bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase IV trial of dose-intense PEFG (cisplatin, epirubicin, 5-fluorouracil, gemcitabine) in advanced pancreatic adenocarcinoma
Authors: Reni M. , Cereda S. , Passoni P. , Bonetto E. , Viganò M. G. , Balzano G. , Zerbi A. , Staudacher C. , Di Carlo V.
Published: March 2020

4121

Background: In a phase III trial (Reni, Lancet Oncol 2005), PEFG regimen (cisplatin and epirubicin 40 mg/m2 day 1, gemcitabine 600 mg/m2 day 1 and 8, 5-fluorouracil (FU) 200 mg/m2/day continuous infusion) significantly improved the outcome of patients with advanced pancreatic adenocarcinoma (PA) with respect to standard gemcitabine. This regimen was subsequently modified by increasing dose-intensity (FU unmodified, cisplatin and epirubicin both at 30 mg/m2, and gemcitabine at 800 mg/m2 every 14 days; Dell’Oro, Ann Oncol 2004). The present study assessed activity and feasibility of dose-intense (DI) PEFG. Methods: DI-PEFG was administered to chemotherapy-naive patients with stage III-IV pancreatic adenocarcinoma, ≤ 75 years, performance status (PS) > 50, till progressive disease or for a maximum of 6 months. Analyses were conducted in the intent-to-treat population. Results: Between January ’04 and June ’05, 49 (31 or 63% metastatic) patients, median age 62 yrs, median PS 80, were treated with DI-PEFG at our institution. Partial response and stable disease was observed in 25 (51%) and 15 (31%) patients, respectively; 31 patients were progression-free at 6 months (PFS-6 = 63%). Median survival was 8.5+ months and 1-yr overall survival (OS) was 46%. 211 courses (range 1–6, median 5) of DI-PEFG were delivered. Main grade 3–4 toxicity was: neutropenia in 9% of cycles, anaemia, stomatitis, fatigue in 3%, nausea/vomit, deep venous thrombosis and diarrhoea in 2%, thrombocytopenia, febrile neutropenia and hand-foot syndrome in 1%. Dose intensity (mg/m2/week) was 13 for both epirubicin and cisplatin, 338 for gemcitabine and 1106 for FU. Conclusion: With respect to classical PEFG, DI-PEFG was not inferior in terms of PFS-6 (63% vs. 42%), 1-yr OS (46% vs. 38.5%) and response rate (49% vs. 38.5%); allowed to increase dose intensity for gemcitabine by 32%, for cisplatin and epirubicin by 36% (FU reduced by 3%), to reduce grade 3–4 hematological toxicity (neutropenia 9% vs. 43%; thrombocytopenia 1% vs. 28.5%) and to reduce by one third the number of outpatients accesses.

No significant financial relationships to disclose.
Second-line therapy with pemetrexed after gemcitabine failure in patients with unresectable locally advanced or metastatic pancreatic cancer: A multicenter phase II trial
Authors: Boeck S. , Weigang-Koehler K. , Fuchs M. , Kettner E. , Quietzsch D. , Trojan J. , Stötzer O. , Mueller E. , Depenbrock H. , Heinemann V.
Published: March 2020

4124

Background: There is no established second-line therapy for advanced pancreatic cancer after failure of standard first-line treatment with gemcitabine. In view of the urgent need of such therapy and the observation of clinically meaningful responses with pemetrexed in previously untreated pancreatic cancer, this phase II study evaluated pemetrexed as second-line therapy. Methods: This study was planned to evaluate the efficacy and safety of pemetrexed in 54 patients (pts) with unresectable locally advanced or metastatic pancreatic cancer (stage II-IV), ECOG performance status ≤2 and estimated life expectancy of ≥12 weeks (wks) after failure of first-line gemcitabine single agent or combination therapy. Pemetrexed was started at 500 mg/m2 q3w (10 min infusion), with vitamin B12 and folic acid supplementation. Dose escalation by 100 mg/m2 every other cycle and an unlimited number of cycles were allowed. Primary endpoint was the 3-month survival rate. Results: A total of 189 treatment cycles (median 2, range 1–20) was given to 52 pts (60% male, median age 63 yrs, median time since initial diagnosis 32 wks, 89% stage IV disease). Doses were escalated in 2 pts (4%) and reduced due to toxicity in 9 pts (17%); median dose per cycle was 500 mg/m2 (range 212–700 mg/m2). The 3-month survival rate was 75% (95% CI 63.2–86.8%). At a median follow-up of 20 wks, the median overall survival estimate was 20 wks, with 9 pts alive including 1 still on pemetrexed. Median TTP was 7 wks (range 1–62 wks). The overall response rate was 3.8% (0 CR, 2 PR); 12 pts (23%) had SD for ≥6 wks, 9 of them for ≥12 wks. CA 19–9 decreased at least once by ≥ 50% in 12 pts (23%). Grade 3/4 hematological toxicity rates per pt were as follows: neutropenia 17.3% (febrile neutopenia: 3.8%), leukopenia 15.4%, thrombopenia 5.8% and anemia 3.8%. Conclusion: Pemetrexed is a feasible option for second-line therapy with mild toxicity and encouraging activity in unresectable locally advanced or metastatic pancreatic cancer after gemcitabine failure.

