bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase I/II trial of BNC105P with everolimus in metastatic renal cell carcinoma (mRCC) patients: Updated phase I results of the Disruptor-1 trial.
Authors: Sarantopoulos John , Dang Long H. , Lauer Richard C. , Starodub Alexander , Hauke Ralph J. , Galsky Matt D. , Bylow Kathryn A. , Cowey Charles Lance , Bibby David C. , Kremmidiotis Gabriel , Doolin Elizabeth E. , Lavranos Tina C. , Iglesias Jose Luis , Sonpavde Guru , Logan Theodore , Hahn Noah M. , Sweeney Christopher , Hutson Thomas E. ,   Hoosier Oncology Group
Published: March 2020

4563

Background: BNC105P is an inhibitor of tubulin polymerization. In vivo exposure to BNC105P leads to selective damage of tumor vasculature in both primary and metastatic lesions, causing disruption of blood flow to tumors, hypoxia and associated tumor necrosis. BNC105P also has a direct anti-proliferative action on cancer cells. Up regulation of the mTOR pathway has been identified as a cellular response to hypoxic stress. The combined use of BNC105P with an agent active against mTOR may improve clinical outcome in patients with progressive mRCC who are refractory to VEGFR-directed tyrosine kinase inhibitors (TKI). Methods: A phase I/II study in mRCC patients who have received 1-2 prior TKIs was undertaken. The phase I component enrolled 12 subjects at 4 dose levels of BNC105P (4.2, 8.4, 12.6, 16 mg/m2; IV infusion Days 1 & 8, 21-day repeating cycle). Everolimus was administered concurrently (10 mg p.o.). PK analysis was performed during Cycle 1. Biomarker samples (pre- and post-dose during Cycle 1) were analyzed for 70 plasma analytes including VEGF, PDGF and other markers associated with angiogenesis and vascular responses. Results: Updated results from the completed phase I component confirm the BNC105P / everolimus combination was well tolerated. No DLTs (drug-related, during cycle 1) were observed in any of the phase I subjects. Toxicities on study deemed to be drug-related (either single agent or combination) included single Grade 3 events of anemia and pericardial effusion. Grade 2 events of fatigue, anemia and oral mucositis were also observed. Eight of the 12 phase I subjects achieved disease stabilization. Across all subjects a median of 6 cycles (range: 1-24) was administered, with removal from study predominantly due to disease progression. PK analysis confirmed no drug-drug interaction. The randomized phase II component of the study continues and will compare everolimus given concomitantly with BNC105P to a sequential approach (everolimus followed by BNC105P). Conclusions: Full dose BNC105P (16 mg/m2) can be combined with full dose everolimus (10 mg) and is being further evaluated in a randomized phase II study. Clinical trial information: NCT01034631.
Pharmacogenetics as predictor of sunitinib and mTOR inhibitors toxicity in patients with metastatic renal cell carcinoma (mRCC).
Authors: Urun Yuksel , Gray Kathryn P. , Signoretti Sabina , McDermott David F. , Atkins Michael B. , Lampron Megan E. , Freedman Matthew , Choueiri Toni K. , Pomerantz Mark M
Published: March 2020

4570

Background: Single nucleotide polymorphisms (SNPs) in major pharmacokinetics (PK) and pharmacodynamics (PD) pathways of targeted agents may affect the incidence of drug toxicities. Methods: Germline DNA was extracted fromwhole blood or normal kidney parenchyma frommRCC pts of European ancestry in two cohorts: those treated with VEGF-targeted therapy (sunitinib) (n=159) or with an mTOR inhibitor (everolimus or temsirolimus) (n=62). Ten SNPs in 6 candidate genes: CYP3A4 (rs2242480, rs4646437, rs2246709), CYP3A5 (rs15524), ABCB1 (rs2032582, rs1045642), VEGFR2 (rs2305948), NR1I3 (rs2307424, rs2307418), FLT3 (rs1933437) were genotyped using Sequenom iPlex Gold platform. Logistic regression model tested the association of genotype variants with adverse events of 1) grade 3/4 (G3/4) toxicity and G3/4 hypertension (for sunitinib cohort) and 2) grade 3/4 toxicity and all grade pneumonitis (for mTOR inhibitors cohort), adjusted for clinical factors associated with toxicity outcomes. Results: In the sunitinib cohort, median treatment duration was 7.7 months (IQR=3-15.5), 83 (52%) pts had grade 3/4 toxicities and 22 (14%) had grade 3/4 hypertension. Rare variant (AG) of CYP3A4 rs464637 was associated with the reduced risk of grade 3/4 toxicities (4 events/17 cases) vs. wild-type (GG, 73 events/134 cases), (Odds Ratio (OR) = 0.27, 95%CI: 0.08-0.88, p=0.03). No association between SNPs and hypertension was observed. In the mTOR inhibitor cohort, median treatment duration was 3.4 months (IQR=1.4-6), 21(34%) pts had G3/4 toxicities and 27 (43%) had all grade pneumonitis. No association between SNPs and G3/4 toxicities was observed. Rare homozygote (GG) of FLT3 SNP rs1933437 was associated with increased risk of all grade pneumonitis (7 events/ 9 cases) vs. wild-type (AA, 4 events/12 cases), however, given the very small variant group size, further investigation is required to verify the association. Conclusions: The minor allele of SNP rs464637 in the gene CYP3A4 may influence sunitinib toxicity. Further validation is needed to determine if the marker could be used for in targeted therapy dosing strategies and direct patient care. (IQR=Interquartile Range).
Treatment response and survival outcome of patients with late relapse (LR) from renal cell carcinoma (RCC) in the era of targeted therapy.
Authors: Kroeger Nils , Lee Jae-Lyun , Bjarnason Georg A. , Knox Jennifer J. , MacKenzie Mary J. , Vaishamayan Ulka N. , Wood Lori , Srinivas Sandy , Rha Sun Young , Pal Sumanta Kumar , Yuasa Takeshi , Donskov Frede , Agarwal Neeraj , Tan Min-Han , Bamias Aristotelis , Kollmannsberger Christian K. , North Scott A. , Rini Brian I. , Choueiri Toni K. , Heng Daniel Yick Chin
Published: March 2020

