bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I dose escalation trial of tremelimumab plus sunitinib in patients (pts) with metastatic renal cell carcinoma (mRCC)
Authors: Gordon M. S. , Stein M. , Shannon P. , Eddy S. , Tyler A. , Catlett L. , Hsyu P. , Huang B. , Healey D. , Rini B. I. 
Published: August 2020

5115 Background: Sunitinib (SU) is an oral multitargeted tyrosine kinase inhibitor that has antitumor activity in mRCC. Recent data show sunitinib reduces levels of myeloid-derived suppressor cells and prevents T-cell suppression in pts with mRCC. CTLA4 blockade with tremelimumab is an immunotherapy that enhances T-cell activation and proliferation, and is associated with durable objective responses in metastatic melanoma. It was hypothesized that combination therapy could safely be administered. Methods: The primary endpoint was to assess maximum tolerated dose (MTD) of tremelimumab Q12W in combination with 2 schedules of SU (50 mg/day for 4 weeks followed by 2 weeks off or 37.5 mg QD continuous) in pts with ≤1 prior treatment. Tremelimumab doses were 6, 10, and 15 mg/kg. Secondary objectives included best overall response (RECIST), duration of response, safety, and pharmacokinetics. Results: Twenty-one pts were enrolled. Two of 5 pts in the SU 50 mg (4/2 schedule) plus tremelimumab 6 mg/kg cohort experienced dose-limiting toxicities (DLTs): 1) G5 ruptured diverticula; 2) prolonged G3 mucositis and fatigue. Further exploration of this schedule for SU was excluded. In the SU 37.5 mg QD continuous cohorts, no DLTs were observed at 6 mg/kg tremelimumab (n = 3), 1 of 6 pts treated with 10 mg/kg tremelimumab in the protocol-defined cohort suffered sudden death, and 3 of 6 pts treated with 15 mg/kg tremelimumab + SU experienced DLTs, including: 1 pt with G3 acute renal failure and G3 lymphopenia, 1 pt with G3 elevated creatinine, and 1 pt with worsening G3 dyspnea. Therefore, SU 37.5 QD + tremelimumab 10 mg/kg Q12W was considered the MTD. Five pts achieved partial response: 1 at SU 50 (4/2) + tremelimumab 6 mg/kg; 3 at SU 37.5 + tremelimumab 10 mg/kg; and 1 at SU 37.5 QD + tremelimumab 15 mg/kg. Six pts stayed on study ≥11 mo. An expansion cohort is enrolling another 12 patients at the MTD to further define toxicity and clinical activity. Conclusions: Tremelimumab 10 mg/kg Q12W + SU 37.5 mg QD was tolerable and associated with antitumor activity in pts with mRCC. Further exploration of this combination is warranted. [Table: see text]
Impact of ultrahigh baseline PSA levels on biochemical and clinical outcomes in two Radiation Therapy Oncology Group (RTOG) prostate clinical trials
Authors: Rodrigues G. , Bae K. , Roach M. , Lawton C. , Donnelly B. , Grignon D. , Hanks G. , Porter A. , Lepor H. , Sandler H. 
