bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of relapse in patients with esophageal and esophagogastric junction (E-EGJ) cancer with surgical stage after trimodality therapy (TMT): Implications for customized surveillance.
Authors: Campagna Maria-Claudia , Taketa Takashi , Correa Arlene M. , Sudo Kazuki , Blum Mariela A. , Wadhwa Roopma , Komaki Ritsuko , Lee Jeffrey H. , Bhutani Manoop S. , Weston Brian , Liao Zhongxing X. , Rice David C. , Swisher Stephen , Hofstetter Wayne Lewis , Ajani Jaffer A.
Published: February 2017

95

Background: The surveillance strategy for E-EGJ cancer patients after TMT is currently not based on evidence and varies considerably. Literature does not provide guidance. Methods: Between 2000 and 2010, 579 patients with E-EGJ cancer who underwent TMT were analyzed. The type and timing of first relapse using 12-month intervals and their association the post-TMT surgical stage. Various statistical methods were utilized. Results: For 579 patients, the median follow-up time was 57.4 months (95% confidence interval [CI], 51.5-63.3 months). A total of 232 (40%) patients had a relapse. First relapses were: distant metastases (199 patients; 34.4%) and local-regional metastases (33 patients; 5.7%). Irrespective of the surgical stage, 95% of all relapses occurred within 36 months of surgery. The timing and frequency of relapses were significantly associated with the surgical stage (see Table; stage 0 or I vs. II or III; p= <0.001). Conclusions: Our data suggest that customization of surveillance is possible based on the surgical stage after TMT. These data can contribute to the development of an evidence-based surveillance strategy. [Table: see text]
Long-term survival of subjects in the prostate cancer prevention trial.
Authors: Goodman Phyllis J. , Thompson Ian Murchie , Tangen Catherine M. , Parnes Howard L. , Godley Paul Alphonso , Ford Leslie G.
Published: February 2017

10

Background: As finasteride could reduce by 25% the number of prostate cancers (PCa) diagnosed in the U.S. annually, the public health benefit of prostate cancer prevention could be enormous. We performed a survival analysis to assess for any evidence of increased risk of death in men randomized to finasteride, a potential indicator of a ‘true’ increased risk of high grade (HG) disease in the PCPT. Methods: A Social Security Death Index search was conducted on all randomized men to ascertain date of death. Cox proportional hazards models adjusting for known risk factors for overall survival and survival from time of diagnosis of PCa overall, low grade (LG) and HG were used to estimate hazard ratios (HR) and construct 95% confidence intervals to determine if survival on finasteride and placebo were equivalent. Results: A total of 5,128 deaths have been reported; 2,584 men on finasteride and 2544 on placebo. 15-year survival rates for all randomized men in each arm is 78%. The HR for overall survival on finasteride compared to placebo is 1.04 (95% CI 0.96, 1.10, p=.19). 10-year survival from diagnosis for men with PCa was slightly higher for men randomized to finasteride (10-year survival 83% vs. 81%) but not statistically significant (HR= 0.87, 95% CI 0.73 - 1.04, p=.14). For the men with HG PCa, there was no evidence of worse survival on finasteride (HR= 1.01; 95% CI 0.73, 1.14, p=.97) while those diagnosed with LG disease finasteride had superior survival (HR= 0.73; 95% CI 0.57, 0.94, p=.01). Conclusions: For men in PCPT with PCa there was no difference in survival from diagnosis date, a slightly-superior 10-year survival with finasteride and a statistically-superior survival among men with LG tumors in the finasteride group. A potential explanation for this phenomenon could be a lead-time bias. Arguing against this bias is the identical survival of HG PCa in both groups. Another potential explanation is that the men with LG PCa on placebo include a greater number with undetected HG disease; HG tumors in men on finasteride were more likely detected due to the improved performance of prostate biopsy. With follow-up of 18 years, finasteride administration for 7-years does not appear to affect mortality but significantly reduces the risk of a PCa diagnosis. Clinical trial information: NCT00288106.
Association of metastasis-free survival (MFS) with overall survival (OS) in men with PSA-recurrent prostate cancer treated with deferred androgen-deprivation therapy.
Authors: Schweizer Michael Thomas , Zhou Xian C. , Wang Hao , Yang Ting , Shaukat Farah , Eisenberger Mario A. , Antonarakis Emmanuel S.
Published: February 2017

109

Background: To support the hypothesis that metastases are a significant clinical event, we aimed to explore the association between MFS with OS in men with biochemically-recurrent prostate cancer. Methods: This is a retrospective analysis of 450 men treated at a single institution between July 1981 and July 2010 with biochemical recurrence following prostatectomy, of which 140 (31%) developed subsequent metastases. In all patients, androgen deprivation therapy was deferred until after the development of radiographic metastases. Univariate and multivariable Cox regression models were developed to investigate factors influencing OS. Results: The median time from biochemical recurrence to metastasis (i.e. MFS) was 10.2 y (95% CI, 7.6–14.0 y), and the median time from first metastasis to death (i.e. OS) was 6.6 y (95% CI, 5.8–8.4 y). Using multivariable Cox regressions, we identified 4 variables that were independently prognostic for OS (Table): MFS (≤3 vs >3 y; P=0.009), number of metastases (≤3 vs ≥4; P=0.001), painful metastases (present vs absent; P<0.001), and ECOG performance status (0 vs ≥1; P=0.001). The concordance index reflecting the association between MFS and OS was 0.67. Conclusions: After adjusting for other prognostic variables, MFS was independently associated with OS in men with biochemically-recurrent prostate cancer. While this observation requires prospective validation, it suggests that MFS may be a reasonable endpoint in future clinical trials. [Table: see text]
Prostate-specific membrane antigen antibody drug conjugate (PSMA ADC): A phase I trial in metastatic castration-resistant prostate cancer (mCRPC) previously treated with a taxane.
Authors: Petrylak Daniel Peter , Kantoff Philip W. , Mega Anthony E. , Vogelzang Nicholas J. , Stephenson Joe , Fleming Mark T. , Stambler Nancy , Petrini Michaela , Huang Kathleen , Israel Robert Joseph
Published: February 2017

