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The nuclear transcription factor brachyury has previously been shown to be a strong mediator of the epithelial-to-mesenchymal transition (EMT) in human carcinoma cells and a strong negative prognostic factor in several tumor types. Brachyury is overexpressed in a range of human carcinomas as well as in chordoma, a rare tumor for which there is no standard systemic therapy. Preclinical studies have shown that a recombinant Saccharomyces cerevisiae (yeast) vaccine encoding brachyury (GI-6301) can activate human T cells in vitro. A phase I dose-escalation (3+3 design) trial enrolled 34 patients at 4 dose levels [3, 3, 16, and 11 patients, respectively, at 4, 16, 40, and 80 yeast units (YU)]. Expansion cohorts were enrolled at 40- and 80-YU dose levels for analysis of immune response and clinical activity. We observed brachyury-specific T-cell immune responses in the majority of evaluable patients despite most having been heavily pretreated. No evidence of autoimmunity or other serious adverse events was observed. Two chordoma patients showed evidence of disease control (one mixed response and one partial response). A patient with colorectal carcinoma, who enrolled on study with a large progressing pelvic mass and rising carcinoembryonic antigen (CEA), remains on study for greater than 1 year with stable disease, evidence of decreased tumor density, and decreased serum CEA. This is the first-in-human study to demonstrate the safety and immunogenicity of this therapeutic cancer vaccine and provides the rationale for exploration in phase II studies. A randomized phase II chordoma study is now enrolling patients. Cancer Immunol Res; 3(11); 1248–56. ©2015 AACR.

Yeast-brachyury progression-free survival; chordoma patients only.

Purpose: Several case reports suggest sorafenib exposure and sorafenib-induced hyperbilirubinemia may be related to a (TA)5/6/7 repeat polymorphism in UGT1A1*28 (UGT, uridine glucuronosyl transferase). We hypothesized that sorafenib inhibits UGT1A1 and individuals carrying UGT1A1*28 and/or UGT1A9 variants experience greater sorafenib exposure and greater increase in sorafenib-induced plasma bilirubin concentration.Experimental Design: Inhibition of UGT1A1-mediated bilirubin glucuronidation by sorafenib was assessed in vitro. UGT1A1*28 and UGT1A9*3 genotypes were ascertained with fragment analysis or direct sequencing in 120 cancer patients receiving sorafenib on five different clinical trials. Total bilirubin measurements were collected in prostate cancer patients before receiving sorafenib (n = 41) and 19 to 30 days following treatment and were compared with UGT1A1*28 genotype.Results: Sorafenib exhibited mixed-mode inhibition of UGT1A1-mediated bilirubin glucuronidation (IC50 = 18 μmol/L; Ki = 11.7 μmol/L) in vitro. Five patients carrying UGT1A1*28/*28 (n = 4) or UGT1A9*3/*3 (n = 1) genotypes had first dose, dose-normalized areas under the sorafenib plasma concentration versus time curve (AUC) that were in the 93rd percentile, whereas three patients carrying UGT1A1*28/*28 had AUCs in the bottom quartile of all genotyped patients. The Drug Metabolizing Enzymes and Transporters genotyping platform was applied to DNA obtained from six patients, which revealed the ABCC2-24C>T genotype cosegregated with sorafenib AUC phenotype. Sorafenib exposure was related to plasma bilirubin increases in patients carrying 1 or 2 copies of UGT1A1*28 alleles (n = 12 and n = 5; R2 = 0.38 and R2 = 0.77; P = 0.032 and P = 0.051, respectively). UGT1A1*28 carriers showed two distinct phenotypes that could be explained by ABCC2-24C>T genotype and are more likely to experience plasma bilirubin increases following sorafenib if they had high sorafenib exposure.Conclusions: This pilot study indicates that genotype status of UGT1A1, UGT1A9, and ABCC2 and serum bilirubin concentration increases reflect abnormally high AUC in patients treated with sorafenib. Clin Cancer Res; 18(7); 2099–107. ©2012 AACR.