Published: August 2020

5123 Background: Controversy exists regarding the outcomes of prostate cancer patients (PCP) presenting with ultra-high (UH; defined as PSA ≥ 50 ng/ml) PSA levels. The objectives of this study were to assess the outcome of this patient population compared to other high-risk patients and to identify predictors associated with biochemical/clinical outcomes. Methods: PCP from two phase III RTOG PC clinical trials (9202 and 9413) were divided into two groups; high-risk patients with and without UH baseline PSA level. Predictive variables included age, Gleason score, T stage, KPS, and treatment arm. Outcomes included overall survival (OS), distant metastasis (DM), and biochemical failure (BF) by Phoenix definition. A Cox proportional hazards regression model was used for OS, and Fine and Gray's regression model was used for DM and BF to test the hypotheses that a difference in each outcome exists between the two groups. Results: There are 401 PCP in the UH PSA and 1792 in the non-UH PSA cohort. Median age was 70 years and PCP were evenly distributed across the Gleason groups (2–6, 7, 8–10) for the non-UH (median PSA 22.4 ng/ml) and the UH PSA (median PSA 72.8ng/ml) cohort. The UH PSA cohort had a larger proportion of T1-T2 disease (p = 0.01) and a smaller proportion of Gleason 8 disease (p = 0.04) than the non-UH group. PCP with UH PSA was found to have inferior OS (HR 1.19, 95% CI 1.02–1.39), DM rate (HR 1.51, 95% CI 1.19–1.92), and BF rate (HR 1.50, 95% CI 1.29–1.73) when compared to other high-risk PCP in multivariable modeling. In the UH cohort, PSA level was found to model risk of DM (HR 1.01, 95% CI 1.001–1.02) but not OS and BF. Gleason grade 8–10 was found to consistently predict for poor OS, DM, and BF outcomes (with HR estimates ranging from 1.41 to 2.36) in both the overall and UH cohort multivariable analyses. Conclusions: UH PSA levels at diagnosis are related with detrimental changes in OS, DM, and BF. All three outcomes assessed in this investigation can be modeled by various combinations all predictive variables tested. Supported by RTOG U10 CA21661, CCOP U10 CA37422, and Stat U10 CA32115 grants from the NCI. This abstract's contents are the sole responsibility of the authors and do not necessarily represent the official views of the NCI. No significant financial relationships to disclose.
A phase II study evaluating the efficacy and safety of single agent IMC A12, a monoclonal antibody (MAb), against the insulin-like growth factor-1 receptor (IGF-IR), as monotherapy in patients with metastastic, asymptomatic castration-resistant prostate cancer (CRPC)
Authors: Higano C. , Alumkal J. , Ryan C. J. , Yu E. Y. , Beer T. M. , Chandrawansa K. , Katz T. , Youssoufian H. , Schwartz J. ,   Prostate Cancer Clinical Trials Consortium
Published: August 2020

5142 Background: IGF-IR-mediated signaling contributes to prostate cancer carcinogenesis and pathogenesis and may be associated with hormone resistance. IMC-A12 is a fully human IgG1 MAb that specifically targets the IGF-IR and inhibits ligand binding and signaling. In xenografts, IMC-A12 inhibits growth of both androgen-dependent and -independent prostate cancer. This phase 2, multicenter study was designed to assess the safety and antitumor activity of IMC-A12 in asymptomatic pts with metastatic CRPC who were chemotherapy-naive. Methods: Pts received IMC-A12 10 mg/kg IV every 2 wks; until evidence of progressive disease (PD), intolerable toxicity, or other withdrawal criteria were met. Radiologic evaluation was performed every 8 wks. PD by bone scan required at least 2 new lesions with confirmation at subsequent imaging per PCWG2. Results: 19 of 31 pts treated have discontinued IMC-A12, 12 due to PD. 9 of 31 pts experienced disease stabilization for ≥6 mos (range: 7.4–12.5 mos), 5 pts (3 with PSA reduction) continue on IMC-A12. The most common AEs possibly or probably related to IMC-A12, were fatigue (25.8%) and hyperglycemia (19.4%). In 4 pts cases of Grade 3 hyperglycemia was treatment related none requiring discontinuation of IMC-A12; 1 pt required insulin but continued on study. Approximately 70% of pts experienced at least transient elevation of nonfasting glucose to above normal range. Other AEs grade ≥3 at least possibly related to IMC-A12 were one case each of thrombocytopenia (requiring IMC-A12 discontinuation), hyperkalemia, fatigue, pneumonia (resulting in death), and Grade 4 pharmacokinetic and pharmacodynamic analayses are pending leukoencephalopathy (probably related; requiring IMC-A12 discontinuation). Pharmakinetic and pharmacodynamic analyses are pending. Conclusions: IMC-A12 monotherapy appears well tolerated in pts with metastatic asymptomatic CRPC. As in phase I, hyperglycemia was largely asymptomatic and manageable. Disease stabilization for > 6 months in 9 of 31 pts suggests that IMC- A12 may have modest antitumor activity. Additional studies of IMC-A12 in CRPC are planned. [Table: see text]
Phase I trial of targeted therapy with PSA-TRICOM vaccine (V) and ipilimumab (ipi) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC)
Authors: Mohebtash M. , Madan R. A. , Arlen P. M. , Rauckhorst M. , Tsang K. Y. , Cereda V. , Vergati M. , Poole D. J. , Dahut W. L. , Schlom J. , Gulley J. L. 