119

Background: The abundant expression of prostate specific membrane antigen (PSMA) on prostate cancer cells provides a rationale for antibody therapy. PSMA ADC, a fully human antibody to PSMA linked to the microtubule disrupting agent monomethyl auristatin E (MMAE), binds PSMA and is internalized within the prostate cancer cell where cleavage by lysosomal enzymes release free MMAE, causing cell cycle arrest and apoptosis. We have completed a phase 1 dose escalation study of PSMA ADC in subjects with taxane-refractory mCRPC. Methods: Eligibility requirements include progressive mCRPC following taxane-containing chemotherapy and ECOG status of 0 or 1. PSMA ADC was administered by IV infusion Q3W for up to 4 cycles. Safety, pharmacokinetics (PK), PSA, circulating tumor cells (CTC), clinical disease progression and immunogenicity to PSMA ADC were assessed. Serum PSMA ADC and total antibody were measured by ELISA, and free MMAE was measured by LC/MS/MS.The dosing cohorts ranged from 0.4 mg/kg to 2.8 mg/kg. Results: 52 subjects with mCRPC were dosed in nine dose levels. All subjects received prior docetaxel, 5 also received cabazitaxel and 3 subjects also received paclitaxel. PSMA ADC was generally well tolerated with the most commonly seen adverse events being anorexia and fatigue. Peripheral neuropathy was reported by 7 subjects after repeated doses. Two were grade 3. Dose limiting toxicities (DLT) seen at 2.8 mg/kg were neutropenia (one death) and reversible liver function tests (LFTs) elevations. Antitumor activity was manifested as reductions either in PSA or CTCs at ≥ 1.8 mg/kg PSMA ADC in approximately 50% of patients. Exposure to PSMA ADC increased with dose and was ~1,000-fold greater than MMAE exposure and no accumulation was observed. Conclusions: PSMA ADC in this study was generally well tolerated in doses up to 2.8 mg/kg every three weeks in subjects with mCRPC, previously treated with taxane. Antitumor activity was seen at higher dose levels. DLTs were neutropenia and reversible LFT abnormalities. The maximum tolerated dose of PSMA ADC was determined to be 2.5 mg/kg. A phase 2 trial in taxane refractory mCRPC has been initiated. Clinical trial information: NCT01414283.
Absence of interaction of cabazitaxel on the pharmacokinetics of midazolam: Results of a drug–drug interaction study in patients with advanced solid tumors.
Authors: Rixe Olivier , Sarantopoulos John , Hsueh Chung-Tsen , Lockhart A. Craig , Ross Sharona , Agarwala Sanjiv S. , Zhang Wendy , Yin Jian Y. , Wack Claudine , Mazuir Florent , Gurtler Jayne S.
Published: February 2017

126

Background: Cabazitaxel (Cbz) is approved in combination with prednisone/prednisolone for the treatment of men with hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing treatment regimen. In vitro studies showed that Cbz is mainly metabolized through CYP3A, resulting in inhibition of this family of enzymes. Midazolam (Mdz) is primarily metabolized by CYP3A4. We aimed to determine the effect of Cbz on CYP3A activity by comparing the pharmacokinetic (PK) properties of Mdz when administered alone and following co-administration with Cbz. Methods: An ongoing safety and PK study of Cbz in patients with metastatic or locally advanced solid tumors and varying degrees of hepatic impairment (NCT01140607) included a cohort with normal hepatic function to assess the effect of a single Cbz dose on the PK profile of a single dose of Mdz. This was an open-label, two-period, fixed-sequence study in patients aged between 45 and 60 years with advanced solid tumors and normal hepatic function. A single dose of Mdz (2 mg) was administered orally alone (Day –1) and at the end of a 1-hour infusion of Cbz (25 mg/m2) (Day 1), with a 24-hour interval between the two administrations of Mdz. Endpoints included AUC and AUClastof Mdz with and without Cbz administration, and safety evaluations. Results: Of the 13 patients enrolled and treated in the cohort, 11 patients were included in the PK analysis. Exposure (AUC and AUClast) and other PK parameters after a single administration of Mdz alone and in combination with Cbz (Day 1) were similar. The AUC ratio for Mdz administered alone or with Cbz was 0.97 (90% CI: 0.76–1.23). The AUClast ratio for Mdz administered alone or with Cbz was 1.04 (90% CI: 0.81–1.34). All 13 patients had ≥1 adverse event (AE), 11 (84.6%) experienced a Grade 3–4 AE, and 4 (30.8%) experienced a serious AE. The majority of Grade 3–4 AEs were haematological and no new or unexpected safety findings were observed. Conclusions: In this study, Cbz did not increase the plasma exposure of Mdz. This indicates that Cbz is not a CYP3A inhibitor in the clinical setting and can be administered in combination with drugs metabolized by CYP3A. Clinical trial information: NCT01140607.
Role for IL2 adjunctive cotherapy for suppression of a solid tumor with designer T cells: Phase I trial data in prostate cancer.
Authors: Junghans Richard Paul
Published: February 2017

