bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adoptive immunotherapy with autologous cytotoxic T lymphocytes (CTLs) pulsed ex vivo with patient-derived tumor cells in heavily pretreated, advanced renal cell carcinoma (aRCC) patients: A feasibility study.
Authors: Porta Camillo , Montagna Daniela , Paglino Chiara , Secondino Simona , Bregant Cristina , Ganini Carlo , Perotti Cesare , Turin Ilaria , Pedrazzoli Paolo 
Published: March 2020

4575 Background: Immunotherapy still remains the only treatment which proved able to induce long-lasting complete responses in aRCC. The aim of the present study was to evaluate the feasibility and safety of adoptive immunotherapy with ex vivo-generated autologous CTLs pulsed with patient-derived tumor cells in heavily pre-treated subjects with aRCC. Methods: This study was performed in accordance with local regulations on the production of cell derivatives; local Ethical Committee approval was obtained on a named patient basis, after obtaining each patient’s informed consent. CTLs were generated stimulating CD8-enriched lymphocytes with dendritic cells (DCs) pulsed with fresh autologous tumor cells in the presence of IL-12 and IL-7; these specific anti-tumor CTLs were expanded and then reinfused after a lymphodepleting chemotherapy with CTX and fludarabine, followed by s.c. administration of low-dose IL-2. Disease status was assessed after every two re-infusions. Eight patients were enrolled, 6 with a clear cell RCC, 1 with a papillary RCC, and 1 with a mixed, papillary and collecting ducts, RCC. All patients have been previously treated with a median of 5 prior treatment lines; the median time between diagnosis of aRCC and tumor biopsy was 55 months (15-185). Results: Six of the 8 enrolled patients have produced suitable tumor cell lines, and 5 of them had been already re-infused with tumor-specific CTLs. All patients received at least 2 CTL infusions (range: 2-5+); mean of totally infused CTLs was 10.7 x 109(range: 4-26.6). All CTLs infusions were well tolerated, with no evidence of autoimmune reactions. In terms of antitumor activity, one patient achieved a partial response, 3 had a slowly progressing disease, and one patient is still not evaluable; furthermore, in 3 patients disease-related symptoms improved. Conclusions: Our preliminary results suggest that immunotherapy with autologous CTLs pulsed ex-vivo with patient-derived tumor cells is feasible and safe in heavily pre-treated aRCC patients. Signs of activity were recorded, suggesting the need to further expand this cohort of patients.
Randomized phase II study of first-line everolimus plus bevacizumab (E+B) versus interferon α-2a plus bevacizumab (I+B) in patients (pts) with metastatic renal cell carcinoma (mRCC): Record-2 final overall survival (OS) and safety results.
Authors: Ravaud Alain , Barrios Carlos H. , Alekseev Boris Y. , Tay Miah Hiang , Agarwala Sanjiv S. , Yalcin Suayib , Lin Chia-Chi , Shkolnik Michail , Matveev Vsevolod , Anak Ozlem , Gogov Sven , Pelov Diana , Louveau Anne-Laure , Vaury Alexandra , Melichar Bohuslav 
Published: March 2020

