First-in-human study of the epichaperome inhibitor PU-H71: clinical results and metabolic profile.

Background Molecular chaperone targeting has shown promise as a therapeutic approach in human cancers of various histologies and genetic backgrounds. The purine-scaffold inhibitor PU-H71 (NSC 750424), selective for Hsp90 in epichaperome networks, has demonstrated antitumor activity in multiple preclinical cancer models. The present study was a first in-human trial of PU-H71 aimed at establishing its safety and tolerability and characterizing its pharmacokinetic (PK) profile on a weekly administration schedule in human subjects with solid tumors refractory to standard treatments. Methods PU-H71 was administered intravenously over 1 h on days 1 and 8 of 21-day cycles in patients with refractory solid tumors. Dose escalation followed a modified accelerated design. Blood and urine were collected during cycles 1 and 2 for pharmacokinetics analysis. Results Seventeen patients were enrolled in this trial. Grade 2 and 3 adverse events were observed but no dose limiting toxicities occurred, thus the human maximum tolerated dose was not determined. The mean terminal half-life (T1/2) was 8.4 ± 3.6 h, with no dependency to dose level. A pathway for the metabolic disposal of PU-H71 in humans was derived from microsome studies. Fourteen patients were also evaluable for clinical response; 6 (35%) achieved a best response of stable disease for >2 cycles, with 2 patients remaining on study for 6 cycles. The study closed prematurely due to discontinuation of drug supply. Conclusions PU-H71 was well tolerated at the doses administered during this study (10 to 470 mg/m2/day), with no dose limiting toxicities.

A Phase II Study of Sorafenib Combined With Cetuximab in EGFR-Expressing, KRAS-Mutated Metastatic Colorectal Cancer.

BACKGROUND: Mutations in the KRAS gene predict for resistance to anti-epidermal growth factor receptor (EGFR) therapies, including cetuximab. Upregulation of vascular endothelial growth factor (VEGF)-A has been implicated in resistance to anti-EGFR treatment. Abrogation of the VEGF and RAS/RAF/MEK/ERK pathways has the potential to restore cetuximab sensitivity. PATIENTS AND METHODS: Adult patients with histologically documented, measurable, EGFR-expressing, KRAS-mutated metastatic colorectal cancer (mCRC) that had progressed after 5-fluorouracil-based regimens were treated with sorafenib 400 mg orally twice daily and intravenous cetuximab weekly in 28-day cycles. The primary endpoint was the response rate (complete response, partial response, and stable disease at 4 cycles). The secondary endpoints included plasma biomarker analysis of angiogenic cytokines and correlative imaging studies with dynamic contrast-enhanced magnetic resonance imaging and zirconium 89-panitumumab. RESULTS: Of the 30 patients enrolled, 26 were evaluable for response. Of the 26 patients evaluated, 4 had stable disease at 4 cycles and 1 had stable disease at 8 cycles. The median progression-free survival was 1.84 months. The common toxicities were rash, diarrhea, and liver enzyme elevations. Of the angiogenic cytokines evaluated, only the placental growth factor increased significantly with treatment (P < .0001). No pharmacodynamic parameters were associated with the treatment response. CONCLUSION: We report the results of a trial that combined cetuximab and sorafenib for the treatment of KRAS-mutated mCRC, with correlative imaging studies and pharmacodynamic angiogenic cytokine profiling as downstream markers of EGFR and VEGF receptor (VEGFR) signaling. No objective responses were observed. Additional development of biomarkers for patient selection is needed to evaluate combined EGFR and VEGFR blockade as a therapeutic option in KRAS-mutated CRC.

Biomarker-driven phase 2 study of MK-2206 and selumetinib (AZD6244, ARRY-142886) in patients with colorectal cancer.

PURPOSE: PI3K/AKT/mTOR and RAS/RAF/MEK pathways are frequently dysregulated in colorectal cancer (CRC). We conducted a biomarker-driven trial of the combination of MK-2206, an allosteric AKT 1/2/3 inhibitor, and selumetinib, a MEK 1/2 inhibitor, in patients with CRC to evaluate inhibition of phosphorylated ERK (pERK) and AKT (pAKT) in paired tumor biopsies. PATIENTS AND METHODS: Adult patients with advanced CRC were enrolled in successive cohorts stratified by KRAS mutation status. Initially, 12 patients received oral MK-2206 90 mg weekly with oral selumetinib 75 mg daily in 28-day cycles. Following an interim analysis, the doses of MK-2206 and selumetinib were increased to 135 mg weekly and 100 mg daily, respectively. Paired tumor biopsies were evaluated for target modulation. RESULTS: Common toxicities were gastrointestinal, hepatic, dermatologic, and hematologic. Of 21 patients enrolled, there were no objective responses. Target modulation did not achieve the pre-specified criteria of dual 70 % inhibition of pERK and pAKT levels in paired tumor biopsies. CONCLUSION: Despite strong scientific rationale and preclinical data, clinical activity was not observed. The desired level of target inhibition was not achieved. Overlapping toxicities limited the ability to dose escalate to achieve exposures likely needed for clinical activity, highlighting the challenges in developing optimal combinations of targeted agents.

