To assess the clinical effect of radium 223 (Ra223) in patients with progressive symptomatic bone metastases on a background of metastatic castrate resistant prostate cancer (mCRPC).

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 347-347
Author(s):  
Christina J. Hague ◽  
Charlotte Fisher ◽  
James Wylie ◽  
Ananya Choudhury ◽  
Tony Elliot ◽  
...  
Keyword(s):  
Bone Metastases ◽  
Clinical Response ◽  
Clinical Benefit ◽  
Median Number ◽  
Post Treatment ◽  
Radium 223 ◽  
Number Of Patients ◽  
Castrate Resistant ◽  
Skeletal Related Event ◽  
Number Of Cycles

347 Background: Ra223 is the first radiopharmaceutical shown in the ALSYMPCA trial to improve survival and achieve a tolerable safety profile in patients with symptomatic bone metastases. It remains unclear as to where Ra223 is best placed in the treatment pathway of CRPC. We assessed the effect of Ra223 in mCRPC in terms of biochemical and clinical response. Methods: Retrospective analysis of mCRPC patients treated with Ra223 via CDF between Dec 2013-May 2015. Clinical benefit assessed by pain response. Toxicities graded as per CTCAE V 4. Results: 58 patients, median follow up 11.6 (1.0-18.1) months. Median age 71 (54-84); median WHO PS 1 (0-2). 58 patients received 50kBq/kg, median number of cycles 5 (1-6). 43% and 33% completed 6 and 3 cycles respectively. Median number of previous treatments 3 (1-6). 52%, 17% and 5 % received prior Docetaxel, Bisphosphonates and Strontium respectively. Median time from radiotherapy for symptomatic bone metastases to initiation of Ra 223 was 433 days. Incidence of Grade (G) 3/ 4 events 5% ; 2% G3 anaemia, 3% G3 neutropenia and 0% G3 thrombocytopenia. No treatment related deaths. 5% developed a skeletal related event, mean time of development from completion of Ra223 was 218 days. Median PSA pre v post treatment was 225 and 418. Median ALP (Alkaline Phosphatase) pre v post treatment was 292 and 138. Median Hb (Haemoglobin) pre v post treatment was 118 and 103. 50% patients had a clinical response. Whilst no significant association was seen between clinical benefit and change in PSA (p 0.973) or ALP (p 0.455) across this cohort, a number of patients had a sharp increase in PSA and decrease in ALP with no clinical benefit and clinical benefit respectively. 36/58 (62%) are alive; 16/58 (44%) alive with progressive disease. Median PFS 7.23 months (95% c.i. 5.73, 7.93) and median OS 8.33 months ((95% c.i. 5.65-13.50). Conclusions: Ra223 is safe and effective in pre-treated mCRPC patients. PSA response is not clinically meaningful whereas ALP may be a useful adjunct in measuring response. The optimum sequence is yet to be defined but better selection and earlier use in patients with predominant bone only disease should be considered.

UnCHAARTED territory: The role of docetaxel rechallenge following chemohormonal therapy for metastatic castrate-sensitive prostate cancer.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 117-117
Author(s):  
Mary Mahler ◽  
Esmail Mutahar Al-Ezzi ◽  
Noa Shani Shrem ◽  
Eric Winquist ◽  
Christina M. Canil ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Lymph Node ◽  
Median Time ◽  
Median Number ◽  
Time To Progression ◽  
Chemohormonal Therapy ◽  
Radium 223 ◽  
Psa Response ◽  
Number Of Cycles