4578

Background: A small subset of localized RCC patients will experience disease recurrence ≥5 years after nephrectomy. Clinical outcome of patients with LR has not been well characterized. Methods: Patients with mRCC treated with targeted therapy were retrospectively characterized according to time to relapse. Replase was defined as diagnosis of recurrent metastatic disease >3 months after initial diagnosis. Patients with synchronous metastatic disease at presentation were excluded. Patients were classified as Early Relapsers (ER) if they recurred within 5 years while Late Relapsers (LR) recurred after 5 years. Demographics and outcomes were compared. Results: 1210 mRCC patients were identified; 903 (74.6%) with relapse within the first 5 years, 200 (16.5%) within >5-10 years, and 107 (8.8%) after 10 years (range 10-35 years). Baseline characteristics are presented in the Table. Overall response rates to targeted therapy were better in LR vs. ER (35% vs. 24%; p=0.009). LR patients had significant longer progression free- (10.7 vs. 8.5 months; log rank p=0.004) and overall survival (34.0 vs. 27.3 months; log rank p=0.003). Conclusions: One quarter of patients that eventually developed metastatic disease treated with targeted therapy relapsed over 5 years from initial diagnosis. The proportion of patients that relapse after five years is substantial. mRCC patients presenting with LR have more favorable prognostic features, treatment response, and overall survival. [Table: see text]
Continuation of sunitinib following RECIST progression on first-line sunitinib.
Authors: Burotto Pichun Mauricio Emmanuel , Wilkerson Julia , Stein Wilfred Donald , Motzer Robert John , Bates Susan Elaine , Fojo Tito
Published: March 2020

4585

Background: In the last seven years the FDA and the EMA have approved seven agents for treatment of RCC. Five of these target the VEGF pathway. Methods: We conducted a detailed analysis of data from the sunitinib registration trial examining the growth and regression rate constants and the stability of the growth rate as measures of effectiveness and to understand development of resistance. Results: Sufficient data was available for the analysis of 350/374 patients enrolled. Statistically valid data was obtained in 321(91.7%). The median regression rate constant was 0.0048 days-1, and in 59 patients no evidence of growth was recorded while on study, only regression. The median growth rate was 0.00082 days-1 and this rate was stable a median of 267 days, remaining stable beyond 300 days in 172 patients, beyond 600 days in 95 patients, and beyond 900 days in 49 pts. A suggestion of a possible increase of the growth rate while sunitinib was administered could be discerned in only 15/321 pts. With a median growth rate 0.00082 days-1 the estimated time to progression were sunitinib discontinued and then re-started would have been a minimum of 7.3 months. Thus a meaningful outcome could be achieved provided continued sunitinib is tolerable. Finally with an estimated 47%, 27% and 13% of tumor still sensitive to sunitinib 100, 200 and 300 days after starting therapy, shrinkage with a new TKI in patients who discontinue sunitinib before day 300 for toxicity may not be a sign of non-cross resistance, but of residual sensitive tumor. Conclusions: Prolonged stability of the growth rate of RCC on sunitinib is consistent with intrinsic and not acquired resistance. Baring toxicity, continued sunitinib beyond RECIST criteria for progression may provide a beneficial outcome and can be considered a treatment alternative in selected patients. Randomized trials to assess the value of VEGF TKI’s in patients whose disease has “progressed” on sunitinib should consider including an arm that continues sunitinib to test this hypothesis.
aTTom: Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years in 6,953 women with early breast cancer.
Authors: Gray Richard G. , Rea Daniel , Handley Kelly , Bowden Sarah Jane , Perry Philip , Earl Helena Margaret , Poole Christopher John , Bates Tom , Chetiyawardana Shan , Dewar John A. , Fernando Indrajit Nalinika , Grieve Robert , Nicoll Jonathan , Rayter Zenor , Robinson Anne , Salman Asad , Yarnold John , Bathers Sarah , Marshall Andrea , Lee Martin ,   on behalf of the aTTom Collaborative Group
Published: March 2020

5

The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Sunday, June, 2, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Sunday edition of ASCO Daily News.
Impact of neoadjuvant chemotherapy plus HER2-targeting on breast conservation rates: Surgical results from CALGB 40601 (Alliance).
Authors: Ollila David W. , Berry Donald A. , Cirrincione Constance , Carey Lisa A. , Amos Keith D. , Henry Norah Lynn , Winer Eric P. , Hudis Clifford , Golshan Mehra ,   Alliance for Clinical Trials in Oncology
Published: March 2020