216

Background: We created chimeric antigen receptors (CAR) against prostate specific membrane antigen (PSMA). When expressed in patient T cells, these “designer T cells” (dTc) kill prostate cancer cells in vitro and in vivo in animal models (Ma et al. Prostate2004:61:12-25). A Phase I trial was performed. Methods: Patient T cells are retrovirally transduced and expanded ex vivoto span doses of 10^9 to 10^10 T cells. Patients undergo prior non-myeloablative (NMA) conditioning to create a “hematologic space” into which dTc are infused for stable engraftment and prolonged in vivo efficacy. Continuous infusion low dose IL2 (LDI: 75 kiu/kg/d) is administered. Results: Infused T cells were documented. Safety was shown and partial responses (PR) obtained in 2/5 subjects (40%), with PSA suppressions of 50-70% over 1-2+ mo and PSA progression delay up to 150d. Against expectation, response correlated inversely with engraftment (p=0.06) but directly with plasma IL2 (p=0.03) that was as much as 20-fold lower in non-responders than responders. Low plasma IL2 correlated with high engraftments (p<0.01), prompting an hypothesis that high engrafted numbers of activated T cells absorb out IL2 to a level too low to sustain dTc activation for tumor killing. Conclusions: Encouraging early results were obtained with anti-PSMA dTc in adoptive immune therapy of advanced prostate cancer. It is proposed that adequate higher plasma IL2 will reveal the expected greater potency of higher dTc doses, thereby potentially inducing PSA reductions of 100%, with durable remissions. A study redesign tests moderate dose IL2 (MDI) (300 kiu/kg/8h bolus) versus LDI in a randomized Pilot at the 10^10 cell dose, which is now open to enrolment. To refer patients, please contact the study referral manager by telephone: 401-456-2507 or email: RDavies@rwmc.org. This trial received partial funding from US Army/DOD. Preclinical work was supported by Prostate Cancer Foundation. Clinical trial information: NCT00664196.
A prostate cancer clinical trials consortium trial of disulfiram (D) in men with nonmetastatic recurrent prostate cancer (PCa).
Authors: Schweizer Michael Thomas , Bardia Aditya , Blackford Amanda L. , Lin Jianqing , Armstrong Andrew J. , King Serina , Rudek Michelle A. , Yegnasubramanian Srinivasan Thomas , Carducci Michael Anthony
Published: February 2017

219

Background: Epigenetic silencing of tumor suppressor genes (TSG) by promoter methylation contributes to carcinogenesis and progression. Targeting these epigenetic changes in PCa has been hindered by a paucity of available agents. D potently inhibits PCa growth in vitro and can cause demethylation and re-expression of known TSGs in PCa cells lines. Methods: To determine if D leads to demethylation changes [i.e. decreased global 5meC DNA content from peripheral blood mononuclear cells (PBMC)] we conducted an open-label, dose escalation trial of D in men with non-metastatic recurrent PCa after local therapy. Dose escalation occurred if a demethylating “response” (i.e. >10% decrease in global 5meC content) in <3 patients was observed in cohort 1. Cohort 1 and 2 received D 250 mg and 500 mg daily respectively; 1 cycle equaled 4 weeks. The primary endpoint was the proportion of subjects with a demethylation response. Secondary endpoints included rate of PSA progression at 6 months (i.e. confirmed >50% rise over baseline and >2 ng/mL above nadir), changes in PSA doubling time (PSADT) and safety/tolerability. Results: Two patients out of 9 (22.2%) in cohort 1 met our primary endpoint. Cohort 2 accrued a total of 10 patients, 3 (30.0%) of which had >10% decrease in global 5meC content. Only 5 subjects were on trial for ≥6 months, all were in cohort 1 and all had PSA progression by 6 months. Median PSADT change post-treatment was not significantly different between responders and non-responders (266.9 vs -7.8 days, P=0.18) or between cohorts 1 and 2 (22.5 vs -39.7 days, P=0.54). While there were no grade (G) 4 adverse events (AE), the drug was poorly tolerated with 6 patients experiencing G3 AE (3 per cohort). There was a trend toward fewer median number of completed cycles in cohort 2 vs cohort 1 (5 vs 9 cycles, P=0.12). Common AE included: fatigue, GI toxicity, ataxia/dizziness, and constitutional symptoms. Conclusions: A minority of patients had global PBMC demethylation changes, consistent with D acting as a probable demethylating agent in those individuals. Given the toxicities associated with D and no significant clinical benefits, further development of this agent should not be pursued in this population. Clinical trial information: NCT01118741.
Clinical-pathologic stage discrepancy in patients with bladder cancer treated with radical cystectomy: Associations with clinical variables and survival.
Authors: Gray Phillip J. , Fedewa Stacey A. , Shipley William U. , Lin Chun Chieh , Virgo Katherine S. , Kibel Adam Stuart , Kamat Ashish M. , Rosenberg Jonathan E. , Jemal Ahmedin , Zietman Anthony L. , Efstathiou Jason Alexander
Published: February 2017

248

Background: Radical cystectomy (RC) is the most common treatment for bladder cancer (BC) in the United States. We examined clinical-pathologic stage discrepancy using the National Cancer Data Base. Methods: 16,953 patients with BC treated with RC between 1998 and 2009 were analyzed. Clinical factors associated with stage discrepancy were assessed by multivariable generalized estimating equation models. Survival analysis was conducted for patients treated between 1998 and 2004 (N=7,270) using a Cox proportional hazards model. Results: 41.9% of patients were upstaged at RC while 5.9% were downstaged. Upstaging was more common in females (OR 1.08, p=.04), the elderly (OR 1.26 for age ≥80 vs. 18-59, p=.001), higher tumor grade (OR 2.29 for grade 3-4 vs. grade 1, p<.0001), non-urothelial histology (OR 1.31, p=.002 for squamous and OR 1.26, p=.03 for adenocarcinoma), and with extended lymphadenectomy (OR 1.27 for ≥10 lymph nodes examined vs. 0-9, p<.0001). Downstaging was less common in the elderly (OR 0.50 for age ≥80 vs. 18-59, p<.0001), in Hispanics (OR 0.58, p=.009) and with variant histology (OR 0.55, p=.003 for squamous and OR 0.3, p<.0001 for adenocarcinoma). Receipt of neoadjuvant chemotherapy (CT) was highly associated with downstaging (OR 2.31, p<.0001). 5-year survival by stage is shown in the table. Upstaging was associated with increased 5-year mortality (HR 1.79, p<.0001) as was receipt of CT (HR 1.28, p=.02 for neoadjuvant and HR 1.23, p<.0001 for adjuvant). Extended lymphadenectomy was associated with decreased 5-year mortality (HR 0.82 for ≥10 lymph nodes examined vs. 0-9, p<.0001). Downstaging was not associated with survival (HR 0.88, p=0.17). Conclusions: This study is the largest to date to analyze stage discrepancy and survival in BC patients treated with RC. Upstaging is common and is associated with decreased 5-year survival. These data can be used in pre-operative risk stratification, treatment decision making and comparison with studies of non-operative management. [Table: see text]
Randomized phase III trial of neoadjuvant chemotherapy (NAC) with methotrexate, doxorubicin, vinblastine, and cisplatin (MVAC) followed by radical cystectomy (RC) compared with RC alone for invasive bladder cancer (BC): Japan Clinical Oncology Group Study, JCOG0209.
Authors: Kitamura Hiroshi , Tsukamoto Taiji , Masumori Naoya , Shibata Taro , Kunieda Futoshi , Fujimoto Hiroyuki , Hirao Yoshihiko , Kitamura Yasuo , Tomita Yoshihiko , Tobisu Kenichi , Niwakawa Masashi , Naito Seiji , Eto Masatoshi , Kakehi Yoshiyuki ,   Urologic Oncology Study Group of the Japan Clinical Oncology Group
Published: February 2017

