bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II trial of combination therapy with intravenous bevacizumab (B), oral satraplatin (S), and prednisone (P) in docetaxel-pretreated (DP) metastatic castrate-resistant prostate cancer (CRPC).
Authors: Vaishampayan U. N. , Heilbrun L. K. , Dickow B. , Heath E. I. , Smith D. W. , Baranowski K. , Cher M. L. , Powell I. , Pontes J. E. , Fontana J. A. 
Published: February 2017

152 Background: Satraplatin is an oral platinum that has demonstrated efficacy and tolerability in metastatic CRPC. Bevacizumab has revealed safety and efficacy in advanced prostate cancer, and synergy was noted between platinum based chemotherapy and B. Methods: Primary endpoint was time to progression (TTP). Latter wasdefined per RECIST 1.0 or onset of a skeletal event, or > 2 new areas of bone metastases. DP metastatic CRPC patients were eligible. S 80mg/m2 orally on days 1-5, P 5 mg twice daily, and B 10mg/kg on day 1, and 15mg/kg on day 15 were administered in 35 day cycles. Results: 31 patients enrolled (13 African American and 18 Caucasian) to complete accrual. Median age was 67 years (range 50-85 years) and 21 patients (68%) were > 65 years of age. Median pretherapy PSA was 180.7 ng/ml (range 4.7-1,433 ng/ml). 21 (68%) had bone pain, Gleason score was > 8 in 20 (65%) patients. Pretherapy 12 patients had measurable disease progression, 17 (55%) had bone scan progression, and 8 had PSA only progression. 176 cycles have been administered; median 4 cycles (range 0-12 cycles). Grade 4 toxicities noted were, pulmonary embolism in 2 patients and thrombocytopenia in 1 patient. Grade 3 toxicities observed were neutropenia and hypertension in 3, anemia in 7 and , thrombocytopenia and diarrhea in 2 patients each. No treatment related deaths. 29 patients are response evaluable to date; 10 (34%) had a ≥30% PSA decline and 3 (10%) had a > 90% PSA decline. Of 12 patients with MD, 2 had a response and 7 had stable disease. Median TTP was 7.4 months (90% CI 4.8-12.8 months) and median survival was 11.2 months (90% CI 9.1-18.3 months). 47% of patients were alive at 12 months. Genotype characterization for excision repair cross-complementation group 1 (ERCC1) polymorphism was performed in 17 patients with 9 having homozygous (CC), 3 with heterozygous, (CT) and 2 patients with absence of ERCC expression respectively. Conclusions: The combination was tolerable and revealed promising efficacy in metastatic CRPC. ERCC1 testing will be correlated with outcome endpoints. Supported in part by Genentech Inc and GPC Biotech. [Table: see text]
Encouraging activity of bicalutamide and everolimus in castration-resistant prostate cancer (CRPC): Early results from a phase II clinical trial.
Authors: Pan C. , Ghosh P. , Lara P. , Robles D. , Beckett L. , de Vere White R. 
Published: February 2017

157 Background: Multiple signaling pathways are involved in the development of CRPC. We previously showed that the mTOR pathway is activated in CRPC cell lines while inhibition of this pathway results in upregulation of androgen receptor (AR) signaling (Wang et al, Oncogene. 2008). Simultaneous blockade of the mTOR and AR pathways synergize in inducing PCa cell death and delaying tumor formation in mouse models. We hypothesize that simultaneous blockade of the AR and mTOR pathways in CRPC patients with bicalutamide and everolimus will result in improved efficacy compared to bicalutamide alone. Methods: A phase II clinical trial with a lead-in safety phase was designed to determine the efficacy and tolerability of the bicalutamide and everolimus combination in CRPC patients compared with bicalutamide alone. Patients must have histologically confirmed disease and demonstrated disease progression (either by PSA or radiographically) while on androgen deprivation therapy. At the lead-in phase, all patients receive both agents. At the phase II stage, patients are randomized to bicalutamide +/− everolimus. The primary endpoint is PSA response. The second endpoints include progression-free survival, time-to-treatment failure, overall survival and toxicity. Here, we report the results of the lead-in phase. Results: Eight patients were recruited at the lead-in phase. The bicalutamide/everolimus combination was well tolerated with no unexpected toxicities. Six of 8 patients have had PSA response after at least 8 weeks of therapy and the remaining two patients had stable PSA response. The median time to disease progression was 6.8 months. Nine patients have been recruited at the phase II stage so far. This clinical trial is being subcontracting to the other sites of the California Cancer Consortium. Tumor and blood specimens are being collected for molecular correlative studies of mTOR pathway markers. Conclusions: The rational combination of bicalutamide and everolimus appears to have promising anti-tumor activity and an acceptable toxicity profile. The randomized phase of the clinical trial is currently ongoing and will be reported. Supported by Novartis. [Table: see text]
The effect of PSA doubling time (PSADT) and Gleason score on the PSA at the time of initial metastasis in men with biochemical recurrence after prostatectomy.