Published: August 2020

5144 Background: There are few treatment options for mCRPC pts. Immunotherapy + adjuvant immunomodulators is a promising modality. PSA-TRICOM V is composed of poxviral vectors encoding PSA and 3 costimulatory molecules (ICAM-I, LFA-3, and B7.1) and has clinical activity in mCRPC. Ipi blocks CTLA-4, a T-cell downregulatory receptor, has clinical activity in mCRPC as monotherapy and has also been shown to enhance anti-tumor responses in combination with V in preclinical studies. Methods: Pts received V and GM-CSF q 4 weeks in 4 sequential cohorts of escalating doses of ipi at 1, 3, 5, and 10 mg/kg (DL1–4 respectively). After 6 courses of ipi, pts could receive a maintenance dose q 3 months (mo) until progression. Results: Study accrual is complete with 30 pts. There was no DLT and no > G2 adverse event (AE) attributed to V. There were 20 ≥ G2 immune-related AE (irAE): 0/3, 2/6, 5/6 and 13/15 pts on DL1–4, respectively. There was no evidence of clinical benefit in the 6 pts who had prior chemo on DL1 and 2, so subsequently we excluded pts with prior chemo. Median TTP for 9 chemo-naïve pts treated on DL2 and 3 was 6.1 mo (2.9–11.6 mo). Median PSA doubling time (DT) ↑ from 2.2 mo at baseline to 3.7 on study (p = 0.17). 5 of 9 had ≥ 50% ↓ in PSA from peak during study and 1 had a sustained ↓ PSA > 95% from baseline. 4 of these pts had stable disease (SD) for ≥ 6 mo and 2 had unconfirmed partial responses by RECIST. Of the 15 pts on DL4, to date 9 have had SD for ≥ 6 mo (2 ≥ 12 mo); 4 remain on trial. 1 had a sustained ↓ in PSA > 99% from baseline and is still on study after 12 mo. Median PSA DT ↑ > 3-fold from 2.6 mo at baseline to 8.2 on study (p = 0.01) in DL4. The 24 chemo-naïve pts had PSA DT ↑ from 2.5 to 6 mo (p = 0.003). 14 of 30 pts had a PSA ↓ from baseline or peak PSA on study. 2 of 14 had no irAE, 12 showed ≥ G2 irAE temporally associated with PSA ↓. 5 of 9 pts had > 2–5 fold ↑ in T-cell responses by ELISPOT assay and 4 of 13 had significant ↓ in their IL-6 levels. Immune responses appeared to correlate with clinical activity. Conclusions: This combination has clinical activity in pts with chemo-naïve mCRPC and seems to correlate with immune responses. It is associated with manageable side effects; however, further studies are required to see if the combination is more effective than either agent alone. No significant financial relationships to disclose.
First-line sunitinib in type I and II papillary renal cell carcinoma (PRCC): SUPAP, a phase II study of the French Genito-Urinary Group (GETUG) and the Group of Early Phase trials (GEP)
Authors: Ravaud A. , Oudard S. , Gravis-Mescam G. , Sevin E. , Zanetta S. , Théodore C. , de Fromont M. , Mahier-Aït Oukhatar C. , Chêne G. , Escudier B. 
