Circulating tumor cell (CTC) detection, N-terminal androgen (AR) characterization, and PTEN loss in metastatic or advanced castration resistant prostate cancer (CRPC).

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 195-195
Author(s):  
Shidong Jia ◽  
Sarah Baird ◽  
Amanda K. L. Anderson ◽  
Shannon L. Werner ◽  
Jane Petersen ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Circulating Tumor Cell ◽  
Response To Therapy ◽  
Castration Resistant Prostate Cancer ◽  
Akt Inhibitor ◽  
Patient Response ◽  
Invasive Approach ◽  
Disease Evolution ◽  
Pten Loss ◽  
Non Invasive

195 Background: Detection and characterization of CTCs offers a minimally invasive mechanism for understanding patient response to therapy and disease evolution. Here we describe a proprietary technology platform to examine CTC incidence, N-terminal AR expression, and PTEN loss in metastatic or advanced CRPC patient samples from a phase II clinical trial (GO27983) testing the combination of the AKT inhibitor ipatasertib and abiraterone. Methods: Blood samples from CRPC patients (n = 283) were collected at screening and shipped to Epic Sciences. Upon receipt, the nucleated cells were plated onto microscope slides and stored at -80C. Two slides were thawed per patient and analyzed with an N-terminal AR CTC assay. CTCs were detected using a combination of CD45 exclusion, CK and N-terminal AR expression, and morphologic criteria. Traditional (CD45-, CK+, DAPI+) and Non-Traditional (CD45-/CK- with distinct morphology or CD45-/CK+ with fragmented nuclei) CTCs were enumerated and N-terminal AR expression was quantified for each CTC. Samples with > 2 Traditional CTCs enumerated per slide were further evaluated for PTEN loss by FISH (n = 170). Results: Traditional CTCs were detected ( ≥ 1 cell/ml) in 86% (242 of 283) of samples. Non-traditional CTCs were detected in 93% (263 of 283) of patients. N-terminal AR positivity was detected ( ≥ 1 AR+ cell/ml) in 53% (128 of 242) of Traditional CTC-positive samples, with the % positivity ranging from 0.4-100%. PTEN status was determined for 66% (160 of 243) of patients with Traditional CTCs detected. Patients with homozygous (HO) PTEN loss had a significantly higher mean CTC/mL (p = 0.0013) and AR+ CTC/mL value (p = 0.0014) than patients with PTEN non-deleted status. Conclusions: The ability of the Epic Sciences platform to detect AR+ CTCs and PTEN loss at screening provides a non-invasive approach to characterizing and monitoring CTCs identified in advanced CRPC patients. The study is ongoing to monitor longitudinal changes in CTC incidence and AR expression in relation to PTEN status. Clinical trial information: NCT01485861.

ProCAID: A phase I clinical trial to combine the AKT inhibitor AZD5363 with docetaxel and prednisolone (DP) chemotherapy for metastatic castration resistant prostate cancer (mCRPC).

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 228-228 ◽  
Author(s):  
Simon J. Crabb ◽  
Alison J. Birtle ◽  
Karen Martin ◽  
Nichola Downs ◽  
Megan Bowers ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Protein Kinase ◽  
Phase I ◽  
Disease Progression ◽  
Phase Ii ◽  
Performance Status ◽  
Research Network ◽  
Castration Resistant Prostate Cancer ◽  
Akt Inhibitor ◽  
Clinical Resistance