4576 Background: RECORD-2 (NCT00719264) primary analysis demonstrated similar median progression-free survival (PFS) for pts with mRCC treated with E+B and I+B (Dec 2011 cut-off). The primary objective was not met; median PFS in E+B/I+B was 9.3/10.0 mo (HRIFN/EVE, 0.91; 95% CI, 0.69-1.19; P=0.485) and probability of success (PoS) of a subsequent phase III trial was 5.1%. Here we present final OS and safety/exposure results (Aug 2012 cut-off). Methods: Untreated pts with clear cell mRCC and previous nephrectomy were randomized 1:1 to B 10 mg/kg every 2 weeks and either E 10 mg/day or I (9 MIU 3 times/week). The primary objective was treatment effect on PFS per central review based on an estimation of PoS (≥50%) of a subsequent phase III study. Secondary objectives included OS and safety. Results: In E+B (n=182) and I+B (n=183) arms, median age was 60/60 years and 76/72% of pts were men, respectively. In both arms, most pts (93%) were of favorable/intermediate MSKCC risk. Median follow-up was 33 mo. In E+B and I+B arms, 51/52% of pts died, respectively. Median OS (95% CI) was 27.1 mo (19.9-35.3) in the E+B arm and 27.1 mo (20.4-30.8) in the I+B arm. After discontinuing study treatment, 64/60% of pts in E+B and I+B arms, respectively, received antineoplastic therapy. Median exposure duration in E+B and I+B arms was 8.5/8.3 mo, respectively; AEs resulted in treatment discontinuation for 23/25% of pts, respectively. The most frequent AEs (%) were stomatitis (63), proteinuria (50), diarrhea (40), hypertension (38), and epistaxis (35) in the E+B arm and decreased appetite (45), fatigue (42), proteinuria (38), asthenia (35), and pyrexia (35) in the I+B arm. The most frequent grade 3/4 AEs (%) were proteinuria (24), stomatitis (11), and anemia (11) for E+B and fatigue (17), asthenia (14), and proteinuria (10) for I+B. Conclusions: OS of E+B and I+B was similar. OS results are consistent with PFS primary analysis. First-line treatment with mTOR inhibitor-based therapy did not impair chance of survival relative to standard therapy. No new safety issues were identified and E+B remained generally well tolerated. Clinical trial information: NCT00719264.
First-, second-, third-line therapy for metastatic renal cell carcinoma (mRCC): Benchmarks for trials design from the International mRCC Database Consortium (IMDC).
Authors: Heng Daniel Yick Chin , Rini Brian I. , Lee Jae-Lyun , Kroeger Nils , Srinivas Sandy , Harshman Lauren Christine , Knox Jennifer J. , Bjarnason Georg A. , MacKenzie Mary J. , Wood Lori , Vaishampayan Ulka N. , Agarwal Neeraj , Pal Sumanta Kumar , Tan Min-Han , Rha Sun Young , Yuasa Takeshi , Donskov Frede , Bamias Aristotelis , North Scott A. , Choueiri Toni K. 
Published: March 2020

4586 Background: Limited data exists on outcomes for mRCC patients treated with multiple lines of therapy. Benchmarks for survival are required for patient counseling and clinical trial design. Methods: Outcomes of mRCC patients from the IMDC treated with 1, 2, or 3+ lines of targeted therapy (TT) were compared and adjusted by proportional hazards regression. Overall survival (OS) and progression-free survival (PFS) benchmarks were calculated using different population inclusion criteria. OS and PFS are calculated from the line of therapy under consideration unless otherwise specified. Results: 2,705 patients were treated with TT of which 1,533 (57%) received only 1st-line TT, 734 (27%) received 2 lines of TT, and 438 (16%) received 3+ lines of TT. The median OS of patients that received 1, 2 or 3+ lines of TT starting from initial TT was 14.9, 21.0, and 39.2 months, respectively (p<0.0001). On multivariable analysis adjusting for baseline Heng prognostic factors, the use of 2nd-line and 3rd-line therapy were each independently associated with better OS (HR=0.738 and 0.626, respectively, both p<0.0001). Survival benchmarks derived from patients in the IMDC using selected inclusion criteria as seen in contemporary mRCC clinical trials are shown below. Conclusions: Patients that are able to receive more lines of TT live longer. Survival benchmarks provide context and perspective when interpreting and designing new clinical trials. [Table: see text]
Clinical and translational results of CALGB 40601: A neoadjuvant phase III trial of weekly paclitaxel and trastuzumab with or without lapatinib for HER2-positive breast cancer.
Authors: Carey Lisa A. , Berry Donald A. , Ollila David , Harris Lyndsay , Krop Ian E. , Weckstein Douglas , Henry Norah Lynn , Anders Carey K. , Cirrincione Constance , Winer Eric P. , Perou Charles M. , Hudis Clifford ,   Alliance
Published: March 2020