501

Background: Neoadjuvant systemic therapy improves breast conserving therapy (BCT) rates, but the magnitude of this benefit is unknown in operable breast cancer. We sought to quantify this benefit in CALGB 40601, a phase III trial of paclitaxel (T) + HER2 blockade with either trastuzumab (TH), lapatinib (TL), or both (THL), by requiring the treating breast surgeon to determine BCT eligibility before and after neoadjuvant therapy and examining surgical results. Methods: Eligible patients (pts) had operable, newly diagnosed, noninflammatory stage II-III HER2+ breast cancer randomized to receive TH, TL or THL. Prior to, and again after neoadjuvant therapy, the treating breast surgeon determined whether the patient was a BCT candidate based on clinical and radiographic criteria, but the subsequent breast cancer operation was at the discretion of the surgeon and patient. Two endpoints examined were: (1) the conversion rate from BCT-ineligible to BCT-eligible and (2) the rate of successful BCT as determined by tumor-free surgical margins. Results: Of 305 pts randomized (118 THL, 120 TH, 67 TL), 294 were evaluable. Prior to neoadjuvant therapy, 136 (46%) patients were candidates and 158 (54%) were non-candidates for BCT. 107/136 (79%) remained BCT candidates following neoadjuvant therapy and 78 chose BCT, of whom 69 (88%) were successful. 29 pts (21%) initially thought to be BCT candidates became non-candidates after neoadjuvant therapy. Conversely, 76/158 (48%) pts considered non-BCT candidates prior to neoadjuvant therapy down-sized sufficiently to be considered BCT candidates; 40 of these opted for BCT with a 75% (30/40) BCT success rate. In total, 183 pts were deemed BCT candidates after neoadjuvant therapy, yet 65 (36%) proceeded directly to mastectomy. Conclusions: This is the first neoadjuvant trial to prospectively quantify a nearly 50% conversion rate from BCT-ineligible to BCT-eligible in HER2+ breast cancer pts treated with modern systemic therapy. Neoadjuvant chemotherapy combined with targeted anti-HER2 treatment permits potential BCT in approximately 80% of properly selected patients. Clinical trial information: NCT00770809.
Survival with newly diagnosed metastatic prostate cancer in the “docetaxel era”: Data from >600 patients in the control arm of the STAMPEDE trial (NCT00268476).
Authors: Clarke Noel W , James Nicholas David , Mason Malcolm David , Aebersold Daniel M. , Dearnaley David Paul , De Bono Johann Sebastian , Parker Chris , Parmar Mahesh , Ritchie Alastair WS , Russell J. Martin , Spears Melissa Ruth , Thalmann George N. , Sydes Matthew Robert ,   STAMPEDE Investigators
Published: March 2020

5012

Background: STAMPEDE (www.stampedetrial.org) recruits men with newly-diagnosed or rapidly relapsing prostate cancer (PCa) that is metastatic (M1) or high-risk locally advanced, all commencing long-term androgen ablation therapy (AAT) for the first time. This is now the largest therapeutic RCT in PCa. We report survival outcomes for newly-diagnosed M1 control arm men in order to inform future trials in this setting. Methods: Newly-diagnosed men with M1 disease in the trial’s control arm (standard of care: AAT alone for at least 2yr), diagnosed up to 6 months prior to randomisation, were identified from trial records in Dec-2012. We report overall survival (OS) and failure-free survival (FFS) from randomisation by primary disease characteristics. Results: 3703 men were recruited to STAMPEDE Oct-2005 to Dec-2012, including a control arm cohort of 630 M1 men with newly-diagnosed disease. This cohort has median age at randomisation 66yr (quartiles 60-71), median PSA 105 (quartiles 34-379) IU/l; metastases to bone only (B) 393 (62%), soft tissue only (ST) 78 (13%) or bone and soft tissue (B+ST) 159 (25%). ST was mainly lymph nodes. Median time from diagnosis to randomisation is 69 days (max 180 days). Median duration of AAT prior to randomisation is 46 days (max 105 days). There were 129 deaths, of which 111 were from PCa. Median OS from randomisation is 42 months, with 2-yr OS 74% (95%CI 68, 78) in this cohort; B 77% (95%CI 71, 83), ST 85% (95%CI 70, 93), B+ST 57% (95%CI 45, 68). Median FFS is 12 months, driven by rising PSA; 2-yr FFS 32% (95%CI 27-37). Median time from FFS event to death was 22 months. Additional data on relapse therapies will be presented. Conclusions: Survival, and particularly FFS, remains relatively poor for men presenting with M1 disease starting long-term AAT, despite potential access when castration-resistant (CRPC) to docetaxel and other newer therapies. Better first-line therapy is required; STAMPEDE will report many comparisons in the future. Different M1 patterns may vary prognostically. Men with M1 disease will now spend most time in a state of CRPC, which has important implications for clinicians and trialists. Clinical trial information: NCT00268476.
Evolving patterns of metastatic disease in castration-resistant prostate cancer (CRPC) reported in clinical trials from 1990 to 2011.
Authors: Doctor Stephanie , Tsao Che-Kai , Godbold James H. , Galsky Matt D. , Oh William K.
Published: March 2020

5015

Background: Bone remains the most common site of metastasis in CRPC. With new therapies extending survival in metastatic CRPC (mCRPC), we hypothesized that the incidence of non-osseous metastases is increasing over time. In this study, we evaluated the pattern of metastatic disease in mCRPC as reported in baseline characteristics of prospective clinical trials over 2 decades. Methods: We identified all therapeutic studies in patients with mCRPC in Pubmed and ASCO abstracts from 1990-2011. Inclusion criteria included phase 2 or 3 clinical trials in mCRPC with available baseline demographic data and no exclusion of specific site of metastatic disease (except brain). ASCO abstracts were limited to presentations in which data were available online. For each study, demographic data and study-reported sites of non-osseous metastatic disease were recorded (lymph node, visceral, soft tissue, liver). For each type of metastasis, weighted least squares linear regression models were used to evaluate temporal trends. Results: We identified a total of 290 eligible studies (270 phase II and 20 phase III) involving 19,110 patients. Of these, 127 studies reported data on non-osseous metastases and prior chemotherapy. There was a significant trend over time (p=0.001) of increasing proportions of patients with non-osseous metastasis in both chemotherapy- naïve and treated groups (1.4% per year increase). Increased lymph node, visceral, and soft tissue metastases were seen over the study period. However, the proportion of patients with liver metastasis remained relatively stable Conclusions: In this study, we noted an increasing trend of non-osseous metastatic disease in patients with mCRPC over 20 years. This included lymph node, visceral and soft tissue metastatic disease, and this trend was observed in both chemotherapy-naïve and treated patients. Longer survival and new therapies may be changing the clinical presentation of patients with mCRPC.
ACOSOG Z1041 (Alliance): Definitive analysis of randomized neoadjuvant trial comparing FEC followed by paclitaxel plus trastuzumab (FEC → P+T) with paclitaxel plus trastuzumab followed by FEC plus trastuzumab (P+T → FEC+T) in HER2+ operable breast cancer.
Authors: Buzdar Aman , Suman Vera J. , Meric-Bernstam Funda , Leitch A. Marilyn , Ellis Matthew James , Boughey Judy Caroline , Unzeitig Gary Walter , Royce Melanie , Hunt Kelly ,   for the Alliance for Clinical Trials in Oncology
Published: March 2020