[Table: see text]
Gefitinib in advanced unresectable hepatocellular carcinoma: Results from the Eastern Cooperative Oncology Group’s Study E1203
Authors: O’Dwyer P. J. , Giantonio B. J. , Levy D. E. , Kauh J. S. , Fitzgerald D. B. , Benson A. B.
Published: March 2020

4143

Background: Worldwide, hepatocellular carcinoma (HCC) is the most common cause of cancer death. Chemotherapy yields no survival benefit, and median survival is < 6 months. Up to 47% of HCCs express the epidermal growth factor receptor (EGFR), which predicts survival. Also, EGFR signaling activates c-Met, the hepatocyte growth factor receptor. Gefitinib is an oral selective EGFR inhibitor that has shown growth inhibition of HCC cell lines. Methods: E1203 was a single arm phase II study of gefitinib in advanced HCC. Eligibility requirements: unresectable measurable (by RECIST) HCC (diagnosed by histology or alpha-fetoprotein criteria); PS ≤ 2; total bilirubin ≤ 2× ULN; SGOT ≤ 5× ULN; INR ≤ 2.3; albumin ≥ 2.8 g/dl; Child Pugh Class < C; no prior systemic therapy. Gefitinib 250 mg taken daily. 1 cycle = 3 weeks. Tumor assessments done every 6 weeks. Objectives: 4.5 month PFS of 63%, OS, RR, toxicity. A two-stage design was used. Results: Thirty-one patients were accrued to the first stage. Median follow-up is 13.2 months. Med age = 64.8 yrs (46–86). M:F 87%:10%. PS 0/1/2: 39%/42%/16%. Med PFS = 2.8 months (95%CI: 1.5, 3.9). Med OS = 6.5 months (95% CI: 4.4, 8.9). Response #s (CR/PR/SD): 0/1/7. Selected grade 3 adverse events: neutropenia ×2; rash ×2; diarrhea ×1. There was only 1 grade 4 AE (neutropenia). The criterion for second-stage accrual was not met. Conclusion: Gefitinib as a single agent is not active in advanced HCC.

No significant financial relationships to disclose.
Bevacizumab in unresectable hepatocellular carcinoma (HCC) for patients without metastasis and without invasion of the portal vein
Authors: Schwartz J. D. , Schwartz M. , Lehrer D. , Cohen E. , Sung M. , Kinkhabwala M. , Siegel A. , Holloway S. , Ocean A. , Wadler S.
Published: March 2020

4144

Background: HCC is a vascular tumor in which angiogenesis contributes to pathogenesis. VEGF-inhibition has not been previously attempted in cirrhosis or HCC. Methods: We enrolled patients with unresectable HCC to treatment with bevacizumab at 5 mg/kg or 10 mg/kg every 14 days to assess safety and preliminary efficacy. Inclusion criteria were BR < 3.0 mg/dl, transaminases 75K and PT within 4 seconds of normal. Additional criteria included no history of myocardial infarction, stroke, or condition requiring ongoing antiplatelet or antithrombotic therapy. Results: Initial safety assessments for patients treated for at least 8 weeks indicate that 10 of 11 patients treated at 5 mg/kg and 7 of 8 patients treated at 10mg/kg tolerated therapy with acceptable toxicity. Of the first 28 patients treated at either dose, four have had therapy discontinued because of adverse events (including one grade 3 transient ischemic attack). Three patients had serious esophageal bleeding which was likely secondary to progression of HCC and liver disease (although contribution of drug to these events cannot be excluded). The protocol has been modified to identify and treat esophageal varices prior to enrollment. Other toxicities have included grade 2 fatigue, abdominal pain, gastric ulcer, hypertension, hyperbilirubinemia, rash and proteinuria and grade 1 gingivitis, diarrhea, vomiting and epistaxis. Of the initial 25 patients evaluable for efficacy, 5 had progressive disease within 16 weeks. Two patients had PR and 18 had SD. Median time-to-progression was 6.5 months (range 3.9–24.2). Nineteen of 25 (76%) patients had HCC that progressed following transplant, surgery, RFA or embolization procedures. Conclusions: Bevacizumab can be given safely at both 5 mg/kg and 10 mg/kg in HCC patients with localized, unresectable HCC, preserved liver function and no significant esophageal varices. Preliminary results suggest significant disease-modifying effect (80% disease-control rate); median time-to-progression to-date has exceeded 6-months.

[Table: see text]
A non-randomized phase II study of sequential irinotecan (CPT) and flavopiridol (F) in patients (pts) with advanced hepatocellular carcinoma (HCC)
Authors: Abou-Alfa G. K. , Carvajal R. D. , Chung K. Y. , Ghossein R. A. , Capanu M. , Gonen M. , Jacobs G. , Kelsen D. P. , Schwartz G. K.
Published: March 2020

4148

Background: F is a CDK inhibitor which potentiates CPT- induced apoptosis. In a phase I trial of CPT 100mg/m2 followed 7 hours later by F given over 1 hour weekly for 4 out of 6 weeks (Shah, Clin Can Res 2005), 2 pts with advanced HCC had stable disease (SD) for 14+ months. In the same phase I study, patients who were p53 wild-type (negative p53 staining), and whose p21 remained stable or was non-detectable on the post-treatment biopsy, were noted to have SD or a partial response. Methods: Pts with advanced HCC, no prior systemic therapy, Child’s-Pugh score A, B7 or B8, and KPS ≥ 70%, received 100 mg/m2 of CPT, followed 7 hours later by 60 mg/m2 of F over 1 hour weekly for 4 out of 6 weeks. The trial had a two stage design, with a planned accrual of 30 pts. The primary endpoint was TTP. Tumor response was assessed every 2 cycles using revised WHO criteria. p53 immuno-staining was performed on pre-treatment paraffin preserved tissues. A cut-off of 20% defined positive mutant versus negative wild-type p53 status. Results: 16 pts were enrolled: median age 64 (range 26–84), KPS 80% (70–90%), and 10 males/6 females. 13 pts received therapy, two progressed before starting, and one patient (pt) was excluded because pathology re-review did not confirm HCC. 1 pt was excluded because of consent withdrawal after first dose of therapy. This pt was included in the toxicity analysis. The median number of cycles given was 2 (range 1–8 cycles). Grade 3 and 4 toxicities included dehydration (4: 30%) diarrhea (2: 15%) febrile neutropenia (6: 46% - 4 events in one pt) and fatigue/weakness (3: 23%). Therapy had to be discontinued in 2 pts because of toxicity. TTP was 2.6 months (95% CI 2.43–8.42). One patient had SD for over a year, 8 had progression of disease (POD), and 4 came off study because of toxicity. Mutational p53 was evaluated in 7 pts. The pt with SD had wild type p53. Three pts with POD had mutant p53, while the other 3 had wild type 53. Conclusions: CPT followed by F is an ineffective therapy for HCC. This therapy was relatively poorly tolerated, likely contributed to by underlying cirrhosis in HCC, but similar to our experience of CPT in HCC. While p21 level pre and post therapy is lacking, the wild type p53 of the patient with SD maybe a predictor of response in HCC where p53 mutations are common.

