Anticancer Activity In Preclinical Models Research Articles

467P - Phase I Study of U3-1287, A Human Monoclonal Antibody Targeting Her3, in Japanese Patients with Advanced Solid Tumors

ABSTRACT Background HER3 is a key dimerization partner for HER-family members that activates oncogenic signaling pathways lead to cell survival and proliferation. Acquired-resistance to EGFR inhibitors may result from the activation of HER3 and/or HER2, which share overlapping the signaling pathways. U3-1287 is a fully human anti-HER3 monoclonal antibody that has demonstrated anticancer activity in preclinical models. In a preceding US phase I study, the tolerability of U3-1287 was evaluated up to the dose of 20 mg/kg without dose-limiting toxicities (DLTs). In this study, we evaluated the tolerability, pharmacokinetics (PK) and potential antitumor activities of U3-1287 in Japanese patients with solid tumors up to the dose of 18 mg/kg. Methods Patients received U3-1287 at a dose of 9 mg/kg or 18 mg/kg intravenously every 3 weeks (q3w). Tumor response, incidence of anti-U3-1287 antibodies (HAHA), and level of soluble HER3 (sHER3) were also evaluated. Results Nine patients, 3 at 9 mg/kg and 6 at 18 mg/kg, were enrolled. Five patients were male and median (range) age of 67 (50-69) years. Tumor types were lung (2), colorectal (2), esophageal (2), breast (1), cervical (1), and sarcoma (1). No DLTs were reported. U3-1287-related AEs were ALT increase (3 patients), thrombocytopenia, diarrhea, stomatitis, cheilitis, rash, and AST increase (2 each). Plasma disappearance was bi-phasic and terminal half-life at the dose of 18 mg/kg was approximately 9 days. PK profiles were similar to those in the US phase I study. Four patients had best responses of stable disease. All patients tested were negative for HAHA formation. Level of sHER3 unexpectedly increased about four times in all patients. Mean sHER3 concentrations at baseline and day 15 were 3.8 ng/mL and 16.5 ng/mL, respectively. These changes did not correlate with clinical response (at day15 in SD and PD patients; 16.7 ng/mL and 16.9 ng/ml, respectively). Conclusions U3-1287 was well tolerated up to 18 mg/kg in Japanese patients with solid tumors. These data support a dosing regimen of 18 mg/kg q3w in future studies. Disclosure All authors have declared no conflicts of interest.

Abstract LB-229: Treatment of advanced cancer patients with a newest poly-epitope peptide vaccine to the thymidylate synthase(TSPP): a phase Ib (TSPP/VAC1) trial

Abstract Background TSPP is a poly-epitope peptide vaccine to the thymidylate syntase (TS) an enzyme commonly over-expressed in replicating cancer cells and recognized as a major target of fluoropyrimidines. TSPP showed immunological and anticancer activity in preclinical models, thus in the present study we investigated its safety and immunobiological activity in advanced cancer patients. This study was designed to identify TSPP Maximum Tolerated Dose (MTD) and Optimal Biological Dose (OBD) when used alone (arm A) or in combination with GM-CSF and IL-2 according to the IG-1 regimen (arm B). Patients and methods TSPP/VAC-1 (Eudract 2009-016897-33) is a monocentric phase Ib trial including 21 pretreated advanced cancer patients (12 in arm A and 9 in arm B) enrolled between April and October 2011 (12 with colorectal, 1 with breast, 1 with gastric, 1 with biliary tract and 6 with non small cell lung cancer). All patients presented a good performance status (ECOG ≤ 1). Each patient received every 3 weeks a sc administration of TSPP diluted in motanide ISA720 (1:1) at the dosage of 100 µg (6 patients), 200 µg (6 patients), and 300 µg (9 patients). Patients enrolled in arm B also received daily sc GM-CSF (100 µg) from day 1 to 5 and sc IL-2 (0.5 MIU) bid from day 6 to 15. Results No life-threatening adverse events were recorded; 1 case of grade 3 hypothyroidism (arm B), 4 cases of poly-articular arthropaty (arm A), and 4 cases of conjuntivitis (arm A) were observed. In arm B, cytokine-related flu-like syndrome, nausea, vomiting, and dyarrhea were commonly reported. An IFN-gamma ELISPOT assay revealed an increase in TS specific CTL precursors in 5 patients in arm A and 2 in arm B. It was also observed an increase in terminal effector memory and central memory T cells in the peripheral blood in both arms. Patients enrolled in arm A showed a significant decline in peripheral immune-regulatory (CD4+CD25hi+FoxP3+) T cells (baseline vs 3 vaccinations (B vs III): 3.8 vs 1.7 %; p= 0.041) and inhibitory myeloid cells (CD11c+CD15+) [Baseline (Bs) vs III vaccinations (Vc): 5.09 vs 1.02%; p= 0.05] associated to an increase in anti-proteinase III (Bs vs III Vs:0.48 vs 1.38; p= 0.04) and anti-myeloperoxidase auto-antibodies (Bs vs III Vc: 0.76 vs 1.50; p= 0.02) and reduced level of inflammatory markers (CRP, ESR, and LDH). A quality of life analysis did not reveal significant treatment-related changes in arm A, while a detrimental effect was observed in arm B. It was recorded 1 partial response (arm A);11 disease stabilitazions (8/12 patients arm A, and 3/9 arm B) and 8 disease progressions (3/12 patients arm A and 5/9 arm B). MTD was not reached, while OBD was defined as a TSPP dosage of 300 µg. Conclusion Our results suggest that the TSPP vaccine is safe and immunologically active. On these bases we believe that TSPP deserves to be evaluated in further phase II trials in cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-229. doi:1538-7445.AM2012-LB-229

