Supplementary Figure 1 - PDF file 90K, A heat-map based on a matrix with patient characteristics and C1-C7 as columns and patients as rows. The clustering of columns and rows are based on the Euclidean distances (root sum-of-squares of difference)

Abstract Purpose: Clinical features characteristic of small-cell prostate carcinoma (SCPC), “anaplastic,” often emerge during the progression of prostate cancer. We sought to determine the efficacy of platinum-based chemotherapy in patients meeting at least one of seven prospectively defined “anaplastic” clinical criteria, including exclusive visceral or predominantly lytic bone metastases, bulky tumor masses, low prostate-specific antigen levels relative to tumor burden, or short response to androgen deprivation therapy. Experimental Design: A 120-patient phase II trial of first-line carboplatin and docetaxel (CD) and second-line etoposide and cisplatin (EP) was designed to provide reliable clinical response estimates under a Bayesian probability model with early stopping rules in place for futility and toxicity. Results: Seventy-four of 113 (65.4%) and 24 of 71 (33.8%) were progression free after four cycles of CD and EP, respectively. Median overall survival (OS) was 16 months [95% confidence interval (CI), 13.6–19.0 months]. Of the seven “anaplastic” criteria, bulky tumor mass was significantly associated with poor outcome. Lactic acid dehydrogenase strongly predicted for OS and rapid progression. Serum carcinoembryonic antigen (CEA) concentration strongly predicted OS but not rapid progression. Neuroendocrine markers did not predict outcome or response to therapy. Conclusion: Our findings support the hypothesis that patients with “anaplastic” prostate cancer are a recognizable subset characterized by a high response rate of short duration to platinum-containing chemotherapies, similar to SCPC. Our results suggest that CEA is useful for selecting therapy in men with castration-resistant prostate cancer and consolidative therapies to bulky high-grade tumor masses should be considered in this patient population. Clin Cancer Res; 19(13); 3621–30. ©2013 AACR.

RB-94 is a truncated form of the RB tumor suppressor gene which has shown marked cytotoxicity in every human tumor type tested to date without affecting normal cells. A systemically administered, tumor-targeted nanocomplex for systemic gene delivery (termed SGT) has been developed. In the SGT nanocomplex, the payload is encapsulated within a cationic liposome. The surface of the liposome is decorated with an anti-transferrin receptor (TfR) single chain antibody fragment (scFv) designed to target cancer cells by binding to the TfR which is highly expressed on tumor cells. Here we describe the results of a DNA dose escalating first-in-man Phase l study of SGT encapsulated RB-94 (SGT-94) for the treatment of metastatic genitourinary tumors. The majority of the cancers treated in this study were bladder cancers. Treatment with SGT-94 was well tolerated with minimal side effects observed. Moreover, among the 11 evaluable patients of 13 treated, a complete remission (CR) in a lung metastasis, two partial remissions (PRs) and three incidences of stable disease (SD) were observed. The CR and PRs occurred at the highest dose (2.4 mg DNA) tested. In addition, there is strong evidence for tumor-specific targeting including data from two resected lung metastases. In these metastatic lesions, the presence of RB94 was documented by both PCR and Western blotting in the tumors. However, RB94 was absent in contiguous normal lung tissue. Therefore, this Phase I study demonstrates not only the safety, but also the anti-cancer potential of the SGT-94 nanocomplex and suggests that additional studies using SGT-94 alone or in combination with chemotherapy, radiation or other modalities are warranted.