Phase I study of heat-deployed liposomal doxorubicin during radiofrequency ablation for hepatic malignancies.

PURPOSE: A phase I dose escalation study was performed with systemically delivered lyso-thermosensitive liposomal doxorubicin (LTLD). The primary objectives were to determine the safe maximum tolerated dose (MTD), pharmacokinetic properties, and dose-limiting toxicity (DLT) of LTLD during this combination therapy. MATERIALS AND METHODS: Subjects eligible for percutaneous or surgical radiofrequency (RF) ablation with primary (n = 9) or metastatic (n = 15) tumors of the liver, with four or fewer lesions as large as 7 cm in diameter, were included. RF ablation was initiated 15 minutes after starting a 30-minute intravenous LTLD infusion. Dose levels between 20 mg/m(2) and 60 mg/m(2) were evaluated. Magnetic resonance imaging, positron emission tomography, and computed tomography were performed at predetermined intervals before and after treatment until evidence of recurrence was seen, administration of additional antitumor treatment was performed, or a total of 3 years had elapsed. RESULTS: DLT criteria were met at 60 mg/m(2), and the MTD was defined as 50 mg/m(2). RF ablation was performed during the peak of the plasma concentration-time curve in an effort to yield maximal drug deposition. LTLD produced reversible, dose-dependent neutropenia and leukopenia. CONCLUSIONS: LTLD can be safely administered systemically at the MTD (50 mg/m(2)) in combination with RF ablation, with limited and manageable toxicity. Further evaluation of this agent combined with RF ablation is warranted to determine its role in the management of liver tumors.

Disconnections of African American public housing residents: connections to physical activity, dietary habits and obesity.

African American (AA) and low SES populations report poor health behaviors and outcomes. This study aimed to increase understanding of barriers to participating in healthful behaviors and programs in AA residents of public housing. Twenty two apparently healthy, AA residents (50% female, M = 43.9 years) completed in depth interviews, which were taped, transcribed and analyzed using a constant comparison approach. Residents demonstrated some awareness of health recommendations, but described limited adherence. Physical activity for recreation was reported as primarily for youth, with adults engaging in limited physical activity (primarily incidental to other activities). Barriers reported by residents were both personal and environmental. Few residents were aware of local neighborhood opportunities for physical activity or healthful eating. Future efforts should focus on increasing understanding of health promoting behaviors and awareness and efficacy of residents to connect with the resources of their surrounding communities.

Clinical, genetic and radiographic analysis of 108 patients with von Hippel-Lindau disease (VHL) manifested by pancreatic neuroendocrine neoplasms (PNETs).

BACKGROUND: von Hippel-Lindau (vHL) disease is an autosomal dominant syndrome associated with neoplasms in multiple organs, which includes the pancreas. Here, we report the greatest single center experience in patients with vHL pancreatic endocrine neoplasm (PNETs). METHODS: Between December 1998 and November 2006, 633 patients with vHL were evaluated and those with PNETs were enrolled on a prospective protocol. RESULTS: Overall, 108 vHL patients had PNETs (17%). Nine patients had metastatic disease (8.3%) from their PNET. Patients with lesions greater than 3 cm (n = 25) were more likely to develop metastases than patients with lesions less than 3 cm (n = 83) (P < .005). Thirty-nine patients underwent resection. Germline sequencing showed that 78% of patients with metastases (7/9) had exon 3 mutations compared with 46% of patients without metastases (32/98; P < .01). Tumor doubling time was calculated for the largest PNET. The group with metastases had an average tumor doubling time of 337 days (range, 180-463 days) compared with 2630 days (range, 103-9614 days) for those without metastases (P < .0001). CONCLUSIONS: By implementing a system of selective operative resection based on defined criteria, vHL patients with PNETs can be managed safely. For patients with small primary lesions (<3 cm), without a mutation of exon 3 and slow tumor doubling time (>500 days), a nonoperative approach may be appropriate for these nonfunctional neoplasms.