Abstract B223: NKP-1339 synergistic activity in both in vitro and in vivo preclinical models highlights the therapeutic opportunity for NKP-1339 combination trials with a broad range of antitumor agents.

Abstract Background: NKP-1339 is a novel transferrin targeted ruthenium based compound that has shown promising single agent anti-cancer activity in preclinical models and in man. The compound has a novel mechanism of action, with GRP78 down-regulation included in its target pathways. In an ongoing Phase I study, the side effects are all mild and do not include those associated with standard cytotoxics or targeted agents, suggesting that NKP-1339 could be safely combined with standard anticancer therapies. The aim of this study was to evaluate the anti-tumor effects of NKP-1339 combination with these agents. Methods: In vitro combination studies were performed in breast, colon, lung, gastric, prostate, pancreatic and liver tumor cell lines with cisplatin, oxaliplatin, 5-FU, docetaxel, doxorubicin, gemcitabine, erlotinib or sorafenib as appropriate for that tumor type. Cells were exposed to NKP-1339 and a combination agent, both agents at their respective ED50, for 72hrs. Cytotoxicity was determined using the MTT assay and combination index (CI) values were calculated using the Chou-Talalay method. The effect of the NKP-1339 and cisplatin combination was further studied in vivo in a gastric carcinoma xenograft model. Results: The in vitro combination studies demonstrated NKP-1339 synergism with other anti-cancer agents in varied tumor types. The CI values ranged from 0.8 (synergism) to 0.1 (strong synergism): cisplatin (CI 0.1), doxorubicin (CI 0.2), 5-FU (CI 0.3), oxaliplatin (CI 0.4), sorafenib (CI 0.5), docetaxel (CI 0.5), erlotinib (CI 0.6), gemcitabine (0.8). In vivo studies on the combination of NKP-1339 and cisplatin in gastric carcinoma xenografts showed significant (P<0.05) tumor growth delay and extended survival when compared to the single agent activity for either compound. Conclusions: NKP-1339's novel mechanism of action and its favorable safety profile in humans suggest that it could be safely combined with standard anti-cancer therapies. The marked synergistic effects of NKP-1339 in combination with a broad range of anti-tumor agents in vitro and in vivo supports the study of this novel agent with standard anticancer therapies in Phase I combination clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B223.

A first-in-human phase I study of U3-1287 (AMG 888), a HER3 inhibitor, in patients (pts) with advanced solid tumors.