Published: August 2020

5146 Background: Sunitinib (Su) has been approved in metastatic clear cell carcinoma due to high objective response rates (ORR) and a prolonged progression-free survival (PFS). Subgroups analysis of previous studies hypothesized that Su may be active in PRCC. Type I and II papillary RCC pts have a poor prognosis, with limited effective agents. Methods: SUPAP is a single-arm prospective study using a 2-stage design including 21 patients (pts) to achieve a 20% ORR and if ≥ 2 pts have an OR, 20 additional pts will be included. SUPAP is exploring type I and II PRCC separately with an identical design. Main eligibility criteria included type I or II PRCC confirmed by central pathological review, PS 0–1, measurable disease, first line of treatment. Sunitinib was given at 50 mg/d, 4/6 weeks. Primary endpoint was ORR, while safety and time to progression were secondary endpoints. Results: From 10/07 to 11/08, 5 pts with type I and 23 pts with II PRCC were included. The median age was 65 years old. 25 (89%) pts had a nephrectomy. PS was 0 in 14 (56%) pts and 1 in 11 (44%) pts. Using the MSKCC scoring system : 5, 14 and 4 pts were in the favorable, intermediate or poor risk group, 4 undetermined. With a median follow-up of 5 months (0.7–12), 22/28 pts were evaluable for response rate and toxicity. In type II PRCC, 1/23 pts had a partial response (PR), 13/23 pts had a stable disease (SD) with 4 pts with a SD ≥ 12 weeks, 5/23 pts were progressive, 3/23 pts were too early for evaluation and 1/23 was not evaluable. In type I PRCC, none had a partial response (PR), 3/5 pts had stable disease (SD) and 2/5 pts were too early for evaluation. A cardiac infarction occurred during treatment and was considered as related to Su. Toxicity of sunitinib was similar as reported in pivotal phase III with Su in metastatic RCC. 12 pts required a dose reduction at any time mainly for non-hematologic toxicities. Conclusions: Although some activity has been observed, response rate was lower than in clear cell tumors. Updated data will be presented at the meeting. [Table: see text]
Dose finding and safety analysis of inecalcitol in combination with a docetaxel-prednisone regimen in hormone-refractory prostate cancer (HRPC) patients
Authors: Medioni J. , Deplanque G. , Maurina T. , Ferrero J. M. , Rodier J. M. , Raymond E. , Allyon J. , Kalla S. , Dufour-Lamartinie J. F. , Oudard S. 
Published: August 2020

5151 Background: Inecalcitol is a novel synthetic vitamin D3 analogue with potent antiproliferative effects in human cancer cell lines and a 100-fold lower hypercalcemic activity than calcitriol in animal models. Methods: Escalating dosages of inecalcitol were combined to chemotherapy in naive HRPC patients (pts). Safety and efficacy were evaluated in groups of 3–6 patients receiving oral inecalcitol daily or every other day on a 21-day cycle in combination with docetaxel (75mg/m2 q3w) and oral prednisone (5mg bid). Biphosphonates were prohibited during the first cycle. Patients received up to six cycles unless unacceptable toxicity or disease progression. Primary endpoint was dose limiting toxicity (DLT) defined as grade 3 hypercalcemia within the first cycle. Calcemia, creatininemia and CBC were assessed weekly; biochemistry, ECG and PSA every 3 weeks. Efficacy endpoint was PSA response defined as ≥30% decline within 3 months. Results: Five dose levels: 40, 80, 160, 300, 600 μg have been evaluated in 34 pts; 9 pts are still being treated at 600 μg; 25 pts have completed 6 cycles (13 bone metastases; 3 extrasqueletic metastasis, 8 bone and extrasqueletic metastases; 1 PSA-only disease). Median age was 72 years (range, 53–87), median Gleason score (Gs) 7 (36% Gs 10–8, 64% Gs 7–6) and median PSA 41.5 ng/mL (range, 0.9–962.4). No increased calcemia was reported. Most adverse events (AE) were G1–2, asthenia (19pts), constipation (14pts), diarrhea (13pts). G3–4 AEs were neutropenia (11pts) lymphopenia (9pts), asthenia (3pts), arrhythmia (2 pts), general health deterioration (2pts) and diarrhea (1pt). None of these AEs was considered related to inecalcitol. Of the 23 evaluable pts for PSA response, 20 (87%) had ≥30% PSA decline. Conclusions: Results from this ongoing study show the safe profile of inecalcitol when given daily in in HRPC pts. PSA responses with this combination are encouraging. As DLT was not reached, a higher dose of inecalcitol (1000 μg/day) will be further tested. [Table: see text]
Treatment of node-negative infra-centimetric HER2+ invasive breast carcinomas: A joint AERIO/REMAGUS study
Authors: Rodrigues M. J. , Wassermann J. , Albiges-Sauvin L. , Stevens D. , Brain E. , Delaloge S. , Mathieu M. , Guillot E. , Vincent-Salomon A. , Cottu P. H. 
