probenecid and benzylpenicillin, suggesting the involvement of organic anion transporters in the efflux of these compounds from the brain, with organic anion transporter 3 (Oat3) being a possibility. Our results suggest that one of the underlying mechanisms behind the limited brain distribution of PMX and MTX is active efflux transport processes at the BBB, including a benzylpenicillin-sensitive transport system and/or the active transporter Bcrp.

Pharmacokinetics and efficacy of pemetrexed in patients with brain or leptomeningeal metastases.

Brain metastases (BM) and leptomeningeal metastases (LM) are devastating neurologic complications. Pemetrexed is a multi-targeted anti-folate agent approved for treatment of nonsquamous non-small cell lung cancer but has anti-tumor activity in other solid tumors. We performed two trials using pemetrexed in patients with BM and LM to assess CSF penetration and anti-tumor activity. Patients were treated with intravenous pemetrexed at doses of 500 (n = 3), 750 (n = 3), 900 (n = 12) or 1,050 mg/m(2) (n = 3) every 3 weeks. Neuro-imaging was done every 6 weeks. Matched CSF and plasma samples were obtained serially from three patients with Ommaya reservoirs; the remaining patients had a single paired collection. Twenty-one patients (15 women and six men) with median age of 50 years and median KPS of 90 were treated. Primary tumors included breast (13), lung (4), colorectal (1), endometrial (1), esophageal (1) and pinealoblastoma (1). Nine patients had prior whole brain RT and median number of prior chemotherapies was two including prior methotrexate in four patients. Median pemetrexed doses administered was three (range 1-14). Responses included one partial response, ten stable disease and ten progressive disease. Median time to progression and survival was 2.7 and 7.3 months; PFS six was 22 %. No major toxicities were seen. Pemetrexed distributed from the plasma to the CSF within 1-4 h with the resulting CSF concentrations < 5 % of plasma. Pemetrexed was tolerated in solid tumor patients with CNS metastases. Limited anti-tumor activity was seen, which might have been due to low CSF concentrations, although some patients displayed prolonged benefit.

First-in-man evaluation of 2 high-affinity PSMA-avid small molecules for imaging prostate cancer.

UNLABELLED: This phase 1 study was performed to determine the pharmacokinetics and ability to visualize prostate cancer in bone, soft-tissue, and the prostate gland using (123)I-MIP-1072 and (123)I-MIP-1095, novel radiolabeled small molecules targeting prostate-specific membrane antigen. METHODS: Seven patients with a documented history of prostate cancer by histopathology or radiologic evidence of metastatic disease were intravenously administered 370 MBq (10 mCi) of (123)I-MIP-1072 and (123)I-MIP-1095 2 wk apart in a crossover trial design. (123)I-MIP-1072 was also studied in 6 healthy volunteers. Whole-body planar and SPECT/CT imaging was performed and pharmacokinetics studied over 2-3 d. Target-to-background ratios were calculated. Absorbed radiation doses were estimated using OLINDA/EXM. RESULTS: (123)I-MIP-1072 and (123)I-MIP-1095 visualized lesions in soft tissue, bone, and the prostate gland within 0.5-1 h after injection, with retention beyond 48 h. Target-to-background ratios from planar images averaged 2:1 at 1 h, 3:1 at 4-24 h, and greater than 10:1 at 4 and 24 h for SPECT/CT. Both agents cleared the blood in a biphasic manner; clearance of (123)I-MIP-1072 was approximately 5 times faster. (123)I-MIP-1072 was excreted in the urine, with 54% and 74% present by 24 and 72 h, respectively. In contrast, only 7% and 20% of (123)I-MIP-1095 had been renally excreted by 24 and 72 h, respectively. Estimated absorbed radiation doses were 0.054 versus 0.110 mGy/MBq for the kidneys and 0.024 versus 0.058 mGy/MBq for the liver, for (123)I-MIP-1072 and (123)I-MIP-1095, respectively. CONCLUSION: (123)I-MIP-1072 and (123)I-MIP-1095 detect lesions in soft tissue, bone, and the prostate gland at as early as 1-4 h. These novel radiolabeled small molecules have excellent pharmacokinetic and pharmacodynamic profiles and warrant further development as diagnostic and potentially when labeled with (131)I therapeutic radiopharmaceuticals.

(4S)-4-(3-18F-fluoropropyl)-L-glutamate for imaging of xC transporter activity in hepatocellular carcinoma using PET: preclinical and exploratory clinical studies.