Authors: Antonarakis E. S. , Keizman D. , Carducci M. A. , Eisenberger M. A. 
Published: February 2017

16 Background: We previously reported on a cohort of men with biochemical recurrence after prostatectomy (n=430) who underwent observation until metastatic progression. Here, we describe the PSA at metastasis for those patients who developed metastatic disease. Methods: PSA at metastasis was defined as the PSA value collected at the time of the first occurrence of metastasis as determined by CT or bone scan. We calculated the median PSA at metastasis and the interquartile range (IQR) for the entire cohort of men with metastatic progression, and also across different strata of PSADT (≤3 vs 3-9 vs 9-15 vs ≥15 mo) and Gleason score (≤7 vs 8-10). We used Pearson's correlation coefficient (r) to examine the relationship between PSADT or Gleason score and PSA at metastasis. Results: With a median follow-up of 4 years after biochemical recurrence, 126/430 men (29.3%) had developed metastases. Sites of first metastasis included bone in 114 men (90.5%), extra-pelvic lymph nodes in 5 men (4.0%), lung in 3 men (2.4%), liver in 3 men (2.4%), and brain in 1 man (0.8%). The median PSA at the time of initial metastasis was 31.4 ng/mL (IQR, 8.8–87.5). Median PSA at metastasis across different PSADT strata is shown below (Table). There was a weak but statistically significant correlation between PSADT and 1/PSA at metastasis (r=0.20, P=0.02). There was no correlation between Gleason score and PSA at metastasis (r=0.01, P=0.83). Median PSA at metastasis was 30.3 ng/mL (IQR, 8.6–74.9) for men with Gleason ≤7 (n=69) and 34 ng/mL (IQR, 7.9–115) for men with Gleason 8-10 (n=57). Conclusions: In patients with biochemical recurrence after prostatectomy, there is an inverse correlation between PSADT and PSA at metastasis, while Gleason sum has no effect on PSA at metastasis. These data may be used by clinicians to estimate at what PSA level metastases are likely to first develop across different strata of PSADT, helping to determine when/if to initiate therapy. [Table: see text] No significant financial relationships to disclose.
Phase II study of maintenance therapy with temsirolimus (TEM) after response to first-line docetaxel (TAX) chemotherapy in castration-resistant prostate cancer (CRPC).
Authors: Emmenegger U. , Berry S. R. , Booth C. , Sridhar S. S. , Winquist E. , Bandali N. , Chow A. , Kerbel R. S. , Ko Y. 