500 Background: Recent trials in HER2-positive (HER2+) breast cancer (BrCa) demonstrate increased pathological complete response (pCR) using dual HER2-targeting in the neoadjuvant setting and increased progression-free survival in metastatic disease. CALGB 40601 aimed to further quantify the pCR rates of weekly paclitaxel (T) and trastuzumab (H) alone or combined HER2-blockade of H with the small molecule lapatinib (L), and to identify biomarkers of sensitivity to these HER2-targeted agents. Methods: Eligible patients had newly diagnosed, noninflammatory stage II-III HER2+ BrCa and were randomized to receive T (80mg/m2/week IV) + H (4mg/kg then 2mg/kg/week IV) alone (TH) or with the addition of L (750 mg/d PO) (THL) for 16 weeks preoperatively. A third arm, T + L (1500 mg/d) (TL), was closed early when negative efficacy and toxicity data emerged from preliminary analysis of ALTTO. After surgery, 4 cycles of adjuvant dose-dense AC and 1 year H was recommended. Tumors were biopsied for research before therapy; post-Rx samples of residual disease were requested. The primary endpoint was in-breast pCR rate; the study had 85% power to detect an increase from 30% (TH) to 50% (THL). Results: 305 patients were randomized (118 THL, 120 TH, 67 TL); 68% were clinical stage II and 59% hormone receptor-positive. Grade 3+ toxicity was higher among L-containing arms, including neutropenia (12% TL, 7% THL, 2% TH), rash (15% TL, 14% THL, 2% TH), and diarrhea (20% TL, 20% THL, 2% TH). Breast pCR rates with 95% confidence limits were: 51% (42-60%) THL, 40% (32-49%) TH, 32% (22-44%) TL. pCR rate in the TH arm was higher than previous studies, and was not significantly different from THL (p=0.11). We will present molecular subtype, sequence and gene copy number abnormalities in primary tumors and residual disease. Conclusions: pCR rate was higher with combined THL compared with standard TH but did not reach statistical significance. These results are qualitatively similar to other neoadjuvant studies in HER2+ BrCa, and contribute to estimates of pCR rates after these agents. Tissue-based studies may illuminate which patients benefit from HER2-targeting using these agents. Clinical trial information: NCT00770809.
Metformin use and all-cause and prostate-cancer-specific mortality among diabetic men.
Authors: Margel David , Urbach David R. , Lipscombe Lorraine , Bell Chaim , Kilkarni Girish , Austin Peter , Joshua Anthony Michael , Fleshner Neil Eric 
Published: March 2020

5007 Background: To evaluate the association between cumulative duration of metformin use after prostate cancer diagnosis and all-cause and prostate cancer-specific mortality among diabetic patients. Methods: We used a population-based retrospective cohort design. Data were obtained from several Ontario health care administrative databases. Within a cohort of men over the age of 66 with incident diabetes who subsequently developed prostate cancer, we examined the effect of duration of anti-diabetic medication exposure, after prostate cancer diagnosis, on all-cause and prostate cancer-specific mortality. Crude and adjusted hazard ratios were calculated using a time-varying Cox proportional hazard model to estimate effects. Results: The cohort consisted of 3,837 patients. Median age (interquartile range IQR) at diagnosis of prostate cancer was 75 (72-79) years. During a median (IQR) follow up of 4.64 (2.7-7.1) years, 1,343 (35%) died, and 291 patients died of prostate cancer (7.6%). Cumulative duration of metformin treatment, after prostate cancer diagnosis, was associated with a significant decreased risk of prostate cancer-specific and all-cause mortality in a dose-dependent fashion. The adjusted hazard ratio, for prostate cancer-specific mortality was 0.76 (95% confidence interval, 0.64-0.89) for each additional six months of metformin use. The association with all-cause mortality was also significant but declined over-time from a HR of 0.76 in the first 6 months to 0.93 between 24-30 months. There was no relationship between cumulative use of other anti-diabetic drugs and either outcome. Conclusions: Increased cumulative duration of metformin exposure after prostate cancer diagnosis was associated with decreases in both all-cause and prostate-cancer-specific mortality among diabetic men.
A double-blind, placebo RCT evaluating the effect of a polyphenol-rich whole food supplement on PSA progression in men with prostate cancer: The U.K. National Cancer Research Network (NCRN) Pomi-T study.
Authors: Thomas Robert J. , Williams Madeleine M A , Sharma Harbiner , Chaudry Aasem , Bellamy Patricia 
Published: March 2020