Abstract Background: Development of gene therapy has been limited by our inability to systemically administer treatment which selectively targets tumor tissue. We developed an SGT-RB94 nanocomplex composed of cationic liposome encapsulating plasmid DNA encoding the RB94 gene which had previously been shown to selectively kill cancer cells but not non-transformed human cells. The surface of the liposome is decorated with a single chain antibody fragment to the transferrin receptor to target the nanocomplex to cancer cells. Methods: We performed a phase I trial of single agent SGT-RB94 in patients with previously treated metastatic cancer. Treatment with SGT-RB94 was administered twice a week for 3 weeks out of four using a fixed at a fixed DNA dose of 0.6, 1.2, or 2.4 mg pDNA. Radiographic imaging was performed every 2 cycles to evaluate for response. When possible, a biopsy of a metastatic site was performed, after beginning treatment to evaluate for targeting of the gene product. PCR was performed to show expression of SGT-94 in RB+ tumors, RB94 protein production was confirmed using Western blotting. Results: Thirteen patients were treated with 11 clinically evaluable for response. Dose-limiting toxicity was not observed at the 2.4 mg dose. A total of 181 doses of SGT-94 were administered. The treatment was well tolerated with the most frequent treatment related toxicities being Grade 1-2 fever and chills (27%), thrombocytopenia (45%), neutropenia (18%), and hypotension (18%). The only grade 3-4 toxicity were lymphopenia (9%), and neutropenia (9%). The fever/chills and hypotension most typically occurred after the first dose, and responding with steroids. The neutropenia and thrombocytopenia were also transient and improved with continued dosing. There was evidence of clinical activity with a complete response in a lung metastases; this patient was retreated upon progression, and had a partial response in his peritoneal implants. Two patients continued to have stable disease after 4-5 cycles of treatment. Two patients had RB- tumors by immunohistochemistry. One had a post-treatment biopsy showing evidence of cytoplasmic staining for the RB protein with extensive tumor necrosis following treatment, but this tumor ultimately progressed. One patient with stable disease had surgical consolidation with wedge resection of his lung metastases which showed RB94 expression by PCR, and protein production by Western blot in two separate tumors, but not in his normal lung tissue. Conclusions: Systemic delivery of SGT-RB94 was well tolerated with evidence of clinical activity and selective targeting of tumor tissue, overcoming a major limitation to current gene therapy strategies. Further development of SGT-RB94 as a treatment modality is warranted. Citation Format: Arlene Siefker-Radtke, Xin-qiao Zhang, Kathleen F. Pirollo, Esther H. Chang, Chris P. Leung, Charles Guo, Randall E. Millikan, William F. Benedict. Systemic administration using targeted gene delivery with SGT-RB94 shows evidence of tumor targeting and anticancer activity: a phase I first-in-man trial. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT059.

Gene therapy development has been limited by our inability to target multifocal cancer with systemic delivery. We developed a systemically administered, tumor-targeted liposomal nanodelivery complex (SGT-94) carrying a plasmid encoding RB94, a truncated form of the RB gene. In preclinical studies, RB94 showed marked cytotoxicity against tumor but not normal cells. SGT-94 was administered intravenously in a first-in-man study in metastatic genitourinary cancer. Minimal side effects were observed; dose-limiting toxicity (DLT) has not been reached in 11 evaluable patients. There was evidence of clinical activity at the 2.4 mg dose with one complete remission (CR) and one partial remission (PR). The patient in CR was retreated upon progression and had a second PR. Furthermore, there was tumor-specific targeting of the SGT-94 complex. One patient had wedge resections of two lung metastases which demonstrated RB94 expression at the DNA level by polymerase chain reaction (PCR) and at the protein level by Western blotting, with no RB94 present in normal contiguous lung. In conclusion, systemically delivered SGT-94 showed evidence of selective tumor targeting and was well tolerated with evidence of clinical activity. Additional studies are warranted to explore the activity of this drug as a single agent and in combination therapy.

We hypothesized that pretreatment serum levels of insulin and other serum markers would predict Progression-free survival (PFS), defined as time to castration-resistant progression or death, in metastatic androgen-dependent prostate cancer (mADPC).

Gene expression profiling identifies subtypes of urothelial cancer that differ dramatically in their natural history and sensitivity to chemotherapy. This is a significant development in unraveling the long-appreciated heterogeneity of this disease.