No significant financial relationships to disclose.
Phase I/II trial of the prostate-specific membrane antigen (PSMA)-targeted immunoconjugate MLN2704 in patients (pts) with progressive metastatic castration resistant prostate cancer (CRPC)
Authors: Milowsky M. I. , Galsky M. , George D. J. , Lewin J. M. , Rozario C. P. , Marshall T. , Chang M. , Nanus D. M. , Webb I. J. , Scher H. I.
Published: March 2020

4500

Background: MLN2704 is an immunoconjugate that utilizes the PSMA-targeted monoclonal antibody MLN591 to deliver the maytansinoid antimicrotubule agent DM1 directly to prostate cancer cells. This multicenter trial was designed to determine the tolerability, optimal dosing schedule and efficacy of MLN2704 in pts with progressive metastatic CRPC. Methods: Pts aged ≥18 yrs with progressive metastatic CRPC received MLN2704 i.v. over 2.5 hr q1wk, q2wks or q3wks for 12 wks, with additional doses permitted in responders. Doses within a given schedule were escalated in 40% increments in the absence of excessive dose-limiting toxicity (DLT). Results: 61 pts have been treated. The most common adverse events (AEs) were nausea, fatigue, and schedule-dependent neurotoxicity. The only DLT was gr 3 hepatic transaminitis in 1/6 pts at 330 mg/m2 q2wks; the only gr 4 AE was transient neutropenia, in 2 pts (330 mg/m2 q2wks and q3wks). Declines in PSA were most frequent at 330 mg/m2 q2wks ( table ), including 49–88% PSA declines in 4/6 pts. However, given the frequency of grade 2–3 peripheral neuropathy an additional cohort is being treated with 330mg/m2 on days 1 and 15 of a 6-wk cycle. Initial results with this 6-wk schedule indicate PSA declines with a lower incidence of gr 2–3 toxicities, particularly neuropathy. Conclusions: Accrual to the dose-escalation phase is complete. Dose-dependent antitumor effects were seen. Peripheral neuropathy has limited continuous dosing at higher dose levels prompting a schedule change. Accrual to the 6-wk schedule is continuing.

[Table: see text]

[Table: see text]
Efficacy of lapatinib in patients with high tumor EGFR expression: Results of a phase III trial in advanced renal cell carcinoma (RCC)
Authors: Ravaud A. , Gardner J. , Hawkins R. , Von der Maase H. , Zantl N. , Harper P. , Rolland F. , Audhuy B. , Machiels J. , El-Hariry I.
Published: March 2020

4502

Background: Lapatinib is an orally-active, reversible inhibitor of EGFR/ErbB2 tyrosine kinases. In Phase I/II trials, lapatinib has demonstrated activity in patients (pts) with advanced breast cancer. We report the first results of a randomized open-label Phase III trial ( EGF20001 ) of lapatinib vs. hormone therapy (HT) in pts with advanced RCC that express EGFR and/or ErbB2 by immunohistochemistry (IHC). The main endpoints were time to progression (TTP) and overall survival (OS). Methods: Pts with advanced RCC of any histology who had failed first-line cytokine therapy were stratified by Karnofsky performance score (KPS) and number of metastatic sites. Pts were randomized to receive oral lapatinib 1250 mg OD or HT. The primary efficacy endpoint was TTP, with 90% power to detect a 50% increase (i.e. 4 vs. 6 months) at a two-sided 5% significance level. All pt scans were interpreted by independent radiologic review. Results: At the time of the TTP analysis, 417 pts were randomized and 298 TTP events were reported. Demographic and baseline characteristics were similar between both arms; pooled results were: median age: 61 yrs; Stage IV disease: 97%, KPS 90–100: 59%, metastatic sites >2: 49%, prior nephrectomy: 94%, prior interferon therapy: 64%. No unexpected toxicities were observed, and drug-related AE (all grades) for lapatinib vs. HT included rash (44%:3%), diarrhoea (40%:3%). When results from all pts were analysed, median TTP was 15.3 weeks for lapatinib vs. 15.4 weeks for HT (hazard ratio (HR) = 0.94; p = 0.60), and median OS was 46.9 weeks for lapatinib vs. 43.1 weeks for HT (HR=0.88; p=0.29). In the major subgroup of 241 pts with EGFR overexpressed disease (3+ by IHC), median TTP was 15.1 weeks for lapatinib vs. 10.9 weeks for HT (HR = 0.76; p = 0.06), and median OS was 46.0 weeks for lapatinib vs. 37.9 weeks for HT (HR = 0.69; p = 0.02). These results were confirmed by Cox Regression analysis, and additional biomarker evaluation, including FISH, is underway. Conclusions: The EGFR/ErbB2 dual targeted inhibitor, lapatinib, appears to prolong overall survival compared to hormone therapy in advanced RCC pts with overexpressed EGFR who failed prior therapy.

[Table: see text]
Systems pathology for building predictive models: The androgen receptor as a prototype biomarker in prostate cancer progression and targeted therapeutic response assessment
Authors: Donovan M. J. , Scher H. , Scardino P. , Kotsianti A. , Cordon-Cardo C.
Published: March 2020