117 Background: Since docetaxel has been advanced to the metastatic castrate-sensitive prostate cancer (mCSPC) setting, there is a lack of evidence guiding its re-introduction upon castrate-resistant (CR) progression. We sought to identify clinical characteristics and outcomes of patients subjected to docetaxel rechallenge (DR) following prior docetaxel exposure in the mCSPC realm. Methods: Patients rechallenged with docetaxel following treatment in the mCSPC setting were identified from three academic centres in Ontario, Canada. Retrospective chart reviews were performed to identify clinical, treatment and outcome variables. Results: Of the 45 patients with DR initiated between 06/2015 and 07/2020, the median age was 65, 60% had a Gleason score of ≥8, and 64% had an ECOG of ≤1. 56% had bone only metastasis, 4% lymph node only metastasis, 29% bone and lymph node metastasis, and 11% had visceral metastasis. In the mCSPC setting, 98% of patients received 6 cycles of docetaxel with 13% requiring dose delays. Of 43 informative patients, all had a PSA response to chemohormonal therapy. 91% achieved at least a 50% PSA response (PSA50), of which 40% had a 50-89% PSA reduction and 51% had a ≥90% PSA reduction. 29% of patients obtained a PSA nadir of < 0.2 ng/mL. 16% had CR progression in < 6 months, 56% in 6-12 months, and 28% in > 12 months. DR was initiated after a median of 20.8 months (range 6.0-40.4) following the last dose of docetaxel for mCSPC, and was given as first line treatment for CR disease to 7%, second line to 51%, third line to 40%, and fourth line or beyond to 2% of patients. 69% of patients had received an androgen-receptor axis targeted therapy prior to DR, 18% radium 223, and 7% had received a trial drug. Notably, no patients had received cabazitaxel prior to DR. The median number of cycles of docetaxel received at rechallenge was 5 (range 1-11) with 18% of patients requiring treatment delays. 64% of patients stopped treatment due to progression, 16% due to side effects, 7% at the patient’s request, 7% due to completion of the planned number of cycles, and 6% due to death or other causes. Among 44 informative patients, 23% achieved at least a PSA50, with 18% having a 50-90% PSA reduction, and 5% having a ≥90% PSA reduction. The median time to progression (biochemical, radiographic, or death) was 2.3 months (95%CI 1.7-4.4) and the median overall survival was 11.0 months (95%CI 8.5-14.3). Conclusions: DR following exposure to docetaxel in the mCSPC setting resulted in a PSA50 in only around one quarter of patients. Both the median time to progression and overall survival were found to be short. With future investigations, we hope to identify clinical variables that will help predict which patients might benefit most from DR.

Expression and Function of the P-Glycoprotein (P-gp) In Myelodysplastic Syndromes (MDS) Treated with Azacytidine (AZA)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5028-5028
Author(s):  
Marie Sebert ◽  
Elodie Lainey ◽  
PAscale Lepelley ◽  
Sylvain Thepot ◽  
Maximilien Tailler ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Clinical Response ◽  
Mononuclear Cells ◽  
Response Rate ◽  
Ex Vivo ◽  
Median Number ◽  
Specific Substrate ◽  
Glycoprotein P ◽  
Number Of Cycles ◽  
And Function