Combining targeted therapy in metastatic renal cell carcinoma has improved response and delayed development of resistance in in vitro and in vivo modeling. Using an adaptive 2-stage dose-finding design, different dose pairs of temsirolimus (T) and sunitinib (S) were tested. Only 1 patient of 23 responded and the maximum tolerated dose (MTD) was not reached due to premature trial closure.Background: Preclinical data suggest that antievascular endothelial growth factor agents combined with mammalian target of rapamycin inhibitors yield synergistic antitumor effects. Aphase I trial with a 3+3 dose escalation design of S with T was stopped after the first dose pair led to 2 of 3 patients experiencing dose-limiting toxicity (DLT). Patients and Methods: To explore multiple potential dosing pairs of S and T, a 2-stage outcome-adaptive Bayesian dose-finding method was designed. The primary objective was to find the MTD of S and T in patients with advanced renal cell carcinoma. A 3-week treatment cycle consisted of daily S, 2 weeks of treatment, 1 week without treatment, and weekly T. Results: Twenty patients received study drugs; the median number of previous therapies was 1. The number of patients (S and T doses in mg) was: 2 (S, 12.5; T, 6), 1 (S, 25; T, 12.5), 1 (S, 12.5; T, 8), 8 (S, 12.5 alternate 25; T, 9), 2 (S, 25; T, 6), 2 (S, 25 alternate 37.5; T, 6), 2 (S, 37.5; T, 6), and 2 (S, 37.5; T, 8). Six patients required dose reduction, 3 because of Grade 3 stomatitis, 2 because of Grade 3 thrombocytopenia; the mean number of cycles was 6.6 +/- 5.3, the mean time during study was 159 +/- 120 days. One patient experienced a DLT in cycle 1 and was nonevaluable, 1 had a partial response, 16 had stable disease, and 2 had progressive disease as best response. There were 21 Grade 3/4 adverse events but no treatmentrelated deaths. Conclusion: The MTD of S and T were not determined because of premature trial closure. S 37.5 mg/d, 2 weeks of treatment, 1 week with no treatment, and T 8 mg to 10 mg weekly are close to the MTD.

BACKGROUNDReceptors in tumor blood vessels are attractive targets for ligand‐directed drug discovery and development. The authors have worked systematically to map human endothelial receptors (“vascular zip codes”) within tumors through direct peptide library selection in cancer patients. Previously, they selected a ligand‐binding motif to the interleukin‐11 receptor alpha (IL‐11Rα) in the human vasculature.METHODSThe authors generated a ligand‐directed, peptidomimetic drug (bone metastasis‐targeting peptidomimetic‐11 [BMTP‐11]) for IL‐11Rα–based human tumor vascular targeting. Preclinical studies (efficacy/toxicity) included evaluating BMTP‐11 in prostate cancer xenograft models, drug localization, targeted apoptotic effects, pharmacokinetic/pharmacodynamic analyses, and dose‐range determination, including formal (good laboratory practice) toxicity across rodent and nonhuman primate species. The initial BMTP‐11 clinical development also is reported based on a single‐institution, open‐label, first‐in‐class, first‐in‐man trial (National Clinical Trials number NCT00872157) in patients with metastatic, castrate‐resistant prostate cancer.RESULTSBMTP‐11 was preclinically promising and, thus, was chosen for clinical development in patients. Limited numbers of patients who had castrate‐resistant prostate cancer with osteoblastic bone metastases were enrolled into a phase 0 trial with biology‐driven endpoints. The authors demonstrated biopsy‐verified localization of BMTP‐11 to tumors in the bone marrow and drug‐induced apoptosis in all patients. Moreover, the maximum tolerated dose was identified on a weekly schedule (20‐30 mg/m2). Finally, a renal dose‐limiting toxicity was determined, namely, dose‐dependent, reversible nephrotoxicity with proteinuria and casts involving increased serum creatinine.CONCLUSIONSThese biologic endpoints establish BMTP‐11 as a targeted drug candidate in metastatic, castrate‐resistant prostate cancer. Within a larger discovery context, the current findings indicate that functional tumor vascular ligand‐receptor targeting systems may be identified through direct combinatorial selection of peptide libraries in cancer patients. Cancer 2015;121:2411–2421. © 2015 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

