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TheraP: a randomized phase 2 trial of 177 Lu-PSMA-617 theranostic treatment vs cabazitaxel in progressive metastatic castration-resistant prostate cancer (Clinical Trial Protocol ANZUP 1603).
Hofman, MS, Emmett, L, Violet, J, Y Zhang, A, Lawrence, NJ, Stockler, M, Francis, RJ, Iravani, A, Williams, S, Azad, A, et al
BJU international. 2019;:5-13
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OBJECTIVE To assess the activity and safety of cabazitaxel chemotherapy vs that of treatment with 177 Lu-PSMA-617, a novel radiolabelled small molecule that binds with high affinity to prostate-specific membrane antigen (PSMA), in men with metastatic castration-resistant prostate cancer (mCRPC) who have received prior docetaxel treatment. PATIENTS AND METHODS The TheraP trial (ANZUP 1603) is an open-label, randomized, stratified, two-arm multicentre phase 2 trial comparing the activity and safety of cabazitaxel chemotherapy vs 177 Lu-PSMA-617 therapy in the treatment of men with mCRPC. Key eligibility criteria include prior docetaxel chemotherapy, rising prostate-specific antigen (PSA) level, sufficient PSMA avidity, as defined by centrally reviewed 68 Ga-PSMA-11 and fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) with no discordant FDG-avid PSMA-negative sites of disease. Patients in the control group receive standard treatment with cabazitaxel (20 mg/m2 ) i.v. every 3 weeks with prednisolone 10 mg daily orally, for a maximum of 10 cycles. Patients in the experimental group receive 177 Lu-PSMA-617 (8.5 GBq decreasing by 0.5 GBq per cycle) i.v. every 6 weeks, for up to a maximum of six cycles. In the event of an exceptional response as defined on centrally reviewed post-therapy single-photon emission CT imaging, treatment will be suspended but can recommence on progression. The trial aims to include 200 patients who will be centrally randomized to one of the two treatment groups, in a 1:1 ratio. The primary endpoint is PSA response. Secondary endpoints are overall survival, progression-free survival (PFS), radiographic PFS, PSA PFS, objective tumour response, pain response, pain PFS, health-related quality of life, and frequency and severity of adverse events. The treatment and outcomes of patients excluded on the basis of low PSMA avidity or discordant FDG-avid disease on screening 68 Ga-PSMA-11 and Fluorine-18 (18 F)-FDG-PET/CT scan will also be assessed. Enrolment in the study commenced on 29 January 2018. RESULTS AND CONCLUSIONS 177 Lu-PSMA-617 offers a potential additional life-prolonging treatment option for men with mCRPC. The results of this trial will determine, for the first time in a randomized design, the activity and safety of 177 Lu-PSMA-617, as compared with cabazitaxel chemotherapy in men with progressive mCRPC.
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Plasma Cell-free DNA Concentration and Outcomes from Taxane Therapy in Metastatic Castration-resistant Prostate Cancer from Two Phase III Trials (FIRSTANA and PROSELICA).
Mehra, N, Dolling, D, Sumanasuriya, S, Christova, R, Pope, L, Carreira, S, Seed, G, Yuan, W, Goodall, J, Hall, E, et al
European urology. 2018;(3):283-291
Abstract
BACKGROUND Noninvasive biomarkers are needed to guide metastatic castration-resistant prostate cancer (mCRPC) treatment. OBJECTIVE To clinically qualify baseline and on-treatment cell-free DNA (cfDNA) concentrations as biomarkers of patient outcome following taxane chemotherapy. DESIGN, SETTING, AND PARTICIPANTS Blood for cfDNA analyses was prospectively collected from 571 mCRPC patients participating in two phase III clinical trials, FIRSTANA (NCT01308567) and PROSELICA (NCT01308580). Patients received docetaxel (75mg/m2) or cabazitaxel (20 or 25mg/m2) as first-line chemotherapy (FIRSTANA), and cabazitaxel (20 or 25mg/m2) as second-line chemotherapy (PROSELICA). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Associations between cfDNA concentration and prostate-specific antigen (PSA) response were tested using logistic regression models. Survival was estimated using Kaplan-Meier methods for cfDNA concentration grouped by quartile. Cox proportional hazard models, within each study, tested for associations with radiological progression-free survival (rPFS) and overall survival (OS), with multivariable analyses adjusting for baseline prognostic variables. Two-stage individual patient meta-analysis combined results for cfDNA concentrations for both studies. RESULTS AND LIMITATIONS In 2502 samples, baseline log10 cfDNA concentration correlated with known prognostic factors, shorter rPFS (hazard ratio [HR]=1.54; 95% confidence interval [CI]: 1.15-2.08; p=0.004), and shorter OS on taxane