3026 Background: Human epidermal growth factor receptor 3 (HER3) is a key dimerization partner for the HER family and activates oncogenic signaling pathways. Its overexpression in many solid tumors has been linked to poor prognosis. U3-1287 (AMG 888) is a fully human anti-HER3 monoclonal antibody with demonstrated anticancer activity in preclinical models. This study had 2 parts: based on the observed tolerability of ≤20 mg/kg and pharmacokinetics (PK) study from the dose-escalation phase (part 1), 9, 14, and 20 mg/kg Q2W dosages were given in the dose-expansion phase (part 2). Methods: Pts with non–small cell lung cancer (NSCLC) and other refractory solid tumors thought to express HER3 were eligible. Study assessments included adverse event (AE) rates, PK, and tumor response (per modified RECIST and overall metabolic tumor response by EORTC). Human antihuman antibody (HAHA) responses were measured to assess immunogenicity. Results: Part 2 data (as of 9/24/10) are reported. Pts (N=31) with head and neck (1 pt), breast (1), ovary (1), cecum/appendix (1), colorectal cancer (CRC, 10), and NSCLC (17) tumor types were given 9 (n=10), 14 (n=2), and 20 mg/kg (n=19) of U3-1287 (AMG 888). Pts had a median (range) of 5 (2–10) prior chemotherapy regimens. 11 serious AEs were reported in 10 pts; none were attributable to U3-1287 (AMG 888). 16 pts (51.6%) experienced AEs ≥ grade (Gr) 3, with 1 Gr 5 dyspnea and 1 Gr 4 hypoglycemia. Two AEs ≥ Gr 3 were considered drug-related: Gr 3 anemia and Gr 3 rash. Gr 1/2 drug-related AEs in ≥10% of pts were fatigue, diarrhea, and nausea. Of 21 pts assessed, no HAHA responses were observed (by 21 days postdose). PK analysis (n=15) showed that steady state is reached after 3 dosing cycles for pts receiving 9, 14, or 20 mg/kg. Mean steady state Cmin was >10-fold greater than the threshold concentration required for 90% HER3 inhibition in xenograft models. Eight pts (6 NSCLC, 2 CRC) had a best response of stable disease at or beyond day-70 visit. One pt (NSCLC, 20 mg/kg) had significant tumor shrinkage (26.3%) and partial metabolic response by FDG-PET scan. Conclusions: U3-1287 (AMG 888) is well tolerated, with an absence of detectable HAHA responses. Part 2 data support 9–20 mg/kg Q2W dosage for future studies.

Cloning and characterization of novel tumor-targeting immunocytokines based on murine IL7

We generated and characterized novel antibody–cytokine fusion proteins (“immunocytokines”) based on murine interleukin-7 (IL7), an immunomodulatory protein which has previously shown anti-cancer activity in preclinical models and whose human counterpart is currently being investigated in clinical trials. The sequential fusion of the clinical-stage antibody fragment scFv(F8), specific to a tumor-associated splice isoform of fibronectin, yielded an immunocytokine (termed “F8-mIL7”) of insufficient pharmaceutical quality and in vivo tumor targeting performance, with a striking dose dependence on tumor targeting selectivity. By contrast, a novel immunocytokine design (termed “F8-mIL7-F8”), in which two scFv moieties were fused at the N- and C-terminus of murine IL7, yielded a protein of excellent pharmaceutical quality and with improved tumor-targeting performance [tumor: blood ratio = 16:1, 24 h after injection]. Both F8-mIL7 and F8-mIL7-F8 could induce tumor growth retardation in immunocompetent mice, but were not able to eradicate F9 tumors. The combination of F8-mIL7-F8 with paclitaxel led to improved therapeutic results, which were significantly better compared to those obtained with saline treatment. The study indicates how the engineering of novel immunocytokine formats may help generate fusion proteins of acceptable pharmaceutical quality, for those immunomodulatory proteins which do not lend themselves to a direct fusion with antibody fragments.

Abstract 1311: Disposition and biotransformation of [14C]-radiolabeled CS-7017 in healthy male subjects