Published: February 2017

160 Background: TAX is the standard first-line chemotherapy for CRPC. However, a number of questions remain regarding the optimal use of TAX following maximal response. Aside from intermittent TAX, maintenance therapy with well-tolerated agents such as the mTOR inhibitor TEM could be one strategy to prolong treatment response and the chemotherapy-free interval, without significantly compromising quality of life. In fact, the mTOR pathway is involved in many aspects of CRPC, and mTOR inhibitors have demonstrated significant anti-CRPC activity in preclinical testing. Methods: CRPC pts eligible for this single-arm, multicenter phase II trial must have received between 6 to 8 cycles of first-line TAX (75 mg/m2 q3wks) with documented treatment response by PSA (>50% decline from baseline) or RECIST criteria. 30 pts will be enrolled and administered weekly TEM (25 mg iv × 4/cycle). The primary endpoint is time to treatment failure (TTF, by RECIST or symptomatic progression). Secondary endpoints include safety (NCI-CTCAE v3.0), quality of life (FACT-P, PPI), changes in PSA doubling time and time to PSA progression, objective tumor response rate (RECIST), and overall survival. We will also study correlative endpoints using plasma and peripheral blood mononuclear cells (i.e., markers of mTOR inhibition, of antiangiogenic TEM effects and of intratumoral hypoxia/acidosis, the latter as potential predictive markers). Results: 10 pts have been enrolled to date: mean age 68 (range 52-80), prior definitive local therapy (7)—radiation (6), prostatectomy (1), mean PSA at entry 99.28 (2.3- 380.7), ECOG 0 (4) or 1 (6), prior cycles of TAX 6 (6) or 8 (4), sites of metastasis—bone (8), lymph nodes (4), visceral (3). 6 pts have been discontinued due to treatment failure after a mean of 5.3±1.9 cycles (range 3-8) - RECIST (1), symptomatic (2), combined (3). 4 pts are on cycle 1-2-8-9, respectively. TEM has been generally well tolerated without unexpected side-effects, but may have contributed to worsening lymphedema in 1 pt. Conclusions: TEM maintenance therapy in CRPC pts that have responded to first-line TAX is well tolerated and appears to result in meaningful TTF. No significant financial relationships to disclose.
Modulating autophagy using hydroxychloroquine (HCQ) in patients with hormone-dependent PSA progression after local therapy for prostate cancer (PC).
Authors: McCarthy T. , Mayer T. M. , Stein M. N. , Anand M. , Collins F. , Jeyamohan C. , Metzger D. , Moore D. , White E. , DiPaola R. S. 
Published: February 2017

164 Background: Autophagy is conserved, genetically controlled catabolic response to starvation and stress whereby cells self- digest intracellular proteins and organelles by targeting them for degradation in lysosomes to generate energy and mitigate damage, thereby supporting cancer cell survival. We hypothesized that HCQ, by blocking autophagy, would slow PC growth. Methods: Pts had rising PSA after primary therapy for PC, no radiographic evidence of metastasis, no (neo)adjuvant ADT within 3 months of enrollment and testosterone > 150 ng/dL. HCQ was dosed at 400 mg/day (cohort 1) or 600 mg/day (cohort 2). Endpoints were PSA response (defined as a change in slope of PSA rise by at least 25%, when log (PSA) is plotted vs. time) and assessment of safety and tolerability. Levels of p62 (which accumulates upon autophagy inhibition) and accumulation of autophagosomes (measured by EM) were assessed in blood mononuclear cells. Results: 38 pts (35 cohort 1; 3 cohort 2) of planned 64 pts with median age 65 (52-81), Gleason scores: 5 (5%), 6 (18%), 7 (55%), 8 (8%), 9 (13%) have been accrued. 30 pts have completed 6 cycles of therapy and 2 pts have completed 4 cycles of HCQ. 14/32 (44%) pts included in the analysis had a decrease in doubling time after treatment. 2 (6%) had declining PSA. Treatment was well tolerated, with grade 1 rash (10%), grade 1 nausea (10%) and grade 1 diarrhea (20%) being the predominant side effects noted. 3 pts had grade 2 toxicities (rash and diarrhea). There were no grade 3/4 toxicities. EM and p62 was assessed in 12 and 20 pts, respectively, and showed evidence of mitochondrial dysfunction and p62 accumulation. Conclusions: HCQ 400 mg/day appears to have some activity in PSA progression after localized therapy with minimal toxicity. Evaluation with higher doses of HCQ is ongoing. Assessing markers of autophagy including EM and p62 are feasible in pts and will require further validation in larger trials. No significant financial relationships to disclose.