Published: August 2020

517 Background: Trials have shown benefit of adjuvant trastuzumab (TZM) for node-positive (N+) or supra-centrimetric HER-2+ breast carcinomas. There are limited data concerning infra-centimetric HER-2+ invasive breast carcinomas (InfraHER-2). These tumors are being recognized as a high-risk group among all T1a/b tumors. Methods: Retrospective multicenter series from 2000 to 2008 of infra-centimetric HER-2+ invasive breast carcinomas (InfraHER-2). Tumors with ≥80% of ductal carcinoma in situ, multifocal and metastatic tumors were excluded. Results: 96 cases have been evaluated, 75 were node negative (N- InfraHER-2). All patients had surgery. 57% (n = 43) had a sentinel lymph node procedure. 73% (n = 55) had a local irradiation and 36 a tumor bed boost. Nodal irradiation of internal mammar and infra/supraclavicular regions was done in 20% and 17% respectively. 44% (n = 33) had chemotherapy (CT), almost all (31) were associated to TZM. Anthracycline-based (A), taxane-based (T) and A/T combinations were chosen for 54%, 4% and 42% respectively. One patient developed myocardial infarction after A resulting in heart failure; 2 had a transient left ventricular ejection fraction decrease below 50% after TZM. Decision of adjuvant CT was associated (all p < 0.05) with hormonal receptors (HR) negative status, Elston-Ellis grade (EE) 2/3 and high mitotic index (MI) while patients with HR+/low MI tumors were rarely treated (p < 0.001). 32/39 HR+ patients received hormonotherapy (80%); 21 received aromatase inhibitors, 6 tamoxifen and 5 LHRH agonists. With a 25 months median follow-up, there was no invasive recurrence in TZM treated patients. 3 of the 44 patients treated without TZM nor CT (7%) had local or metastatic recurrence including one fatal; they had initially HR- EE 2/3 T1b tumors. Conclusions: In our practice, decision of TZM-based therapy for InfraHER-2 N- tumors is associated with high-risk profile. Indeed, N- InfraHER-2 tumors may have a significant risk of recurrence which could be avoided by adjuvant TZM. Patients with N- InfraHER-2 tumors should be included in HER-2-targeted adjuvant trials. [Table: see text]
Baseline and recurrence levels of soluble HER2 (sHER2) in early-stage HER2-neu positive breast cancer (HER2+BC) from the NCCTG adjuvant Intergroup trial N9831
Authors: Moreno-Aspitia A. , Hillman D. W. , Dueck A. C. , Carney W. P. , Lingle W. L. , Tenner K. S. , Lafky J. M. , Reinholz M. M. , Kutteh L. A. , Perez E. A. 