Abstract Background: CS-7017 is a novel, oral, highly potent and selective peroxisome proliferator-activated receptor gamma agonist with demonstrated anticancer activity in preclinical models. Currently, CS-7017 is in phase 2 trials for the treatment of non-small cell lung and colorectal cancer. CS-7017 disposition and biotransformation were investigated in healthy male subjects following oral administration of [14C]-radiolabeled CS-7017. Methods: Blood, plasma, urine, and fecal samples were collected and analyzed for radioactive levels to determine CS-7017 disposition following a single 0.5 mg oral dose containing approximately 50 µCi of [14C]-radiolabeled CS-7017 in 6 healthy male subjects. Metabolite separation, identification, and quantification were performed using radio/HPLC followed by LC-ESI/MS and LC-MS/MS. Plasma samples were also analyzed using LC-MS/MS for CS-7017 and by accelerator mass spectrometry for metabolite profiling. Results: CS-7017 was rapidly absorbed (plasma Tmax: 1.52 h) and steadily eliminated following oral administration. The majority of radioactivity was eliminated in feces (∼70% vs ∼20% in urine). In blood, the radioactivity was mainly distributed in plasma with little or no association with blood cells, as indicated by a blood to plasma ratio of 0.5. The parent molecule is the main circulating analyte in plasma contributing 60-70% of the total exposure. R-239457 (dearyl form) and its sulphate were the two highest circulating metabolites contributing 4.5% and 6.3% of the total radioactivity at 12 h post-dose, respectively. Several other radioactive peaks (∼12) were detected in plasma at a low level (<2.5%). In both urine and feces, several metabolites such as N-glucuronide of CS-7017, and R-239457 and its sulphate and glucuronide forms were observed, whereas little or no parent CS-7017 was detected. Conclusion: CS-7017 was rapidly absorbed and steadily eliminated with the parent molecule contributing the majority of the exposure; this indicates that CS-7017 itself contributes toward in vivo pharmacological activity. Traces of the parent molecule in urine and feces indicate that the majority of the drug is eliminated by metabolism. Therefore, CS-7017 exposure may be impacted by hepatic impairment, but may not be significantly changed in subjects with impaired renal function as renal excretion contributes to a relatively low proportion of clearance (∼20%). Based on the metabolite profiles, the metabolic routes in human and animals (rats and monkeys) are similar. The two highest metabolites detected in human plasma were also present in the plasma of at least one of the preclinical toxicology species, therefore, safety concerns raised by the metabolites would be minimal in humans. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1311. doi:10.1158/1538-7445.AM2011-1311

Phase I dose-escalation study of E6201, a MEK-1 inhibitor, in advanced solid tumors.

2505 Background: E6201 is a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK)-1 and MEK kinase-1, with anticancer activity in preclinical models. Methods: This phase I, open-label study evaluated E6201 MTD in advanced solid tumors. Inclusion criteria were ECOG PS ≤1 and adequate bone marrow, renal, and liver function. Sequential cohorts of 3-6 subjects were given E6201 30-min IV infusion on Days 1, 8, and 15 of a 28-day cycle starting at 20 mg/m2 and increasing in 100% increments up to 320 mg/m2 until 2 Grade 2 toxicities or 1 DLT was observed. Doses were then increased by ≤50% up to 720 mg/m2 or until the MTD was determined. Blood samples were collected on days 1 and 15 for PK analysis. PD assessment included evaluation of CTC, serum IL-6 and IL-8 levels, and effects on proliferation and signal transduction pathway in skin and tumor biopsies. Results: 25 subjects (median age 66.6 [range 44-87] yr) received E6201 doses from 20 to 40, 80, 160, 320, and 480 mg/m2. At 480 mg/m2, 2 subjects had DLTs (QTc prolongation [Grade 3] and confusional state [Grade 4]). E6201 was reduced to 400 mg/m2, at which 1 subject had CNS toxicity (dizziness). Therefore, the 320 mg/m2 cohort was expanded to 3 additional subjects (total 6); 1 subject had 1 DLT (Grade 2 QTc prolongation) and Grade 2 CNS toxicities (dizziness, dysarthria, ataxia), confirming 320 mg/m2 as the MTD. Most-frequent AEs across doses were nausea (16%), constipation, dizziness, peripheral edema, and vomiting (all 12%, all Grade 1/2). E6201 was rapidly eliminated (mean t3/4=2.47- 5.60 hr). Exposure to E6201 was dose related and comparable on days 1 and 15. A trend for decreasing IL-6 and IL-8 levels was observed without clear dose dependency or duration of effect. Surrogate tissue (skin) biopsies were not informative. One subject with metastatic ocular melanoma had stable disease (>10 months) (B-Raf wild-type) and another, with B-Raf mutant papillary thyroid cancer, a partial remission. Conclusions: The E6201 MTD of 320 mg/m2 IV once weekly for 3 out of a 4-week cycle was well tolerated in patients with advanced solid tumors. An expansion phase at MTD will continue to assess efficacy and determine the optimal schedule using biomarker-driven endpoints and tumor response. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eisai Eisai

Evaluating the effects of zoledronic acid (ZOL) on overall survival (OS) in patients (Pts) with multiple myeloma (MM): Results of the Medical Research Council (MRC) Myeloma IX study.