Multiple rechallenges (ReCs) with docetaxel (DOC) as an option after first-line therapy in patients (pts) with castration-resistant prostate cancer (CRPC).
Authors: Caffo O. , Brugnara S. , Caldara A. , Ferro A. , Frisinghelli M. , Murgia V. , Soini B. , Valduga F. , Veccia A. , Galligioni E. 
Published: February 2017

165 Background: Responder pts to first-line DOC, who have stopped the treatment in absence of progression, usually experience a disease progression within few months. In recent years, ReC with DOC has emerged as a therapeutic option for these pts, able to achieve again a response. The available data usually report on the clinical outcome of pts who have received one or two ReCs, but it is unclear whether more ReCs may be offered to these pts and if there is a maximum number of affordable ReCs. Methods: We retrospectively reviewed the clinical record of the pts with CRPC treated in our Department with DOC from March, 2002 to September, 2010. We selected pts who received multiple ReCs until the appearance of a true resistance to DOC: we consider as DOC-resistant pts showing a clinical and/or biochemical progression during DOC treatment. Results: We have identified a consecutive series of 26 pts, who have received a median number of 2 ReCs (range 2- 6). The median age was 68 yrs (range 58-82 yrs). The ReC consisted of DOC q 3 wks in 7 cases, DOC + estramustine q 3 wks in 38, weekly DOC + estramustine in 23. Multiple ReCs were well tolerated with no more than grade 1 hematological and non-hematological toxicities. To date, 11 pts are still DOC-sensitive (after 2-6 ReCs, median 2) and are receiving ReCs or are in the off-therapy period after ReCs. After a median follow-up of 30 months, 14 pts are dead and 12 alive. The median survival is 40 mos and the projected 3-years overall survival is 54%. Conclusions: In our experience multiple DOC ReCs may be administered in DOC-sensitive pts with CRPC. This may provide a long-term disease control with remarkable survival rate compared to those of DOC pivotal studies (19 mos) and a second line treatment may be retarded until the appearance of a true DOC-resistance. [Table: see text] No significant financial relationships to disclose.
Correlation of serum cytokines with clinical responses in patients treated with BPX-101, a drug-activated vaccine for metastatic castration-resistant prostate cancer (mCRPC).
Authors: Spencer D. M. , Lapteva N. , Levitt J. M. , Seethammagari M. , Sonpavde G. , McMannis J. D. , Bai Y. , Bull J. M. , Slawin K. M. 
Published: February 2017

167 Background: We report the correlation of clinical and immune monitoring results for subjects enrolled in a phase I/IIa clinical trial of BPX-101, a drug-activated dendritic cell vaccine for mCRPC. Methods: Men with progressive mCRPC were enrolled in a 3+3 dose escalation trial evaluating BPX-101 and activating agent AP1903. BPX-101 was administered intradermally every 2 weeks for 6 doses, during the induction phase, and for non-progressing patients, every 8 weeks for up to 5 doses during the maintenance phase. AP1903 (0.4 mg/kg) was infused 24 hours after each BPX-101 dose. Blood samples for immune monitoring were collected weekly during the induction phase, and before and one week after each maintenance dose. GM-CSF, TNF-α, IFN-γ, IP-10, MCP-1, MIP-1α, MIP-1β, and RANTES levels were measured by Luminex microspheres, and IL-6 by ELISA. Results: Planned enrollment of 12 subjects is complete, including 3 each at 4 × 106 and 12.5 × 106 cells/dose, and 6 at 25 x 106 cells/dose. A pattern of spiking levels of serum cytokines one week after each dose, returning to baseline the following week, was observed in subjects with greater disease burden. In one low dose subject who experienced a PR after one year on study, panel cytokines spiked 4-fold on average after each induction phase dose, less than 2-fold after the first two boosters, and between 6-fold and 56-fold after the final three boosters. IL-6, which had declined during the induction phase to below 1 pg/mL through two boosters, spiked between 1,680-fold and 13,000-fold after each of the last three boosters. In a second, high dose subject (#1008), who experienced a near CR of multiple lung metastases with otherwise stable disease, panel cytokines spiked 150-fold on average during the induction phase. In both cases, TNF-α, MIP-1α and MIP-1β spiked the most, including a more than 1,000-fold average spike in TNF-α for subject 1008. Cytokine spikes were not associated with AEs. Conclusions: BPX-101 induces a spiking pattern of cytokine elevations after each dose. In patients who experienced measurable disease reductions, more dramatic spikes in serum inflammatory cytokine levels were seen. [Table: see text]
Phase I study of at-101 (R-(-)-gossypol) in combination with paclitaxel (P) and carboplatin (C) in solid tumors including castrate-resistant prostate cancer (CRPC).