Abstract Abstract 5028 Background In MDS and AML, P-gp expression is associated with low response rate to conventional anthracycline-AraC chemotherapy (Lepelley et al., Leukaemia, 1994; Mahadevan and List, Blood, 2004). Since hypomethylating agents, notably AZA, can improve survival and have become a reference first line treatment in high and int 2 risk MDS (Lancet Oncol, 2009), we assessed whether P-gp expression and function in ex vivo MDS cells from patients treated with AZA was associated to clinical response to that drug. Methods Bone marrow (BM) cells from 30 patients with MDS or AML post MDS treated with AZA were studied, at onset of AZA. All patients received AZA for at least one cycle (75 mg/m2/d during 7 days every 28 days), and response was evaluated according to IWG 2006 criteria. Mononuclear cells from samples were isolated using a Ficoll-Paque PLUS density gradient. The evaluation of P-gp expression and functionality was made on CD45dim cells (blast population) and CD45dim CD34+ population, gated by flow cytometry. Quantification of P-gp expression was evaluated by FACS, using a phycoeythrin(PE)-conjugated antibody specific for ABCB1(P-gp)(clone UIC2). P-gp functionality was quantified by flow cytometry evaluation of Rhodamine123 (Rhoda: a specific substrate of P-gp) efflux in the presence or the absence of ciclosporine A (CSA, an inhibitor of P-gp). Patient cells were considered Rhoda pos when the RFI (Relative Fluorescence Intensity) CSA+/CSA- was >1.5. Results WHO diagnosis at onset of AZA was MDS in 19 pts (1 RA, 1 RCMD, 1 LMMC2, 5 RAEB-1, 10 RAEB-2, 1 RAEB-t) and AML post MDS in 11 pts. Median age was 76, M/F: 19/11. Karyotype (IPSS) was fav (n=10), int (n=3) unfav (n=14) and a failure (n=3). In MDS, IPSS was int-1 in 3pts, int-2 in 9 pts and high in 5 pts (and not evaluable in 2). The median number of cycles of AZA administered was 6 [2–19]. Fourteen pts (47%) responded including 6 (20%) CR and 8 hematological improvements (HI). Median OS from initiation of AZA was 418 d. No correlation between response and karyotype was found. P-gp expression was found in 64% of pts, and 65% of the pts had Rhoda pos cells, with some discordant cases for P-gp expression and functionality (including 23% P-gp pos Rhoda neg and 10% P-gp neg Rhoda pos). Karyotype was not correlated to P-gp expression or Rhoda RFI. The response rate was 39% in P-gp pos and 71% in P-gp neg pts (p=0.2) and the CR rate 17% in P-gp pos pts vs 28% in P-gp neg pts (P=0.6) The response rate was 47% in Rhoda pos and 33% in Rhoda neg pts (p=0.6) and the CR rate 23% in Rhoda pos vs 0% in Rhoda neg pts (P=0.26).Median OS was 373 d. in P-gp pos and not reached in P-gp neg pts (p= 0.18), and 428 d in Rhoda pos pts vs 292 d. in Rhoda neg pts (P=0.07). Conclusion Contrary to what is observed with anthracycline based chemotherapy, P-gp expression and functionality did not negatively affect clinical response to AZA in this cohort of MDS and AML post MDS, with even a trend for longer OS in patient with Rhoda pos cells. This difference may further explain the possible efficacy of AZA in chemoresistant cases of MDS and AML post MDS Disclosures: Fenaux: Celgene: Honoraria, Research Funding.

Phase 1 study of the PSMA-targeted small-molecule drug conjugate EC1169 in patients with metastatic castrate-resistant prostate cancer (mCRPC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 5038-5038 ◽  
Author(s):  
Michael J. Morris ◽  
Nicholas J. Vogelzang ◽  
Oliver Sartor ◽  
Alison Armour ◽  
Michael Groaning ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Median Number ◽  
Selection Strategy ◽  
Microtubule Inhibitor ◽  
Normal Tissues ◽  
Castrate Resistant ◽  
Number Of Cycles ◽  
Spect Scan

5038 Background: Prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancers, but not in most normal tissues, making it a potential therapeutic target. We are conducting a two-part phase 1 dose escalation/expansion study of EC1169, a PSMA-targeted conjugate of the microtubule inhibitor tubulysin B hydrazide in mCRPC. The utility of the PSMA-targeted companion imaging agent 99mTc-EC0652 is also being evaluated as a patient selection tool. The safety, efficacy, and imaging-based PSMA selection strategy are being investigated in Part A (dose escalation) and Part B (2-stage, 2-cohort expansion). Methods: Part A pts were eligible if they progressed on abiraterone or enzalutamide, and were treated with a taxane. EC1169 was administered as an IV bolus on days 1, 8 every 21 days. Part B pts are enrolled in 1 of 2 cohorts, mCRPC taxane naïve (cohort 1, 45 pts) and taxane exposed (cohort 2, 40 pts). Prior to treatment, pts undergo a 99mTc-EC0652 SPECT scan. The primary endpoint of Part B is median radiographic progression-free survival (rPFS). Other study evaluations are OS, PSA, and CTC-based biomarkers. Results: Part A is now complete: the RP2 dose is 6.5 mg/m2, on the basis of non-DLT transaminitis. 20 Part A/B pts have been treated at the RP2 dose (7 taxane naïve, 13 taxane exposed). Median age is 69 (range: 59-82). Median number of cycles is 2 (range: 1-7). 10 pts (50%) reported at least 1 treatment related AE. Most treatment related AEs are Gr1 and 2; G3 thrombocytopenia, fatigue, and constipation have occurred in 1 pt each. No Grade 4 treatment related AEs have been reported. No DLT or toxicity requiring dose reductions occurred. Four taxane-exposed pts in Part B have reached their first 9 wk radiographic assessment, of which two have soft tissue disease. One of those two patients (50%) has achieved an unconfirmed RECIST PR. Conclusions: The RP2 dose of EC1169 is 6.5 mg/m2. EC1169 has been well tolerated in 20 pts at the RP2 dose. Imaging with 99mTc-EC0652 suggests excellent disease localization supporting a PSMA-targeted therapeutic strategy. There is evidence of anti-tumor activity in both the dose escalation and expansion cohorts. Clinical trial information: NCT02202447.