433 Background: Anti-VEGF agents and mTOR inhibitors are mainstay therapies in mRCC. Pre-clinical data suggests synergistic anti-tumor effect when combining these 2 classes. A previous phase I trial using sunitinib (S) 25 mg/d 4 wks on, 2 wks off, and temsirolimus (T) 15 mg/wk was stopped after 2 of the first 3 pts developed dose limiting toxicity (DLT). Methods: Pts with any subtype mRCC (PS 0-1) were eligible. Each cycle consisted of daily S for 14 days on, 7 days off, and weekly T. The continuous reassessment method (CRM) was used. The primary objective was to find the maximum tolerated doses (MTD) of S and T. The total planned accrual was 60 pts. Results: Accrual was stopped after 20 pts received study drugs. Median age was 63.5 years; 13 pts received prior targeted therapy, 7 pts were treatment naïve; median number of prior treatments 1 (range 0-6). Treatment cohorts (#pts, S, T, dose in mg): 2 (S12.5,T6), 1 (S25,T12.5), 1 (S12.5,T8), 8 (S12.5alt25,T9), 2 (S25,T6), 2 (S25alt37.5,T6), 2 (S37.5,T6), 2 (S37.5,T8). Dose reduction was required in 6 of 20 pts; the most common DLT was mucositis in 3 of 20 pts, followed by thrombocytopenia in 2 of 20 pts. The mean number of cycles for all pts was 6.6±5.36, with mean time on study 159±120 days. One pt experienced DLT in cycle 1 and received no study related imaging, 1 had a partial response, 16 pts had stable disease, and 2 pts had progressive disease (PD) as best response. A total of 21 grade 3/4 adverse events (AEs) attributed to drug occurred in 11 of 20 pts. Reasons for study discontinuation were PD in 12 pts, toxicity in 6 pts, and pt preference in 2 pts. There were no treatment related deaths. Conclusions: The MTD of S and T using the CRM were not reached due to premature trial closure. However, we believe S 37.5 mg/d, 2 wks on, 1 wk off, and T 8-10 mg weekly may well be close to MTD. Clinical trial information: NCT01122615.

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background: Gene expression profiling (GEP) of bladder cancer at cystectomy suggests 3 main intrinsic subtypes of urothelial cancer: basal, which historically has the worst prognosis and is associated with high proliferation, increased EMT plasticity, TP63, and HIF-1 expression; p53-like/luminal A, a subtype with decreased proliferation and increased markers of extracellular matrix; and luminal B which has increased proliferation compared with luminal A tumors. We hypothesized that GEP of transurethral resections (TUR) and cystectomy specimens from patients on a neoadjuvant trial would predict subtypes more likely to benefit from chemotherapy. Methods: Sixty patients enrolled on a neoadjuvant trial of DDMVAC+B. TUR and cystectomy specimens were available for gene expression profiling in 39 and 33 patients, respectively, with matched specimens in 23 patients. Results: Chemotherapy was quite active with pT0N0 and ≤ pT1N0 down-staging rates of 38% and 45%, respectively. GEP of TUR suggested the greatest downstaging with basal (n=11, pT0N0 = 45%, ≤pT1N0=55%) and luminal B tumors (n=16, pT0N0=31%, ≤pT1N0=56%), compared to luminal A (n=12, pT0N0=25%, ≤pT1N0=33%). The basal subtype had an improved survival as compared to the luminal subtypes (5 year OS 91% and 51%, respectively, log-rank p=0.047.) On multivariate analysis, pathologic stage and TUR subtype were independent predictors of outcome (pStage: HR 4.6, CI 2.0-10.3, p=0.0003, luminal B: HR 13.2, CI 1.4-120.9, p=0.02, luminal A:HR 5.7, CI 0.69-46.9, p=0.1). Development of bone metastases had a poor prognosis (OS 15 months, vs not reached, p≤ 0.00001), and were associated with luminal A subtype developing in 50% of the luminal A, 19% of luminal B, and none in the basal subtypes(p=0.015). All three of the luminal B tumors at TUR with bone metastases displayed a luminal A subtype at cystectomy. The luminal A subtype was the most frequent subtype remaining at cystectomy, and was observed in 19/33 (58%) of cases overall, with basal changing to luminal A subtype in 2/5 (40%) and luminal B to luminal A in 7/9 (77%) of cases, suggesting that luminal A is associated with chemotherapy-resistance. Conclusions: In contrast to historical expectations, the basal subset had an improved survival in patients receiving neoadjuvant chemotherapy, potentially reflecting increased chemosensitivity observed in this group. Bone metastases were associated with the luminal A subtype on TUR and/or cystectomy, potentially related to the impact of stromal factors in patients with these tumors. The “shift” to luminal A at cystectomy in those who failed neoadjuvant chemotherapy, suggests this subtype may be associated with chemotherapy-resistance. Citation Format: Arlene O. Siefker-Radtke, Woonyoung Choi, John Melquist, Yu Shen, Ashish Kamat, Surena Matin, Randall Millikan, Colin P. Dinney, Bodgan A. Czernial, David J. McConkey. Gene expression profiling in the context of neoadjuvant chemotherapy with DDMVAC+B (dose dense methotrexate, vinblastine, doxorubicin, cisplatin, and bevacizumab) can predict clinical outcomes and tumor biology. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT241. doi:10.1158/1538-7445.AM2014-CT241

