Nirogacestat, a γ-Secretase Inhibitor for Desmoid Tumors.

BACKGROUND: Desmoid tumors are rare, locally aggressive, highly recurrent soft-tissue tumors without approved treatments. METHODS: We conducted a phase 3, international, double-blind, randomized, placebo-controlled trial of nirogacestat in adults with progressing desmoid tumors according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Patients were assigned in a 1:1 ratio to receive the oral γ-secretase inhibitor nirogacestat (150 mg) or placebo twice daily. The primary end point was progression-free survival. RESULTS: From May 2019 through August 2020, a total of 70 patients were assigned to receive nirogacestat and 72 to receive placebo. Nirogacestat had a significant progression-free survival benefit over placebo (hazard ratio for disease progression or death, 0.29; 95% confidence interval, 0.15 to 0.55; P<0.001); the likelihood of being event-free at 2 years was 76% with nirogacestat and 44% with placebo. Between-group differences in progression-free survival were consistent across prespecified subgroups. The percentage of patients who had an objective response was significantly higher with nirogacestat than with placebo (41% vs. 8%; P<0.001), with a median time to response of 5.6 months and 11.1 months, respectively; the percentage of patients with a complete response was 7% and 0%, respectively. Significant between-group differences in secondary patient-reported outcomes, including pain, symptom burden, physical or role functioning, and health-related quality of life, were observed (P≤0.01). Frequent adverse events with nirogacestat included diarrhea (in 84% of the patients), nausea (in 54%), fatigue (in 51%), hypophosphatemia (in 42%), and maculopapular rash (in 32%); 95% of adverse events were of grade 1 or 2. Among women of childbearing potential receiving nirogacestat, 27 of 36 (75%) had adverse events consistent with ovarian dysfunction, which resolved in 20 women (74%). CONCLUSIONS: Nirogacestat was associated with significant benefits with respect to progression-free survival, objective response, pain, symptom burden, physical functioning, role functioning, and health-related quality of life in adults with progressing desmoid tumors. Adverse events with nirogacestat were frequent but mostly low grade. (Funded by SpringWorks Therapeutics; DeFi ClinicalTrials.gov number, NCT03785964.).

A phase II randomized placebo-controlled trial of pomegranate fruit extract in men with localized prostate cancer undergoing active surveillance.

INTRODUCTION OR OBJECTIVE: Men with favorable-risk prostate cancer (PCa) on active surveillance may benefit from intervention strategies to slow or prevent disease progression and the need for definitive treatment. Pomegranate and its extracts have shown antiproliferative and proapoptotic effects in cell lines and animal models, but its effect on human prostate cancer as a target tissue remain unclear. Objectives of this trial include pomegranate's ability to alter serum and prostate tissue biomarkers and the ability of an active surveillance cohort to adhere to a chemoprevention trial for 1 year. METHODS: Men with organ-confined, favorable-risk PCa on AS were randomly assigned to receive pomegranate fruit extract (PFE) 1000 mg (n = 15) or placebo (n = 15) once daily for twelve months. Prostate biopsies were performed at study entry and upon completion of the 1-year intervention. Plasma and urinary biomarkers were analyzed utilizing immunoassays and HPLC. Tissue proteins were assessed by immunohistochemistry (IHC) and measured by automated quantitation. RESULTS: PFE was well-tolerated with no significant toxicities. One patient withdrew before study initiation and 29 completed the 1-year intervention. No differences in plasma insulin-like growth factor-1 (IGF-1) levels, prostate-specific antigen doubling time, or biopsy kinetics were observed. Metabolites including urolithin A and urolithin A-gluc were detected more frequently in the PFE arm in both urine and plasma (p < .001 and p = .006, respectively). IHC analyses revealed reductions from baseline in 8-OHdG (a DNA damage marker) (p = .01) and androgen receptor expression (p = .04) in prostate tumor associated with PFE treatment. CONCLUSION: PFE administration for 12-month was well-tolerated and the protocol followed in an active surveillance population. Analyses suggest that PFE contains bioactive compounds capable of altering biomarkers involving oxidative stress and androgen signaling in prostate tumor and normal-appearing adjacent tissue. No alterations in the IGF axis were noted. This finding of study adherence and target activity provides a rationale for the further investigation of PFE in the active surveillance population.