4504

Background: A functional androgen receptor (AR) signaling axis plays a critical role in prostate cancer (PCA) development and progression across the clinical spectrum of the illness. Following diagnosis, most prostate cancers respond to treatments that block circulating androgen levels or block AR action. The measurement of AR levels in tumor tissue samples has the potential to provide prognostic information, to treatment selection, and a measure of the pharmacodynamic effect of a therapeutic agent(s) designed to reduce AR levels or block AR action. Existing methods to assess AR antigen levels in tissue are subjective, we have developed a systems pathology strategy for interrogating biomarker assessment in a predictive model by integrating clinical data with histological and quantitative antigen profiles. Methods: Tissue microarrays from 366 MSKCC patients were stained with H&E, images captured, analyzed and quantitative cellular features produced. Immunohistochemistry (IHC) was performed for AR and a staining index generated. A multiplex immunofluorescent (IF) assay using DAPI, CK18 and AR was performed on a subset of patients. IF mages were acquired and specific IF scripts were used to generate quantitative features of AR which were compared with AR IHC data. Results: Androgen Receptor levels by IHC in PCA demonstrated that a high-level of expression was associated with a greater risk of PSA-relapse within 5 years. (P < 0.0001; cut point 100). The correlation of AR IF with AR IHC established that all derived AR-IF measurements were statistically associated with the AR-IHC data. Furthermore, in a very preliminary model using machine learning and feature selection to predict PSA recurrence, 1AR-IF feature (epithelial and stromal AR) along with 2 clinical variables was selected with a concordance index of 0.80. Conclusion: AR levels in newly diagnosed localized prostate cancer are associated with clinical outcome. The levels can be assessed accurately and in a standardized manner using quantitative multiplex antigen methods. Such approaches are critical for evaluating biomarkers, especially when determining therapeutic response and clinical endpoints.

[Table: see text]
Predicting the outcome of salvage radiotherapy for recurrent prostate cancer after radical prostatectomy
Authors: Stephenson A. J. , Pollack A. , Kattan M. W. , Scardino P. T.
Published: March 2020

4514

Background: Salvage radiotherapy may potentially cure patients with recurrent prostate cancer after radical prostatectomy (RP). However, the outcome is highly dependent on patient selection factors and current diagnostic modalities for locally recurrent prostate lack acceptable sensitivity and specificity. We developed a model to predict the likelihood of a durable response to salvage radiotherapy for patients with post-RP biochemical recurrence (BCR). Methods: Using multivariable Cox proportional hazards regression analysis, we modeled the clinical data for 1540 patients who received salvage radiotherapy at 1 of 17 North American tertiary referral centers for post-RP BCR. The primary endpoint was disease progression after salvage radiotherapy, defined as a serum prostate-specific antigen (PSA) value ≥ 0.2 ng/mL followed by another increase, initiation of systemic therapy, or clinical recurrence. The median follow-up was 53 months. Results: Disease progression was observed in 866 patients and the 5- and 10-year progression-free probability was 38% (95% CI, 35–40) and 19% (95% CI, 15–23), respectively. Significant variables in the nomogram were: pre-radiotherapy PSA (P < .001), RP Gleason score (P < .001), neoadjuvant androgen-deprivation therapy (P< .001), negative surgical margins (P < .004), PSA at BCR (P = .011), PSADT (P = .029), and regional lymph node metastasis (P = .034). The nomogram was accurate and discriminating with a concordance index of 0.68. Published models predicting the probability of metastasis progression or PCSM for BCR patients based on disease-free interval, prostatectomy Gleason score, and/or PSA doubling time discriminated poorly for a durable response to salvage radiotherapy among patients in our cohort (concordance index, 0.56–0.61). Conclusions: A nomogram has been developed that predicts the 5-year progression-free probability after salvage radiotherapy for men with post-RP BCR. This represents the first model to predict the outcome of salvage therapy for BCR and is useful for quantifying the anticipated benefit of salvage radiotherapy for prostate cancer recurrence. Published predictive models for metastasis progression or PCSM are of limited clinical utility in selecting patients for salvage radiotherapy.

No significant financial relationships to disclose.
Absolute PSA value after androgen deprivation (AD) is a strong independent predictor of survival in new metastatic (D2) prostate cancer (PCa): Data from Southwest Oncology Group Trial 9346 (INT-0162)
Authors: Hussain M. , Tangen C. M. , Schellhammer P. F. , Crawford E. D. , Higano C. S. , Wilding G. , Akdas A. , Small E. J. , Donnelly B. , Raghavan D.
Published: March 2020

4517

Background: PSA is a biomarker for monitoring disease activity in PCa. It is not well established if absolute PSA values achieved after AD is prognostic in patients (pts) with new D2 PCa. Methods: Hormone naive D2 pts with baseline PSA ≥ 5ng/mL are treated with 7 months (ms) AD induction. Pts achieving PSA-n (PSA ≤ 4.0 ng/ml that is stable or declining on ms 6 and 7) are randomized to continuous vs. intermittent AD on month 8. To be eligible for this analysis (approved by Data Safety Monitoring Committee), pts had to have a prestudy PSA with at least 2 subsequent PSAs during induction and be registered at least 1 year prior to analysis date. Survival was defined from 8 months to death due to any cause. Associations were evaluated by proportional hazards regression models. P≤0.05 was statistically significant. Results: Of the first 1,395 registered pts, 1345 were eligible for this analysis. Median age was 70 years, median baseline PSA 76.1 ng/mL, 38% had bone pain (BP) and 47 % had Gleason sum (GS) > 7. Median number of on-study PSAs during induction was 5 (range: 2 -18). Of the 1,345 pts, 1134 achieved PSA-n with 965 maintaining PSA-n at end of induction. Of those achieving PSA-n, 604 (45% of all pts) had an undetectable PSA (PSA-u, ≤ 0.2 ng/mL) at end of induction. In multivariate analysis, 4 significant independent risk factors were associated with post-induction survival: Performance status, GS, BP, and being randomized. After adjustment for these factors, pts who had a PSA-n at the end of induction but not PSA-u had less than half the risk of death (RoD) as those who did not have PSA-n (HR: 0.41; 95% CI 0.32, 0.54, p < 0.001), and pts with PSA-u had about one-quarter the RoD as pts with no PSA-n (HR: 0.26; 95% CI 0.20, 0.35, p < 0.001). After adjustment for covariates, pts with PSA-u had significantly better survival than those with only PSA-n at end of induction (p < 0.001). The median overall survival was 13 ms for the 383 not normalized (95% CI: 11 to 16 ms), 44 ms for the 360 pts normalized but not undetectable (95% CI: 39 to 55 ms), and 75 ms for the 602 pts with PSA-u (95% CI: 62, 91 ms). Conclusion: Achieving a PSA-n or PSA-u after 7 ms of AD is a strong predictor of survival and should be used to tailor future trial design in new D2 pts.