249

Background: Cisplatin-based NAC for patients (pts) with invasive BC is considered to provide a 5–8% overall survival (OS) advantage, although several studies failed to prove the survival benefit of NAC. Methods: Eligibility criteria included histologically proven urothelial carcinoma, invasive (T2-4aN0M0) bladder cancer within 8 weeks from TURBT, PS 0-1, age 20 to 75 years old. Patients were randomized to receive either 2 cycles of neoadjuvant MVAC followed by RC (NAC arm) or RC alone (RC arm). MVAC comprised M (30 mg/m2) on days 1, 15, and 22; V (3 mg/m2) on days 2, 15, and 22; A (30 mg/m2) on day 2; C (70 mg/m2) on day 2. The primary endpoint was OS. Secondary endpoints were progression-free survival (PFS), the surgery-related complication rate, adverse events during NAC, the rate of no residual tumor in the RC specimens (pT0), and quality of life. The sample size was 180 pts in each arm with a one-sided alpha of 5% and a power of 80% to detect a difference in 5-year OS from 45% in the RC arm to 57% in the NAC arm. Results: From March 2003 to March 2009, 130 pts were randomized to the NAC arm (n=64) and RC arm (n=66). The patient registration was terminated early because of slow accrual. At the second interim analysis conducted after the completion of patient accrual, the OS of the NAC arm was better than that of the RC arm (median, 102 and 81 months, respectively), although the difference was not statistically significant (HR, 0.65; multiplicity adjusted 99.99%CI, 0.19 - 2.18; one-sided log-rank p = 0.07). Considering the current situation in which NAC with gemcitabine and cisplatin (GC) is widely used in clinical practice, the Data and Safety Monitoring Committee recommended early publication of the results. The median PFS times in the RC arm and NAC arm were 78 and 99 months, respectively (p=0.04). No differences in perioperative complications, other than lymph leakage, were observed between the groups. pT0 in the NAC arm and RC arm was 34 % vs. 9 %, respectively (p<0.01). Conclusions: Although NAC with GC is widely used for invasive BC, NAC with MVAC can still be considered promising. Clinical trial information: 000000093.
HER2 expression in patients (pts) with surgically resected urothelial cancer at high risk of recurrence screened for the phase II randomized, open-label trial of DN24-02, an autologous cellular immunotherapy targeting HER2.
Authors: Press Michael F. , O'Donnell Peter H. , Plimack Elizabeth R. , Gomella Leonard G. , Quinn David I. , Sharma Padmanee , DeVries Todd , Sims Robert Brownell , Chen Melissa , Bajorin Dean F.
Published: February 2017

292

Background: HER2 overexpression has been suggested as a poor prognostic factor in pts with high-risk urothelial carcinoma (UC). Published data note a wide range of HER2 overexpression in UC, with some reports showing <10% of cases and others exhibiting >50% of cases with ≥2+ HER2 expression by immunohistochemistry (IHC). NeuACT (N10-1; NCT01353222) is a phase 2 trial to determine whether DN24-02, an autologous cellular immunotherapy targeting HER2 based on the same platform used for sipuleucel-T, given as adjuvant therapy following surgical resection can prolong survival (Bajorin, et al. ASCO 2012). Here we report preliminary data for HER2 expression on primary tumor and positive lymph node samples from this study. Methods: Trial eligibility criteria include surgical resection of a primary UC, with either ≥pT2 or pN+ staging, and HER2 expression ≥1+ IHC. Surgical specimens are screened for HER2 expression by central pathology laboratory review and HER2 positivity is scored using the Dako HercepTest scoring system. Results: As of August 2012, tumor specimens from 61 pts have been screened for HER2 expression. Of these pts, 49 (80%; 95% CI: 68–89%) had a HER2 expression score of ≥1+ in the primary tumor, with 27 (44%) having ≥2+ score and 3 (5%) having a 3+ score. Twenty-three pts (38%) also had HER2 expression levels evaluated in tumor from involved lymph nodes. A total of 20 (87%; 95% CI: 66–97%) of these pts had a HER2 expression score of ≥1+ in the lymph nodes, with 12 (52%) having a ≥2+ score and 3 (15%) having a 3+ score. Two pts had primary tumor samples that expressed HER2 but were negative for HER2 expression in the lymph nodes submitted for analysis. Conclusions: Although preliminary, a high frequency (≥80%) of HER2 expression score of ≥1+ in primary tumor and lymph node samples was observed. These data highlight the prevalence of HER2 protein expression in high-risk UC. Furthermore, the HER2 expression data are consistent with previously published data in pts with invasive UC. Clinical trial information: NCT01353222.
Survival outcomes in patients undergoing neoadjuvant chemotherapy for upper tract urothelial cell carcinoma.
Authors: Porten Sima P. , Siefker-Radtke Arlene O. , Kamat Ashish M. , Dinney Colin P.N. , Matin Surena F.
Published: February 2017