A phase I study of tivantinib in combination with temsirolimus in patients with advanced solid tumors.

Background A wide variety of human cancers exhibit dysregulated c-Met activity that has implications in oncogenesis. Phosphorylation of c-Met results in activation of the PI3K/AKT/mTOR pathway. Combined blockade of c-Met and mTOR pathways has shown efficacy in preclinical studies. Tivantinib is a c-Met inhibitor and temsirolimus is a selective mTOR inhibitor. We aimed to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D), dose-limiting toxicities (DLT), adverse events (AEs), clinical activity and pharmacokinetic (PK) parameters of the combination. Methods This open-label phase I study used a 3 + 3 dose escalation design. Patients (pts) were treated with escalating doses of tivantinib (120-360 mg tablets orally twice daily) and temsirolimus (20 mg IV weekly) followed by dose expansion at the MTD. Separate cohorts were planned for extensive (normal) and poor tivantinib metabolizers based on CYP2C19 genotypes. Cycles were 28 days besides cycle 1 that was 35 days to allow for PK analysis. Results Twenty-nine pts. [median age 58 (range 28-77)] were enrolled (21 in dose escalation and 8 in dose expansion). All were extensive CYP2C19 metabolizers. The most common types of cancer were colorectal, ovarian and non-small cell lung. Sixteen out of 21 and 6 out of 8 pts. were evaluable for DLT evaluation per protocol in the dose escalation and dose expansion phases, respectively. Pts remained on study for a median of 71 days (range 18-296). The MTD and RP2D was tivantinib 240 mg twice daily and temsirolimus 20 mg weekly. DLTs included grade (gr) 4 neutropenia (2 pts.; 1 with gr 3 febrile neutropenia), gr 3 abdominal pain (1 pt) and gr 2 mucositis resulting in inadequate drug delivery. The most common treatment related AEs grade ≥ 2 included: anemia (gr 2 in 9 pts., gr 3 in 3 pts), fatigue (gr 2 in 10 pts), anorexia (gr 2 in 9 pts), hypoalbuminemia (gr 2 in 6 pts., gr 3 in 2 pts), hypophosphatemia (gr 2 in 2 pts., gr 3 in 5 pts) and nausea (gr 2 in 6 pts., gr 3 in 1 pt). One pt. with ovarian cancer had a confirmed partial response and remained on study for 10 months, a second patient with ovarian cancer had stable disease and remained on study for 6 months and a third pt. with squamous cell carcinoma of the tongue had stable disease and remained on study for 7 months. Pharmacokinetic analysis showed that there is no interaction in the plasma concentrations between tivantinib and temsirolimus. Conclusions The combination of tivantinib with temsirolimus appears to be well tolerated with evidence of clinical activity.

Pilot study of intravenous melphalan combined with continuous infusion L-S,R-buthionine sulfoximine for children with recurrent neuroblastoma.