[Table: see text]
Intermittent chemotherapy in metastatic androgen-independent prostate cancer (AIPC): Initial results from ASCENT
Authors: Beer T. M. , Ryan C. W. , Venner P. M. , Petrylak D. P. , Chatta G. , Ruether J. , Chi K. N. , Arroyo A. , Clow F. W.
Published: March 2020

4518

Background: Phase III studies document a survival benefit for 10–12 cycles of docetaxel-containing chemotherapy in AIPC. Further management of patients who complete chemotherapy in response status remains ill-defined. Single-institution phase II data suggest that re-treatment with the same regimen after a treatment holiday is feasible in selected patients. This approach was prospectively tested in a multi-institutional trial. Methods: ASCENT was a multi-institution randomized clinical trial designed to compare the activity and safety of weekly DN-101 (45 μg on day 1) plus docetaxel (36 mg/m2 iv on day 2 for 3 weeks of a 4-week cycle) to placebo + docetaxel in patients with chemotherapy-naïve metastatic AIPC. ASCENT was the first large trial to prospectively evaluate intermittent chemotherapy. Patients could opt to suspend treatment if they had a confirmed ≥ 50% reduction in serum PSA and a serum PSA ≤ 4 ng/ml. PSA was monitored every 4 weeks (CT scans every 8 weeks in patients with measurable disease) during the treatment holiday. Treatment was resumed when serum PSA rose by ≥ 50% and was ≥ 2 ng/ml or for other evidence of disease progression. The study was not powered to compare treatment holiday outcomes between the two arms. Results: 250 patients were randomized 1:1. Overall PSA response rates were: DN-101: 63%, Placebo 52% (p = 0.07). Overall 18% (DN-101: 20%, Placebo: 16%) of patients entered the intermittent chemotherapy. The median duration of the first chemotherapy holiday was 16 weeks (range 4–74+) (DN-101: 15 weeks, Placebo: 16 weeks). Upon resumption of treatment after the first holiday, 50% of patients responded with a ≥ 50% reduction in serum PSA from their post-holiday baseline, 35% met criteria for stable PSA for at least 12 weeks, and 15% progressed on therapy. Conclusions: This is the first report of intermittent chemotherapy in AIPC prospectively tested in a large multi-institutional trial. This strategy results in a clinically meaningful duration of chemotherapy holidays and can be offered to a minority (18%) of patients. Upon re-treatment, most patients (85%) again respond or stabilize PSA values.

[Table: see text]
Pegylated interferon alpha-2B (PEG-Intron) for metastatic renal cell cancer (mRCC): Results of a phase II clinical trial and biologic correlates of response
Authors: Kondagunta G. V. , Bacik J. , Ishill N. , Reuter V. , Schwartz L. H. , Korkola J. , Deluca J. , Sweeney S. , K. Chaganti R. S. , Motzer R. J.
Published: March 2020

4528

Background: PEG-Intron (PEG-I) is a pegylated derivative of interferon alpha-2b (IFN), recombinant, with a single molecule of mono methoxy polyethylene glycol which increases serum half-life. Methods: A single arm, one-stage phase II trial was conducted between 6/02 and 6/04 in 32 previously untreated patients (pts) with mRCC to assess time to progression and biologic correlates (primary and secondary endpoints). Eligibility included measurable disease and fresh tumor procured at surgery for genetic and immunohistochemical (vascular endothelial growth factor [VEGF] and carbonic anhydrase IX [CAIX]) studies. PEG-I was given SC at a weekly dose of 4.5 μg/kg until progression or intolerability. Quality of life (QOL) was assessed using the FACT-BRM. Results: All 32 were evaluable, 91% had prior nephrectomy, and MSKCC risk group (JCO 20:289–96, 2002) was: 41% good, 53% intermediate, 6% poor. 10 pts (31%; 95% CI: 16%-50%) achieved a partial response (PR). Median time to progression was 5.0 mos (95% C.I. [3, 7]); median survival was 31 mos (95% C.I. [18, not reached]). There were no grade IV toxicities; primary grade III toxicities were hematologic (6/32 pts; 19%) and fatigue (4/32 pts; 13%). FACT-BRM scores showed an initial decrease in QOL at 2 weeks followed by partial recovery. Genomic profiling of tumor samples identified four novel genes that correlated with IFN resistance: ABCD3, Hs.76704, Hs.11325, and Hs.94122. Change in serum VEGF levels did not correlate with response. Tumor tissue samples are being immunohistochemically stained for CAIX. Conclusions: PEG-I treatment results in a 31% response rate and similar median time to progression as standard IFN (JCO 18:2972–80, 2000) in this population with predominantly good and intermediate risk pts. Once weekly dosing was generally well tolerated. Future investigation of PEG-I in combination with novel targeted agents in mRCC is warranted. Further study of the four identified genes may provide insight into IFN resistance. Supported by Schering-Plough, Inc.

[Table: see text]
Neoadjuvant paclitaxel (P), carboplatin (Ca) and gemcitabine (G) in patients with locally advanced transitional cell carcinoma (TCC) of the bladder: A final report
Authors: Smith D. C. , Mackler N. J. , Hussain M. H. , Dunn R. , Montie J. E. , Wood D. , Lee C. T. , Petrylak D. , Quinn D. , Vaishampayan U.
Published: March 2020