Osteonecrosis of the jaw (ONJ) in radium 223 (Ra223)-treated metastatic castration-resistant prostate cancer (mCRPC) patients (pts) with exposure to zoledronic acid and/or denosumab.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5575-5575
Author(s):  
Yen Thi Kim Hong Cao ◽  
Janson Trieu ◽  
Vanessa Rojas ◽  
Michael Elias ◽  
Michael J. Anderson ◽  
...  
Keyword(s):  
Zoledronic Acid ◽  
Bone Metastases ◽  
Data Entry ◽  
Sequential Therapy ◽  
Median Number ◽  
Osteonecrosis Of The Jaw ◽  
Sequential Treatment ◽  
Castration Resistant Prostate Cancer ◽  
Radium 223 ◽  
Sequential Group

5575 Background: Bone health agents (BHA) including denosumab, a monoclonal antibody, and Zoledronic acid (ZA), a bisphosphonate, are recommended for men with CRPC and bone metastases to prevent skeletal-related complications. ONJ occurs in about 5% of patients (pts) on BHA. The incidence of ONJ in pts treated with Ra223 and BHA remains unknown, particularly in those who receive sequential treatment of BHAs. Here we describe the rate of ONJ in a real-world setting in mCRPC pts treated with Ra223 in 3 groups: 1) denosumab alone, 2) ZA alone, and 3) sequential ZA /denosumab or vice versa. Methods: A retrospective analysis of a cohort of mCRPC pts with bone metastases who received Ra223. Follow-up was until date of death or last data entry. Chart inclusion criteria included patients who received Ra223 between November 2010 to August 2018 with documentations of data points. Results: A total of 177 pts received Ra223 between 11/2010 and 8/2018. Median age 73 at 1st Ra223 (range 40-93); Median PSA 15.8- at 1st Ra223 (range 0.1-1952); Demographics-AA-10, C-130, Asian-9, unspecified-28; Median Alk Phos 95 at 1st Ra233 (range 25-1515). 93 % (164/177) received BHA. Of the 164 who received BHA, 45% (73/164) received denosumab only, 37% (61/164) received ZA only, and 18% (30/164) received sequential treatment. ONJ developed in 9.7% (16/164) of all patients on BHA. Denosumab alone caused ONJ in 7 of 73 pts (9.6%). ZA alone caused ONJ in 6 of 61 pts (9.8%). ONJ occurred in 3 of 30 pts (10%) in the sequential group. The median number of doses of BHA before development of ONJ was 10 with denosumab, 20 with ZA, and 19.5 (denosumab) and 22 (ZA) in the sequential group. Conclusions: In patients treated with Ra223 and a BHA, the rate of ONJ is 9.7%. The rate of ONJ was similar in groups treated with denosumab alone, ZA alone, and sequential treatment of ZA and denosumab However, ONJ developed more quickly in patients on denosumab. We conclude that the risk of ONJ is increased in patients treated with Ra223 and BHA. ZA or sequential therapy appears to delay time to onset of ONJ compared to denosumab. Clinicians should be mindful of the toxic synergy between Ra223 and BHA. ZA may be the preferred BHA partner with Ra223.