Purpose: Clinical features characteristic of small-cell prostate carcinoma (SCPC), "anaplastic," often emerge during the progression of prostate cancer. We sought to determine the efficacy of platinum-based chemotherapy in patients meeting at least one of seven prospectively defined "anaplastic" clinical criteria, including exclusive visceral or predominantly lytic bone metastases, bulky tumor masses, low prostate-specific antigen levels relative to tumor burden, or short response to androgen deprivation therapy.Experimental Design: A 120-patient phase II trial of first-line carboplatin and docetaxel (CD) and second-line etoposide and cisplatin (EP) was designed to provide reliable clinical response estimates under a Bayesian probability model with early stopping rules in place for futility and toxicity.Results: Seventy-four of 113 (65.4%) and 24 of 71 (33.8%) were progression free after four cycles of CD and EP, respectively. Median overall survival (OS) was 16 months [95% confidence interval (CI), 13.6-19.0 months]. Of the seven "anaplastic" criteria, bulky tumor mass was significantly associated with poor outcome. Lactic acid dehydrogenase strongly predicted for OS and rapid progression. Serum carcinoembryonic antigen (CEA) concentration strongly predicted OS but not rapid progression. Neuroendocrine markers did not predict outcome or response to therapy.Conclusion: Our findings support the hypothesis that patients with "anaplastic" prostate cancer are a recognizable subset characterized by a high response rate of short duration to platinum-containing chemotherapies, similar to SCPC. Our results suggest that CEA is useful for selecting therapy in men with castration-resistant prostate cancer and consolidative therapies to bulky high-grade tumor masses should be considered in this patient population. Clin Cancer Res; 19(13); 3621-30. (C)2013 AACR.

e15612 Background: Noninfectious pneumonitis (NIP) is a known adverse effect of mTOR inhibitors, with a reported incidence of 25-45%. The goal of this review was to characterize the incidence, onset, management, and clinical outcomes of pts with mRCC who experienced mTOR inhibitor-associated NIP at our tertiary cancer center. Methods: Retrospective review of 310 mRCC pts who received everolimus and/or temsirolimus between 6/1/2007 and 10/1/2010. Clinical correlation was made in conjunction with serial radiologic imaging studies. Results: 36 mRCC pts (12%) treated with an mTOR inhibitor developed NIP with a median time to symptom onset of 65 d (21-855) and radiographic appearance of 62.5 d (35-736). 23 pts (21%) received everolimus compared to 13 pts (6%) who received temsirolimus (P<0.0001). Median time to onset, radiographic appearance, and NCI CTCAE pneumonitis grade did not differ significantly between treatments (P=NS). Increased age (OR 1.04; 95% CI: 1.004-1.08) and everolimus (OR 4.106; 95% CI: 1.96-8.6) were associated with a greater risk of NIP. NCI CTCAE grade 2 NIP severity was most common (78%). mTOR inhibitor therapy was discontinued in 9 pts (25%); continued at same dose in 7 pts (19%), dose reduced in 2 pts (6%); held and resumed at lower dose in 2 pts (6%), and held and then resumed at same dose in 1 pt (3%). Median time on treatment was greater for pts who developed NIP; 4.1 vs 2 mo (P=0.035). Median OS was significantly greater for NIP pts; 15.4 vs 7.4 mo (P<0.0001). 3-yr survival of NIP pts was 35.4% vs 7.2% (P<0.0001). Predictors of improved OS included NIP (HR 0.315; 95% CI: 0.2-0.495; P<0.0001). Conclusions: A higher incidence of NIP was observed in mRCC pts treated with everolimus than temsirolimus. The finding of improved OS in pts who developed NIP is intriguing and should be further investigated.