502

Background: Neoadjuvant chemotherapy (NAC) and concomitant trastuzumab (T) have produced high pathologic complete response (pCR) rates in HER2+ breast cancers. Z1041 addresses the timing of initiation of T with NAC. Methods: Women with operable HER2+ invasive breast cancer were randomized 1:1 to: FEC → P+T (Arm 1) or P+T → FEC+T (Arm 2) where treatment was administered as 5-FU 500 mg/m2, epirubicin 75 mg/m2 and cyclophosphamide 500 mg/m2 day 1 of a 21-day cycle x 4 (FEC); paclitaxel 80 mg/m2 weekly x 12 and trastuzumab 4 mg/kg once then 2 mg/kg weekly x 11. Eligibility also included: tumor > 2 cm or a positive lymph node and left ventricular ejection fraction > 55%. The primary aim was to compare the pCR rates in the breast (pBCR) between the regimens. Secondary endpoints were pCR rate in the breast and lymph nodes (pBNCR) and safety profile. All pts who began study treatment were included in the analyses. With 128 pts per regimen, a two-sided alpha=0.05 test of proportions would have a 90% chance of detecting a difference of 20% or more in the pBCR rates, when the pBCR rate with the poorer regimen is ≤ 25%. Results: From September 15, 2007 to December 15, 2011, 282 women (Arm 1: 140 pts) were enrolled. Two pts (Arm 1) withdrew without receiving treatment. The two arms were similar in age, stage, and hormone receptor (HR) status (HR neg: 40%). The severe (grade 3+) treatment-related toxicities included: neutropenia (Arm 1: 24.6%; Arm 2: 32.4%), fatigue (Arm 1: 4.3%; Arm 2: 8.5%), and neurosensory problems (Arm 1: 3.6%; Arm 2: 4.9%). The pBCR rate and pBNCR rates (Table) were not found to differ between the two regimens (Fisher’s exact p values: 0.905 and 0.811, respectively). Conclusions: High pCR rates can be achieved with trastuzumab in combination with anthracyclines and taxanes. The pBCR or pBNCR was not different between regimens based on the timing of initiation of trastuzumab. Clinical trial information: NCT00513292. [Table: see text]
Prospective evaluation of testosterone (T) recovery and PSA relapse following 18 months of androgen deprivation (ADT) after prostatectomy (RP): Results from the TAX-3501 trial.
Authors: Schweizer Michael Thomas , Huang Peng , Sternberg Cora N. , De Wit Ronald , Ecstein-Fraisse Evelyne Brana , Kattan Michael W. , Kibel Adam S , Eisenberger Mario A.
Published: March 2020

5023

Background: Surgical adjuvant trials in men with prostate cancer (PCa) employing progression free (PFS) and overall survival (OS) endpoints require large sample sizes and long-term follow-up, challenging planned study completion. Recent adjuvant trials are designed to evaluate PSA progression as the primary study endpoint. Since PSA is T-responsive, a thorough understanding of T recovery kinetics after ADT is needed. Methods: TAX-3501 was a randomized phase III adjuvant study post-RP in men with high-risk PCa (n=228) comparing 18 months of hormonal therapy with (CHT) or without (HT) docetaxel either immediately (I) or deferred (D). We analyzed the T recovery data in 108 patients treated with HT who had at least one post-treatment T value. Results: After a median post-treatment follow-up of 676 days (d) (interquartile range 478-847 d) 90 (83%) and 64 (59%) of men had T recovery to >150 ng/dL and to baseline respectively. No significant differences in T recovery between groups were observed (Table). The median time to T recovery from the last day of treatment to >150 ng/dL was 306 d (95% CI, 294-345 d) and to baseline was 487 d (95% CI, 457-546 d). The baseline T recovery in the combined docetaxel [i.e. I(CHT)+D(CHT)] and HT arms [i.e. I(HT)+D(HT)] was not significantly different at 458 d (95% CI, 336-529 d) and 535 d (95% CI, 457-749 d) respectively (HR 1.4, P=0.18). After a median total follow-up of 3.4 years(IQR 2.3–3.8 years) 39/228 (17%) patients had PSA progression, metastatic progression occurred in 1 patient. Conclusions: Prospective analyses of T kinetics in TAX-3501 indicate that recovery is prolonged after 18 months of HT and PSA relapses occur late. Given that PSA is androgen responsive, concomitant post-HT T monitoring is critical for understanding PSA relapse rates after HT. Further, since the correlation of PSA relapse with PFS and OS in the adjuvant setting remains poorly defined, metastasis-free survival may be a more reliable and meaningful clinical endpoint. Clinical trial information: NCT00283062. [Table: see text]
Evaluation of clinical phenotype, survival, and circulating tumor cell (CTC) enumeration in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Bitting Rhonda Lynn , Healy Patrick , Halabi Susan , George Daniel J. , Ko Jung Hyun , Armstrong Andrew J.
Published: March 2020