Radium-223 in the treatment of metastatic castrate-resistant prostate cancer: A real-world Irish experience.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 228-228
Author(s):  
Niamh Peters ◽  
John Gaffney ◽  
Emma Connolly ◽  
Richard Bambury ◽  
Derek Gerard Power ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Alkaline Phosphatase ◽  
Real World ◽  
Median Number ◽  
Prior Chemotherapy ◽  
Factors Associated ◽  
Radium 223 ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

228 Background: Radium 223 (Ra-223) has been successfully utilised in the trial setting for the treatment of men with metastatic castrate resistant prostate cancer (mCRPC). To date, no real world outcomes from its use in the Irish population have been described. Methods: From September 2016 to March 2019, data from men referred for Ra-223 treatment at our institution was retrospectively collected. We recorded patient characteristics, treatments received and outcomes. Overall Survival (OS) was analysed using the Kaplan-Meier method. Results: 81 men were referred for Ra 223. Complete data was available for 56 men. Median age was 75. 79%(45/56) had over 6 bone metastases and 21%(12/56) had lymph node involvement. The median number of prior systemic treatments for mCRPC was 2. 84%(47/56) of patients were previously treated with Androgen deprivation therapy (ADT); 48%(27/56) Abiraterone, 36%(20/56) Docetaxel, 45%(25/56) Enzalutamide and 9%(5/56) Cabazitaxel. All patients were receiving bone protection agents; 57%(32/56) Zolendronic acid and 43%(24/56) Denosumab. Median ECOG was 1 at the start of treatment and 2 at completion. The median number of treatments received was 4 with 36%(20/56) completing all 6 treatments. The most common toxicity seen was grade1 fatigue occurring in10% (6/56). 17% (10/56) required a blood transfusion during their treatment course. 53%(30/56) required opioid analgesia prior to Ra 223 treatment. 76% of these men (22/30) described improved pain following Rad-223. At a median follow up of 13 months,41%(23/56) were alive. The median OS for the entire group was 7 months. Factors associated with improved OS included ECOG 0-1,fewer than 6 bone metastases, normal alkaline phosphatase level at start of treatment and no prior chemotherapy use. Median OS for those who had not received prior chemotherapy was significantly better than those who had (9 vs 5 months p=0.04). Conclusions: This real world study demonstrates Ra 223 is a well tolerated palliative treatment amongst Irish men with mCRPC. Good performance status, lower alkaline phosphatase, chemotherapy naivety and a low burden of metastatic disease are factors associated with an improved overall survival.

Safety of neoadjuvant oxaliplatin-based chemotherapy (N-FOLFOX) in patients undergoing resection of colorectal liver metastases (R-CLM). Interim results

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14550-14550
Author(s):  
M. Verghese ◽  
S. Pathak ◽  
C. Foster ◽  
M. Haqqani ◽  
G. J. Poston
Keyword(s):  
Normal Liver ◽  
Liver Function Tests ◽  
Total Sample ◽  
Median Number ◽  
Significant Activity ◽  
Sinusoidal Dilatation ◽  
Post Surgery ◽  
Number Of Patients ◽  
Clinically Significant ◽  
Number Of Cycles