Authors: Zhao Y. , Gounder M. , Lin H. , Harris Addo K. , Taber Levinson K. , LaRosiliere M. , Goodin S. , Moss R. A. , Tan A. R. , Stein M. N. 
Published: February 2017

169 Background: The combination of paclitaxel (P) and carboplatin (C) has broad anti-tumor activity in multiple tumor types including prostate and bladder cancer. Overexpression of Bcl-2 is a common mechanism of resistance to cytotoxic chemotherapy. AT-101 is an oral inhibitor of Bcl- 2-family-anti-apoptotic proteins. We conducted a phase I study of the combination of AT-101, P and C. Methods: Ph I study in pts with refractory solid tumors, ECOG 0-1, using a standard 3+3 design to evaluate safety, tolerability and pharmacokinetics/pharmacodynamics (PK/PD). AT-101 was administered orally on Days 1-3 Q12 hr. P and C were administered intravenously on day 1 every 21 days. Dosing levels (DL) were 1: AT-101 40 mg BID, P 150mg/m2, C AUC 5; and DL 2: AT-101 40 mg BID, P 175/m2, C AUC 6. 12 additional pts treated at the MTD dose level were divided into two groups – with AT-101 omitted in the morning of C1D1 or C2D1 to assess apoptotic markers during P and C chemotherapy with and without AT-101. Results: 24 pts (CRPC-11, colon-3, breast-3 melanoma-2, penile-1, esophageal adeno-1, thymus adeno-1, bladder neuroendocrine-1, NSCLC-1) with median age of 61.5 were enrolled. 6 pts were treated in DL1, and 18 in DL2 (the MTD). Dose limiting toxicities were G3 abdominal pain (1 pt, DL1) and G3 ALT (1pt, DL2). Common G1/G2 AEs were nausea, vomiting, fatigue, anorexia and neutropenia. 4 pts had dose reductions after cycle 1 due to AEs. 12 pts had GCSF added after C1 due to neutropenia. 4/11 (36%) pts with CRPC (all previously treated with docetaxel) had PSA declines of ≥50% and 4 pts had stable disease from 4 to 14 cycles. 2 pts with CRPC had a PR by RECIST. Additionally, 1 pt with esophageal CA had a CR and 1 pt with NSCLC had a PR. PK analysis demonstrated P PK was not influenced by co- administration of C and AT-101 when compared with historical reports (Siddiqui BJC 1997). The PK of AT-101 was not altered significantly by the P dose levels. Conclusions: The addition of AT-101 to PC chemotherapy is well tolerated and clinically active in advanced cancer pts. The combination of AT-101 and PC may be appropriate for further study in pts with chemorefractory CRPC. No significant financial relationships to disclose.
Phase I dose-escalation trial of tremelimumab in combination with bicalutamide in patients with recurrent prostate cancer.
Authors: Lang J. M. , Staab M. J. , Liu G. , Wilding G. , McNeel D. G. 
