Trending Topic

Breast Cancer
29 mins

Trending Topic

Developed by Touch
Mark CompleteCompleted
BookmarkBookmarked

Endocrine therapy (ET) has changed the natural history of hormone receptor-positive (HR+) breast cancer (BC) and is the cornerstone of the treatment of HR+ BC. There are several ETs approved for the treatment of BC, including selective oestrogen receptor modulators (SERMs; tamoxifen), aromatase inhibitors (AIs; anastrazole, letrozole and exemestane) and selective oestrogen receptor degraders (SERDs; fulvestrant […]

Single Case of a Complete Response in a Metastatic Urothelial Carcinoma Patient Treated with Zoptarelin Doxorubicin

Gustavo Fernandez-Castro, Norman L Block, Andrew V Schally, Tulay Koru-Sengul, Merce Jorda, Jaime R Merchan, Aurea M Flores, Maria Restrepo
Share
Facebook
X (formerly Twitter)
LinkedIn
Via Email
Mark CompleteCompleted
BookmarkBookmarked
Copy LinkLink Copied
Download as PDF
Published Online: Dec 29th 2014 European Oncology & Haematology, 2014;10(2):82–5 DOI: https://touchoncology.com/single-case-of-a-complete-response-in-a-metastatic-urothelial-carcinoma-patient-treated-with-zoptarelin-doxorubicin/
Select a Section…
1

Abstract

Overview

Background: Zoptarelin doxorubicin (AEZS-108, AN-152) is an luteinising hormone-releasing hormone (LHRH)-cytotoxic hybrid drug consisting of an agonist coupled to the cytotoxic radical, doxorubicin. Methods: This is a single case report of a 66-year-old male who was diagnosed in May 2009 with metastatic urothelial carcinoma (UC) of the prostatic urethra. He presented with pelvic and retroperitoneal lymph nodes (LNs). Initially he was treated with cisplatin and gemzar, followed by radical cystoprostatectomy in October 2009. He relapsed in December 2009 and he received two more lines of chemotherapy with no response. The patient entered a phase I clinical trial with zoptarelin doxorubicin, in 2011. He received zoptarelin doxorubicin every 3 weeks for nine cycles from May to October 2011. Results: After two cycles of the investigational drug, all pain and palpable lymph neck nodes disappeared. A computed tomography (CT) scan 20 months post-treatment showed a complete response. Thirty months after treatment started, the patient is symptom free with no evidence of disease. Conclusions: This is the first case of a patient with LHRH-receptor (LHRH-R) positive UC treated with zoptarelin doxorubicin that has been reported. Considering the generally poor outcome of progressive UC and the short survival of these patients, the effect of this drug in this patient has been remarkable.

Keywords

Urothelial carcinoma, relapse, targeted, LHRH, AEZS-108, zoptarelin doxorubicin

2

Article

It was estimated that more than 429,000 new cases of urothelial cancer (UC) were diagnosed worldwide in 2012.1 There are limited treatments for locally advanced, unresectable, metastatic, platinum refractory UC.2 As a single agent, doxorubicin has a response rate of 17 % in patients with previously treated and untreated advanced bladder cancer. Complete responses (CRs) are uncommon and the median duration of response was only 3 to 4 months.3–6

Luteinising hormone-releasing hormone receptors (LHRH-Rs) are found on human cells of urothelial origin. Their high expression on the neoplastic cells and minimal expression in non-neoplastic cells, makes the LHRH-R an attractive therapeutic target.7,8

Zoptarelin doxorubicin is an LHRH-cytotoxic hybrid drug, in which an LHRH agonist is coupled to the cytotoxic radical, doxorubicin. The binding permits zoptarelin doxorubicin to accumulate on the surface of cells expressing LHRH-R allowing the uptake of the doxorubicin, thereby exploiting these receptors to gain access to the targeted tumour cells. Once internalised, the cytotoxic properties of doxorubicin provoke the anti-tumour response.9,10

Phase I and II studies of zoptarelin doxorubicin have been reported in females with LHRH-R-positive endometrial and ovarian cancer and have demonstrated that this drug has activity and can be safely given with few side effects.11,12 The first phase I study with zoptarelin doxorubicin included 17 women with epithelial cancers of ovary, endometrium or breast, and which were unresectable or metastatic. Each patient received intravenous doses of 10, 20, 40 or 80 mg/m2 of zoptarelin doxorubicin, six received 160 mg/m2 and seven 267 mg/m2 at 3 week intervals. The half-life of Zoptarelin doxorubicin was estimated to be about 2 hours. Dose-limiting leukopenia and neutropenia were observed only at the highest dose. A total of six patients, three in each of the high-dose groups (three at 160 mg/m2; three at 267 mg/m2), showed responses to zoptarelin doxorubicin. The 267 mg/m2 dose at intervals of 3 weeks was then selected as the starting dose for phase II studies.11 The first phase II trial included 42 patients with taxane-resistant and platinum-resistant LHRH-R positive ovarian cancer. In this study, patients were treated with up to 6 cycles of zoptarelin doxorubicin at doses of 267 mg/m2. Six patients (14.3 %) achieved a partial response (PR) and 16 patients (38.1 %) achieved disease stabilisation with a clinical benefit of 52.4 %. Median time to progression (TTP) was 12 weeks and median overall survival was 53 weeks. The safety profile of the 267 mg/m2 dose was confirmed.12 In the second phase II study, 43 patients with LHRH-R positive, International Federation of Gynecology and Obstetrics (FIGO) III/IV or recurrent endometrial cancer were included and were treated with six courses of zoptarelin doxorubicin at the 267 mg/m2 dose. Two patients had CR (5 %), eight patients had a PR (19 %) and 20 patients had stable disease (47 %). Clinical benefit was thus seen in 70 %. Median TTP was 7 months and overall survival was 15 months.13