4541

Background: PCaG has activity in the treatment of TCC. Studies have shown that neoadjuvant chemotherapy may improve survival in TCC, with pathologic complete responders (pT0) having the most benefit. This study was designed to assess the pT0 rate and resectability following neoadjuvant PCaG in patients with TCC of the bladder. Methods: Patients with adequate organ function, performance status 0–2, and clinical T3 or T2 with hydronephrosis, N0, M0 TCC (Arm I) received 3 cycles of PCaG (P: 200 mg/m2, IV over 3 hours day 1, C: target AUC=5 IV day 1, and G: 800 mg/m2; IV day 1 & 8 every 21 days) followed by cystectomy with a primary endpoint of pT0. T4 or node positive (Tany, N1–3, M0) patients (Arm II) received 6 cycles with an endpoint of resectability. Each arm had a Minimax two-stage accrual with planned initial enrollment of 26 evaluable subjects in arm I (up to 54 total) and 19 in arm II (up to 33). Results: 68 patients were registered (31 arm I, 37 arm II). Median age was 65 years in arm I and 58 years in arm II. 22/31 (71%) patients in arm I are evaluable and 7 were pT0 at cystectomy. pT0 rate is 32% (95% CI: 13.9–54.9%) of evaluable, 23% (9.6–41.1%) by intent to treat (ITT). 30/37 (81%) on arm II are evaluable for response and 20 had cystectomy for a resection rate of 67% (47.2–82.7%) of evaluable, 54% (36.9–70.5%) by ITT. 5 patients resected on arm II had pT0 and 2 had only residual carcinoma in situ. A total of 252 cycles of therapy were delivered (80 in arm I, 172 in arm II) with 161 at full dose. 54/68 patients (79%) had grade 3/4 hematologic toxicity, primarily neutropenia with 4 other episodes of grade 3 toxicity (2-neuropathy, 1-myalgia, 1-fatigue). 4 patients died during chemotherapy (2-bowel obstruction, 1-coronary artery disease, 1-intracranial bleed) and 2 post-op (1-multiorgan failure, 1-enterocolitis). Only 1 death was clearly chemotherapy related, but the study was halted early due to these deaths. Conclusions: Neoadjuvant PCaG has demonstrated activity in locally advanced TCC of the bladder, but has considerable toxicity. The pT0 rate with this combination is comparable to the rates reported in the literature for other regimens. Support from Bristol-Myers Squibb, Eli Lilly, and 2P30 CA 46592–14 from the National Cancer Institute

[Table: see text]
Phase II trial of epothilone B analogue BMS-247550 in advanced carcinoma of the urothelium (E3800): A trial of the Eastern Cooperative Oncology Group
Authors: Dreicer R. , Li S. , Manola J. , Haas N. , Roth B. , Wilding G.
Published: March 2020

4543

Background: Patients (pts) with advanced urothelial carcinoma who progress following first line therapy have limited effective therapeutic options. The epothilones are a class of antineoplastics with a broad range of antitumor activity. We evaluated BMS-247550 in pts with advanced urothelial cancer having received 1 prior systemic therapy regimen. Methods: Pts with TCC or mixed histologies containing TCC received BMS-247550 40 mg/m2 IV over 3 hours on day 1 of a 3-week cycle. Dose modifications occured for low granulocytes and/or platelets, mucositis, sensory neuropathy, and other Grade 3 or 4 toxicities. Pts remained on treatment until disease progression or unacceptable toxicity. Standard ECOG response criteria were used. Results: Total accrual (allowing for ineligible pts) was 45 pts, of whom 17 had received prior taxanes. One pt was ineligible (2 prior regimens) and was excluded from this analysis. Sixteen pts are still being evaluated for eligibility. The pt cohort was 82% male and 86% Caucasian. The median age was 63 (range 37–81), 70%, 7% and 23% had 1, 2 and 3 MSKCC risk factors respectively. Eighty-two % of pts had distant metastatic disease at study entry. A median of 2 cycles were administered (range, 1–8). The most common reasons for discontinuing treatment were progressive disease (65%) and toxicity (25%). Twelve pts experienced grade 4 toxicity, including leukopenia (n = 5), neutropenia (n = 9), ventricular arrhythmia, hypotension, DIC, stomatitis, elevated bilirubin, dyspnea, febrile neutropenia, hypoxia, acidosis, and elevated creatinine (n = 1 patient each). One pt died of cardiac failure following numerous grade 4 toxicities, including neutropenic infection. Two other deaths due to progressive disease occurred while pts were receiving treatment. Response information is available for 37 of 44 potentially eligible pts. There have been 5 partial responses, 3 among pts who had previously received taxanes, 17 pts had stable disease for at least 6 weeks. Conclusions: BMS-247550 has modest activity in pts with previously treated advanced TCC of the urothelium, but at the cost of modest-significant toxicity. Activity in pts previously treated with paclitaxel is of interest, however its ultimate utility remains undefined.

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Adjuvant chemoradiotherapy after radical cystectomy in advanced high risk bladder cancer: A prospective randomized trial
Authors: Zaghloul M. S. , Khaled H. M. , Lotayef M. , William H.
Published: March 2020

4545

Background: High risk locally advanced bladder cancer patients experienced low survival rates, high local recurrence and extensive distant metastasis. Postoperative radiotherapy (PORT) though improved the survival through improving local control. Methods: A prospective randomized trial was performed at NCI, Cairo, Egypt including 142 patients in 2 arms. Patients who underwent radical cystectomy and pelvic lymphadenectomy had to have one more of the following: P3b or P4a stage, G3 or involved lymphadenopathy. Arm I (71 patients) received PORT 45 G/30 fractions/3 weeks. Arm II (71 patients) received 2 courses of adjuvant chemotherapy (Gemcitabine 1 gm/m2 D1 and D8 and cisplatin 70 mg/m2 D2), same PORT regimen followed by another 2 courses of Gemcitabine-cisplatin. Results: Chemotherapy was tolerated with grade 1/2 toxicities. Early radiation reactions were also tolerable in both arms, slightly more in arm II. Delayed toxicity was comparable in both arms. The 2-year DFS was 67.6 ± 5.9% in the whole group. This was affected significantly by performance status (p = 0.009), pathological stage (p = 0.001), tumor cell type (p = 0.053), nodal involvement (p = 0.07) and number of risk factors (p = 0.09). Though there was improvement of DFS from 61.5 ± 7.4% in PORT group to 70.9 ± 6.1% in chemoradiotherapy group, yet it was not statistically significant (p = 0.2). Patients having one risk factor, low pathological stage or no nodal involvement in arm II experienced better DFS than those in arm I (p = 0.07, 0.08 and 0.09 respectively). Conclusions: Adjuvant chemoradiotherapy using Gemcitabine-cisplatin and PORT was tolerable with minimal severe toxicities. There was DFS improvement with the addition of chemotherapy to PORT (not statistically significant yet). Patients with one risk factor, lower pathological stage or no nodal involvement seemed to benefit more from added chemotherapy.