PURPOSE: To evaluate BSO-mediated glutathione (GSH) depletion in combination with L-PAM for children with recurrent or refractory high-risk neuroblastoma (NB) as a means to enhance alkylator sensitivity. PROCEDURE: This pilot study (NCI #T95-0092) administered L-S,R-buthionine sulfoximine (BSO) as a bolus followed by 72 hr continuous infusion of either 0.75 g/m(2)/hr (level 1) or 1.0 g/m(2)/hr (level 2) and melphalan (L-PAM) (15 mg/m(2) bolus at hour 48 of BSO infusion). GSH in blood mononuclear cells and bone marrow was measured by enzymatic assay, BSO in plasma by HPLC. RESULTS: Thirty two patients received 58 courses of therapy (median 1, range 1-4 courses). Blood mononuclear cell GSH decreased (48 hr) to 47% ± 15.7%. Level 2 mean steady-state concentration (Css) for BSO = 524 ± 207 µM and peak L-PAM concentration = 3.32 ± 1.2 µM. Grade 3-4 leukopenia and thrombocytopenia were common. There were two deaths from CNS toxicity and acute tubular necrosis; one had a large, intracranial mass, both were receiving cephalosporin antibiotics. No other significant toxicities were seen. There were six responses (five partial and, one mixed) representing an 18% response rate; four/six responses occurred in patients that relapsed following myeloablative therapy and included a 98% reduction in volume (cm(3)) of a pelvic mass, and three/five patients with >3 log reduction of tumor in marrow as measured by immunocytology (sensitivity 1/10(5)). CONCLUSIONS: BSO/L-PAM has activity against recurrent high-risk NB. Exclusion of cephalosporin antibiotics in future clinical trials of BSO may diminish the potential for serious renal and CNS toxicity.

A phase I study to determine the maximum tolerated dose and safety of oral LR-103 (1α,24(S)Dihydroxyvitamin D2) in patients with advanced cancer.

BACKGROUND: The objective of this study was to determine the maximum tolerated dose and safety of LR-103, a Vitamin D analogue, in patients with advanced cancer. METHODS: In Step A, patients received oral LR-103 once daily in 14-day cycles with intra-patient dose escalation per accelerated dose escalation design. Dose limiting toxicity for Step A was defined as ≥grade 2 hypercalcemia and/or >grade 2 other toxicities. Starting dose was 5 µg/day. Step B used a 3+3 design starting at Step A maximum tolerated dose with 28-day cycles. Dose limiting toxicity was defined as ≥grade 3 hypercalcemia or any grade 3 or 4 non-hematologic toxicity, except hypercalciuria. RESULTS: Twenty-one patients were enrolled; eight were treated in Step A. At dose level 3 (15 µg/day), two patients had dose limiting toxicity. One had grade 4 hyperuricemia. The other had grade 4 GGT plus grade 3 alkaline phosphatase, fatigue and urinary tract infection (UTI). Dose level 2 (10 µg/day) was the maximum tolerated dose for Step A and was starting dose for Step B. The dose was escalated to dose level 5 (30 µg/day) with a patient experiencing grade 3 dose limiting toxicity of hypercalcemia. The study was discontinued before reaching the maximum tolerated dose due to sponsor decision. Modest increases in serum osteocalcin and calcium and decrease in parathyroid hormone were noted. Best response was stable disease; four patients were on therapy for six months or longer. CONCLUSION: Step A dose limiting toxicities limited accelerated dose escalation. The maximum tolerated dose of LR-103 was not reached prior to study termination and this agent is no longer being developed.

Soy food frequency questionnaire does not correlate with baseline isoflavone levels in patients with bladder cancer.

BACKGROUND: The isoflavone genistein, a natural soy product with receptor tyrosine kinase-inhibiting activity, as well as phytoestrogenic and other potential anticarcinogenic effects, is being studied as an anticancer agent. Since isoflavones are commonly consumed in food products containing soy proteins, a method to control for baseline isoflavone consumption is needed. METHODS: HPLC was used to evaluate baseline plasma and urine concentrations of isoflavone in fifty-four participants with bladder cancer enrolled on a phase II chemoprevention study of G-2535. The soy food frequency questionnaire was used to assess participant's baseline soy intake. The association between baseline isoflavone concentrations and intakes for genistein and daidzein was assessed by the Spearman's rank correlation coefficient. RESULTS: The majority of participants had no detectable genistein or daidzein in plasma at baseline. The median and range of values were 0 (0-1480) nmol/L for genistein, and 0 (0-1260) nmol/L for daidzein. In urine, the median and range of values were 91.0 (0-9030) nmol/L for genistein and 623 (0-100,000) nmol/L for daidzein. The median and range of weekly estimated genistein intake was 0 (0-236) mg/wk; the median and range of weekly estimated daidzein intake was 0 (0-114) mg/wk. There was no relationship to soy intake as measured by the food frequency questionnaire and baseline isoflavone levels in plasma or urine and the Spearman's rank correlation coefficients were not significant. CONCLUSION: The soy food frequency questionnaire did not correlate with plasma or urine concentrations of either isoflavone. IMPACT: Alternative methods for controlling for soy consumption, including measuring plasma and urine concentrations, in isoflavone chemoprevention trials should be considered.