311

Background: High-grade upper tract urothelial carcinoma (UTUC) is frequently upstaged at surgery and has uniformly poor survival rates. Neoadjuvant chemotherapy (NAC) may provide an avenue to improve clinical outcomes in these patients prior to loss of renal function after nephroureterectomy. Methods: We performed a retrospective review of patients with high risk UTUC who received NAC followed by surgical extirpation from 2004 to 2008, a time period during which NAC was uniformly offered to patients. The study group was then compared to a historical cohort of similar risk patients who underwent initial surgical treatment from 1993-2004. Results: Of the 120 patients, 31 patients with high-risk cN0 disease received NAC, 76 had initial surgery, and 13 had surgical consolidation of clinically involved lymph nodes after chemotherapy. Those receiving NAC had an improved OS and DSS (p=0.018 and p=0.0005, respectively). The 3 and 5 year DSS for cN0 patients receiving NAC was 90% and 90% (OS 87% and 80% respectively) with median follow up of 64 months. The 3 and 5 year DSS and OS for the historical group was 70% and 62%, with median follow up of 87 months. The two groups had similar demographics and clinical features, except for a higher proportion of sessile tumor architecture in the NAC group (p=0.021). Full dose cisplatin or high dose ifosfamide based chemotherapy was given to 22 (71%) patients, while 4 (13%) received a modified dose of cisplatin, and 5 (16%) received a nephron sparing combination. Pathologic downstaging to <=pT1N0 was significantly associated with NAC (65% vs 26% initial, p=0.004). The 13 patients with node positive disease at presentation received NAC followed by surgical consolidation with median OS 78 months. The 3 and 5 year DSS was 77% and 67% (OS 69% and 60% respectively). Conclusions: Neoadjuvant chemotherapy improves survival in patients with UTUC compared with historical expectations. Patients with high-risk UTUC should be considered for neoadjuvant chemotherapy especially considering the limitations of administering curative cisplatin-based chemotherapy after nephrectomy.
Quality of life (QoL) among patients with renal cell carcinoma (RCC) treated with pazopanib versus sunitinib in the COMPARZ study.
Authors: Cella David , Hackshaw Michelle Denise , Diaz Jose , Huang Chun , Deen Keith C. , Crescenzo Rocco , Motzer Robert John
Published: February 2017

346

Background: Pazopanib and sunitinib are targeted therapies associated with particular treatment-related side effects that may affect patients’ QoL. COMPARZ was a randomized, open-label, parallel group, phase III study of pazopanib vs. sunitinib in 1,110 subjects with advanced RCC who had not received prior systemic therapy. The study demonstrated pazopanib is non-inferior to sunitinib with respect to progression-free survival. The study also confirmed the differentiated safety profiles of the two drugs. Methods: QoL endpoints were assessed using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), the Functional Assessment of Cancer Therapy-Kidney Symptom Index-19 (FKSI-19), the Cancer Therapy Satisfaction Questionnaire (CTSQ), and a Supplementary Quality of Life Questionnaire (SQLQ). Research to validate the SQLQ is currently ongoing. Each instrument was administered at baseline (except CTSQ) and then day 28 of every cycle. Changes in mean scores over time were analyzed and compared using a repeated measures analysis of covariance. Comparisons were pre-specified at the first 6 months of treatment as this time was expected to be a key interval during which tolerability issues may have occurred. Results: During the first 6 months, treatment differences in change from baseline for 11 of the 14 QoL domains studied were statistically significant (p < 0.05), all of which favored pazopanib. Further analysis up to 12 months of treatment, showed the treatment differences observed for fatigue scores increased over time with pazopanib improving and sunitinib remaining relatively flat. The difference in limitations due to foot soreness between the two treatments also progressively increased with time over 12 months favoring pazopanib. Conclusions: In this study, better patient-reported QoL scores for pazopanib indicate subjects experienced less worsening of fatigue, as well as mouth/throat, hands, and feet soreness, and fewer limitations due to soreness, while on pazopanib compared with sunitinib. The differences observed are likely to be clinically meaningful. The FACIT-F and SQLQ results are also highly consistent with the previously-reported PISCES study.
Inhibition of tumor growth in a VEGFR TKI-resistant model of renal cell carcinoma using dalantercept combined with sunitinib.
Authors: Bhatt Rupal Satish , Wang Xiaoen , Solban Nicolas , Wei Lin , Signoretti Sabina , Alsop David , Alimzhanov Marat , Pearsall Scott , Atkins Michael B. , Kumar Ravi , Sherman Matthew L. , Mier James Walter
Published: February 2017

370

Background: Antagonists of VEGF/VEGFR pathway have demonstrated clinical utility in patients with metastatic renal cell carcinoma (RCC); however, the therapeutic responses tend to be short-lived. Thus, there is a need for new treatments to overcome the acquired resistance to the current standards of care. Methods: We have used a murine xenograft model of RCC to study the relationship of the bone morphogenetic protein (BMP)/transforming growth factor-β (TGF-β) superfamily pathways and the VEGF pathways. Additionally, we have studied the effects of BMP9/10 inhibition on RCC tumor growth and performed MRI based tumor blood flow analyses to study antiangiogenic activity of the treatments. To explore the role of BMP9/10/ALK1 signaling in resistance to VEGFR inhibition, we used dalantercept (human ALK1-Fc fusion protein) as a ligand trap for BMP9 and 10. Results: We have found evidence of upregulation of BMP10 in A498 RCC xenograft tumors that have developed resistance to sunitinib. In tumors that had developed resistance to sunitinib, addition of ALK1-Fc to sunitinib led to prolonged tumor stabilization compared to either agent alone. Imaging of tumors revealed that addition of ALK1-Fc to sunitinib prevented the resumption in blood flow that is generally seen with continued sunitinib. Conclusions: These murine xenograft model data demonstrate that inhibition of ALK1 receptor pathway in combination with inhibition of VEGFR pathway may be a useful strategy for the treatment of RCC. A phase II randomized study of dalantercept in combination with axitinib in patients with metastatic RCC after progression on VEGFR/TKI therapy is ongoing.
Defining the molecular tumor margin regions of clear cell renal carcinoma tissues by MALDI-MS imaging of lipid and glycan species.
Authors: Drake Richard , Powers Thomas , Jones Ellen , Mehta Anand , Lance Raymond S. , Troyer Dean A.
Published: February 2017