5031

Background: The presence of ≥ 5 CTCs is prognostic for shorter survival in mCRPC men. However, many men have low CTCs despite widespread metastatic disease, suggesting heterogeneity in CTC phenotype or detection. We evaluated the association of baseline CTC enumeration with clinical characteristics and survival in mCRPC men at our institution. Methods: CTCs were enumerated with the standard CellSearch method in mCRPC men in a prospective correlative clinical study. The association between baseline CTC count and prostate-specific antigen (PSA), alkaline phosphatase (AP), lactate dehydrogenase (LDH) was explored using the Spearman correlation (r), and the relationship with Gleason sum, sites of metastasis (mets), and prior docetaxel exposure was explored using summary statistics. The overall survival probability (OS) was estimated by the Kaplan-Meier method. Results: In our cohort, 59/82 men had prior docetaxel exposure, and the median CTC count was 16.5. There were 25 men with visceral mets, 55 with bone-predominant mets, and 2 with lymph node only mets. We found a weak relationship between CTCs and PSA (r=0.20), but a more moderate and significant association with AP (r=0.48) and LDH (r= 0.50). We found no relationship between CTCs and Gleason sum, site of mets, or prior docetaxel. 66 men died, and the median OS was 11.2 months (95% CI: 9.2, 12.7). OS was improved in patients with <5 CTCs at baseline compared to ≥ 5 (8.9 vs. 16.6 months, HR=0.47 (95% CI: 0.27, 0.80)). CTC enumeration may further stratify outcomes in men with mCRPC and either visceral or bone metastasis as shown in the table below. Conclusions: The prognostic significance of CTCs is distinct from other established biomarkers and may reflect a unique biology of metastasis, dissociated in part from androgen receptor activity (as reflected by PSA values) but related in part to bone microenvironment, hypoxia, and tumor burden (as reflected by AP and LDH values). These associations need to be validated in larger trials. [Table: see text]
Impact of prior docetaxel (D) on sipuleucel-T (sip-T) product parameters in PROCEED patients (pts).
Authors: Higano Celestia S. , Armstrong Andrew J. , Cooperberg Matthew R. , Kantoff Philip W. , Bailen James , Concepcion Raoul S. , Kassabian Vahan , Dakhil Shaker R. , Finkelstein Steven E. , Vacirca Jeffrey L. , Rifkin Robert M. , Sandler Andrew , McCoy Candice , Whitmore James Boyd , Tyler Robert Claude , Sartor A. Oliver
Published: March 2020

5034

Background: Sip-T is an autologous cellular immunotherapy indicated for asymptomatic or minimally symptomatic mCRPC. The IMPACT trial excluded pts who received D ≤3 months prior to registration. PROCEED is an ongoing, phase IV registry, enrolling pts treated with commercial sip-T. Use of D prior to sip-T is not restricted, so prior D affect on sip-T immune manufacturing parameters can be evaluated. Methods: Pts treated with sip-T ≤ 6 mo were eligible to provide informed consent. Sip-T parameters assessed included: total nucleated cell (TNC) count, antigen presenting cell (APC) count (CD54+large cells) and APC activation (upregulation of CD54). Results: By Nov. 2012, 108/761 (14%) received D prior to sip-T and had similar median cumulative APC counts (1.83 [Q1, Q3: 1.16, 2.71] vs. 1.82 [1.27, 2.70] x 109) and TNC counts (10.16 [7.30, 13.69] vs. 11.47 [8.56, 15.31] x 109) vs. D naïve, whereas median cumulative APC activation appeared slightly lower (32.39 [25.05, 41.02] vs. 34.84 [28.71, 42.83]), but was well above the release criterion for each infusion (2.6 fold). The group was then split by Eastern Cooperative Oncology Group Performance Status (ECOG PS) and Gleason scores (Table). Conclusions: Pts with D prior to sip-T appeared to have product parameters comparable to pts without prior D, albeit with a slightly lower APC activation. Further analysis showed that pts receiving D within 3 months of sip-T had higher Gleason and ECOG scores. The clinical significance of these findings is unclear, but suggests that APC activation is not impaired following docetaxel. Clinical trial information: NCT01306890. [Table: see text]
The association between pre-treatment serum 25-hydroxyvitamin D and survival in stage IV prostate cancer.
Authors: Vashi Pankaj G. , Gupta Digant , Trukova Kristen , Lambert Gwendolyn M , Lammersfeld Carolyn
Published: March 2020

5036

Background: Emerging evidence in the literature suggests a positive association between serum 25-hydroxyvitamin D [25(OH)D], a standard indicator of vitamin D status, and survival in certain types of cancer. We investigated this relationship in newly diagnosed stage IV prostate cancer patients. Methods: A case series of 54 newly diagnosed stage IV prostate cancer patients underwent a baseline serum 25(OH)D evaluation prior to receiving any treatment at our institution between Jan 2008 and Dec 2010. We defined vitamin D insufficiency as serum 25(OH)D levels of <=32 ng/ml. Patient survival was defined as the time between date of first patient visit and date of death from any cause/date of last contact. Cox regression was used to evaluate the prognostic significance of serum 25(OH)D after adjusting for age, prostate specific antigen (PSA) and functional status. Results: Mean age at diagnosis was 59.6 years. During a median follow-up of 23.6 months, 16 deaths occurred. The mean serum 25(OH)D was 30.1 ng/ml, among whom 38 (70.4%) were insufficient in vitamin D (<=32 ng/ml). Mean overall survival was 49.4 months (95% CI: 38.1-60.7). Mean survival was 32.6 months and 62.4 months for patients in <=32 ng/ml and >32 ng/ml groups respectively (p = 0.02). On univariate analysis, patients with levels >32 ng/ml had a significantly lower risk of mortality compared to those with levels <=32 ng/ml (HR=0.19; 95% CI: 0.04-0.87; p=0.03). On multivariate analysis controlling for age, performance status and PSA, patients with levels >32 ng/ml demonstrated significantly lower mortality (HR=0.13; 95% CI: 0.02-1.0; p=0.05) compared to those with levels <=32 ng/ml. Conclusions: Higher circulating levels of serum 25(OH)D were positively associated with survival in patients with metastatic prostate cancer. While these results need to be confirmed in prospective clinical trials, our study adds to the growing body of literature on the prognostic role of serum vitamin D in cancer. Given the high prevalence of vitamin D insufficiency in prostate cancer and the fact that this insufficiency is easily correctable by supplementation, we recommend early vitamin D assessment and intervention for a potential impact on patient survival.
Phase II trial of intravenous carboplatin (C), oral everolimus (E), and prednisone (P) in docetaxel-pretreated (DP) metastatic castrate-resistant prostate cancer (mCRPC): A Prostate Cancer Clinical Trials Consortium study.
Authors: Veeraputhiran Muthu Kumaran , Shevrin Daniel H. , Stein Mark N. , Heilbrun Lance K. , Smith Daryn , Li Jing , Dickow Brenda , Heath Elisabeth I. , Vaishampayan Ulka N.
Published: March 2020