228 Background: DP extends survival in mCRPC. However emergent clinical resistance is effectively inevitable. Serine/threonine protein kinase AKT (protein kinase B) pathway activation is highly prevalent in mCRPC contributing to disease progression and DP therapeutic resistance. AZD5363 is a potent oral pan-AKT inhibitor. Pre-clinical data suggest activity in mCRPC and synergy with docetaxel. This phase I trial was to develop a DP/AZD5363 combination in mCRPC. Methods: Eligibility included chemotherapy naive histologically/cytologically proven measurable/evaluable mCRPC, PSA or radiographic disease progression, ECOG performance status 0 or 1, serum testosterone <1.7 nmol/L. Treatment comprised DP up to 10 cycles (75 mg/m2, IV, day 1; prednisolone 5 mg BID, PO, day 1–21) and AZD5363 to disease progression. Planned AZD5363 dose levels were 320 mg (DL1), 400 mg (DL2) and 480 mg (DL3), BID, PO, 4 days on/3 days off, from cycle 1, day 2. We utilised a conventional 3+3 dose escalation to determine a recommended phase II dose (RP2D) for AZD5363 combined with DP according to defined dose limiting toxicity (DLT) using CTCAEv4. Results: 10 patients were recruited (4 DL1, 6 DL2), median age 67.5 (Range: 56-72). A median of 6.5 cycles (Range: 3-10) of DP and 4 cycles (Range: 1-13) of AZD5363 were administered. No DLTs were seen in DL1. 2 patients in DL2 experienced DLTs (G3 rash, G3 diarrhoea). 7 pts (70%) had at least one G3/4 IMP-related AE with neutropenia (n=3) and maculo-papular rash (n=3) the most common. G3/4 AEs considered related to AZD5363 occurred in 3 patients (0 DL1, 3 DL2) including maculo-papular rash, diarrhoea and neutropenia. Transient hyperglycaemia occurred in all patients (Random glucose C1D2 pre dose mean 6.0 mmol/L, 2 hour mean 8.7 mmol/L, 4 hour mean 9.5 mmol/L, 8 hour mean 6.5 mmol/L). Conclusions:The RP2D for AZD5363 is 320 mg bd 4 days on/3 days off in combination with full dose DP for mCRPC. A placebo controlled randomised phase II trial for this approach has commenced recruitment. This work was supported by CRUK [C9317/A16029]. CRUK Reference: CRUK/12/042. This research was conducted with support from the Investigator-Sponsored Study Collaboration between AstraZeneca and the National Cancer Research Network. Clinical trial information: NCT02121639.

Opipramol and Chlorthalidone in the Treatment of Premenstrual Tension

1973 ◽  
Vol 1 (3) ◽  
pp. 172-179
Author(s):  
G Kagan ◽  
G Beaumont
Keyword(s):  
Clinical Trial ◽  
Response To Therapy ◽  
Emotional Lability ◽  
Patient Response ◽  
Favourable Response ◽  
Premenstrual Tension ◽  
The Third ◽  
Valid Comparison ◽  
Individual Patient Response ◽  
Effect Of Age

Thirty-three patients under the age of 38 suffering from premenstrual tension were admitted to a clinical trial and treated for three cycles. Five received opipramol alone and twenty-eight received a combination of opipramol and chlorthalidone. Slightly better results were obtained with the combination than with opipramol alone, although the number of opipramol patients was too small for valid comparison. There was a progressive improvement over the three cycles. By the third cycle there was a 47.92% improvement in the total score for ten symptoms on opipramol and 59.2% improvement on the combination. As far as the combination was concerned, best results were obtained for the symptoms, swelling of breasts (90%) mastalgia (88.8%), swelling of ankles (83.3%), oliguria (64.2%) and emotional lability (59.2%). The effect of age, marital state and gravidity on the syndrome was examined. No major differences were found in the symptomatology as far as these three factors were concerned. Young, single nulligravid women however, showed a consistently more favourable response to therapy. In terms of individual patient response, twenty-eight patients showed moderate or much improvement by the end of the third cycle.

CK- and small nuclear size circulating tumor cell (CTCs) phenotypes in metastatic castration-resistant prostate cancer (mCRPC).

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 209-209 ◽  
Author(s):  
Roberta Ferraldeschi ◽  
Andrew McDaniel ◽  
Rachel Krupa ◽  
Jessica Louw ◽  
Eric Tucker ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Cell ◽  
White Blood Cells ◽  
Circulating Tumor Cell ◽  
Nuclear Size ◽  
Castration Resistant Prostate Cancer ◽  
Pten Loss ◽  
Castration Resistant ◽  
Glass Slides ◽  
Pten Deletion