365 Background: We previously reported on improved tolerability and maintained efficacy of low-dose IFN in pts with mRCC treated in the cytokine era (Tannir, et al. Cancer 2006). Although VEGFR targeted agents have supplanted cytokines for most pts, IFN, in combination with bevacizumab, is a standard front-line therapy for good-risk and intermediate-risk clear-cell RCC. Methods: Between March 2002 and December 2003, a total of 118 pts (59/arm) were randomized to receive IFN 0.5 million units (MU) twice/day [IFN1] or 5 MU/day [IFN5]. Patients who were progression-free and tolerating therapy well continued IFN for a total of 5 years. The primary endpoint was progression-free survival (PFS). Secondary endpoints were objective response rate (ORR), overall survival (OS), safety, and quality of life (QOL). Results of PFS, ORR, safety, and QOL were previously reported. We provide here updated OS and long-term outcome of complete responders (CR). Results: At 10 years of follow-up, >95% of participants have died. There was no significant difference in OS between the 2 arms (HR=1.32, 95% CI: 0.91-1.91), but favored IFN1 (median OS 2.1 years vs. 1.5 years, log-rank test p=0.14). Compared with IFN5, IFN1 was less toxic and was associated with better QOL. Two nephrectomised pts, 1 from each arm, 1 with multiple hepatic and lung metastases, and 1 with multiple lung and mediastinal metastases, performance status 1 and intermediate-risk clear-cell RCC, remain in unmaintained CR 10 years since starting IFN. Among pts who did not respond to IFN but remain alive, 1 patient received high-dose IL-2 and achieved durable CR; the other patient received multiple approved and investigational targeted agents sequentially. All responders to IFN had tumor regression as early as 8 wks, with PR or CR declared at 16 wks. Conclusions: IFN produces durable CRs and potential cure in about 2% of mRCC pts. Our data have implications for the front-line therapy of mRCC and suggest that IFN, like high-dose IL-2, can be discontinued after 16 wks, if a major response is not achieved. Our updated results are of interest, considering the paucity of durable CRs to VEGFR agents.

Clinical Practice Points •Sarcomatoid renal cell carcinoma(SRCC) is an aggressive malignancy and carries a poor prognosis. •Cytotoxic chemotherapy or biochemotherapy should be considered as treatment options for SRCC. •Durable remissions are achievable in SRCC with nontargeted therapy. •Sarcomatoid renal cell carcinoma(SRCC) is an aggressive malignancy and carries a poor prognosis. •Cytotoxic chemotherapy or biochemotherapy should be considered as treatment options for SRCC. •Durable remissions are achievable in SRCC with nontargeted therapy.