Published: August 2020

539 Background: An increased baseline sHER-2 concentration is an indicator of poor prognosis in the metastatic and adjuvant settings of HER-2+BC. This study evaluated the levels of sHER-2 during treatment and at time of recurrence in N9831. Methods: Aims were to describe sHER-2 levels during treatment and at time of recurrence in patients (pts) randomized to Arms A (standard chemotherapy) and C (standard chemotherapy with concurrent trastuzumab). Baseline serum samples of 1506 pts from both arms along with 86 recurrence serum samples were analyzed for sHER-2 (ng/mL). In addition, 556 serial samples were obtained in 148 patients over the treatment period. Median follow up was 4.5 years. Statistical methods included repeated measures linear models, Wilcoxon rank sum tests, and Cox regression models. Results: Analyzing serial sHER-2 levels during treatment, mean log sHER-2 remained constant in Arm C (estimated slope = 0.004, p = 0.44) while the estimated increase per month was 0.026 (on log e scale) for Arm A (p = 0.0003). Based on the linear model at 18 months, the mean log sHER-2 was 2.98 (95% CI: 2.87–3.09) and 2.55 (95% CI: 2.40–2.70) for Arms A and C, respectively. Among pts with disease recurrence, sHER-2 levels increased in Arm A from baseline to time of recurrence (mean = 72.9, median = 1.7, p =0.005) while sHER-2 levels remained unchanged in Arm C (mean = 9.2, median = -0.9, p = 0.65). While all 86 recurrence patients had baseline sHER2 levels <50, 24% (15/63) of Arm A patients had very high recurrence sHER-2 levels (≥50) as compared to 9% (2/23) on Arm C (p=0.10). Patients with recurrence sHER-2 levels ≥15 had shorter survival time following recurrence with 3 year overall survival of 51% compared to 76% for the <15 sHER-2 group (HR = 2.77; 95% CI: 1.20–6.43, p = 0.02). Conclusions: Based on serial specimens during treatment, the concurrent trastuzumab arm (C) had constant sHER-2 levels, whereas the standard chemotherapy arm (A) had increasing sHER-2 levels. In arm A, recurrence sHER-2 levels increased significantly from baseline while recurrence sHER-2 levels did not change in arm C. Additionally, pts with high sHER-2 levels at recurrence had shorter overall survival following recurrence. Partial support: CA25224, CA114740 , Genentech, Siemens, and the BCRF. [Table: see text]
Clinicopathological features and sites of recurrence according to breast cancer subtype in the National Comprehensive Cancer Network (NCCN)
Authors: Lin N. U. , Vanderplas A. , Hughes M. E. , Theriault R. L. , Edge S. B. , Wong Y. , Blayney D. W. , Niland J. C. , Winer E. P. , Weeks J. C. 
Published: August 2020

543 Background: Gene expression profiling has defined multiple breast cancer subtypes which can approximated using standard immunohistochemical markers. Methods: We assessed clinicopathological features and sites of recurrence for patients (pts) presenting to NCCN sites with stage I-III breast cancer from Jan 2000 to Dec 2006 where estrogen receptor (ER), progesterone receptor (PR), and HER2 status were known. Tumors were grouped as luminal A (ER+ and/or PR+, and HER2-), HER2+ (any ER or PR, and HER2+), or triple-negative (ER-, PR-, and HER2-). Chi-square compared proportions across tumors; univariate logistic regression estimated risk of first site of recurrence. Results: 12,858 pts met inclusion criteria. Median follow-up from NCCN presentation was 3.2 years. Subtype distribution was: triple-negative (TN) 17%; HER2+ 18%; luminal A 66%. Compared to pts with luminal A and HER2+ tumors, TN were younger (p<0.0001), more likely African-American (p<0.0001) and overweight (p=0.0006). TN and HER2+ tumors were less often detected by screening mammography (TN, 28.9%; HER2+, 33.6%; luminal A, 48.4%) and less likely to present as T1 (TN, 46.5%; HER2+, 50.5%; luminal A, 67.0%) or diagnosed as stage I (TN, 32.6%; HER2+ 33.2%; luminal A, 49.4%) than luminal A (all p<0.0001). Rate of node positivity was lowest in TN (TN, 37.1%; HER2+, 44.9%; luminal A, 38.1%; p<0.0001). 83% of TN tumors were high grade; 93% were invasive ductal histology. Extensive intraductal component and lymphovascular invasion were more often associated with HER2+, compared to TN or luminal A (p<0.0001). Recurrences were recorded for 1,235 pts. Relative to luminal A, TN and HER2+ were more likely to experience lung (TN, odds ratio [OR] 2.27, 95% confidence interval [CI] 1.50, 3.43; p=0.0001; HER2+, OR 1.65, 95% CI 1.05, 2.60; p=0.03) and brain (TN, OR 5.32, 95% CI 2.85, 9.91; p<0.0001; HER2+, OR 5.53, 95% CI 2.93, 10.43; p<0.0001) as first site of recurrence; bone was less likely (TN, OR 0.23, 95% CI 0.16, 0.33; p<0.0001; HER2+, OR 0.38, 95% CI 0.28, 0.53; p<0.0001). Conclusions: Clinicopathological features and patterns of recurrence differed significantly by subtype and may inform the design of future clinical trials. No significant financial relationships to disclose.