8021 Background: Bisphosphonates (BPs) are standard of care for reducing the risk of skeletal-related events (SREs) in pts with bone metastases from solid tumours or bone lesions from MM. Several BPs have also demonstrated anticancer activity in preclinical models. With the highest level of activity among approved BPs, ZOL has shown anticancer activity in preclinical and clinical studies in various cancer types, including MM. Of note, in pts with early breast cancer, ZOL improved disease-free survival by 36% (P = 0.01) vs endocrine therapy alone (Gnant, et al. NEJM. 2009). Among other endpoints, the MRC Myeloma IX Study investigated effects of ZOL vs clodronate (CLO) on SREs, progression-free survival (PFS), and OS in MM pts. Methods: Newly diagnosed MM pts were randomised to ZOL (4 mg q 21-28 days) or CLO (1,600 mg q day) plus antimyeloma therapy. Treatment continued at least until disease progression. Results: Of 1,970 pts randomised,1,960 were evaluable, with a median follow-up of 3.7 yrs. To date, app...

Drugging the PI3 Kinome: From Chemical Tools to Drugs in the Clinic

The phosphatidylinositide 3-kinase (PI3K) pathway is very commonly activated in a wide range of human cancers and is a major driving force in oncogenesis. One of the class I lipid kinase members of the PI3K family, p110alpha, is probably the most commonly mutated kinase in the human genome. Alongside genetic, molecular biological, and biochemical studies, chemical inhibitors have been extremely helpful tools in understanding the role of PI3K enzymes in signal transduction and downstream physiological and pathological processes, and also in validating PI3Ks as therapeutic targets. Although they have been valuable in the past, the early and still frequently employed inhibitors, wortmannin and LY294002, have significant limitations as chemical tools. Here, we discuss the case history of the discovery and properties of an increasingly used chemical probe, the pan-class I PI3K and mammalian target of rapamycin (mTOR) inhibitor PI-103 (a pyridofuropyrimidine), and its very recent evolution into the thienopyrimidine drug GDC-0941, which exhibits excellent oral anticancer activity in preclinical models and is now undergoing phase I clinical trials in cancer patients. We also illustrate the impact of structural biology on the design of PI3K inhibitors and on the interpretation of their effects. The challenges and outlook for drugging the PI3 kinome are discussed in the more general context of the role of structural biology and chemical biology in innovative drug discovery.

Phase I Trial of MS-275, a Histone Deacetylase Inhibitor, Administered Weekly in Refractory Solid Tumors and Lymphoid Malignancies

MS-275 is a histone deacetylase inhibitor that has shown potent and unique anticancer activity in preclinical models. The aims of this phase I trial were to determine the dose-limiting toxicities and maximum tolerated dose of oral MS-275 in humans administered with food on a once weekly schedule and to study the pharmacokinetics of oral MS-275. Patients with refractory solid tumors and lymphoid malignancies were treated with oral MS-275 on a once weekly schedule for 4 weeks of a 6-week cycle. Samples for pharmacokinetic and pharmacodynamic analyses were collected during cycle 1. Protein acetylation in subpopulations of peripheral blood mononuclear cells was measured using a multivariable flow cytometry assay. A total of 22 patients were enrolled, and 19 were considered evaluable for toxicity. The maximum tolerated dose was 6 mg/m(2). No National Cancer Institute Common Toxicity Criteria grade 4 toxicities were observed. Dose-limiting grade 3 toxicities were reversible and consisted of hypophosphatemia, hyponatremia, and hypoalbuminemia. Non-dose-limiting grade 3 myelosuppression was also observed. The mean terminal half-life of MS-275 was 33.9 +/- 26.2 and the T(max) ranged from 0.5 to 24 h. Although there was considerable interpatient variability in pharmacokinetics, the area under the plasma concentration versus time curve increased linearly with dose. MS-275 is well tolerated at a dose of 6 mg/m(2) administered weekly with food for 4 weeks every 6 weeks. Drug exposure increases linearly with dose, and protein acetylation increased in all the subpopulations of peripheral blood mononuclear cells following MS-275 administration.