A Phase I study of intermittently dosed vorinostat in combination with bortezomib in patients with advanced solid tumors.

BACKGROUND: Accumulating evidence shows evidence of efficacy with the combination of vorinostat and bortezomib in solid tumors. We previously examined a once-daily continuous dosing schedule of vorinostat in combination with bortezomib which was well tolerated in cycles 1 and 2; however, there was concern regarding the tolerability through multiple cycles. This study was conducted to evaluate an intermittent dosing schedule of vorinostat with bortezomib. METHODS: Vorinostat was initially administered orally twice daily on days 1-14 with bortezomib IV on days 1, 4, 8, and 11 of a 21 day cycle. Two DLTs (elevated ALT and fatigue) were observed at dose level 1, thus the protocol was amended to administer vorinostat intermittently twice daily on days 1-4 and 8-11. RESULTS: 29 patients were enrolled; 13 men and 16 women. Common cancer types included sarcoma, pancreatic, colorectal, GIST, and breast. The most common Grade 3-4 toxicities at any dose level included thrombocytopenia, fatigue, increased ALT, elevated INR, and diarrhea. DLTs in the intermittent dosing scheduled included thrombocytopenia and fatigue. The Cmax and AUC for the intermittent dosing regimen were similar to those observed in the daily dosing. In this heavily pretreated population, stable disease was observed in patients with sarcoma, colorectal adenocarcinoma and GIST. CONCLUSIONS: The MTD was established at vorinostat 300 mg BID on days 1-4 and 8-11 and bortezomib 1.3 mg/m(2) IV on days 1, 4, 8, and 11 of a 21 day cycle. Tolerability was not improved with the intermittent dosing schedule of vorinostat when compared to continuous dosing.

Non-melanoma skin cancer event rates in a formalized clinical trial setting: considerations for clinical trial design.

BACKGROUND: Here we report clinical risk factors and event rates for the development of new non-melanoma skin cancer (NMSC) in a randomized, double-blind, placebo-controlled trial of the irreversible ornithine decarboxylase (ODC) inhibitor, difluromethylornithine (DFMO), over a 3-5-year follow-up. METHODS: 147 placebo patients (white; mean age 60.2 years; 60% male) were evaluated for event rates and association of initial skin biomarkers and baseline patient characteristics with the development of squamous cell (SCC) and basal cell (BCC) carcinomas. RESULTS: Post-study evaluation (median follow-up 4.4 years) indicates the measures of prior NMSCs ( P  ≤ 0.001), prior BCCs ( P  ≤ 0.001), prior SCCs ( P  = 0.011), prior tumor rate ( P  = 0.002), hemoglobin ( P  = 0.022), and gender ( P  = 0.045) as significant predictors for new NMSC development. Similarly, all measures of prior BCCs and NMSCs ( P  < 0.001), prior tumor rate ( P  = 0.014), and SCCs in the prior 2 years ( P  = 0.047) were statistically significant predictors for new BCC development. Total prior NMSCs and those in the prior 5 years ( P  < 0.001), total prior SCCs and those in the prior 5 years ( P  < 0.001), total prior BCCs and those in the prior 5 years ( P  ≤ 0.001), prior tumor rate ( P  = 0.011) as well as age ( P  = 0.008), hemoglobin ( P  = 0.002), and gender ( P  = 0.003) were statistically significant predictors of new SCC development. TPA-induced ODC activity at baseline showed no statistically significant association with the development of new NMSC ( P  = 0.35), new BCCs ( P  = 0.62), or new SCCs ( P  = 0.25). CONCLUSION: In the studied population, the history of and rate at which prior NMSCs occur are predictive and should be controlled for in future NMSC prevention trials.