Characterization of rF-brachyury-TRICOM

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Purpose: In solid tumors such as prostate cancer, novel paradigms are needed to assess therapeutic efficacy. We utilized a method estimating tumor growth and regression rate constants from serial PSA measurements, and assessed its potential in patients with metastatic castration resistant prostate carcinoma (mCRPC).Experimental Design: Patients were enrolled in five phase II studies, including an experimental vaccine trial, representing the evolution of therapy in mCRPC. PSA measurements obtained before, and during, therapy were used. Data analysis using a two-phase mathematical equation yielded concomitant PSA growth and regression rate constants.Results: Growth rate constants (g) can be estimated while patients receive therapy and in such patients g is superior to PSA-DT in predicting OS. Incremental reductions in growth rate constants were recorded in successive trials with a 10-fold slower g in the most recent combination therapy trial (log g = 10−3.17) relative to single-agent thalidomide (log g = 10−2.08) more than a decade earlier. Growth rate constants correlated with survival, except in patients receiving vaccine-based therapy where the evidence demonstrates prolonged survival presumably due to immunity developing subsequent to vaccine administration.Conclusion: Incremental reductions in tumor growth rate constants suggest increased efficacy in successive chemotherapy trials. The derived growth rate constant correlates with survival, and may be used to assess efficacy. The PSA-TRICOM vaccine appears to have provided marked benefit not apparent during vaccination, but consistent with subsequent development of a beneficial immune response. If validated as a surrogate for survival, growth rate constants would offer an important new efficacy endpoint for clinical trials. Clin Cancer Res; 17(4); 907–17. ©2010 AACR.

Purpose: The transcription factor brachyury has been shown in preclinical studies to be a driver of the epithelial-to-mesenchymal transition (EMT) and resistance to therapy of human tumor cells. This study describes the characterization of a Modified Vaccinia Ankara (MVA) vector–based vaccine expressing the transgenes for brachyury and three human costimulatory molecules (B7.1, ICAM-1, and LFA-3, designated TRICOM) and a phase I study with this vaccine.Experimental Design: Human dendritic cells (DC) were infected with MVA-brachyury-TRICOM to define their ability to activate brachyury-specific T cells. A dose-escalation phase I study (NCT02179515) was conducted in advanced cancer patients (n = 38) to define safety and to identify brachyury-specific T-cell responses.Results: MVA-brachyury-TRICOM-infected human DCs activated CD8+ and CD4+ T cells specific against the self-antigen brachyury in vitro. No dose-limiting toxicities were observed due to vaccine in cancer patients at any of the three dose levels. One transient grade 3 adverse event (AE) possibly related to vaccine (diarrhea) resolved without intervention and did not recur with subsequent vaccine. All other AEs related to vaccine were transient and ≤grade 2. Brachyury-specific T-cell responses were observed at all dose levels and in most patients.Conclusions: The MVA-brachyury-TRICOM vaccine directed against a transcription factor known to mediate EMT can be administered safely in patients with advanced cancer and can activate brachyury-specific T cells in vitro and in patients. Further studies of this vaccine in combination therapies are warranted and planned. Clin Cancer Res; 23(22); 6833–45. ©2017 AACR.

Supplementary Figures S1-S6.

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Background Prostate cancer recurrence is found in up to 40% of men with prior definitive (total prostatectomy or whole-prostate radiation) treatment. Prostate-specific membrane antigen PET agents such as 2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine 3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid (

We evaluated the kinetics of (18)F-sodium fluoride (NaF) and reassessed the recommended dose, optimal uptake period, and reproducibility using a current-generation PET/CT scanner.In this prospective study, 73 patients (31 patients with multiple myeloma or myeloma precursor disease and 42 with prostate cancer) were injected with a mean administered dose of 141 MBq of (18)F-NaF. Sixty patients underwent 3 sequential sessions of 3-dimensional PET/CT of the torso beginning approximately 15 min after (18)F-NaF injection, followed by whole-body 3-dimensional PET/CT at 2 h. The remaining 13 prostate cancer patients were imaged only at 2 and 3 h after injection. Twenty-one prostate cancer patients underwent repeated baseline studies (mean interval, 5.9 d) to evaluate reproducibility.The measured effective dose was 0.017 mSv/MBq, with the urinary bladder, osteogenic cells, and red marrow receiving the highest doses at 0.080, 0.077, and 0.028 mGy/MBq, respectively. Visual analysis showed that uptake in both normal and abnormal bone increased with time; however, the rate of increase decreased with time. A semiautomated workflow provided objective uptake parameters, including the mean standardized uptake value of all pixels within bone with SUVs greater than 10 and the average of the mean SUV of all malignant lesions identified by the algorithm. The values of these parameters for the images beginning at approximately 15 min and approximately 35 min were significantly different (0.3% change per minute). Differences between the later imaging time points were not significant (P0.01). Repeated baseline studies showed high intraclass correlations (0.9) and relatively low critical percentage change (the value above which a change can be considered real) for these parameters. The tumor-to-normal bone ratio, based on the maximum SUV of identified malignant lesions, decreased with time; however, this difference was small, estimated at approximately 0.16%/min in the first hour.(18)F-NaF PET/CT images obtained with modest radiation exposures can result in highly reproducible imaging parameters. Although the tumor-to-normal bone ratio decreases slightly with time, the high temporal dependence during uptake periods less than 30 min may limit accurate quantitation. An uptake period of 60 ± 30 min has limited temporal dependence while maintaining a high tumor-to-normal bone ratio.

Purpose: This study was undertaken to determine the toxicities, pharmacokinetics, and maximum tolerated doses of oxaliplatin in patients with renal impairment and to develop formal guidelines for oxaliplatin dosing in this patient population. Patients and Methods: Thirty-seven adult cancer patients with variable renal function received intravenous oxaliplatin at 60 to 130 mg/m2 every 3 weeks. Patients were stratified by 24-hour creatinine clearance (CrCL) into four cohorts: group A (controls, CrCL ≥60 mL/min), group B (mild dysfunction, CrCL 40 to 59 mL/min), group C (moderate dysfunction, CrCL 20 to 39 mL/min), and group D (severe dysfunction, CrCL Results: No dose-limiting toxicities were observed in any patient group during the first cycle of therapy. Escalation of oxaliplatin to the maximum dose of 130 mg/m2 was well tolerated in all patient groups with a CrCL ≥20 mL/min (groups A, B, and C). Pharmacokinetic analysis showed that patients with decreased CrCL had a corresponding decrease in the clearance of plasma ultrafiltrable platinum (r2 = 0.765). However, oxaliplatin-induced side effects were not more common or severe in patients with mild to moderate renal dysfunction, despite the decrease in ultrafiltrable platinum clearance. Conclusion: Oxaliplatin at 130 mg/m2 every 3 weeks is well tolerated by patients with mild to moderate degrees of renal dysfunction. These data strongly support the recommendation that dose reductions of single-agent oxaliplatin are not necessary in patients with a CrCL greater than 20 mL/min.

Targeting angiogenesis is an evolving field of cancer research. Tumor angiogenesis is considered as an important step in the progression and metastasis of prostate cancer. Several pathways that converge toward promotion of growth, proliferation, and survival of prostate cancer cells have been targeted, including modulation of proangiogenic factors such as vascular endothelial growth factor (VEGF), tyrosine kinases, cytokines, and the extracellular matrix. Accurately measuring antitumor activity remains a challenge with the use of investigational angiogenesis inhibitors in prostate cancer.

The most common sites of metastatic disease from prostate cancer include the bones, lymph nodes and less commonly the lungs, adrenal glands, brain and kidneys. Acute fulminant hepatic failure secondary to cancer metastasis is rare and has unique clinical presentation. We describe a case of fatal liver failure in a 71-year-old male due to metastases to the liver from a prostatic adenocarcinoma. Thus in patients with metastatic cancer and elevated liver function tests, the possibility of hepatic involvement by the cancer should be considered as a possible cause of hepatic failure.