263 Background: Preclinical studies suggested that bortezomib (B) enhanced the activity of gemcitabine and doxorubicin (GA) in UC; thus we sought to define possible combinations of bortezomib with this doublet. We employed a novel phase I trial design systematically exploring doses in 2 dimensions. The method estimates an isotoxic curve allowing not only a combination with approximately equal (with respect to single component MTD) contributions of the two components to be found, but also combinations emphasizing one component or the other. Methods: Since 11/06, 74 patients with previously treated metastatic cancer were enrolled (70 UC, 3 prostate, 1 renal). GA was treated as a single component and given in a fixed ratio to a maximum of 900 and 50 mg/m2, and B to a maximal dose of 1.6 mg/m2 IV, with dosing every 14 days. After determining the MTD along the diagonal, we then decreased the dose of B, increasing GA, and vice versa, exploring doses along an isotoxic curve aiming for ≤ 30% dose limiting toxicity (DLT) in cycle 1. The objective response rate (ORR) includes PR or CR, and excludes SD. Results: The MTD along the diagonal for GAB was 756, 42, and 1.4 mg/m2, respectively. Doses maximizing the GA (900, 50) required reduction of B to 1.2 mg/m2. Likewise, doses maximizing B (1.6) required reduction of GA to 559 and 33 mg/m2. The most common DLT were thrombocytopenia 14%, neutropenic fever 5%, and mucositis 1%. There was minimal activity at the on-diagonal MTD with an ORR 1/10. Of the tolerable doses along the isotoxic curve, the greatest activity was seen when maximizing B (1.5-1.6 mg/m2, ORR 7/12 (58%)). The ORR when maximizing GA was 4/10. The most frequent ≥ G3 toxicities include: thrombocytopenia (26%), neutropenia (26%), anemia (24%), fatigue (8%), and neutropenic fever or infection (12%). Treatment was tolerable in poor renal function; 36 patients (49%) had a GFR < 50 ml/min. Conclusions: The combination of GAB has promising activity at doses maximizing proteosome inhibition, despite relatively low doses of GA. Traditional phase I design dosing to the MTD "along the diagonal" would have lead to the incorrect conclusion that there was minimal activity. Clinical trial information: NCT00479128.

e16038 Background: Duration of response to androgen-deprivation therapy (ADT) is highly variable in patients with mADPC and prognostic markers are needed. Insulin resistance and hyperinsulinemia may contribute to prostate cancer progression. We hypothesized that pretreatment serum insulin levels would predict time to castration-resistant progression (PFS) and overall survival (OS). Methods: Sera from men treated on a randomized phase 3 trial of first line ADT vs. ADT plus chemotherapy were retrospectively analyzed using a multiplex ELISA for cytokines and angiogenic factors (CAFs). Univariate and multivariate Cox proportional hazards regression models were used to identify associations between CAFs and PFS/OS. Results: 66 pts were evaluable, 86% Caucasian, median age 72 yrs, median PSA 31.5ng/mL, 77% Gleason score of ≥8, and 53% high volume metastatic disease (HVM). Thirty-five pts received ADT; 31 pts received ADT+chemo. In univariate analysis, higher pretreatment insulin and C-peptide were positively correlated with PFS, whereas higher hepatocyte-growth factor (HGF), osteopontin (OPN) and HVM were negatively correlated with PFS. In multivariate analysis, only higher insulin was associated with longer PFS (HR=0.72, 95%CI 1.32 -0.87; p<0.001), whereas higher HGF and OPN were associated with reduced PFS (HR=1.82, 95%CI 0.59-2.83, p<0.01 and HR=1.81, 95%CI 1.18-2.47, p<0.001, respectively). Higher Insulin and Program Death 1 (PD1) were associated with longer OS on multivariate analysis (HR=0.78 p<0.02 and HR=0.55 p<0.02, respectively), whereas HVM and higher OPN were associated with reduced OS (HR=2.28 p<0.01 and HR=1.60 p<0.02). Using low insulin, high HGF and high OPN as 3 independent risk factors (RF), 3 distinct risk groups could predict PFS: good (zero RF), intermediate (1 or 2 RF) and poor risk (3 RF), with median PFS of 6.90, 1.97, and 0.86 years, respectively (p<0.001). Conclusions: Higher pretreatment insulin was associated with prolonged PFS and OS in men with mADPC treated with ADT. Our data suggest that insulin levels are a biomarker for sensitivity to ADT and highlight the complex interactions between metabolism and PCa progression.

