Daniel Robles

Prospective evaluation of low-dose ketoconazole plus hydrocortisone in docetaxel pre-treated castration-resistant prostate cancer patients.

Background:Ketoconazole is a well-known CYP17-targeted systemic treatment for castration-resistant prostate cancer (CRPC). However, most of the published data has been in the pre-chemotherapy setting; its efficacy in the post-chemotherapy setting has not been as widely described. Chemotherapy-naïve patients treated with attenuated doses of ketoconazole (200–300 mg three times daily) had PSA response rate (>50% decline) of 21–62%. We hypothesized that low-dose ketoconazole would likewise possess efficacy and tolerability in the CRPC post-chemotherapy state.Methods:Men with CRPC and performance status 0–3, adequate organ function and who had received prior docetaxel were treated with low-dose ketoconazole (200 mg orally three times daily) and hydrocortisone (20 mg PO qAM and 10 mg PO qPM) until disease progression. Primary endpoint was PSA response rate (>50% reduction from baseline) where a rate of 25% was to be considered promising for further study (versus a null rate of <5%); 25 patients were required. Secondary endpoints included PSA response >30% from baseline, progression-free survival (PFS), duration of stable disease and evaluation of adverse events (AEs).Results:Thirty patients were accrued with median age of 72 years (range 55–86) and median pre-treatment PSA of 73 ng ml−1 (range 7–11,420). Twenty-nine patients were evaluable for response and toxicity. PSA response (>50% reduction) was seen in 48% of patients; PSA response (>30% reduction) was seen in 59%. Median PFS was 138 days; median duration of stable disease was 123 days. Twelve patients experienced grade 3 or 4 AEs. Of the 17 grade 3 AEs, only 3 were attributed to treatment. None of the two grade 4 AEs were considered related to treatment.Conclusions:In docetaxel pre-treated CRPC patients, low-dose ketoconazole and hydrocortisone is a well-tolerated, relatively inexpensive and clinically active treatment option. PSA response to low-dose ketoconazole appears historically comparable to that of abiraterone in this patient context. A prospective, randomized study of available post-chemotherapy options is warranted to assess comparative efficacy.

Automated Mobile System for Accurate Outdoor Tree Crop Enumeration Using an Uncalibrated Camera

This paper demonstrates an automated computer vision system for outdoor tree crop enumeration in a seedling nursery. The complete system incorporates both hardware components (including an embedded microcontroller, an odometry encoder, and an uncalibrated digital color camera) and software algorithms (including microcontroller algorithms and the proposed algorithm for tree crop enumeration) required to obtain robust performance in a natural outdoor environment. The enumeration system uses a three-step image analysis process based upon: (1) an orthographic plant projection method integrating a perspective transform with automatic parameter estimation; (2) a plant counting method based on projection histograms; and (3) a double-counting avoidance method based on a homography transform. Experimental results demonstrate the ability to count large numbers of plants automatically with no human effort. Results show that, for tree seedlings having a height up to 40 cm and a within-row tree spacing of approximately 10 cm, the algorithms successfully estimated the number of plants with an average accuracy of 95.2% for trees within a single image and 98% for counting of the whole plant population in a large sequence of images.

Abstract 5750: Synergistic effects of everolimus and bicalutamide in castration-resistant prostate cancer: Results from a phase I/II clinical trial