A dose finding pharmacokinetic study of the tumor-targeting human L19-IL2 monoclonal antibody-cytokine fusion protein in patients with advanced solid tumors

3057 Background: L19-IL2 is a tumor targeting immunocytokine constituted by a single chain Fragment variable format directed against ED-B domain of fibronectin and the human cytokine interleukin-2 (IL-2). It has striking anticancer activity in preclinical models. We evaluated safety, pharmacokinetic profile (PK) and activity of L19-IL2 in advanced cancer patients. Patients and Methods: Five cohorts of patients with recurrent/refractory solid tumors received a dose escalation intravenous infusion of L19-IL2 (5, 10, 15, 22.5 e 30 Mio IU IL2 equivalent dose) on days 1, 3 and 5 every 21 days. Serum samples for PK assessment, immunophenotyping and assays for detection of human antifusion protein antibodies to L19 (HAFA) were collected at screening and on day 1, 3, 5 and 10 of each cycle. Results: Eighteen solid cancer patients were enrolled from 11/05 to 9/06 (6 colorectal and 3 renal cell cancer (RCC) patients, 3 with melanoma, and 1 neuroendocrine tumor, thymic carcinoma, biliary tract carcinoma, breast cancer, peritoneal mesothelioma and parotid gland carcinoma). Median age was 49 years (range 35–69), 14 patients were male and 4 female. All patients were evaluable for safety and activity. The maximum tolerated dose was determined to be 22.5 Mio IU IL-2 equivalent. Drug-related dose-limiting toxicities at 30 Mio IU L19-IL2 were hypotension requiring vaso-pressor support and acute renal failure. Treatment-related deaths did not occur, and all toxicities were reversible. Five patients achieved stable disease (RCC, n=3; biliary tract carcinoma, n=1; peritoneal mesothelioma, n=1). All other patients progressed. Immunophenotyping disclosed IL2-typical transient activation of T-cell subsets. Very preliminary data showed a weak induction of HAFA at day 10 in 5 patients. These data could not be confirmed by competition ELISA experiments. Conclusions: Up to 22.5 Mio IU IL2 equivalent of L19-IL2 can be safely administered to advanced solid cancer patients in an outpatient setting. Some evidence of clinical activity in patients susceptible to immunomodulatory therapy (RCC) was found. All observed toxicity was mild and reversible. An expanded study at recommended dose in RCC patients is currently ongoing. [Table: see text]

A Phase I Study of 17-Allylaminogeldanamycin in Relapsed/Refractory Pediatric Patients with Solid Tumors: A Children's Oncology Group Study

To determine the recommended phase 2 dose, dose-limiting toxicities (DLT), pharmacokinetic profile, and pharmacodynamics of the heat shock protein (Hsp) 90 inhibitor, 17-allylaminogeldanamycin (17-AAG). 17-AAG was administered as a 60-min infusion, on days 1, 4, 8, and 11 of a 21-day cycle at dose levels of 150, 200, 270, and 360 mg/m(2)/dose. Pharmacokinetic studies and evaluations for Hsp72 and Akt levels in peripheral blood mononuclear cells were done during the first course of therapy. Seventeen patients (7 males), median 7 years of age (range, 1-19 years), were enrolled using a standard dose escalation scheme. No DLTs were observed. Although there were no objective responses, three patients remain on therapy at 6+, 7+, and 9+ months with stable disease. One patient with hepatoblastoma had a reduction in alpha-fetoprotein and stable disease over three cycles. At 270 mg/m(2)/dose, the C(max) and areas under the plasma concentration-time curves of 17-AAG were 5,303 +/- 1,591 ng/mL and 13,656 +/- 4,757 ng/mL h, respectively, similar to the exposure in adults. The mean terminal half-life for 17-AAG was 3.24 +/- 0.80 h. Induction of Hsp72, a surrogate marker for inhibition of Hsp90, was detected at the 270 mg/m(2) dose level. Drug exposures consistent with those required for anticancer activity in preclinical models were achieved without DLT. Evidence for drug-induced modulation of Hsp90 systemically was also detected. The recommended phase II dose of 17-AAG is 360 mg/m(2)/d. Non-DMSO-containing formulations may improve acceptance of this drug by children and their families.