UNLABELLED: (4S)-4-(3-(18)F-fluoropropyl)-l-glutamate ((18)F-FSPG, or BAY 94-9392) is a new tracer to assess system x(C)(¯) transporter activity with PET. The aim of this study was to explore the tumor detection rate of (18)F-FSPG, compared with that of (18)F-FDG, in patients with hepatocellular carcinoma (HCC). METHODS: Preclinically, in vivo HCC models of orthotopically implanted Huh7 and MH3924a cancer cells were studied with (18)F-FSPG in Naval Medical Research Institute nude mice (n = 3) and August-Copenhagen Irish rats (n = 4), respectively. Clinically, 5 patients with HCC who had hyper- or isometabolic lesions on (18)F-FDG PET were enrolled for evaluation of the tracer. Dynamic whole-body PET images with (18)F-FSPG were acquired for up to 120 min after injection of approximately 300 MBq of (18)F-FSPG. Immunohistochemical expression levels of the xCT subunit of the system x(C)(¯) and CD44 of HCC were studied in 4 patients with HCC. RESULTS: Strong tumor uptake and low background from nontarget tissue allowed excellent tumor visualization in animal models with orthotopically implanted liver tumors. (18)F-FSPG PET procedures were well tolerated in all patients. (18)F-FSPG PET and (18)F-FDG detected lesions in 5 of 5 and 3 of 5 patients, respectively. The maximal standardized uptake values (SUV) were comparable ((18)F-FSPG, 4.7 ± 3.2; (18)F-FDG, 6.1 ± 2.9). The ratios of maximal SUV of the tumor to mean SUV of normal liver were also comparable ((18)F-FSPG, 3.6 ± 2.2; (18)F-FDG, 2.7 ± 1.3), but the mean SUV of normal liver of (18)F-FSPG was significantly lower than that of (18)F-FDG (P < 0.05). Two patients with HCC who showed both xCT and CD44 expression had moderate or intense accumulation of (18)F-FSPG, but the remaining 2 patients with negative CD44 expression showed mild uptake. CONCLUSION: (18)F-FSPG was successfully translated from preclinical evaluation into patients with HCC. (18)F-FSPG may be a promising tumor PET agent with a high cancer detection rate in patients with HCC.

Sunitinib combined with pemetrexed and cisplatin: results of a phase I dose-escalation and pharmacokinetic study in patients with advanced solid malignancies, with an expanded cohort in non-small cell lung cancer and mesothelioma.

PURPOSE: To determine the maximum tolerated dose (MTD), safety and tolerability of sunitinib plus pemetrexed and cisplatin for advanced solid malignancies. METHODS: Using a 3 + 3 dose-escalation design, patients received oral sunitinib (37.5 or 50 mg) qd on a continuous daily dosing (CDD) schedule or Schedule 2/1 (2 weeks on, 1 week off treatment) plus pemetrexed (400 or 500 mg/m(2) IV) and cisplatin (75 mg/m(2) IV) q3w up to 6 cycles. RESULTS: Sunitinib 37.5 mg/pemetrexed 400 mg/m(2)/cisplatin 75 mg/m(2) CDD (n = 5) was not tolerated. Lower doses on this schedule were not explored. The Schedule 2/1 MTD (n = 15) was sunitinib 37.5 mg/pemetrexed 500 mg/m(2)/cisplatin 75 mg/m(2), based on one dose-limiting toxicity (myocardial infarction) out of six patients. The MTD was further studied in an expansion cohort of 10 non-small cell lung cancer (NSCLC) patients and one mesothelioma patient. There were no clinically significant drug-drug interactions. Cumulative myelosuppression was problematic: the median relative dose intensity (% actual/intended) across all cycles was 61 % for sunitinib, 78 % for pemetrexed, and 74 % for cisplatin. Four of eight NSCLC patients in the dose-escalation and expansion cohorts at the Schedule 2/1 MTD who were evaluable for efficacy had stable disease ≥ 8 weeks, and the one patient with mesothelioma had a partial response. CONCLUSIONS: In patients with advanced solid malignancies, sunitinib was not tolerated at 37.5 mg CDD with standard pemetrexed and cisplatin doses. Dose reductions were often needed due to cumulative myelosuppression following cycle 1. The MTD showed modest antitumor activity.

Phase Ib trial of the oral angiogenesis inhibitor pazopanib administered concurrently with pemetrexed in patients with advanced solid tumors.

INTRODUCTION: We sought to define the maximum tolerated dose (MTD) and evaluate the safety, pharmacokinetics, and preliminary clinical activity of pazopanib plus pemetrexed in patients with solid tumors. METHODS: This dose-escalation study used a standard 3 + 3 design to evaluate once daily pazopanib (400-800 mg) plus pemetrexed (400-500 mg/m(2) on Day 1 of each 21-day cycle). Eight additional patients were enrolled into an expansion cohort. RESULTS: Twenty-five patients were enrolled. Pazopanib 800 mg plus pemetrexed 500 mg/m(2) was the MTD. The most common adverse events at all dose levels included fatigue, neutropenia, diarrhea, and thrombocytopenia. The frequencies of non-hematologic adverse events were consistent with those of the individual agents. The rates of all-grade and Grade 4 hematologic toxicities (reversible neutropenia with median duration of 4 days) were higher with the combination regimen than with either monotherapy. Exploratory analyses revealed no association between the plasma levels of 3 biomarkers of vitamin B12 metabolism (cystathionine, homocysteine, and methylmalonic acid) and the risk of Grade 4 neutropenia and Grade 3 febrile neutropenia. Of 20 patients evaluated for efficacy, 2 (10 %) had a partial response. Pazopanib did not affect pemetrexed clearance, but increased pemetrexed maximal concentration by 22 %. In exploratory pharmacogenetic analyses, allelic variants of the VEGFA gene demonstrated weak correlation with development of severe neutropenia. CONCLUSIONS: Concomitant administration of pazopanib 800 mg once daily plus pemetrexed 500 mg/m(2) once every 21 days is feasible, albeit associated with a high frequency of brief, reversible neutropenia. Preliminary activity was observed in non-small-cell lung cancer.