therapy (HR=1.53; 95% CI: 1.18-1.97; p=0.001). In multivariable analyses, baseline cfDNA concentration was an independent prognostic variable for rPFS and OS in both first- and second-line chemotherapy settings. Patients with a PSA response experienced a decline in log10 cfDNA concentrations during the first four cycles of treatment (per cycle -0.03; 95% CI: -0.044 to -0.009; p=0.003). Study limitations included the fact that blood sample collection was not mandated for all patients and the inability to specifically quantitate tumour-derived cfDNA fraction in cfDNA. CONCLUSIONS We report that changes in cfDNA concentrations correlate with both rPFS and OS in patients receiving first- and second-line taxane therapy, and may serve as independent prognostic biomarkers of response to taxanes. PATIENT SUMMARY In the past decade, several new therapies have been introduced for men diagnosed with metastatic prostate cancer. Although metastatic prostate cancer remains incurable, these novel agents have extended patient survival and improved their quality of life in comparison with the last decade. To further optimise treatment allocation and individualise patient care, better tests (biomarkers) are needed to guide the delivery of improved and more precise care. In this report, we assessed cfDNA in over 2500 blood samples from men with prostate cancer who were recruited to two separate international studies and received taxane chemotherapy. We quantified the concentration of cfDNA fragments in blood plasma, which partly originates from tumour. We identified that higher concentrations of circulating cfDNA fragments, prior to starting taxane chemotherapy, can be used to identify patients with aggressive prostate cancer. A decline in cfDNA concentration during the first 3-9 wk after initiation of taxane therapy was seen in patients deriving benefit from taxane chemotherapy. These results identified circulating cfDNA as a new biomarker of aggressive disease in metastatic prostate cancer and imply that the study of cfDNA has clinical utility, supporting further efforts to develop blood-based tests on this circulating tumour-derived DNA.
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Serum biomarkers of bone metabolism in castration-resistant prostate cancer patients with skeletal metastases: results from SWOG 0421.
Lara, PN, Ely, B, Quinn, DI, Mack, PC, Tangen, C, Gertz, E, Twardowski, PW, Goldkorn, A, Hussain, M, Vogelzang, NJ, et al
Journal of the National Cancer Institute. 2014;(4):dju013
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BACKGROUND Prior studies suggest that elevated markers of bone turnover are prognostic for poor survival in castration-resistant prostate cancer (CRPC). The predictive role of these markers relative to bone-targeted therapy is unknown. We prospectively evaluated the prognostic and predictive value of bone biomarkers in sera from CRPC patients treated on a placebo-controlled phase III trial of docetaxel with or without the bone targeted endothelin-A receptor antagonist atrasentan (SWOG S0421). METHODS Markers for bone resorption (N-telopeptide and pyridinoline) and formation (C-terminal collagen propeptide and bone alkaline phosphatase) were assayed in pretreatment and serial sera. Cox proportional hazards regression models were fit for overall survival. Models were fit with main effects for marker levels and with/without terms for marker-treatment interaction, adjusted for clinical variables, to assess the prognostic and predictive value of atrasentan. Analysis was adjusted for multiple comparisons. Two-sided P values were calculated using the Wald test. RESULTS Sera from 778 patients were analyzed. Elevated baseline levels of each of the markers were associated with worse survival (P < .001). Increasing marker levels by week nine of therapy were also associated with subsequent poor survival (P < .001). Patients with the highest marker levels (upper 25th percentile for all markers) not only had a poor prognosis (hazard ratio [HR] = 4.3; 95% confidence interval [CI] = 2.41 to 7.65; P < .001) but also had a survival benefit from atrasentan (HR = 0.33; 95% CI = 0.15 to 0.71; median survival = 13 [atrasentan] vs 5 months [placebo]; P interaction = .005). CONCLUSIONS Serum bone metabolism markers have statistically significant independent prognostic value in CRPC. Importantly, a small group of patients (6%) with highly elevated markers of bone turnover appear to preferentially benefit from atrasentan therapy.
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Impact of pathologic complete response on disease-free survival in patients with esophagogastric adenocarcinoma receiving preoperative docetaxel-based chemotherapy.