Combination therapy for treating breast cancer using antiestrogen, ERA-923, and the mammalian target of rapamycin inhibitor, temsirolimus

The effect of combinations of a mammalian target of rapamycin (mTOR) inhibitor, temsirolimus, and an estrogen receptor-alpha (ERalpha) antagonist, ERA-923, on breast carcinoma in culture and in a xenograft model has been studied. Phase III trials are underway using temsirolimus for several cancers. ERA-923 was studied in a phase I trial for tamoxifen refractory metastatic breast cancer and was shown to have good safety profiles. Combination of noninhibitory doses of temsirolimus with suboptimal doses of ERA-923 synergistically inhibited the growth of MCF-7 cells. Synergy was found across a wide range of doses and could also be achieved by combining temsirolimus with other antiestrogens such as raloxifene and 4-hydroxytamoxifen. In vivo combination of temsirolimus and ERA-923 at certain doses and schedules completely inhibited tumor growth, while individual agents were only partially effective. Although the mechanism underlying the synergism remains to be understood, the results were associated with the ability of temsirolimus to block the transcriptional activity mediated by ERalpha as well as an increase in G1 arrest when it was combined with ERA-923. Results demonstrated for the first time that the combination of temsirolimus and a pure antiestrogen has excellent anticancer activity in preclinical models and, therefore, may have clinical use in treating hormone-dependent tumors.

Prolonged stabilization of platinum-resistant ovarian cancer in a single patient consuming a fermented soy therapy

Background. Women with ovarian cancer who experience disease progression during or within 6 months of first-line treatment with platinum-based anticancer drugs are considered to have platinum-resistant tumors. These patients have an unfavorable prognosis, and they frequently seek complementary and alternative therapies (CAM). Historically, this represents an understudied and underreported component of ovarian cancer treatment. Case. This report describes the case of a woman with rapidly progressive, platinum-resistant ovarian cancer. Upon initiating self-directed treatment with Haelan951®, a commercially available fermented soy beverage, she entered into a phase of prolonged disease stabilization including improvement in the serum tumor marker CA-125. Conclusion. Fermented soy products are known to contain high concentrations of the isoflavone, genistein, and other compounds that exhibit anticancer activity in preclinical models. This case report supports the prospective evaluation of alternative therapies such as these in patients with platinum-refractory ovarian cancer.

Plasma and cerebrospinal fluid pharmacokinetics of depsipeptide (FR901228) in nonhuman primates.

Acetylation of histones by histone acetyl transferases (HATs) leads to transcriptional activation, while histone deacetylase (HDAC) activity leads to transcriptional repression. Abnormalities of histone acetylation are associated with the malignant phenotype. Depsipeptide (FR901228) inhibits HDAC and has shown anticancer activity in preclinical models. We studied the plasma and cerebrospinal fluid (CSF) pharmacokinetics of depsipeptide in a nonhuman primate model that is highly predictive of human CSF penetration. Depsipeptide was administered intravenously at a dose of 10 mg/m(2) over 4 h to three different animals. Serial blood samples were obtained from all animals and serial CSF samples were obtained from two animals. Plasma and CSF concentrations of depsipeptide were measured using liquid chromatography/tandem mass spectrometry. Concentration-versus-time data were modeled using model-independent and model-dependent methods. The peak plasma concentration (median+/-SD) was 245+/-50 n M and occurred within the first 2 h of the infusion. The terminal half-life was 205+/-315 min, the AUC extrapolated to infinity was 50+/-15 micro M.min, and the total body clearance was 350+/-65 ml/min/m(2). In the two animals that had CSF sampling performed, the CSF peak concentration was 3.6 n M in one animal and 2.3 n M in the other, and the CSF half-lives were 250 and 325 min. The CSF penetration of depsipeptide (AUC(CSF):AUC(plasma)) was 2% in each animal. Observed changes included anorexia, fatigue, elevation of creatine phosphokinase (CPK) enzyme levels (muscle fraction), and transient early leukopenia. All animals recovered without sequelae. Although the CSF exposure to depsipeptide after intravenous administration was only 2%, CSF concentrations approached the IC(50) of depsipeptide in vitro for some tumors. Systemic administration of this agent may be useful for the treatment of leptomeningeal tumors.