No significant financial relationships to disclose.
Expression of the endothelin axis and microvessel density in bladder cancer
Authors: Herrmann E. , Bierer S. , Boegemann M. , Eltze E. , Hertle L. , Wülfing C.
Published: March 2020

4583

Background: Endothelin-1 (ET-1) and its receptors ETAR and ETBR, referred to as the Endothelin (ET)-axis play an emerging role in cancer. The ET-axis has been shown to be involved in proliferation, angiogenesis and metastasis. We investigated the effect of the ET-axis on microvessel density (MVD) and on the clinical prognosis in patients with invasive carcinoma of the bladder. Methods: Archival tumor tissue of 157 consecutive patients was reviewed and representing tumor blocks were selected. Paraffin sections were assessed immunhistochemically using mono- and polyclonal antibodies for ET-1, ETAR,ETBR and CD34 (MVD). Staining intensities were analyzed semiquantitatively and the MVD was calculated as vessels per field. The results were correlated with various pathological and clinical factors, as well as with disease-free and overall survival. Results: Overexpression of ET-1, ETAR and ETBR was identified in 26.8%, 58.8% and 76.9% of cases, respectively. Normal urothelium was constantly negative. No association with TNM staging and histologic grading was found. However, patients with ETBR expression tended to have organ-confined tumors (P = 0.16) and no vascular invasion (P = 0.09), the latter being statistically significant in the subgroup of G3 tumors (P = 0.02). T1 and T2 (MVD = 32,2) tumors had greater MVD compared to T3 and T4 tumors (MVD = 21,2) (P = 0.02), showing an association of MVD and overexpression of ET-1 (P = 0.027). ETBR-positive tumors were associated with favorable disease-free survival (P = 0.04). In urothelial carcinomas the MVD was 23,7, whereas squamous cell carcinomas had a MVD of 17,8 (P = 0.04). Conclusion: The ET-axis is overexpressed in invasive bladder cancer. Urothelial carcinomas are significantly greater vascularized compared to squamous cell carcinomas. Organ-confined tumors showed more MVD than T3 and T4 tumors, which is related to ET-1 expression in this subgroup. ETBR appears to predominate in bladder cancer and is associated with a more favorable prognosis.

No significant financial relationships to disclose.
Antitumor effects of sorafenib and sunitinib in patients (pts) with metastatic renal cell carcinoma (mRCC) who had prior therapy with anti-angiogenic agents
Authors: Tamaskar I. , Shaheen P. , Wood L. , Hodnick S. , Nemec C. , Garcia J. , Dreicer R. , Rini B. , Bukowski R.
Published: March 2020

4597

Background: Sorafenib and sunitinib are multi-targeted kinase inhibitors (TKI’s) with clinical activity in mRCC. Their effect in mRCC pts refractory to prior anti-angiogenic agents is unclear. We investigated the anti-tumor effect of sorafenib and sunitinib in patients with mRCC who failed prior treatment with anti-angiogenic agents. Methods: Pts with mRCC receiving sorafenib and sunitinib on compassionate use trials were identified. Those pts who had received prior treatment with anti-angiogenic agents defined as thalidomide, lenalidomide, M200 (anti-α5β1 integrin monoclonal antibody), bevacizumab, AG013736, sunitinib or sorafenib were selected and their treatment response to current sorafenib or sunitinib evaluated. Results: Seventy-two pts (39 receiving sorafenib and 33 receiving sunitinib) were identified. Of these 72 pts, 23 pts (32%) had received prior anti-angiogenic therapy as defined above. Demographics included: 19 male and 4 female, median age 61 years (range 44 to 77). Thirteen pts (57%) are currently evaluable; the remainder are too early for assessment. Twelve pts (92%) demonstrated tumor reduction including 4 pts with objective partial response (PR); 8 pts had stable disease with tumor shrinkage ranging from 4 to 27% and 1 pt had disease progression. Of the 4 PR pts, prior therapy included M200 (1 pt), lenalidomide (2 pts) and sorafenib (1 pt). Of the 13 evaluable pts 4 had failed a prior TKI and received a subsequent TKI and all had evidence of tumor shrinkage to subsequent therapy (sunitinib followed by sorafenib, 1pt - 16% shrinkage, sorafenib followed by sunitinib 2 pts - 33.4% and 24% and AG013736 followed by sunitinib 1 pt - 12% ). Conclusion: Sorafenib and sunitinib have anti-tumor activity in mRCC pts who have received prior anti-angiogenic agents.

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Predicting the histology of renal masses using pre-operative Doppler ultrasonography
Authors: Raj G. V. , Iasonos A. , Bach A. , Hann L. , Russo P.
Published: March 2020

4598

Background: Traditional imaging techniques cannot differentiate between benign, indolent and malignant renal neoplasms. Since conventional clear cell carcinomas are highly vascular, we evaluated the association between vascular flow within a renal mass on pre-operative color and/or power Doppler ultrasonography (CDUS) and surgical pathology. Methods: Nephrectomies performed at our institution between 1/2001 and 12/2004 were retrospectively evaluated. Detection of flow within the renal mass on CDUS was defined as vascular flow. A prospective validation study was performed from 1/2005 to 10/2005, and a nomogram predicting clear cell histology created using vascular flow along with clinical and radiologic parameters. Results: Of 299 renal lesions in the retrospective cohort, 210 (70%) had evidence of vascular flow, including 156 of 169 (92%) conventional clear cell carcinomas (p < 0.0001). On logistic regression analyses, vascular flow was associated with conventional clear cell histology with an odds ratio of 16.9, CI: 8.7–32.8, p < 0.0001. These findings were validated prospectively in 97 patients; CDUS detected vascular flow in 54 of 65 (83%) renal masses with conventional clear cell histology (p < 0.0001) and was associated with an odds ratio of 10.8 (95% CI 4.0–29.0; p < 0.0001). On multivariable analyses, vascular flow was still a statistically significant predictor of conventional clear cell histology. A nomogram incorporating vascular flow along with clinical and radiologic variables (clinical size, patient gender and age) to predict conventional clear cell histology was constructed on the retrospective cohort and validated on the prospective data set (concordance index 0.82 and 0.76 respectively). Conclusions: Vascular flow within a renal mass detected by CDUS is strongly associated with conventional clear cell histology with an odds ratio of 10.8–16.9. A nomogram incorporating vascular flow on CDUS and clinical and radiographic parameters may aid in the non-invasive characterization of renal lesions.