5041

Background: A phase II clinical trial was conducted of the combination of C and E due to the synergy noted. Methods: The primary endpoint was time to progression (TTP). Intravenous C at a target AUC of 5 on day 1, and oral E 5mg once daily and P 5mg twice daily were administered in 21 day cycles. PSA was assessed every 21 days and radiologic response was assessed every 3 cycles. Secondary endpoints included overall survival (OS), the correlation of TTP with phosphorylated (p) mTOR, pAKT, p70S6, and circulating tumor cells (CTC). A 1-stage study design assumed: a reference median TTP = 1.5 months; 1-sided alpha = 0.15; and power = 0.90, requiring 26 patients (pts). Results: 26 pts enrolled; median age 69 years (range 54-86) ;8 African American and 18 Caucasians. Median pretherapy PSA was 190 ng/ml (range 13 - 2174). 18 pts (69%) each had bone pain and Gleason score > 8. 125 cycles have been administered; median 3 cycles (range 1 - 16). Predominant grade 3 or 4 toxicities were thrombocytopenia in 8 pts, pulmonary embolism in 2 and neutropenia in 3. No treatment related deaths occurred. 4 (15%) had a > 30% PSA decline and 1 had a >90% PSA decline. 8/19 pts had stable disease but no objective responses in MD. The median TTP and OS were 2.5 months (90% CI: 1.8 - 4.3), and 12.5 months (90% CI: 6.7 - 16.1), respectively. Median area under curves were 5.9 (range, 4.3 – 11.0) and 4.5 (range, 4.1 – 7.1) mg/mL*min with C given alone and in combination with E, respectively. E did not influence pharmacokinetics of C. Median baseline CTC (n=18) was 30 (range 0-2372). 5/18 pts had favorable CTC (CTC<5/7.5 mL) pretherapy. Patients with TTP >18 weeks had reduction in post-therapy CTC with a median decrease of 63% (range 11%-100%). Lack of IHC staining for pAKT was noted in 2/2 pts on therapy for > 30 weeks vs increased expression was noted in 8/8 pts on therapy for < 9 weeks. Testing for TSC1 mutation is planned and will be reported. Conclusions: The combination was tolerable but revealed modest clinical efficacy. Biomarker evaluations such as pAKT may help identify a subset likely to benefit from mTOR inhibitor strategy in mCRPC. Clinical trial information: NCT01051570.
The impact of technology diffusion on treatment for prostate cancer.
Authors: Schroeck Florian Rudolf , Kaufman Samuel R , Jacobs Bruce L , Miller David Christopher , Hollenbeck Brent K.
Published: March 2020

5044

Background: Robotic prostatectomy and intensity modulated radiotherapy (IMRT) hold the promise of improving cancer control and minimizing side-effects for patients with prostate cancer, but are associated with significant upfront investments. Many worry that the perceived advantages of these new technologies and the need to recoup start-up costs could shift decision making in favor of local therapy in lieu of expectant management. In this context, we examined the association of market-level technology penetration with receipt of local therapy. Methods: We used the Surveillance Epidemiology and End Results (SEER) - Medicare linked database to identify all patients with loco-regional prostate cancer who were treated or managed expectantly from 2003 to 2007 (n=59,241). We measured technology penetration as the number of providers performing robotic prostatectomy or IMRT per population in a market (hospital referral region). We then performed multinomial logistic regression to examine the association of technology penetration with receipt of prostatectomy, radiotherapy, or no local therapy. Results: For each 1,000 patients diagnosed with prostate cancer, 171 underwent prostatectomy, 493 radiotherapy, and 336 had no local therapy. Markets with high robotic prostatectomy penetration had higher use of prostatectomy (175 vs. 141 per 1,000 men, p=0.004) but decreased use of radiotherapy (584 vs. 613 per 1,000 men, p=0.046), resulting in a stable rate of local therapy (Table). High versus low IMRT penetration did not significantly impact use of prostatectomy and radiotherapy (Table). Conclusions: Increased penetration of robotic surgical technology was associated with more use of prostatectomy and less use of radiotherapy. However, increased penetration of both robotic prostatectomy and IMRT did not change the overall rate of local therapy. Our findings allay concerns that new technology spurs additional local therapy of prostate cancer. [Table: see text]
Phase III, randomized, double-blind, placebo-controlled multicenter trial of daily everolimus plus weekly trastuzumab and vinorelbine in trastuzumab-resistant, advanced breast cancer (BOLERO-3).
Authors: O'Regan Ruth , Ozguroglu Mustafa , Andre Fabrice , Toi Masakazu , Jerusalem Guy Heinrich Maria , Wilks Sharon , Isaacs Claudine , Xu Binghe , Masuda Norikazu , Arena Francis P. , Yardley Denise Aysel , Yap Yoon Sim , Mukhopadhyay Pabak , Douma Shyanne , El-Hashimy Mona , Taran Tanya , Sahmoud Tarek , Lebwohl David Edward , Gianni Luca
Published: March 2020