A phase I study of vorinostat in combination with bortezomib in patients with advanced malignancies.

BACKGROUND: A phase I study to assess the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK) and antitumor activity of vorinostat in combination with bortezomib in patients with advanced solid tumors. METHODS: Patients received vorinostat orally once daily on days 1-14 and bortezomib intravenously on days 1, 4, 8 and 11 of a 21-day cycle. Starting dose (level 1) was vorinostat (400 mg) and bortezomib (0.7 mg/m(2)). Bortezomib dosing was increased using a standard phase I dose-escalation schema. PKs were evaluated during cycle 1. RESULTS: Twenty-three patients received 57 cycles of treatment on four dose levels ranging from bortezomib 0.7 mg/m(2) to 1.5 mg/m(2). The MTD was established at vorinostat 400 mg daily and bortezomib 1.3 mg/m(2). DLTs consisted of grade 3 fatigue in three patients (1 mg/m(2),1.3 mg/m(2) and 1.5 mg/m(2)) and grade 3 hyponatremia in one patient (1.5 mg/m(2)). The most common grade 1/2 toxicities included nausea (60.9%), fatigue (34.8%), diaphoresis (34.8%), anorexia (30.4%) and constipation (26.1%). Objective partial responses were observed in one patient with NSCLC and in one patient with treatment-refractory soft tissue sarcoma. Bortezomib did not affect the PKs of vorinostat; however, the Cmax and AUC of the acid metabolite were significantly increased on day 2 compared with day 1. CONCLUSIONS: This combination was generally well-tolerated at doses that achieved clinical benefit. The MTD was established at vorinostat 400 mg daily × 14 days and bortezomib 1.3 mg/m(2) on days 1, 4, 8 and 11 of a 21-day cycle.

Predictors of willingness to participate in window-of-opportunity breast trials.

OBJECTIVE: We conducted a pilot survey to evaluate breast cancer patients' willingness to participate in a preoperative chemoprevention (ie, window-of-opportunity) study. Design A 27-question written survey was developed and administered to participants. Setting A breast cancer specialty clinic at the University of Wisconsin Hospital and Clinics. Participants 30 adult patients with newly diagnosed operable breast cancer participated after signing informed consent. METHODS: A convenience sample of 30 participants was recruited from July 2005 through January 2006. Participants were administered the survey in clinic. Univariate ordinal logistic regression models were used to identify predictors of willingness to participate in window-of-opportunity trials. RESULTS: Overall, 26.7% of respondents were willing to participate in a research trial between the time of breast cancer diagnosis and surgery. Univariate ordinal logistic regression models identified that women with a prior history of breast cancer (P=0.060), prior research participation (P=0.006), more education (P=0.034), and self-reported breast cancer knowledge (P=0.043) were more willing to participate. On average, women preferred to have surgery 7 days (range 1-14) after their diagnosis, but the actual average wait time between diagnostic biopsy and surgery was 37.5 days (standard deviation = 23.4 days). CONCLUSION: There is ample time before breast surgery to conduct preoperative window-of-opportunity trials. Interventions aimed at expanding patients' breast cancer knowledge may improve accrual to window-of-opportunity studies.

Ototoxicity of Long-Term α-Difluoromethylornithine for Skin Cancer Prevention.

OBJECTIVE: Evaluate the effects of α-difluoromethylornithine (DFMO) on hearing thresholds as part of a randomized, double-blind, placebo-controlled trial. METHODS: Subjects were randomized and assigned to the control (placebo) or experimental (DFMO) group. DFMO or placebo were administered orally (500 mg/m2 /day) for up to 5 years. RESULTS: Subjects taking DFMO had, on average, increased hearing thresholds from baseline across the frequency range compared to subjects in the control group. Statistical analysis revealed this was significant in the lower frequency range. CONCLUSIONS: This randomized controlled trial revealed the presence of increased hearing thresholds associated with long-term DFMO use. As a whole, DFMO may help prevent and treat certain types of cancers; however, it can result in some degree of hearing loss even when administered at low doses. This study further highlights the importance of closely monitoring hearing thresholds in subjects taking DFMO. Laryngoscope, 133:676-682, 2023.