421

Background: The frequent tumor recurrence associated with clear cell renal cell carcinoma (ccRCC) suggests that there are underlying molecular processes present in the remaining tissue following nephrectomy that are not identified through conventional histopathological techniques. At the molecular level, transcript, metabolomic, and protein expression patterns have indicated a striking Warburg Effect profile in ccRCC tissues, with major affects on sugar and lipid metabolism. Our group has been applying MALDI mass spectrometry imaging approaches to uniquely profile lipids and glycans associated with disease progression directly in frozen tissue slides. Methods: Frozen ccRCC tissues with tumor, non-tumor adjacent, and tumor margin regions were selected by a pathologist. Lipid profiles from fresh-frozen tissue slides coated in DHB matrix were obtained on a dual source Bruker Solarix 70 FTICR mass spectrometer. Glycans were imaged in a similar fashion in ethanol-washed tissues using on-tissue protein N glycanase F digestion to release surface N-glycans. Detected lipid and glycan ion intensities were converted to a color pixel scale for creating an image of individual peaks, linked directly to the histopathology of the tissue. Results: Five groups of lipid and N-glycan species were identified following MALDI tissue imaging, those present in the immediate margin area of non-tumor tissue adjacent to tumor; only in non-tumor regions; only in tumor regions; primarily in tumor regions but extended beyond the margin; and present throughout the tissue. Specific lipid and glycan species associated with margin and tumor regions are being correlated with disease progression and pathology data. Conclusions: Analysis of the periphery of the tumor tissue and the normal parenchyma or capsule regions at this biomolecule level may better define the metastatic potential of the tumor as compared to analysis of the central tumor region. This approach has the potential to not only improve prognostic assessment and treatment choices, but also to inform on the underlying biology of ccRCC metastasis and new rational targets for therapeutic intervention.
The initial biopsy Gleason score as a predictive marker for docetaxel survival benefit in patients with prostate cancer: Data from the TAX 327 study.
Authors: van Soest Robert , de Morrée Ellen , Shen Liji , Tannock Ian , Eisenberger Mario A. , De Wit Ronald
Published: February 2017

44

Background: The TAX 327 study was conducted in 1,006 men with metastatic castration-resistant prostate cancer (mCRPC) who were randomized to receive 3-weekly docetaxel (D3), weekly docetaxel (D1) or 3-weekly mitoxantrone (M), each with prednisone. Survival and symptom control were superior following D3 as compared to M. In this post-hoc analysis we aimed to identify factors that could characterize subgroups of patients who obtained the greatest benefit from the use of D3 as compared to M. Methods: The TAX 327 database was used to investigate if patients with poorly differentiated tumors (Gleason 7-10) at diagnosis had greater benefit from D3 as compared to M, than patients with better differentiated tumors (Gleason ≤6). Using a Cox model, we compared overall survival (OS) between the treatment groups within each subgroup of Gleason score. Results: Baseline characteristics known to predict OS including visceral metastasis and time from first hormonal treatment to the start of chemotherapy were well balanced between patient groups, except for an imbalance in the small group of patients with impaired Karnofsky performance score (PS) (see table). The TAX 327 data showed that the OS benefit of D3 versus M is greater in patients with high grade tumors (median OS 18.9 vs 14.5 months) than in patients with low grade tumors (median OS 21.6 vs 20.7 months). Conclusions: The survival benefit obtained with docetaxel as compared to mitoxantrone is greater in patients with high Gleason score tumors. Although this finding is hypothesis-generating and needs confirmation in other trials, it may provide additional guidance in treatment decisions regarding the use of chemotherapy as first line treatment for patients with mCRPC. [Table: see text]
Effect of pazopanib on myeloid-derived suppressor cells and T-cell function in patients with metastatic renal cell carcinoma.
Authors: Khurana Kiranpreet K. , Rayman Pat A. , Elson Paul , Rini Brian I. , Finke James
Published: February 2017

455

Background: Tyrosine kinase inhibitors have been shown to have an effect on T cell function. Sunitinib decreases immunosuppression in patients with metastatic renal cell carcinoma (mRCC) as seen by a reduction in myeloid derived suppressor cells (MDSC) that inhibit T cell function. The effect of pazopanib on immune function is unknown. Methods: Peripheral blood mononuclear cells from 21 patients with mRCC treated with pazopanib were thawed for cycle 1 day 1, cycle 1 day 28, cycle 2 day 28, and cycle 4 day 28. Total MDSC and neutrophilic, monocytic, and lineage-negative MDSC subsets were measured by flow cytometry. T cell response was measured by interferon-gamma production after in vitro stimulation by anti-CD3/anti-CD28 beads. Pre-treatment cycle 1 day 1 levels were compared to cycle 4 day 28. Results: In mRCC patients, MDSCs comprise 4.7 % (median, range 1.7-32.9 %) of the peripheral blood mononuclear cells pre-treatment. Neutrophilic MDSC subset is the most prevalent at 2.0 % (median, range 0.3-30.4 %). Monocytic MDSCs comprise 1.5 % (median, range 0.4-5.3 %), and lineage-negative MDSCs comprise only 0.15 % (median, range 0.01-1.03 %). We found that pazopanib does not significantly decrease the percentage of MDSCs (total or subpopulations) over time with the exception of a modest decrease in the lineage-negative MDSC subset (p = 0.08). In terms of T cell function, pre-treatment level of CD3+ interferon-gamma was found to be 10.6 % (median, range 1.3-22.3 %). In contrast, pazopanib significantly increased CD3+ interferon-gamma level over time to 18.1 % (median, range 3.0-25.0 %), p = 0.03. Conclusions: Our study shows that pazopanib does not significantly reduce MDSC levels in patients with mRCC. However, pazopanib improves T cell function over time, as seen by a significant increase in CD3+ interferon-gamma production.
CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC).
Authors: Venook Alan P. , Niedzwiecki Donna , Lenz Heinz-Josef , Innocenti Federico , Mahoney Michelle R. , O'Neil Bert H. , Shaw James Edward , Polite Blase N. , Hochster Howard S. , Atkins James Norman , Goldberg Richard M. , Mayer Robert J. , Schilsky Richard L. , Bertagnolli Monica M. , Blanke Charles David ,   Cancer and Leukemia Group B (Alliance), SWOG, and ECOG
Published: February 2017