209 Background: Circulating tumor cell (CTCs) are traditionally defined as EpCAM/CK+ cells, CD45-, and morphologically distinct. However, recent evidence suggests that other populations of CTC candidates exist including cells that are EpCAM/CK- or smaller in size than traditional CTCs. CTC positive selection techniques that isolate CTCs based on size, density, or EpCam positivity may miss subpopulations. We aimed to molecularly characterize novel CTC candidates utilizing the Epic Sciences platform, which performs no physical selection. Methods: Blood from 10 healthy volunteers (HV) and 39 patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) were collected and shipped to Epic Sciences, where all nucleated cells were plated onto glass slides and subjected to immunofluorescence (IF) staining and CTC identification by fluorescent scanners and algorithms. Traditional CTCs were identified as CK+CD45- cells with intact DAPI nuclei and after pathologist review of their morphology. Candidate CK- CTC populations were identified as CK-CD45- that were morphologically malignant. Small nuclear size candidate CTCs were identified as CK+CD45- cells with diameters similar to or smaller than that of a typical white blood cells (WBCs). All candidate CTC were evaluated with prostate cancer relevant biomarkers, including androgen receptor (AR) by IF and PTEN loss and ERG rearrangements by FISH. Results: Thrity eight out of 39 pts had one or more traditional CTCs/mL and 36 out of 39 pts had one or more CK- CTCs/mL of blood. Eight out of 39 samples had more than 10 CK- CTCs/mL. Fifteen out of 39 samples had evidence of small nuclear size CTCs at varying incidences and sizes of cells. We observed PCa biomarkers including high AR expression, PTEN deletion, and ERG rearrangements in both CK- and small nuclear size CTCs. These features were not observed in over 1,000 WBCs evaluated and HV. Conclusions: Candidate CTC that are CK-CD45- and/or with a small nucleus are identified on the Epic Sciences platform in blood from mCRPC pts. Studies are ongoing to determine their clinical relevance.

NGS, RNA-Seq, TIL, and PTEN analyses in prostate cancer specimens from patients enrolled in the study of the Akt inhibitor ipatasertib (Ipat) combined with abiraterone acetate (AA).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 310-310
Author(s):  
Liangxuan Zhang ◽  
Hartmut Koeppen ◽  
Daniel J. Maslyar ◽  
Dimitri Fillos ◽  
Na Xu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Checkpoint Inhibitors ◽  
Abiraterone Acetate ◽  
Phase Iii ◽  
Immune Checkpoints ◽  
Rna Seq ◽  
Castration Resistant Prostate Cancer ◽  
Akt Inhibitor ◽  
Pten Loss ◽  
High Level

310 Background: In Phase III studies, ipilimumab did not extend OS in unselected populations with metastatic castration-resistant prostate cancer (mCRPC) (Kwon, 2014; Beer, 2014), suggesting that successful cancer immunotherapy development strategies require the evaluation of treatment effects in biomarker-driven segments. In addition, PTEN loss has been identified as a potential mechanism of resistance to immunotherapy (Peng, 2016). Therefore, we explored possible associations between cancer immunity (CI)-related biomarkers and PTEN loss in mCRPC samples. Methods: Tumor samples obtained in the Phase II study of AA ± Ipat in patients with mCRPC (de Bono, ESMO 2016) were retrospectively profiled. DNA alterations and tumor mutational burden (TMB) were assessed by FoundationOne. RNA-seq analysis of multiple CI-related expression signatures was performed. Tumor-immune lymphocyte (TIL) scores were analyzed in 3 compartments (stromal, sTIL; intratumoral, iTIL; peritumoral, pTIL) based on H&E stained specimens. Up to 10 evenly distributed fields were examined; the average of these fields was used to estimate the %TILs for each compartment. Results: Strong associations were observed between multiple CI-related signatures (e.g., INFγ-induced, immune checkpoints, Treg, checkpoint inhibitors). Fewer than 10% of the samples had a high level (≥ 10% of the tumor area) of TIL infiltration in any compartment (Table). TIL scores, TMB values, PTEN status and Gleason score all appeared to be independently associated, and none were associated with CI-related gene signatures, except for a possible association between pTILs and the B-cell signature (ρ = 0.49, P < 0.0001). Conclusions: Comprehensive high-content profiling of prostate cancer samples suggests that PTEN status and CI-related biomarkers were independently associated, while TMB and TIL values were generally not associated with CI-related signatures. Clinical trial information: NCT01485861. [Table: see text]

A phase III trial of capivasertib and abiraterone versus placebo and abiraterone in patients with de novo metastatic hormone-sensitive prostate cancer characterized by PTEN deficiency (CAPItello-281).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. TPS178-TPS178
Author(s):  
Karim Fizazi ◽  
Daniel J. George ◽  
Maria De Santis ◽  
Noel Clarke ◽  
Andre P. Fay ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Radiographic Progression ◽  
De Novo ◽  
Castration Resistant Prostate Cancer ◽  
Akt Inhibitor ◽  
Phase 3 ◽  
Free Survival ◽  
Pten Loss ◽  
Castration Resistant ◽  
Hormone Sensitive