5008 Background: Polyphenol-rich foods such as pomegranate, green tea, broccoli and turmeric have demonstrated anti-neoplastic effects in cell lines and animal models. Although some have been investigated in small phase II studies, this combination had never been evaluated within an adequately powered nationally certified RCT. Methods: 203 men, average age 74 yrs, had localised prostate cancer, 59% managed with active surveillance and 41% with watchful waiting (progressive PSA relapse following previous radical interventions). They were randomised to receive a b.d. oral capsule containing a blend of pomegranate seed, green tea, broccoli and turmeric or an identical placebo for 6 months. The groups were statistically balanced in terms of gleason grade, body mass index (BMI), treatment category and fasting cholesterol although there was a difference in average age at baseline; 71.8 yrs in the food supplement group (FSG) versus 76.4 years in the placebo group (PG). Four men withdrew after randomisation. Results: The median rise in PSA in the FSG was 14.7% (95% CI 3.4-36.7%) versus 78.5% in the PG (95% CI 48.1-115.5%) (63.8% difference, ANCOVA analysis of covariance, p=0.0008). 46% of men had stable or lower PSA at trial completion in the FSG versus 14% in the PG (32% difference, chi2, p=0.00001). There were no significant differences in PSA% change within the predetermined subgroups (age, gleason grade, treatment category, BMI). There were no differences in cholesterol, blood pressure, blood sugar or c-reactive protein. 24% men recorded events in the FSG and 34% in the PG (non significant). Mild gastro-intestinal effects were (17%) in the FSG but 8% of these reported an improvement in stool quality. Conclusions: This study found a statistically significant short-term favourable effect on the percentage rise in PSA in these men managed with observation following intake of this specific food supplement. Although many men would see this as useful addition to their self help strategies, future trials should look at the longer-term clinical benefits particularly in terms of preventing medical intervention. Clinical trial information: 81263.
A prognostic model for predicting overall survival in metastatic castrate-resistant prostate cancer (mCRPC) men treated with second-line chemotherapy.
Authors: Halabi Susan , Lin Chen-Yen , Small Eric Jay , Armstrong Andrew J. , Kaplan Ellen B. , Petrylak Daniel Peter , Sternberg Cora N. , Shen Liji , Oudard Stephane , De Bono Johann Sebastian , Sartor A. Oliver 
Published: March 2020

5011 Background: Although several prognostic models for overall survival (OS) have been developed and validated in men with chemotherapy naïve mCRPC, this work sought to develop and validate a prognostic model to predict OS in men who had progressed following first-line chemotherapy, and were receiving second line chemotherapy. Methods: Data from a phase III trial of cabazitaxel plus prednisone compared to mitoxantrone plus prednisone in mCRPC men who had developed progressive disease following first-line chemotherapy (TROPIC trial) were used. The TROPIC data was randomly split into training (n=507) and testing (n=248) sets. A separate data set consisting of 488 men previously treated with docetaxel who were randomly assigned to either satraplatin and prednisone or placebo and prednisone (SPARC trial), was used as a second testing set for external validation. Adaptive Lasso selected nine baseline prognostic factors of OS. A predictive score was computed from the estimated regression coefficients and used to classify patients into low (<-1.25) and high (≥-1.25) risk groups in the two testing sets. The model was assessed on the testing sets for its predictive accuracy using area under the curve (AUC). Results: The 9 prognostic variables in the final model included: ECOG performance status, time since last docetaxel use, measurable disease, presence of visceral disease, pain, duration of prior hormonal use, hemoglobin, prostate specific antigen and alkaline phosphatase. The median OS in the TROPIC testing set were 11 and 16 months in the high and low risks, respectively, with a hazard ratio (HR) 2.3 (p-value<0.0001). The median OS in SPARC were 11 and 20 months in the high and low risk groups, respectively (HR=2.0, p<0.0001). The AUC for this model was 0.73 (95 CI 0.68-0.72) and 0.70 (95 CI 0.72-0.74) on the two testing sets (TROPIC, and SPARC), respectively. Conclusions: A prognostic model of OS in the post-docetaxel second line chemotherapy mCRPC setting was developed and externally validated. This model can be used to select patients to participate in clinical trials on the basis of their prognosis. Prospective validation is needed.
A randomized phase II study evaluating the optimal sequencing of sipuleucel-T and androgen deprivation therapy (ADT) in biochemically recurrent prostate cancer (BRPC): Immune results.
Authors: Antonarakis Emmanuel S. , Kibel Adam S , Adams George , Karsh Lawrence Ivan , Elfiky Aymen , Shore Neal D. , Vogelzang Nicholas J. , Corman John M. , Tyler Robert Claude , McCoy Candice , Wang Yang , Sheikh Nadeem A. , Drake Charles G. 
Published: March 2020