Stress Keratin 17 Is a Predictive Biomarker Inversely Associated with Response to Immune Check-Point Blockade in Head and Neck Squamous Cell Carcinomas and Beyond.

Low response rates in immune check-point blockade (ICB)-treated head and neck squamous cell carcinoma (HNSCC) drive a critical need for robust, clinically validated predictive biomarkers. Our group previously showed that stress keratin 17 (CK17) suppresses macrophage-mediated CXCL9/CXCL10 chemokine signaling involved in attracting activated CD8+ T cells into tumors, correlating with decreased response rate to pembrolizumab-based therapy in a pilot cohort of ICB-treated HNSCC (n = 26). Here, we performed an expanded analysis of the predictive value of CK17 in ICB-treated HNSCC according to the REMARK criteria and investigated the gene expression profiles associated with high CK17 expression. Pretreatment samples from pembrolizumab-treated HNSCC patients were stained via immunohistochemistry using a CK17 monoclonal antibody (n = 48) and subjected to spatial transcriptomic profiling (n = 8). Our findings were validated in an independent retrospective cohort (n = 22). CK17 RNA expression in pembrolizumab-treated patients with various cancer types was investigated for predictive significance. Of the 48 patients (60% male, median age of 61.5 years), 21 (44%) were CK17 high, and 27 (56%) were CK17 low. A total of 17 patients (35%, 77% CK17 low) had disease control, while 31 patients (65%, 45% CK17 low) had progressive disease. High CK17 expression was associated with a lack of disease control (p = 0.037), shorter time to treatment failure (p = 0.025), and progression-free survival (PFS, p = 0.004), but not overall survival (OS, p = 0.06). A high CK17 expression was associated with lack of disease control in an independent validation cohort (p = 0.011). PD-L1 expression did not correlate with CK17 expression or clinical outcome. CK17 RNA expression was predictive of PFS and OS in 552 pembrolizumab-treated cancer patients. Our findings indicate that high CK17 expression may predict resistance to ICB in HNSCC patients and beyond.

Phase I trial of motexafin gadolinium and doxorubicin in the treatment of advanced malignancies.

PURPOSE: To assess the safety, maximum-tolerated dose (MTD), and dose-limiting toxicities (DLT), of motexafin gadolinium (MGd), given in combination with doxorubicin, in patients with advanced solid tumors. STUDY DESIGN: The combination of MGd and doxorubicin was administered every 28 days (cycle 1) and then every 21 days (subsequent cycles). The dose of MGd, given daily for 3 days, was escalated from 1.0 mg/kg/d to 3.3 mg/kg/d, while the dose of doxorubicin was held at 30 mg/m². RESULTS: Fifteen patients received 37 cycles of treatment, for a median of 2 cycles per patient (range 0-6 cycles). Three patients (20%) completed 6 cycles of therapy. The MTD was identified as MGd, 2 mg/kg/day and doxorubicin, 30 mg/m². Dose limiting toxicities included grade 3 hypertension, pneumonia, bacteremia, and elevated GGT. Serious adverse events also included pulmonary embolism and urinary tract infection requiring hospitalization. There was no exacerbation of cardiac toxicity. No patients attained a response to treatment. Six patients (54%) had stable disease. The median time to disease progression, or to last assessment, was 49 days (range 8-195 days). CONCLUSIONS: The combination of MGd and doxorubicin was fairly well tolerated. However, due to emerging preclinical data suggesting that MGd inhibits ribonucleotide reductase, further development of the combination of MGd plus doxorubicin is not recommended.

A randomized, double-blind, dose-ranging, pilot trial of piperine with resveratrol on the effects on serum levels of resveratrol.