TPS178 Background: In metastatic hormone-sensitive prostate cancer (mHSPC), abiraterone combined with androgen deprivation therapy (ADT) is highly effective in improving patient outcomes. However, around 20% of patients progress to castration-resistant disease within 12 months of treatment; these patients have shorter survival and limited treatment options. Aberrant activation of the PI3K/AKT pathway, predominately due to PTEN loss, is common in prostate cancer, especially in later-stage disease. The androgen receptor signaling and AKT pathway are reciprocally cross-regulated such as that inhibition of one leads to upregulation of the other. Therefore, combining abiraterone therapy with AKT inhibition may be beneficial in patients with mHSPC who have PTEN deficiency. In preclinical studies, capivasertib, a selective oral pan-AKT inhibitor, inhibited proliferation of models of hormone-sensitive and castration-resistant prostate cancer with PTEN loss. The results of the IPATential150 phase 3 study (NCT03072238) demonstrated that another oral AKT inhibitor, ipatasertib, prolonged radiographic progression-free survival (rPFS) when combined with abiraterone compared with placebo plus abiraterone in metastatic castration-resistant prostate cancer, particularly among patients with PTEN loss. CAPItello-281 (NCT04493853) is a global, multicenter, phase 3 trial to evaluate capivasertib in combination with abiraterone, on a background of ADT, as a treatment for de novo mHSPC patients with PTEN-deficient tumors. Methods: Eligible patients for this double-blind, randomized trial are men aged 18 years or older with confirmed newly diagnosed previously untreated metastatic hormone-sensitive prostate adenocarcinoma with immunohistochemically confirmed PTEN deficiency and Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. Following screening, approximately 1000 patients will be randomized 1:1 to receive either capivasertib (400 mg) or placebo (twice daily; 4 days on, 3 days off) in combination with abiraterone (1000 mg once daily) and ADT until radiographic progression or intolerable toxicity. The primary endpoint is rPFS. Secondary endpoints include overall survival, time to start of first subsequent therapy or death, symptomatic skeletal event-free survival, time to pain progression and safety profile. Enrolment started in July 2020. Acknowledgments: We thank Julia Grigorieva, PhD, of Oxford PharmaGenesis, Philadelphia, USA, for providing medical writing assistance. Funding: The CAPItello-281 trial is funded and overseen by AstraZeneca. Clinical trial information: NCT04493853.

scholarly journals Prospective assessment of AR splice variant and PSMA detection on circulating tumor cells of mCRPC patients: preliminary analysis of patients enrolled in PRIMERA trial (NCT04188275)

2021 ◽  
Vol 38 (5) ◽  
pp. 451-458
Author(s):  
G. Francolini ◽  
M. Loi ◽  
V. Salvestrini ◽  
M. Mangoni ◽  
B. Detti ◽  
...  
Keyword(s):  
Preliminary Analysis ◽  
Circulating Tumor Cell ◽  
Response To Therapy ◽  
Micro Rna ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistance ◽  
Observational Trial ◽  
Mutational Status ◽  
Prospective Assessment ◽  
Patient Prognosis

AbstractIn our institution, a prospective observational trial testing micro-RNA (miRNA) and ARV7 mutational status in metastatic, castration resistant prostate cancer (mCRPC), is currently recruiting (PRIMERA trial, NCT04188275). A pre-planned interim analysis was performed when 50% of the planned accrual was reached. In this report, we explored the predictive value of Circulating Tumor Cell (CTC) detection in mCRPC patients undergoing 1st line therapy. Moreover, ARV7, ARFL, PSMA and PSA expression on CTC was reported to explore potential correlation with patient prognosis and response to therapy. PRIMERA is a prospective observational trial enrolling mCRPC patients undergoing standard treatment (ARTA + ADT) after I line ADT failure. Clinical and pathological features were collected. Outcomes selected for this preliminary analysis were time to castration resistance (TTCR), PSA at 8 weeks after ARTA therapy start, PSA drop at 8 weeks, Overall PSA drop, PSA nadir. Correlation between these outcomes and CTC detection was tested. Expression of ARV7, ARFL, PSA and PSMA was explored in CTC+ patients to assess their prevalence in this cohort and their impact on selected outcomes. Median TTCR was significantly shorter in CTC+ vs CTC− patients (32.3 vs 75 months, respectively, p = 0.03) and in ARFL+ vs ARFL− patients (30.2 vs 51.1 months, respectively, p = 0.02). ARV7, PSMA and PSA expression on CTC had no impact on median TTCR, nor on biochemical response to therapy. Patients in whom CTC and ARFL expression were detected had significant reduced TTCR. However, PSA response was not influenced by CTCs detection and specific biomarkers expression.

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