Lorenzen, S, Thuss-Patience, P, Al-Batran, SE, Lordick, F, Haller, B, Schuster, T, Pauligk, C, Luley, K, Bichev, D, Schumacher, G, et al
Annals of oncology : official journal of the European Society for Medical Oncology. 2013;(8):2068-73
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BACKGROUND The aim of this study was to evaluate the impact of pathologic complete response (pCR) on outcome in patients with gastric or esophagogastric junction (EGJ) adenocarcinoma after neoadjuvant docetaxel/platin/fluoropyrimidine-based chemotherapy. PATIENTS AND METHODS Patients received at least one cycle of chemotherapy for potentially operable disease. Pretreatment clinicopathologic factors and pCR were investigated. Disease-free survival (DFS), overall survival (OS) and tumor-related death were correlated with pCR. RESULTS One hundred twenty patients were included in this analysis. Eighteen patients (15%) achieved a pCR. Tumor localization in the EGJ was identified as the only significant predictor of pCR (P = 0.019). Median follow-up was 41.1 months. Median DFS and OS for all patients were 24.1 and 48.6 months, respectively. Median DFS for patients with a pCR was not reached versus 22.1 months non-pCR patients (hazard ratio, HR 0.38; 3-year DFS: 71.8% and 37.7%, respectively, P = 0.018). While OS was not significantly different, the risk for tumor-related death was significantly lower for pCR patients compared with non-pCR patients (3-year cumulative incidences of 6.4% and 45.4%, respectively, P = 0.009). CONCLUSION A pCR following preoperative docetaxel/platin/fluoropyrimidine indicates favorable outcome in patients with gastric or EGJ adenocarcinoma. Tumor location in the EGJ is associated with a higher pCR rate.
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Phase 1b dose-finding study of motesanib with docetaxel or paclitaxel in patients with metastatic breast cancer.
De Boer, RH, Kotasek, D, White, S, Koczwara, B, Mainwaring, P, Chan, A, Melara, R, Ye, Y, Adewoye, AH, Sikorski, R, et al
Breast cancer research and treatment. 2012;(1):241-52
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The purpose of this study was to investigate the safety, tolerability, and pharmacokinetics of motesanib when combined with docetaxel or paclitaxel in patients with metastatic breast cancer. In this open-label, dose-finding, phase 1b study, patients received motesanib 50 or 125-mg orally once daily (QD), beginning day 3 of cycle 1 of chemotherapy, continuously in combination with either paclitaxel 90 mg/m(2) on days 1, 8, and 15 every 28-day cycle (Arm A) or docetaxel 100 mg/m(2) on day 1 every 21-day cycle (Arm B). Dose escalation to motesanib 125 mg QD occurred if the incidence of dose-limiting toxicities (DLTs, primary endpoint) was ≤ 33 %. If the maximum tolerated dose (MTD) of motesanib was established in Arm B, additional patients could receive motesanib at the MTD plus docetaxel 75 mg/m(2). Forty-six patients were enrolled and 45 received ≥ 1 dose of motesanib. The incidence of DLTs was <33 % in all cohorts; thus, motesanib 125 mg QD was established as the MTD. Seven patients (16 %) had grade 3 motesanib-related adverse events including cholecystitis (2 patients) and hypertension (2 patients). Pharmacokinetic parameters of motesanib were similar to those reported in previous studies. The objective response rate was 56 % among patients with measurable disease at baseline who received motesanib in combination with taxane-based chemotherapy. The addition of motesanib to either paclitaxel or docetaxel was generally tolerable up to the 125-mg QD dose of motesanib. The objective response rate of 56 % suggests a potential benefit of motesanib in combination with taxane-based chemotherapy.
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Phase II study of eribulin mesylate (E7389) in patients with metastatic castration-resistant prostate cancer stratified by prior taxane therapy.