Depsipeptide (FR901228) is a bicyclic peptide isolated from Chromobacterium violaceum that has demonstrated potent in vitro cytotoxic activity against human tumor cell lines and in vivo efficacy against human tumor xenografts. The primary mechanism of action is through inhibition of histone deacetylase. Initial development was halted due to significant cardiac toxicity. Subsequent studies performed at the National Cancer Institute demonstrated administration without cardiotoxicity was possible by varying the schedule of administration. A phase I trial was designed to determine the maximum tolerated dose and toxicity profile when administered as a 4-hour infusion weekly x 3 with one week rest. 33 Patients with advanced, incurable cancers were enrolled into this trial and treated with doses of Depsipeptide ranging from 1 mg/m2 to 17.7 mg/m2. At doses above 5 mg/m2, we observed common symptoms of nausea, vomiting, fatigue, and anorexia. Subtle changes in ECGs were seen in several patients. However, no cardiac enzyme abnormalities or reduction in ejection fraction were observed. The MTD was defined as 13.3 mg/m2 with dose limiting toxicities being grade 3 thrombocytopenia and fatigue. Depsipeptide can be safely administered when given as a 4-hour infusion and further clinical trials are warranted.

Suramin, a polysulphonated napthylurea, has been extensively evaluated over the past 10 years as an anticancer agent, with the most interest in the treatment of prostate cancer. Early clinical results were promising with response rates of up to 70% being reported. However, a recent double-blind study showed only modest palliative effect in patients with androgen independent prostate cancer. In retrospect, it appears those initial reports failed to control for confounding variables such as antiandrogen withdrawal and hydrocortisone. Suramin causes numerous reversible toxicities (lethargy, rash, fatigue, anemia, hyperglycemia, hypocalcemia, coagulopathies, neutropenia, renal and hepatic complications). Neurotoxicity has been the most significant complication and appears to be related to the intensity of the dosing regimen. An optimal therapeutic dose has not been determined, but it is clear that adaptive controls add little benefit. Aside from moderate toxicities and the low therapeutic index in patients with prostate cancer, suramin's development has taught us some valuable lessons (i.e., anti-androgen withdrawal was noted during suramin's development, the use of PSA as an indicator of tumor burden was initiated during the evaluation of suramin). These lessons can be applied to all clinical trials in hormone refractory prostate cancer. Suramin has significantly enhanced the evolution of our knowledge in several areas of prostate cancer biology and treatment.

PURPOSE To investigate the pharmacokinetics and pharmacodynamics of 9-aminocamptothecin (9-AC) infused over 72 hours at doses of 5 to 74 micrograms/m2/h. PATIENTS AND METHODS 9-AC lactone and total (lactone plus carboxylate) plasma concentrations were measured in 44 patients with solid tumors using a high-performance liquid chromatography (HPLC) assay. Fifteen patients underwent extended pharmacokinetic sampling to determine the distribution and elimination kinetics of 9-AC. RESULTS At steady-state, 8.7% +/- 4.7% (mean +/- SD) of the total drug circulated in plasma as the active 9-AC lactone. Clearance of 9-AC lactone was uniform (24.5 +/- 7.3 L/h/m2) over the entire dose range examined; however, total 9-AC clearance was nonlinear and increased at higher dose levels. In 15 patients treated at dose levels > or = 47 micrograms/m2/h, the volume of distribution at steady-state for 9-AC lactone was 195 +/- 114 L/m2 and for total 9-AC it was 23.6 +/- 10.6 L/m2. The elimination half-life was 4.47 +/- 0.53 hours for 9-AC lactone and 8.38 +/- 2.10 hours for total 9-AC. In pharmacodynamic studies, dose-limiting neutropenia correlated with steady-state lactone concentrations (Css) R2 = .77) and drug dose (R2 = .71). CONCLUSION Plasma 9-AC concentrations rapidly declined to low levels following the end of a 72-hour infusion and the mean fraction of total 9-AC circulating in plasma as the active lactone was less than 10%. The pharmacokinetics of 9-AC may have a great impact on its clinical activity and should be considered in the design of future clinical trials of this topoisomerase I inhibitor.