The multi-tyrosine kinase inhibitor pazopanib prolongs progression-free survival (PFS) versus placebo in treatment-naive and cytokine-refractory metastatic clear-cell renal cell carcinoma (ccRCC). Outcomes and safety data with pazopanib after targeted therapy (TT) are limited.We retrospectively evaluated records of consecutive patients with metastatic ccRCC who had progressive disease (PD) after TT and received pazopanib from November 2009 through November 2011. Tumour response was assessed by a blinded radiologist using Response Evaluation Criteria In Solid Tumours (RECIST). PFS and overall survival (OS) were estimated by Kaplan-Meier methods.Ninety-three patients were identified. Median number of prior TTs was 2 (range, 1-5). There were 68 events (PD or death). Among 85 evaluable patients, 13 (15%) had a partial response. Median PFS was 6.5 months (95% CI: 4.5-9.7); median OS was 18.1 months (95% CI: 10.26-NA). Common adverse events (AEs) included fatigue (44%), elevated transaminases (35%), diarrhoea (30%), hypothyroidism (18%), nausea/vomiting (17%), anorexia (14%) and hypertension exacerbation (14%); 91% of AEs were grade 1/2. Eleven patients (12%) discontinued therapy due to AEs. There were no treatment-related deaths.Pazopanib demonstrated efficacy in patients with metastatic ccRCC after PD with other TTs. Toxicity overall was mild/moderate and manageable.

Objective To characterise the incidence, onset, management, predictors, and clinical impact of mammalian target of rapamycin (mTOR) inhibitor‐associated non‐infectious pneumonitis (NIP) on patients with metastatic renal cell carcinoma (mRCC). Patients and Methods Retrospective review of 310 patients with mRCC who received temsirolimus and/or everolimus between June 2007 and October 2010. Clinical correlations were made with serial radiological imaging. Fisher's exact, Wilcoxon rank‐sum, and logistic regression analyses were used to evaluate the association of NIP with demographic or clinical factors. Log‐rank and Cox proportional hazards regression analyses were used for the time‐to‐event analysis. Results NIP occurred in 6% of temsirolimus‐treated and 23% of everolimus‐treated patients. Symptoms included cough, dyspnoea, and fever (median of two and three symptoms per patient, respectively). The median National Cancer Institute Common Toxicity Criteria for Adverse Events pneumonitis grade was 2 for both groups. Older age and everolimus treatment were predictive of NIP. Patients who developed NIP had a significantly longer time on treatment (median 4.1 vs 2 months) and overall survival (OS) (median 15.4 vs 7.4 months). NIP was a predictor of improved OS by multivariate analysis. Conclusions There was an increased incidence of NIP in everolimus‐treated patients. Improved OS in patients who developed NIP is an intriguing finding and should be further investigated. Given the incidence, morbidity, and outcomes seen in patients on everolimus who develop NIP, management should include proactive monitoring and treatment of NIP with the goal of preserving mTOR inhibitor therapy.

We present new statistical analyses of data arising from a clinical trial designed to compare two-stage dynamic treatment regimes (DTRs) for advanced prostate cancer. The trial protocol mandated that patients be initially randomized among four chemotherapies, and that those who responded poorly be re-randomized to one of the remaining candidate therapies. The primary aim was to compare the DTRs’ overall success rates, with success defined by the occurrence of successful responses in each of two consecutive courses of the patient’s therapy. Of the 150 study participants, 47 did not complete their therapy as per the algorithm. However, 35 of them did so for reasons that precluded further chemotherapy, that is, toxicity and/or progressive disease. Consequently, rather than comparing the overall success rates of the DTRs in the unrealistic event that these patients had remained on their assigned chemotherapies, we conducted an analysis that compared viable switch rules defined by the per-protocol rules but with the additional provision that patients who developed toxicity or progressive disease switch to a non-prespecified therapeutic or palliative strategy. This modification involved consideration of bivariate per-course outcomes encoding both efficacy and toxicity. We used numerical scores elicited from the trial’s principal investigator to quantify the clinical desirability of each bivariate per-course outcome, and defined one endpoint as their average over all courses of treatment. Two other simpler sets of scores as well as log survival time were also used as endpoints. Estimation of each DTR-specific mean score was conducted using inverse probability weighted methods that assumed that missingness in the 12 remaining dropouts was informative but explainable in that it only depended on past recorded data. We conducted additional worst- and best-case analyses to evaluate sensitivity of our findings to extreme departures from the explainable dropout assumption.