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Background: We previously showed that the mTOR pathway is activated in castrate resistant prostate cancer (CRPC) while inhibition of this pathway upregulated androgen receptor (AR) signaling. Based on these data, a phase I/II clinical trial was designed to determine the efficacy and tolerability of the combination of the AR inhibitor bicalutamide and the mTOR inhibitor everolimus in CRPC patients compared with bicalutamide alone. Methods: Eligible patients had histologically confirmed disease and disease progression (PSA or radiographically) while on androgen deprivation therapy (failed the therapy); and could have less than 2 months of bicalutamide at the initiation of androgen deprivation to prevent flare. The primary endpoint is PSA response. Complete response (CR) was defined as complete disappearance of all measurable and non-measurable disease. Results: In all, 19 patients were enrolled in the study, but data from only 18 have been included because one patient passed away before he could be started on the drugs. No unexpected toxicity was observed in the 18 patients enrolled in this study. 5 patients were on placebo+bicalutamide and 13 were on everolimus+bicalutamide. Of the 13 patients on everolimus+bicalutamide, nine (69.23%) had partial response (PR, a decline in PSA by at least 30%), one (7.69%) unconfirmed PR (patients have PSA response less than two cycles), and three (23.08%) had stable disease (SD, no symptomatic deterioration, PSA increase 50%) and 4 did not, were further analyzed for levels of ErbB3. Significantly, ErbB3 levels were increased in the serum from patients who did not show any decline or partial decline in PSA, but not in the ones who responded well to the drug combination. Conclusions: The combination of everolimus+bicalutamide doubled the time to relapse in patients who had failed androgen deprivation therapy, compared to bicalutamide alone. Relapse in these patients may be related to the increase in ErbB3, hence an ErbB3 inhibitor in combination with everolimus may further benefit this group of patients. We intend to investigate in the future whether expression of ErbB3 in the serum can be used to predict whether a patient will respond to the treatment or not. 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 5750. doi:1538-7445.AM2012-5750

Pembrolizumab Combined With Either Docetaxel or Gemcitabine in Patients With Advanced or Metastatic Platinum-Refractory Urothelial Cancer: Results From a Phase I Study

Introduction: Cytotoxic chemotherapy might prime urothelial cancer (UC) to checkpoint inhibition, prompting a trial of chemotherapy with the programmed death receptor‐1 inhibitor pembrolizumab. Patients and Methods: Patients with advanced, platinum‐refractory UC received pembrolizumab and either docetaxel (arm A) or gemcitabine (arm B). Primary end points were assessments of maximum tolerated dose and dose‐limiting toxicity (DLT). Secondary end points were overall response rate (ORR) and progression‐free survival (PFS). Results: Twelve patients were enrolled in the initial cohorts; 6 in each arm. One DLT was seen in each arm: Grade 3 hypophosphatemia (arm A), Grade 3 diarrhea (arm B). Adverse events of Grade >3 were observed in 7 (54%), the most common being anemia (6; 50%), fatigue (6; 50%), hyponatremia (4; 33%) and neutropenia (3; 25%), with no treatment‐related deaths. There were 5 confirmed responses (1 complete, 4 partial), with an ORR of 42% and disease control rate (DCR) of 58%. Arm A had an ORR of 50% and DCR of 67%, whereas arm B had an ORR of 33% and DCR of 50%. Median PFS was 4.8, 5.7, and 3.7 months for the overall cohort, arm A, and arm B, respectively. Conclusion: Pembrolizumab with either docetaxel or gemcitabine is feasible for treatment of platinum‐refractory advanced UC patients. Preliminary efficacy was observed. Further examination is warranted.

Prospective evaluation of low-dose ketoconazole plus hydrocortisone (HC) in chemotherapy-pretreated castration-resistant prostate cancer (CRPC) patients.

227 Background: Ketoconazole (keto), a known CYP17 inhibitor, is a traditional systemic treatment for CRPC. However, most of the published data has been in the pre-chemo setting; its efficacy in the post-chemo setting has not been as widely reported. Chemo-naive patients treated with attenuated doses of keto (200-300 mg TID) had prostate specific antigen (PSA) response rate (> 50% decline) ranges from 21%-62% and treatment was well tolerated. We hypothesized that low dose keto would likewise possess efficacy and tolerability in the CRPC post-chemo state. Methods: CRPC patients with ECOG PS 0-3, adequate end organ function, who had received at least one chemo were treated with low-dose keto (200 mg PO TID) and HC (20 mg PO q AM and 10 mg PO q PM) until progression, as defined by either RECIST or PSA rise > 50% from nadir or baseline. Primary endpoint was PSA response rate (> 50% reduction from baseline). A Simon minimax design was used. PSA response of > 25% was to be considered promising for further study...