Bioequivalence evaluation of a folate-supplemented oral contraceptive containing ethinylestradiol/drospirenone/levomefolate calcium versus ethinylestradiol/drospirenone and levomefolate calcium alone.

BACKGROUND: Neural tube defects (NTDs) are congenital malformations that occur during early embryonic development. Suboptimal maternal folate status is a well-known risk factor for the occurrence of NTDs, and periconceptional folic acid supplementation has been shown to reduce the risk of NTDs. Folate-supplemented oral contraceptives (OCs) offer a means of improving folate status in women of childbearing potential by increasing their likelihood of having raised folate levels at the time of conception. OBJECTIVE: This study aimed to demonstrate bioequivalence of ethinylestradiol (EE), drospirenone and L-5-methyl-tetrahydrofolate (L-5-methyl-THF; active moiety of levomefolate calcium) when taken as a new folate-supplemented OC containing EE/drospirenone/levomefolate calcium, with the respective OC containing EE/drospirenone and a tablet containing levomefolate calcium only. METHODS: This was a randomized, open-label, three-period crossover study carried out at a single centre in Germany. The study included 45 healthy women (age range 18-38 years). The women were randomly assigned to single doses of (i) EE 0.03 mg/drospirenone 3 mg/levomefolate calcium 0.451 mg (SAFYRAL®), (ii) EE 0.03 mg/drospirenone 3 mg (Yasmin®), and (iii) levomefolate calcium 0.451 mg, administered using a crossover design, with one or more menstrual cycle washout between doses. The primary variables were maximum concentrations (C(max)) and area under the concentration versus time curve (AUC) values for EE, drospirenone and L-5-methyl-THF. RESULTS: The bioavailability of EE and drospirenone was similar after administration of EE/drospirenone/levomefolate calcium and EE/drospirenone. The geometric mean ratios (GMRs) and its 90% confidence intervals (CIs) for AUC values and C(max) were within the pre-specified range (80.00-125.00%) for bioequivalence for EE and drospirenone in both formulations. The bioavailability of L-5-methyl-THF was similar after administration of EE/drospirenone/levomefolate calcium and levomefolate calcium. The respective GMRs and 90% CIs of baseline-uncorrected and -corrected AUC(last) (AUC from time zero to time of last measurable concentration) and C(max) were also within the 80.00-125.00% range. CONCLUSION: The novel folate-supplemented OC EE/drospirenone/levomefolate calcium is bioequivalent to the established OC Yasmin® (EE/drospirenone components) and to levomefolate calcium (folate component).

Exploratory clinical trial of (4S)-4-(3-[18F]fluoropropyl)-L-glutamate for imaging xC- transporter using positron emission tomography in patients with non-small cell lung or breast cancer.

PURPOSE: (4S)-4-(3-[(18)F]fluoropropyl)-l-glutamate (BAY 94-9392, alias [(18)F]FSPG) is a new tracer to image x(C)(-) transporter activity with positron emission tomography (PET). We aimed to explore the tumor detection rate of [(18)F]FSPG in patients relative to 2-[(18)F]fluoro-2-deoxyglucose ([(18)F]FDG). The correlation of [(18)F]FSPG uptake with immunohistochemical expression of x(C)(-) transporter and CD44, which stabilizes the xCT subunit of system x(C)(-), was also analyzed. EXPERIMENTAL DESIGN: Patients with non-small cell lung cancer (NSCLC, n = 10) or breast cancer (n = 5) who had a positive [(18)F]FDG uptake were included in this exploratory study. PET images were acquired following injection of approximately 300 MBq [(18)F]FSPG. Immunohistochemistry was done using xCT- and CD44-specific antibody. RESULTS: [(18)F]FSPG PET showed high uptake in the kidney and pancreas with rapid blood clearance. [(18)F]FSPG identified all 10 NSCLC and three of the five breast cancer lesions that were confirmed by pathology. [(18)F]FSPG detected 59 of 67 (88%) [(18)F]FDG lesions in NSCLC, and 30 of 73 (41%) in breast cancer. Seven lesions were additionally detected only on [(18)F]FSPG in NSCLC. The tumor-to-blood pool standardized uptake value (SUV) ratio was not significantly different from that of [(18)F]FDG in NSCLC; however, in breast cancer, it was significantly lower (P < 0.05). The maximum SUV of [(18)F]FSPG correlated significantly with the intensity of immunohistochemical staining of x(C)(-) transporter and CD44 (P < 0.01). CONCLUSIONS: [(18)F]FSPG seems to be a promising tracer with a relatively high cancer detection rate in patients with NSCLC. [(18)F]FSPG PET may assess x(C)(-) transporter activity in patients with cancer.