505

Background: Everolimus (EVE) is an inhibitor of mammalian target of rapamycin (mTOR), a protein kinase central to a number of signaling pathways regulating cell growth and proliferation. Data from preclinical and phase 1/2 clinical studies indicated that adding EVE to trastuzumab (TRAS) plus chemotherapy may restore sensitivity to and enhance efficacy of human epidermal growth factor receptor 2 (HER2)-targeted therapy. The international BOLERO-3 phase 3 study is being conducted to evaluate the addition of EVE to TRAS plus vinorelbine. Methods: Adult women with HER2+ advanced breast cancer and who received prior taxane therapy and experienced recurrence or progression on TRAS were randomized 1:1 to receive either EVE or placebo (5 mg/day) in combination with weekly TRAS and vinorelbine (25 mg/m2). The primary endpoint is progression-free survival (PFS). Secondary endpoints included overall survival, response rate, clinical benefit rate, safety, quality of life, and pharmacokinetics. Final analysis will be conducted after approximately 417 PFS events. Results: The trial accrued 569 patients between October 2009 and May 2012. Previous therapy included TRAS (100%), a taxane (100%), and lapatinib (28%). The median age was 54 years, and 76% of patients had visceral metastases, 5% had stable brain metastases, 56% had hormone-receptor–positive disease, 33% had Eastern Cooperative Oncology Group performance status of 1 or 2, and 41% had 3 or more metastatic sites. The median number of prior chemotherapy lines in the metastatic setting was 1. As of February 4, 2013, a total of 396 PFS events were reported. Conclusions: Final PFS analysis will be performed in early May 2013; primary and secondary efficacy endpoints will be presented. Clinical trial information: NCT01007942.
Clinical outcome (CO) evaluation of very old (≥ 80 years) castration resistant prostate cancer (CRPC) patients (pts) treated with docetaxel (DOC): Preliminary results of an Italian multicenter retrospective study (DELPHI study).
Authors: Maines Francesca , Burgio Salvatore Luca , Di Lorenzo Giuseppe , Scognamiglio Florinda , Zustovich Fable , Facchini Gaetano , Gamucci Teresa , Procopio Giuseppe , Bortolus Roberto , Lo Re Giovanni , La Russa Francesca , Bonetti Andrea , Messina Caterina , Lodde Michele , Perin Alessandra , Iacovelli Roberto , Pappagallo Giovanni L. , Veccia Antonello , Caffo Orazio , Galligioni Enzo
Published: March 2020

5050

Background: Since prostate cancer is mainly diagnosed in pts over 65 yrs of age, castration resistance is usually observed in older pts. In the case of very old pts (≥ 80 years), fear of high toxicity degree limit chemotherapy use due to both pts frailty and several comorbidities occurrence. Moreover, if treated these pts usually receive an adapted chemotherapy, often with a weekly schedule, which in TAX327 trial failed to show survival advantage compared to mitoxantrone. The present retrospective study is aimed to assess CO in this very elderly CRPC population. Methods: In this multicentric retrospective study, after Ethical Committee approval, we have reviewed the clinical records of all ≥ 80 yrs CRPC pts from participating institutions, treated with DOC in clinical practice, recording the pre and post-DOC clinical history, the DOC treatment details and outcomes. Results: To date we collected a consecutive series of 81 pts from 17 Italian hospitals. The median age was 82 yrs (range 80-90). The median baseline PSA was 107 ng/ml (range 3-1597); 81% of the pts had bone metastases, while nodal, lung and liver metastases were observed in 37%, 6%, and 6% of the pts, respectively. Median Cumulative Illness Rating Scale score was 3 (range 0-11), median Activity Daily Living index score was 0 (range 0-5), median Instrumental Activities of Daily Living score was 0 (range 0-5). The DOC was administered on 3-week or weekly schedule basis (41%/59%). A PSA reduction > 50% and an objective response were observed in 74% and 11% of the pts, respectively. Grade 3-4 toxicities were: neutropenia (11%) , fatigue (8%), diarrhea (1%), renal (2%), and febrile neutropenia (1%). The median PFS and OS were 7 mos and 22 mos, while the 1-year PFS and OS rates were 17.3% and 43.9%, respectively. Conclusions: This data suggests that DOC treatment, both on 3-week or weekly schedule, is able to produce good survival outcomes, comparable to pivotal trials (18 mos), also in highly selected very older (≥ 80 yrs) CRPC pts.
Hematologic safety of Ra-223 dichloride (Ra-223) in castration-resistant prostate cancer (CRPC) patients with bone metastases from the phase III ALSYMPCA trial.
Authors: Parker Chris , Garcia-Vargas Jose E. , O'Bryan-Tear C. Gillies , Fang Fang , Vogelzang Nicholas J.
Published: March 2020