de Bono, JS, Molife, LR, Sonpavde, G, Maroto, JP, Calvo, E, Cartwright, TH, Loesch, DM, Feit, K, Das, A, Zang, EA, et al
Annals of oncology : official journal of the European Society for Medical Oncology. 2012;(5):1241-1249
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BACKGROUND Treatment options remain limited for patients with castration-resistant prostate cancer (CRPC). We evaluated eribulin mesylate (E7389), a nontaxane halichondrin B analog microtubule inhibitor, in patients with metastatic CRPC with or without previous taxane exposure. PATIENTS AND METHODS Men with histologically proven CRPC, with or without prior taxane exposure, were enrolled in an open-label, single-arm phase II trial. Patients received eribulin mesylate 1.4 mg/m(2) as a 2- to 5-min i.v. bolus infusion on days 1 and 8 of a 21-day cycle. The primary efficacy end point was prostate-specific antigen (PSA) response rate. RESULTS In total, 108 patients were assessable for safety (50 were taxane-pretreated) and 105 for efficacy in the per-protocol population. The median age of patients was 71 years and median number of cycles was 4. PSA decreases of ≥ 50% were achieved in 22.4% and 8.5% of taxane-naive and taxane-pretreated patients, respectively. The most common grade 3/4 adverse event was neutropenia, seen in 22.4% of chemo-naive and 40% of taxane-pretreated men. Grade 3 peripheral neuropathy occurred in none of the taxane-naive patients and 6.0% of taxane-pretreated patients. CONCLUSION Eribulin mesylate demonstrated activity and a relatively favorable toxicity profile in metastatic CRPC.
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Monitoring of neoadjuvant chemotherapy using multiparametric, ²³Na sodium MR, and multimodality (PET/CT/MRI) imaging in locally advanced breast cancer.
Jacobs, MA, Ouwerkerk, R, Wolff, AC, Gabrielson, E, Warzecha, H, Jeter, S, Bluemke, DA, Wahl, R, Stearns, V
Breast cancer research and treatment. 2011;(1):119-26
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We prospectively investigated using advanced magnetic resonance imaging (MRI) and positron emission tomography/computed tomography (PET/CT) to identify radiological biomarkers for treatment response in patients receiving preoperative systemic therapy (PST) for locally advanced breast cancer. Patients with a stage II or III breast cancer receiving PST were selected and underwent positron emission tomography (PET), magnetic resonance imaging (MRI), and breast biopsies at baseline and after the first cycle of PST (days 7-8) during the full course of treatment. PET/CT was acquired after injection of 2-deoxy-2-[18F]-fluoro-D-glucose (¹⁸FDG, 0.22 mCi/kg) and quantified with standardized uptake value assessment (SUV). Diagnostic breast MRI and sodium (²³Na) was acquired at 1.5 T. Total tissue sodium concentration (TSC), response criteria in solid tumors (RECIST), and volumes were quantified. Treatment response was determined by pathological assessment at surgery. Immunohistochemistry values of the proliferative index (Ki-67) were performed on biopsy specimens. Six of nineteen eligible women (43 ± 11 years) who received PST underwent radiological imaging of ¹⁸FDG-PET/CT and MRI for at least two cycles of treatment. Five patients had a pathological partial response (pPR) and one had pathological non-response (pNR). TSC decreased 21% in responders with increases in the non-responder (P = 0.03). Greater reduction in SUV was observed in responders (38%) compared to the non-responder (22%; P = 0.03). MRI volumes decreased after cycle 1 by 42% (responders) and 35% (non-responder; P = 0.11). Proliferation index Ki-67 declined in responders in the first cycle (median = 47%, range = 29-20%), but increased (4%) in the non-responder. Significant decreases in TSC, SUV, and Ki-67 were observed in responders with increases in TSC and Ki-67 in non-responders. Our results demonstrate the feasibility of using multi-modality proton, ²³Na MRI, and PET/CT metrics as radiological biomarkers for monitoring response to PST in patients with operable breast cancer.
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Persistent, biologically meaningful prostate cancer after 1 year of androgen ablation and docetaxel treatment.
Tzelepi, V, Efstathiou, E, Wen, S, Troncoso, P, Karlou, M, Pettaway, CA, Pisters, LL, Hoang, A, Logothetis, CJ, Pagliaro, LC
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011;(18):2574-81
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PURPOSE Clinicians are increasingly willing to treat prostate cancer within the primary site in the presence of regional lymph node or even limited distant metastases. However, no formal study on the merits of this approach has been reported. We used a preoperative clinical discovery platform to prioritize pathways for assessment as therapeutic targets and to test the hypothesis that the primary site harbors potentially lethal tumors after aggressive treatment. PATIENTS AND METHODS Patients with locally advanced or lymph node-metastatic prostate cancer underwent 1 year of androgen ablation and three cycles of docetaxel therapy, followed by prostatectomy. All specimens were characterized for stage by accepted criteria. Expression of select molecular markers implicated in disease progression and therapy resistance was determined immunohistochemically and compared with that in 30 archived specimens from untreated patients with high-grade prostate cancer. Marker expression was divided into three groups: intracellular signaling pathways, stromal-epithelial interaction pathways, and angiogenesis. RESULTS Forty patients were enrolled, 30 (75%) of whom underwent prostatectomy and two (5%) who underwent cystoprostatectomy. Twenty-nine specimens contained sufficient residual tumor for inclusion in a tissue microarray. Immunohistochemical analysis showed increased epithelial and stromal expression of CYP17, SRD5A1, and Hedgehog pathway components, and modulations of the insulin-like growth factor I pathway. CONCLUSION A network of molecular pathways reportedly linked to prostate cancer progression is activated after 1 year of therapy; biomarker expression suggests that potentially lethal cancers persist in the primary tumor and may contribute to progression.