LBA3

Background: Irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6), combined with bevacizumab (BV) or cetuximab (CET), are first-line treatments for metastatic adenocarcinoma of the colon or rectum (MCRC). The optimal antibody combination is unknown. Methods: Patients (pts) with KRAS wild-type (wt)(codons 12 and 13) MCRC and performance status 0-1 received FOLFIRI or mFOLFOX6 (MD/pt choice at enrollment) and randomized to either CET 400 mg/m2 X 1, then 250 mg/m2 qw or BV 5 mg/kg q2w. The original study included unselected MCRC pts receiving FOLFIRI or mFOLFOX6 and randomized to CET, BV, or both. After 1,420 pts accrued the study amended as follows: only pts with KRAS wt tumors (codon 12 and 13) were included and the combination CET + BV arm was deleted. Rx continued until progression, death, unacceptable toxicity, curative surgery; treatment holidays of 4 wks permitted. Subsequent Rx not mandated. Accrual goal was 1,142 pts. One° endpoint was overall survival (OS). Results: Between November 2005 and March 2012, 3,058 unselected pts enrolled, 2,334 KRAS wt pts randomized; final N =1137 (333 pre-amend eligible retrospective KRAS test, 804 post-amend), median f/u = 24 mos; Median age – 59 y; 61% male. Chemo/BV – 559; chemo/CET – 578. FOLFIRI = 26.6%, mFOLFOX6 = 73.4%. OS analysis planned at 849 events; efficacy futility boundary crossed at 10th interim analysis on 1/29/14. OS - chemo/BV v. chemo/CET = 29.04 (25.66 - 31.21) v. 29.93 (27.56 - 31.21) mos; HR = 0.92 (0.78, 1.09) (p value = 0.34). PFS (by investigator): chemo/BV v. chemo/CET: 10.84 (9.86 - 11.4) v. 10.45 (9.66 - 11.33) mos. There were 94 pts free of disease following surgery, median f/u 40 mos (range 8.0 - 86.0). Outcomes similar by gender. On-study toxicity and deaths as expected. Analyses underway: Expanded RAS, FOLFOX v. FOLFIRI, subsequent therapies, long-term survivors, correlates. Conclusions: Chemo/CET and chemo/BV equivalent in OS in pts KRAS wt (codons 12 + 13) MCRC; either is appropriate in first line. Overall OS of 29 + mos and 8% long-term survivors confirms progress in MCRC. The preference for FOLFOX limits chemotherapy comparison. Expanded RAS and other molecular and clinical analyses may identify subsets of pts who get more or less benefit from specific regimens. Clinical trial information: NCT00265850.
HPV-targeted tumor-infiltrating lymphocytes for cervical cancer.
Authors: Hinrichs Christian S. , Stevanovic Sanja , Draper Lindsey , Somerville Robert , Wunderlich John , Restifo Nicholas P. , Sherry Richard , Giao Phan Q , Kammula Udai S. , Yang James C. , Rosenberg Steven A.
Published: February 2017

LBA3008

Background: Adoptive T-cell therapy (ACT) is a promising cancer treatment modality with potentially broad application. It is not known if ACT can mediate regression of carcinomas, the most common solid tumors in humans. We studied carcinoma of the uterine cervix, a virally induced malignancy that constitutively expresses the HPV E6 and E7 oncoproteins, as a model cancer to test if ACT can mediate regression of an epithelial malignancy. Methods: We initiated a clinical trial to treat metastatic HPV+ cancers with tumor-infiltrating lymphocytes (TIL) selected for HPV E6- and E7-reactivity (HPV-TIL). Patients from the cervical cancer cohort are reported here. HPV-TIL infusion was preceded b y non-myeloablative conditioning and followed by high-dose bolus aldesleukin. HPV-reactivity was assessed by ELISPOT, IFN-gamma production, and CD137 expression assays. Results: Nine patients were treated on the study. They received a median of 81 x 109 T cells (range 33 to 159 x 109) as a single infusion. The infused cells possessed reactivity against high-risk HPV E6 and/or E7 in 6/8 patients. The two patients with no HPV reactivity did not respond to treatment. 3/6 patients with HPV reactivity demonstrated objective tumor responses by RECIST (1 PR and 2 CR). One patient had a 39% best response. Two patients with widespread metastases had complete tumor responses that are ongoing 18 and 11 months after treatment. One patient with a complete response had a chemotherapy-refractory HPV-16+ squamous cell carcinoma and the other a chemoradiation-refractory HPV-18+ adenocarcinoma. Both patients demonstrated prolonged repopulation with HPV-reactive T cells following treatment. Increased frequencies of HPV-specific T cells were detectable after 13 months in one patient and 6 months in the other. Two patients with HPV-reactive TIL that did not respond to treatment did not display repopulation with HPV-reactive T cells. Conclusions: HPV-TIL can mediate durable, complete regression of metastatic cervical cancer. Continued investigation of HPV-TIL for cervical cancer, and possibly other HPV+ malignancies, is warranted. Cellular therapy can mediate complete regression of an epithelial malignancy. Clinical trial information: NCT01585428.
A phase 3, multicenter, double-blind, placebo-controlled trial of lenvatinib (E7080) in patients with 131I-refractory differentiated thyroid cancer (SELECT).
Authors: Schlumberger Martin , Tahara Makoto , Wirth Lori J. , Robinson Bruce , Brose Marcia S. , Elisei Rossella , Dutcus Corina E. , de las Heras Begoña , Zhu Junming , Habra Mouhammed Amir , Newbold Kate , Shah Manisha H. , Hoff Ana O. , Gianoukakis Andrew G , Kiyota Naomi , Taylor Matthew Hiram , Kim Sung-Bae , Krzyzanowska Monika K , Sherman Steven I.
Published: February 2017