5016 Background: ADT is a standard treatment for men with BRPC after failure of local therapy, and has immunomodulatory effects. Sipuleucel-T is an autologous cellular immunotherapy approved for asymptomatic/minimally symptomatic metastatic castrate resistant prostate cancer. The STAND trial (NCT01431391) aimed to evaluate optimal sequencing of sipuleucel-T and ADT in men with BRPC at high risk for metastases (ie PSA doubling time ≤12 mo). Methods: Men were randomized (1:1) to Arm 1: sipuleucel-T followed by ADT (2 wks after 3rd infusion); or Arm 2: ADT (3 mo lead in) followed by sipuleucel-T. All men had 3 doses of sipuleucel-T and 12 mo of ADT (45 mg leuprolide SQ at 6 mo intervals). The primary endpoint is cellular immune response (ELISPOT to PA2024 [PAP-GMCSF]). Secondary endpoints are humoral and cytokine responses, product parameters and safety. Results: 68 men were randomized. Preliminary data show higher levels of serum cytokines in Arm 2 vs Arm 1, with a pattern suggesting a mixed TH1/TH2 cellular immune response; elevations were seen in TH1 (IFNγ, IL 12), TH2 (IL 4, 5, 10, 13) and TH17 (IL 17) subsets (all P<.05). The increase in TH1 cytokines was consistent with a trend toward higher PA2024-specific ELISPOT responses 2 wk after the 3rd sipuleucel-T infusion in Arm 2 vs Arm 1 (40.5 vs 12.8 spots; P=.086), suggesting increased T cell activation in Arm 2. Antigen-specific humoral responses were induced in both arms with no differences yet observed between arms. Sipuleucel-T product parameters were roughly equivalent in both arms with APC activation data indicating a robust prime-boost effect. Conclusions: While confirmation is required, these preliminary data suggest that tumor-specific T cell responses and broad based immune responses are augmented when sipuleucel-T is given after rather than before ADT initiation. These data are consistent with preclinical studies showing that ADT enhances T cell activity, and provide preliminary evidence that combining ADT with sipuleucel-T may augment adaptive immunity. Further follow up will determine whether augmented immune responses correlate with clinical parameters (eg PSA recurrence). Clinical trial information: NCT01431391.
Sulforaphane treatment in men with recurrent prostate cancer.
Authors: Alumkal Joshi J. , Slottke Rachel , Mori Motomi , Schwartzman Jacob , Graff Julie Nicole , Beer Tomasz M. , Ryan Christopher W. , Koop Dennis R , Cherala Ganesh , Munar Myrna , Flamiatos Jason Frederick , Gao Lina , Tucker Erin 
Published: March 2020

5017 Background: Diets high in cruciferous vegetables are strongly associated with lower prostate cancer risk. Sulforaphane is a constituent of these foods postulated to harbor the anti-neoplastic activity based on pre-clinical evidence in multiple tumor models. Our own work demonstrates that sulforaphane inhibits HDAC function and suppresses AR signaling in prostate cancer cells (Gibbs, et al PNAS 2009). However, the anti-tumor efficacy and safety of sulforaphane in men with prostate cancer was unknown. Methods: In this single arm study, we treated patients with biochemical (PSA)-recurrence of prostate cancer with 200 µmol of sulforaphane extracts for up to 20 weeks. The primary endpoint was PSA response rate (>50% decline in PSA). Other efficacy endpoints included: maximal PSA decline and percent change in PSA from baseline to end of study. We also analyzed PSA doubling time changes using a mixed effects model. Genotyping for GSTM1 that contributes to sulforaphane metabolism, sulforaphane pharmacokinetics (PK), and pharmacodynamic (PD) measurements of HDAC inhibition in mononuclear cells (MCs) were also performed. Results: Twenty patients were enrolled, and 16/20 (80%) completed the pre-planned 20 weeks of treatment. One patient experienced a PSA decline >50%. Thirty-five percent of patients had lesser PSA declines (3% to 20%), and 15% of patients had a final PSA lower than baseline. There was a significant reduction in PSA doubling time (6 months pre-study vs. 9.4 months on-study, p=.013). Of note, testosterone levels remained non-castrate in all subjects. PK analysis demonstrated that GSTM1 null genotype correlated with longer sulforaphane T1/2 (half-life) (2.6 hours for GSTM1 null vs. 2.1 hours for GSTM1 intact, p=0.04). Sulforaphane treatment also increased histone acetylation in PD assays in MCs. Finally, no grade three adverse events were seen, and only one patient discontinued study treatment for toxicity (grade one GI discomfort). Conclusions: Treatment with 200 µmol per day of sulforaphane is feasible, safe, and inhibits HDAC function. This combined with the preliminary observation of PSA modulation, which may indicate biologic activity, provides the basis for dose escalation studies of sulforaphane in men with prostate cancer. Clinical trial information: NCT01228084.