Resveratrol (3,4,5-trihydroxystilbene) is a naturally occurring phytoalexin with purported health-promoting effects, but with limited oral bioavailability. Our prior murine modeling research observed enhanced resveratrol bioavailability with piperine co-administration. In this study, single-dose pharmacokinetics of resveratrol with or without piperine and the associated toxicities were studied on a cohort of healthy volunteers. We performed a double-blind, randomized, three-arm pilot study. Participants were randomized to receive a single dose of resveratrol 2.5 g, with piperine in 0 mg, 5 mg, or 25 mg dose. An improved liquid chromatography/mass spectrometry assay was used to determine serum levels of resveratrol and resveratrol-glucuronide. Baseline through 24 h post-study drug serum analyses were performed and adverse events were followed for 30 days. Twenty-four participants were enroled. No significant relationship between dose and pharmacokinetic values were found. In the sex stratified analysis, Cmax for resveratrol in women showed a trend (P = 0.057) toward an increase with piperine. Pharmacokinetic values for resveratrol were: Cmax - 18.5 ± 16 ng/mL resveratrol alone, 29 ± 29 resveratrol + 5 mg piperine, 16 ± 13 resveratrol + 25 mg piperine; area under the concentration × time curve - 1270 ± 852 ng/h/mL resveratrol alone, 2083 ± 2284 resveratrol + 5 mg piperine, 1132 ± 222 resveratrol + 25 mg piperine. All subjects tolerated their protocol therapy with minimal to no toxicity and no evidence of differences between the three groups. The co-administration of resveratrol with piperine at 5 and 25 mg doses did not sufficiently alter the pharmacokinetics of resveratrol or resveratrol-glucuronide to demonstrate the significant enhancement observed in murine modeling.

Brief report: Measuring the attitudes of health care professionals in Dane County toward adolescent immunization with HPV vaccine.

OBJECTIVE: Evaluate regional health care professionals' views of human papillomavirus (HPV) vaccination recommendations for adolescent patients through a mailed survey. METHODS: A 16-question self-administered questionnaire was mailed to 518 physicians, physician assistants, and nurse practitioners in Dane County, Wis, working in family medicine, pediatrics, or gynecology in September 2006. The survey addressed health care professionals' willingness to recommend the HPV vaccine, populations they would target for a recommendation, and justifications provided to patients regarding the benefits of HPV vaccination. RESULTS: Of the health care professionals who were mailed a survey, 39% responsed. The majority (95%) of professionals were willing to recommend the HPV vaccine to their adolescent patients. Most practitioners (67%) were planning to recommend the vaccine to their female patients only and are most comfortable vaccinating patients >10 years of age. Health care professionals were looking to their own health profession organizations for vaccination recommendations. CONCLUSION: Health care professionals in family medicine, pediatrics, and gynecology in Dane County, Wis, have positive attitudes regarding HPV vaccine recommendation for their adolescent patients.

Oncologic Implications of Chronic Hepatitis C Virus Infection.

Chronic hepatitis C virus (HCV) infection increases the risk for several types of cancer, including hepatocellular carcinoma (HCC) and B-cell non-Hodgkin lymphoma, as primary and second primary malignancies. HCV-infected patients with cancer, particularly those undergoing anticancer therapy, are at risk for development of enhanced HCV replication, which can lead to hepatitis flare and progression of liver fibrosis or cirrhosis. Risk factors for HCV infection include injection drug use, blood transfusion, or solid organ transplantation before 1992, receipt of clotting factor concentrates before 1987, long-term hemodialysis, chronic liver disease, HIV positivity, and occupational exposure. Widely available direct-acting antivirals are highly effective against HCV and well tolerated. Identification of HCV-infected individuals is the essential first step in treatment and eradication of the infection. One-time screening is recommended for persons born from 1945 to 1965; screening is also recommended for persons with risk factors. Recently, a public health recommendation has been drafted to screen all adults age 18 to 79 years. Two oncology organizations recommend screening all patients with hematologic malignancies and hematopoietic cell transplant recipients, and a recently published multicenter prospective study supports universal HCV screening for all patients with cancer. HCV screening entails testing for anti-HCV antibodies in serum and, when results are positive, HCV RNA quantitation to confirm infection. Direct-acting antiviral therapy eradicates HCV in almost all cases. Virologic cure of HCV prevents chronic hepatitis and progression to liver fibrosis or cirrhosis. HCV eradication also decreases the risk of developing HCV-associated primary and second primary malignancies, and it may allow HCV-infected patients access to important cancer clinical trials. Patients with HCV-related cirrhosis require lifelong surveillance for HCC, even after viral eradication.