LBA6008

Background: Lenvatinib (LEN) is an oral tyrosine kinase inhibitor of the VEGFR1-3, FGFR1-4, PDGFRβ, RET, and KIT signaling networks. Based on efficacy results of the phase 2 study of patients (pts) with 131I-refractory differentiated thyroid cancer (RR-DTC), this phase 3 Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT) was developed. Methods: This randomized, double-blind, placebo (PBO)-controlled study enrolled pts with RR-DTC with documented disease progression within 13 months (mo). Pts were stratified by age (≤65, >65 years), region and ≤1 prior VEGFR-targeted therapies and randomized 2:1 to LEN or PBO (24mg/d, 28-d cycle). Upon progression, pts receiving PBO could crossover to open-label LEN. The primary endpoint was PFS assessed by Independent Radiologic Review; secondary endpoints included overall response rate (ORR; complete response [CR] + PR), overall survival (OS) and safety. Results: 392 pts (63.0 years median age; 51.0% male) were randomized. Pts on LEN had a significantly prolonged PFS vs PBO (hazard ratio 0.21, 95% confidence interval [CI] 0.14–0.31; P <.0001); median PFS was LEN: 18.3 mo (95% CI 15.1–not evaluable), PBO: 3.6 mo (95% CI 2.2–3.7). A LEN PFS benefit was observed in all predefined subgroups; median LEN PFS for pts with prior vs no prior VEGF-therapy was 15.1 mo (n=66) and 18.7 mo (n=195), respectively. Rates (n) of CRs were LEN: 1.5% (4), PBO: 0; PRs were LEN: 63.2% (165), PBO: 1.5% (2).Median exposure duration was LEN: 13.8 mo, PBO: 3.9 mo; median time to LEN response was 2.0 mo. Median OS has not been reached; deaths per arm were LEN: 71 (27.2%), PBO: 47 (35.9%). The 5 most common LEN treatment-related adverse events (TRAEs; any grade) were hypertension (68%), diarrhea (59%), appetite decreased (50%), weight loss (46%), nausea (41%). LEN grade ≥3 TRAEs (≥5%) were hypertension (42%), proteinuria (10%), weight loss (10%), diarrhea (8%), appetite decreased (5%). The dose was reduced in 78.5% of pts and discontinued due to adverse events (AEs) in 14.2% of pts. Conclusions: LEN significantly improved PFS compared with PBO in pts with progressive RR-DTC. There were no unexpected toxicities and AEs were manageable. Clinical trial information: NCT01321554.
Efficacy and safety of the anti-PD-1 monoclonal antibody MK-3475 in 411 patients (pts) with melanoma (MEL).
Authors: Ribas Antoni , Hodi F. Stephen , Kefford Richard , Hamid Omid , Daud Adil , Wolchok Jedd D. , Hwu Wen-Jen , Gangadhar Tara C. , Patnaik Amita , Joshua Anthony M. , Hersey Peter , Weber Jeffrey S. , Dronca Roxana Stefania , Zarour Hassane M. , Gergich Kevin , Li Xiaoyun (Nicole) , Iannone Robert , Kang Soonmo Peter , Ebbinghaus Scot , Robert Caroline
Published: February 2017

LBA9000^

Background: The humanized monoclonal IgG4 anti-PD-1 antibody MK-3475 has demonstrated durable antitumor activity in MEL and NSCLC. We evaluated MK-3475 efficacy and safety in a pooled analysis of 411 MEL pts. Methods: A nonrandomized cohort of ipilimumab-naive (IPI-N) and IPI-treated (IPI-T) pts treated with MK-3475 10 mg/kg Q2W, 10 mg/kg Q3W, or 2 mg/kg Q3W and randomized cohorts of IPI-N and IPI-T pts treated with 2 Q3W or 10 Q3W were included. Response was assessed every 12 wk by RECIST 1.1 by independent central review and by immune-related response criteria (irRC) by investigator. Results: 162 pts were treated at 2 Q3W, 192 at 10 Q3W, and 57 at 10 Q2W. 190 pts were IPI-N and 221 were IPI-T. As of the 10/18/2013 cutoff, all pts had ≥6 mo follow-up and >75% had ≥9 mo follow-up. Among the 365 pts with measurable disease at baseline, ORR by RECIST was 40% (95% CI 32%-48%) in IPI-N and 28% (95% CI 22%-35%) in IPI-T pts. Responses were durable (88% ongoing at analysis). Median PFS by RECIST was 24 wk in IPI-N and 23 wk in IPI-T pts. Median OS was not reached, with 1-y OS of 71% in all pts. Benefit was observed by both RECIST and irRC at all doses and schedules in IPI-N and IPI-T pts (Table). MK-3475 demonstrated activity in all major subgroups irrespective of ECOG PS, LDH levels, BRAFmutation, M stage, and number and type of prior therapy. Overall, 12% of pts experienced drug-related grade 3/4 AEs and 4% discontinued due to a drug-related AE. There were no drug-related deaths. Conclusions: MK-3475 showed durable responses and a manageable safety profile across dose and schedules in IPI-N and IPI-T MEL pts. The observed efficacy and safety suggest MK-3475 may be an appropriate treatment for all pts with MEL. Clinical trial information: NCT01295827. [Table: see text]