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A phase II study of weekly docetaxel and cisplatin plus oral tegafur/uracil and leucovorin as first-line chemotherapy in patients with locally advanced or metastatic gastric cancer.
Li, CP, Chen, JS, Chen, LT, Yen, CJ, Lee, KD, Su, WP, Lin, PC, Lu, CH, Tsai, HJ, Chao, Y
British journal of cancer. 2010;(9):1343-8
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BACKGROUND Docetaxel plus cisplatin and 5-fluorouracil has become a new standard for treating advanced gastric cancer. However, high rates of severe neutropenia limit its application. Modification of the regimen could be the solution to get similar activity but less myelosuppression. METHODS Patients with histologically confirmed, locally advanced, or recurrent/metastatic gastric adenocarcinoma without previous chemotherapy were enrolled. This regimen consisted of docetaxel (Tyxan, TTY, Taipei, Taiwan) 30-min infusion at a dose of 36 mg m(-2), followed by cisplatin 30 mg m(-2) infusion over 1 h on days 1 and 8, and oral tegafur/uracil 300 mg m(-2) per day plus leucovorin 90 mg per day on days 1-14, every 3 weeks. Tumour response was evaluated after every 2 cycles of treatment. RESULTS From August 2007 to March 2009, 45 patients were enrolled. The median age was 56 years (range: 22-75). Among the 40 patients evaluable for tumour response, one achieved a complete response, 22 had partial responses and 11 had stable disease. The overall response rates of the evaluable and intent-to-treat (ITT) populations were 58% (95% CI: 41-74%) and 53% (95% CI: 38-68%), respectively. The disease control rates in these populations were 85% (95% CI: 70-94%) and 82% (95% CI: 68-92%), respectively. In the ITT analysis, the median time to progression and overall survival were 6.8 and 13.9 months, respectively. Major grade 3-4 toxicities were neutropenia (51%), anaemia (22%), diarrhoea (16%), and infections (20%). No patient died of treatment-related toxicities. CONCLUSION Concurrent weekly docetaxel and cisplatin plus oral tegafur/uracil and leucovorin are effective and well tolerated in the treatment of advanced gastric cancer.
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Matched case-control phase 2 study to evaluate the use of a frozen sock to prevent docetaxel-induced onycholysis and cutaneous toxicity of the foot.
Scotté, F, Banu, E, Medioni, J, Levy, E, Ebenezer, C, Marsan, S, Banu, A, Tourani, JM, Andrieu, JM, Oudard, S
Cancer. 2008;(7):1625-31
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BACKGROUND Onycholysis occurs in approximately 30% of patients treated with docetaxel. The efficacy and safety of an Elasto-Gel frozen sock (FS) was investigated for the prevention of docetaxel-induced nail and skin toxicity of the feet. METHODS Patients receiving docetaxel at a dose of 70 to 100 mg/m(2) every 3 weeks were eligible for this matched case-control study. Each patient wore an FS for 90 minutes on the right foot. The unprotected left foot acted as control. Nail and skin toxicities were assessed using National Cancer Institute Common Toxicity Criteria (version 3) and compared using a 2-sample Wilcoxon matched-pairs rank test adjusted for tied values. RESULTS Fifty consecutive patients were included between April 2005 and January 2007. Nail toxicity was significantly lower in the FS-protected foot compared with the control foot (grade 0: 100% versus 79%; and grade 1 and 2: 0% versus 21%, respectively) (P= .002). Skin toxicity was grade 0: 98% versus 94%; and grade 1 and 2: 2% versus 6% in the FS-protected and the control feet, respectively. The median times until toxicity occurrence were not found to differ significantly between the groups. One patient experienced discomfort because of cold intolerance. CONCLUSIONS Cold therapy using FS significantly reduced the incidence of docetaxel-induced foot nail toxicity, as previously demonstrated using frozen gloves for the hands.