Published: February 2017

174 Background: Antibodies targeting CTLA-4 have demonstrated anti-tumor efficacy in human clinical trials. The mechanism of this effect is presumably in part mediated by the expansion of tumor-specific T cells. Androgen deprivation (AD), the cornerstone of treatment for patients with metastatic prostate cancer, has been demonstrated to cause prostate tissue apoptosis and lymphocytic inflammation. We hypothesized that treatment with AD, followed by an anti-CTLA-4 antibody, could have benefit by augmenting a tumor-specific immune response elicited with AD. We report the initial results from the dose-escalation portion of a phase I trial evaluating tremelimumab in combination with high-dose bicalutamide. Methods: Eligible patients were those with clinical stage D0 prostate cancer (rising serum PSA but no evidence of metastatic disease). Subjects were treated in two courses, 3 months apart, in which they received bicalutamide 150 mg daily for 28 days and tremelimumab on day 29. Patients were treated in cohorts of six, defined by tremelimumab dose (3 mg/kg, 6 mg/kg, 10 mg/kg, 15 mg/kg). The primary endpoint of the trial was safety. Secondary endpoints included measures of PSA kinetics and identification of a maximum tolerated dose (MTD). Results: Eleven patients were enrolled and completed the dose-escalation portion of the trial and at least one year of follow up. Dose-limiting toxicities (DLTs) were observed in 2/5 subjects treated at 6 mg/kg, and included grade 3 diarrhea and a grade 3 skin rash. One of six subjects treated at 3 mg/kg tremelimumab required hospitalization for colitis. No other grade 3 or grade 4 events were observed. Common grade 1/2 events included fatigue, hot flashes, diarrhea, abdominal discomfort, rash, pruritis, and gynecomastia. Two patients experienced a prolongation in PSA doubling time detectable months after completing treatment. Conclusions: Tremelimumab, administered at 3 mg/kg every 3 months in combination with AD, was found to be the MTD and with reasonable safety in this population. The identification of patients with prolonged stable disease following treatment suggests that future studies could explore repetitive administration of this combination. [Table: see text]
ECF chemotherapy for liver metastases due to castration-resistant prostate cancer (mCRPC).
Authors: Gupta S. , Potvin K. R. , Whiston F. , Winquist E. 
Published: February 2017

175 Background: Although 45% of mCRPC patients (pts) achieve prostatic-specific antigen (PSA) response with docetaxel, the objective response rate (ORR) is only 12% (Tannock 2004). Liver metastatic CRPC is uncommon and associated with shorter survival (Armstrong 2010). More active treatment might benefit these pts. ECF is highly active in gastric cancer (Findlay 1994) and response was reported in 3 of 5 liver mCRPC pts (Chao 1997). ECF has been used selectively for mCRPC pts at our centre and we retrospectively reviewed our results in pts with liver metastases with the primary objective of determining its antitumor activity. Methods: Patients with mCRPC who received ECF were identified from electronic databases. ECF (epirubicin 50 mg/m2 IV day 1, cisplatin 60 mg/m2 IV day 1 and fluorouracil 200 mg/m2 IV daily as a continuous infusion) q21d was given as per Findlay et al. Patient, tumor, treatment and outcome data were extracted from medical records. Results: 14 mCRPC pts were treated with ECF 1996-2010. 7 pts had liver metastases: median age 57 years (42-76), median PSA 320 μg/L (17-494) and ECOG PS 1:2 (6:1). All 7 pts had multiple other poor prognostic features: pain (6), >2 metastatic sites (6), anemia (6), ALP >200 IU/L (6) and less than 3 years from diagnosis (6). A median 6 cycles (4-10) of ECF were administered. PSA dropped > 50% for > 4 weeks in 5 pts (71%) with a PSA drop >90% in 4 pts. The ORR was 57% (95%CI, 20-94%) with 4 PR, 1 SD and 2 PD. Response was associated with improved symptoms and hepatic function. Adverse effects were similar to previous reports. Median PFS was 5.2 months (1.3-7.8+) and median overall survival 7.4 months (3.8-31.9). Pooling ORR data with that of Chao et al suggested a higher ORR than expected with docetaxel (58% vs 12%, p=0.03 Fisher's exact test). Conclusions: ECF was highly active in this small selected group of younger men with liver mCRPC and multiple poor prognostic features, and may be of interest for further study as a therapeutic alternative to docetaxel in mCRPC pts with liver metastases when prompt tumor shrinkage is necessary. No significant financial relationships to disclose.