5060

Background: In the updated analysis of the ALSYMPCA study, Ra-223 significantly improved median survival by 3.6 mo vs placebo (Pbo) in 921 CRPC patients (pts) with bone mets (HR = 0.695; 95% CI, 0.581-0.832; p = 0.00007) and had a highly favorable safety profile (Parker et al. ASCO 2012). The hematologic safety profile and results from a post hoc analysis assessing prognostic factors for changes in hematologic parameters in ALSYMPCA pts are presented. Methods: Pts were randomized 2:1 to 6 injections (inj) of Ra-223 (50 kBq/kg IV) q4wk or matching Pbo and stratified by prior docetaxel (D) use, total alkaline phosphatase (tALP), and current bisphosphonate use.Multivariate regression analysis was performed to explore the relationship of 6 baseline factors (Table) with maximum % change of hematologic parameters from baseline up to 24 wk on treatment (tx). Results: The updated analysis included 901 pts (safety population; Ra-223, n = 600; Pbo, n = 301). Overall grade 3/4 AEs were similar between Ra-223 and Pbo groups, with neutropenia in 2% and 1%, thrombocytopenia in 6% and 2%, and anemia in 13% and 13% of Ra-223 and Pbo groups, respectively. Tx with Ra-223, prior D use, extent of disease (EOD) > 6 bone mets, and tALP ≥ 220 U/L, but not current bisphosphonate use, were associated with decreases from baseline in hemoglobin (Hb), neutrophils, or platelets; prior EBRT to bone for pain was associated with an increase. The significance of the relationship between baseline factors and changes in hematologic parameters is summarized in the Table. Conclusions: Overall, there was a low risk for hematologic AEs with Ra-223 tx in CRPC pts with bone mets. The strongest prognostic factors for decreases in neutrophils and platelets were Ra-223 tx and prior D use. Baseline tALP ≥ 220 U/L was a strong predictor of decrease in Hb. Clinical trial information: NCT00699751. [Table: see text]
Prognostic factors of survival in patients with metastatic castration resistant prostate cancer (mCRPC) treated with cabazitaxel: Sequencing might matter.
Authors: Angelergues Antoine , Maillet Denis , Flechon Aude , Ozguroglu Mustafa , Mercier Florence , Guillot Aline , Le Moulec Sylvestre , Gravis Gwenaelle , Beuzeboc Philippe , Massard Christophe , De La Motte Rouge Thibault , Elaidi Reza-Thierry , Oudard Stephane
Published: March 2020

5063

Background: Recently, several new drugs have demonstrated an overall survival (OS) benefit in patients (pts) with mCRPC. Their use must be optimized to maximize patient outcomes. We evaluated prognostic factors of OS in mCRPC pts treated with cabazitaxel (C), a new taxane developed to overcome docetaxel (D) resistance. Methods: Records of 125 consecutive mCRPC pts (median 67 yrs) treated with C (after D) were retrospectively collected in 9 centers (France, n=8; Turkey, n=1). Baseline characteristics, disease history, PSA response, OS and radiological and/or clinical progression-free survival (PFS) were collected. The influence of selected variables on OS was analyzed by multivariate logistic regression. Results: At C initiation, 83.3% of pts were ECOG 0-1, 50.8% had an initial Gleason score of 8-10, 62.9% had pain and 84.8% had radiological or clinical progression. Median duration of response to first-line androgen deprivation therapy was 20 months (mo) and 22% received ≥2 prior D lines. New hormonal agents (abiraterone or enzalutamide) were given before C in 33% of pts and after C in 16%. Median number of C cycles received was 6 (range 2-14). A PSA decrease of ≥50% and ≥30% was reached in 41.3% and 48.8% of patients treated with C. Median OS from first C cycle was 13.3 mo and median clinical and/or radiological PFS was 6.5 mo. In multivariate analysis, OS was significantly reduced in pts with ECOG 2 (HR: 6.05), alkaline phosphatase ≥1.5 ULN (HR: 2.64), lymph node involvement (HR: 1.89). Conversely, OS was significantly prolonged in pts with ≥2 prior D lines (HR: 0.35), prior curative therapy (HR: 0.55), a PSA decrease ≥30% with C (HR: 0.21) and in pts treated with abiraterone/enzalutamide after C (HR: 0.37). Median OS from the first D dose was 65 mo in pts treated with abiraterone or enzalutamide after C versus 39 mo in pts receiving these agents before C. Conclusions: Patients with ≥ 2 prior D lines, PSA response ≥30% with C and treated with new hormonal agents after C experienced a prolonged OS. Conversely, intake of new hormonal agents before C rather than after was associated with a reduced OS from the first D dose. Prospective randomized trials are needed to confirm these results.
Results from a phase I study of enzalutamide in combination with docetaxel in men with prostate cancer.
Authors: Fleming Mark T. , Rathkopf Dana E. , Gibbons Jackie , Peterson Amy C. , Hannah Alison , Forer David , Scher Howard I. , Morris Michael J.
Published: March 2020

5066

Background: Enzalutamide (ENZA) is a novel androgen receptor (AR) inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer (mCRPC) who had received prior docetaxel (DOC). DOC also prolongs survival in mCRPC and also appears to have anti-tumor effects mediated through the androgen-receptor axis, providing a compelling rationale for combining the two agents. CYP3A4 plays a role in DOC clearance and is induced by ENZA. We therefore conducted a phase I study to explore the PK and safety profiles of this combination. Methods: This study (NCT01565928) evaluated the safety and pharmacokinetics (PK) of DOC co-administered with ENZA in men with mCRPC on androgen deprivation therapy. Pts received DOC (75 mg/m2) by 1-h infusion every 3 weeks with corticosteroids. ENZA (160 mg/d) was started 24 h after the first DOC infusion. Plasma PK samples were collected for 24 h after Cycle (C) 1 and C2 DOC infusions to enable within-subject comparisons of DOC PK ± ENZA. A sample size of 18 pts able to receive ≥ 2 full doses of DOC was specified for PK analyses. Results: Twenty-two pts were enrolled, 4 did not receive 2 full doses of DOC. As of 21 Sept 2012, preliminary PK and C1 and C2 safety data were available from 15 pts. The median age was 65 (range 46-80 yrs); 11 had ECOG performance status 1 (vs 0). Prior primary therapy included surgery (n=2), radiation (n=4) or both (n=5); median PSA was 44.7ng/mL (1.9-585). ANC<1000/mm3 was reported in 14 pts (1 febrile neutropenia), other adverse events in ≥4 pts included fatigue (11), dyspnea (6), alopecia (5), peripheral neuropathy (5), anemia (4) and dysgueusia (4). No seizures were reported. Preliminary PK data (n=15) show similar DOC exposure (within 20%) for DOC in combination with ENZA vs. DOC alone.Final PK and updated tolerability and efficacy data beyond Cycle 2 will be presented. Conclusions: In mCRPC pts, ENZA does not appear to affect tolerability of DOC or have a clinically meaningful impact on DOC PK. Clinical trial information: NCT01565928.