14550 Background: Oxaliplatin-5-fluorouracil-leucovorin (FOLFOX) has significant activity against CRC in both the metastatic and adjuvant settings. Consequently, neoadjuvant FOLFOX (N-FOLFOX) is being investigated in R-CLM. This has raised concerns regarding the safety and rate of post-operative complications (P-OCs) with N-FOLFOX, specifically, development of sinusoidal dilatation (SD), fibrosis and steatosis. This single-center cohort study was conducted to prospectively evaluate safety of N-FOLFOX in R-CLM patients. Methods: Planned total sample size is 40 patients [20 N-FOLFOX; 20 no chemotherapy (N-C)]. The N-C group consists of patients undergoing surgery for other hepatic pathology. Normal liver was examined by light (LM) and electron (EM) microscopy for SD, perisinusoidal fibrosis, and steatosis/necrosis; severity was graded from 0 (absent) to 2. The rate of P-OCs, hospital stays, and liver function tests (LFTs) were assessed. Results: At the time of this analysis, 20 patients (10 N-FOLFOX; 10 N-C) have undergone surgery. In the N- FOLFOX group, median number of cycles of N-FOLFOX was 6, with 2 patients receiving only 4 cycles. The median time between completion of N-FOLFOX and surgery was 6 weeks. There were no statistical differences between N-FOLFOX and N-C groups in potentially confounding factors, including previous chemotherapy, alcohol consumption, medical history, or concomitant medications. Number of patients with SD was 8 in each group (all were grade 1 except for 1 patient in N-C who had grade 2). Steatosis was seen in 7 and 6 patients in N-FOLFOX, and N-C groups, respectively (2 patients in each group were grade 2; remaining were grade 1). Fibrosis was noted in only 1 patient in N-C group. No nodular regeneration was observed in either group. There was a subjective loss on EM of mitochondria and Golgi apparatus/body with N-FOLFOX. Median post-operative hospital stay was 12 days in both groups. Conclusions: N-FOLFOX appears to have no clinically significant deleterious effects on normal liver architecture, function, or recovery post-surgery in R-CLM patients. The study is ongoing to accrue up to 40 patients; updated data will be presented. No significant financial relationships to disclose.

Comparison of survival of African-American (AA) patients (pts) in docetaxel (D)-based combination therapies in metastatic castrate-resistant prostate cancer (mCRPC).

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 272-272
Author(s):  
Fatima Karzai ◽  
Ravi Amrit Madan ◽  
Yang-Min Ning ◽  
Marc Robert Theoret ◽  
Philip M. Arlen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Median Number ◽  
Incidence And Mortality ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant ◽  
Number Of Cycles ◽  
Ecog Ps

272 Background: AA pts experience greater prostate cancer (PC) incidence and mortality compared to Caucasian (C) pts but are underrepresented in clinical trials (CTs). Greater representation of AAs is required to explore differences in clinical benefit in advanced disease where recent data has reaffirmed the role of D. Methods: In a retrospective analysis, baseline characteristics, Gleason score (GS), ECOG PS, number of cycles (cys), maximum prostate-specific antigen (PSA) declines, radiographic responses, overall survival (OS) and progression-free survival (PFS) were captured in 2 recent D based CTs. Results: Of 136 pts, 28 (21%) self-identified as Black or AA. Median age of AA pts is 66 (50-78 yrs). Median GS is 8 (5-10). Median ECOG PS is 1 (0-2). 15 pts have bone and soft tissue disease; 13 pts have bone only disease. Median number of cys is 28.5 (1-63). Of 27 evaluable pts, 26 had PSA declines (-26 to -99%). Radiographic responses include 11 (39%) partial responses and 16 (57%) pts with stable disease. Median OS for AAs is 29.0 months (mos) (95% CI: 20.9-34.7 mos); median PFS is 21.5 mos (95% CI: 13.7-28.9 mos). Median OS for all non-AA pts is 24.8 mos (95% CI: 21.8-29.5 mos); median PFS is 16.1 mos (95% CI: 14.1-20.1 mos). The VEGF-634G > C SNP, associated with a more aggressive phenotype of PC, was evaluated in 54 pts. No evidence was found that genotype frequency varies between C and AA pts. Conclusions: In this analysis, AA pts did not have inferior OS (29 mos) or PFS (21.5 mos) outcomes compared to non-AA pts (24.8, 16.1 mos). Further analysis from larger studies is required to determine differential benefits of D for AA pts compared to non-AA pts. Clinical trial information: NCT00089609, NCT00942578.

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