A Randomized, Placebo-Controlled, Double-Blind, Dose Escalation, Single Dose, and Steady-State Pharmacokinetic Study of 9cUAB30 in Healthy Volunteers.

9cUAB30 is a synthetic analogue of 9-cis retinoic acid with chemoprevention activity in cell lines and animal models. The purpose of this phase I placebo-controlled, double-blinded, dose escalation study of 9cUAB30 was to evaluate its safety, pharmacokinetics, and determine a dose for future phase II studies. Participants received a single dose of study drug (placebo or 9cUAB30) on day 1 followed by a 6-day drug-free period and then 28 days of continuous daily dosing starting on day 8. Fifty-three healthy volunteers were enrolled into five dose cohorts (20, 40, 80, 160, and 240 mg). Participants were randomized within each dose level to receive either 9cUAB30 (n = 8) or placebo (n = 2). 9cUAB30 was well tolerated, with no dose limiting toxicities reported and no evidence of persistent elevations in serum triglycerides or cholesterol. Treatment-emergent grade 3 hypertension occurred in 1 of 8 participants at the 20 mg dose level and in 2 of 8 at the 240 mg dose level, all considered unlikely related to study agent; no other grade 3 adverse events were observed. The AUC increased, as expected, between day 1 (single dose) and day 36 (steady state). Pharmacokinetics were linear in dose escalation through 160 mg. 9cUAB30 administered by daily oral dosing has a favorable safety and pharmacokinetic profile. On the basis of the observed safety profile and lack of linearity in pharmacokinetics at doses greater than 160 mg, the recommended phase II dose with the current formulation is 160 mg once daily.

Phase II trial of daily oral perillyl alcohol (NSC 641066) in treatment-refractory metastatic breast cancer.

PURPOSE: Perillyl alcohol (POH) is a naturally occurring lipid with preclinical activity against mammary carcinomas. We conducted a phase II multi-institutional study of oral POH administered four times daily in women with advanced treatment-refractory breast cancer. METHODS: Eligible women were treated with POH four times daily at 1,200-1,500 mg m(-2) dose(-1) on a 28-day cycle. Patients tolerating 1,200 mg m(-2) day(-1) four times daily after one cycle were dose-escalated to 1,500 mg/m(2). The primary endpoint was 1-year freedom-from-progression (FFP) rate. Secondary endpoints were response rate, tolerability and correlative evaluations. RESULTS: Twenty-nine cycles of POH were administered to 14 women. Three patients were dose-escalated to 1,500 mg/m(2). Grade 1 and grade 2 gastrointestinal effects and fatigue were predominant toxicities. Of seven patients receiving up to one cycle, three stopped therapy due to intolerance. Only two patients received more than two cycles, with disease stabilization of 3 and 8 months. Thirteen patients were evaluable for response. One-year FFP rate was zero. No objective responses were seen. The median time to progression was 35 days (95% CI, 29-123 days). Median overall survival was 389 days (95% CI, 202-776 days). Pharmacokinetic parameters were similar to previous investigations. The ability to correlate plasma TGF-beta1 levels with outcome was limited by lack of clinical benefit and inter- and intra-patient variability. CONCLUSIONS: Enrollment was suspended short of planned accrual because of lack of response and poor tolerance to POH. This regimen does not appear to provide benefit in advanced treatment-refractory breast carcinoma.