[Table: see text]

No significant financial relationships to disclose.
Anti-proliferative effects of sorafenib in clear cell renal cell carcinoma (CCRCC) cell lines: Relationship to von Hippel Lindau protein (pVHL) expression and hypoxia
Authors: Al Hazzouri A. , Vaziri S. A. , Lynch M. , Schwartz B. , Rini B. I. , Bukowski R. , Ganapathy R.
Published: March 2020

4601

Background: Sorafenib, a multikinase inhibitor targeting raf kinase and several receptor tyrosine kinases including VEGFR-2 and PDGFR, has demonstrated clinical activity in the treatment of metastatic CCRCC. To further characterize the molecular basis of response to this agent, we tested the functional role of pVHL and hypoxia in the anti-tumor activity of sorafenib in a panel of CCRCC cell lines. Methods: CCRCC cell lines CAKI-1 (wild-type pVHL), CAKI-2 (mutant VHL) and the isogenic pair, 786–0-neo (vector control) and 786–0-VHL (pVHL expressing) cells were treated with sorafenib (2.5 - 20 μM) for 24 - 96 hours at 37°C in a atmosphere of either normoxia (21% oxygen) or hypoxia (1% oxygen), 5% carbon dioxide and remainder nitrogen. Gene expression analysis of control and sorafenib treated CCRCC cell lines was carried out using a custom cancer cDNA array containing probes to 9240 cDNA clones corresponding to 4900 Unigenes or unclustered ESTs relevant to cancer or kidney development. Results: Anti-proliferative effects of sorafenib were both concentration and time of treatment dependent; the IC50 of sorafenib (inhibitory concentration for 50% cell kill) ranged from 7.5-10 μM and required continuous treatment for at least 48-72 hours for maximal cell kill. In contrast to CAKI-2 and 786–0-neo cells harboring mutant VHL, both CAKI-1 and 786–0-VHL cells expressing wild type VHL were ∼2-fold more resistant to the anti-proliferative effects of sorfaenib when treated under hypoxic conditions. No difference in resistance was observed under normoxic conditions. In contrast to 786–0-neo cells, there were ∼40 genes overexpressed (>5-fold) under hypoxia in control 786–0-VHL cells, that were predominantly related to anti-apoptosis (e.g. bcl2-associated athanogene) or angiogenesis (e.g. PDGF beta). Bcl2-associated athanogene and PDGF beta were down regulated >2-fold in hypoxia with sorafenib treatment. Conclusions: CCRCC with wild type VHL under hypoxic conditions can promote overexpression of anti-apoptotic and angiogenesis genes that attenuate the anti-proliferative effects of sorafenib. pVHL and hypoxia related genes may be important biomarkers for assessing the clinical efficacy of sorafenib in CCRCC.

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Phase 2 trial of 177Lutetium (177Lu) radiolabeled anti-prostate-specific membrane antigen (PSMA) monoclonal antibody (mAb) J591 (177Lu-J591) in patients (pts) with metastatic androgen-independent prostate cancer (AIPC)
Authors: Morris M. J. , Milowsky M. I. , Pandit-Taskar N. , Divgi C. , David K. A. , Rozario C. P. , Vallabhajosula S. , Goldsmith S. J. , Scher H. I. , Nanus D. M.
Published: March 2020

4613

Background: J591 is an anti-PSMA mAb targeting the extracellular domain of PSMA, a highly PC restricted glycoprotein. 177Lu linked to J591 via a DOTA chelate was evaluated in a phase 1 trial in pts with metastatic AIPC demonstrating acceptable toxicity (MTD = 70 mCi/m2), excellent targeting of metastatic sites and biologic activity. Methods: Pts with progressive metastatic AIPC receive a single dose of 177Lu -J591 in two cohorts (65 and 70 mCi/m2). Cohort 1: 15 pts; Cohort 2: 17 pts. The primary endpoint is PSA and measurable disease response assessed at wk 12. Secondary endpoint is to evaluate toxicity. One 177Lu imaging study is done at 1 week post-treatment to confirm tumor targeting. Results: 14 pts, median age 73 (5 chemo-naïve), have been treated on this ongoing 2-center study. One pt with bone-only metastases achieved an 87% decline in PSA by day 85 with resolution of bone pain. Bone scan at wk 12 revealed a flare response. As of day 222, the pt has not required additional therapy. PSA stabilization (< 25% PSA rise above baseline) has been seen in 4 pts lasting 16 wks in 2 pts, 18 wks (1 pt) and 23 wks (1 pt), respectively. One pt withdrew at wk 56 without PSA progression. Of 5 pts with measurable disease, no objective responses were seen. Grade 3 and 4 thrombocytopenia occurred in 6 and 4 pts, respectively. 12/14 pts recovered plt counts to ≥ 150 x 109/L (median time to recovery = 22 d). Grade 3 and 4 neutropenia occurred in 7 and 1 pts, respectively. 13/14 pts had ANC recovery to ≥ 2 x 109/L (median time to recovery = 13 d). No significant drug-related non-hematologic toxicity has occurred. Excellent targeting of known sites of PC metastases has been observed in all pts. Conclusions: 177Lu-J591 demonstrates anti-tumor activity in pts with AIPC with one pt achieving the primary endpoint (≥ 50% PSA decline) and 4 pts with PSA stabilization at a dose of 65 mCi/m2. Support: NIH CA102544 , NCRR M01RR00047, DOD PC031175 , David H. Koch Foundation, Cancer Research Institute, MSKCC Experimental Therapeutics Ctr, McCoey Fund, BZL Biologics, Inc. and Millennium Pharmaceuticals, Inc.

No significant financial relationships to disclose.