In a recent phase I study, zoptarelin doxorubicin was a tolerable agent with activity in men with castration- and taxane-resistant prostate cancer. The dose for further study in this patient population was recommended to be 210 mg/m2 given intravenously every 3 weeks.14

In the US, a zoptarelin doxorubicin phase I clinical trial for metastatic UC was opened in November 2010. (ClinicalTrials.gov identifier: NCT01234519, Study ID Number: AEZS-108-046). Inclusion criteria for the study were:

  • Histologically or cytologically confirmed locally advanced or metastatic UC Eastern Cooperative Oncology Group (ECOG) status of 0, 1 or 2 patients with measurable disease and documented progression on at least one prior chemotherapy regimen, which must have incorporated platinum-based therapy.
  • Expression of LHRH receptors confirmed by immunohistochemistry on archival cancer tissue.
  • Left ventricular ejection fraction (LVEF) >50 %.


Case Report

A 66-year-old white male with past medical history of hypertension and emphysema presented with microscopic hematuria in 2007. Several superficial bladder tumours were found and resected. He then had multiple recurrences that required transurethral resection and intravesical treatment. On May 2009, he was found to have high-grade papillary UC of the bladder, and of the prostatic urethra, involving the prostatic stroma. A computed tomography (CT) scan demonstrated multiple enlarged retroperitoneal and pelvic lymph nodes (LNs), the largest measuring 2.1 cm. He underwent four cycles of chemotherapy with cisplatin 70 mg/m2 on day 1 and 1,000 mg/m2 gemcitabine on day 1, 8 and 15, from July 2009 to October 2009 and achieved PR. Following chemotherapy, he underwent radical cystoprostatectomy with lymphadenectomy and neobladder. Pathology showed no residual UC in bladder or prostatic urethra; however, 11 of 24 (46 %) LNs were positive for metastatic disease, including positive nodes in the left obturator space and the left pre-sacral area. The largest metastatic LN measured 1.5 cm. A repeat CT scan in November 2009, 1 month post-operatively, revealed interval development of severe left hydronephrosis and left hydroureter. In December 2009, left nephrostomy tube was placed and a positron emission tomography (PET) scan revealed a left, para-aortic, metabolically active LN. He then received six cycles of carboplatin (area under the curve [AUC]=5) plus paclitaxel 175 mg/m2 between January and April 2010 producing stable retroperitoneal LNs. A CT scan in August 2010 revealed a further increase in size of the retroperitoneal LNs, the biggest now measured 2.5 cm. He then received four cycles of carboplatin (AUC=5), paclitaxel 130 mg/m2 and gemcitabine 750 mg/m2 from September to November 2010. A follow-up CT scan in December 2010 revealed further progression of his disease with additional enlargement of the retroperitoneal lymphadenopathy, the biggest node located in the left para-aortic region now measured 3.5 x 3.7 cm. The patient had entered a clinical trial with a Bcl-2 inhibitor (investigational drug) plus docetaxel 75mg/m2 from January to March 2011.

Unfortunately, a study in March 2011 showed further worsening retroperitoneal LNs and new liver metastasis. (see Figure 1). The patient now had an ECOG performance status of 2, with severe back pain requiring large doses of narcotics. He now developed palpable left cervical LNs. The patient started zoptarelin doxorubicin in a phase I clinical trial (ClinicalTrials.gov identifier: NCT01234519, Study ID Number: AEZS-108- 046), designed for metastatic LHRH-R positive metastatic UC in patients who had failed platinum-based chemotherapy. Patient’s tumour cells were positive (25 %) for LHRH-R by immunohistochemistry. He received 160 mg/ m² of zoptarelin doxorubicin as a 2-hour infusion every 3 weeks for nine cycles from May to October 2011. After two cycles of this drug, all his pain and all palpable cervical LNs disappeared: he stopped all narcotics. He tolerated treatment very well. Toxicities were mostly grade 1–2 with an episode of neutropenic fever (grade 3). A CT scan 2 months after starting treatment and three cycles of investigational drug showed response in all sites of disease (see Figure 2). CR was evident at 20 months posttreatment (see Figure 3). Thirty months (2.5 years) after starting treatment the patient is asymptomatic with no evidence of disease.

Discussion

The standard chemotherapy treatment for advanced disease in patients with UC has been cisplatin-based and with a median survival of 15 months. Unfortunately, long-term survival has been suboptimal – most patients die from their disease.15–17 Once the cancer progresses after firstline cisplatin-based therapy, there are limited good treatment options. The average median overall survival of these patients is 6–9 months.2,3,18–20 A randomised phase III trial with 370 patients compared vinflunine (VFL) plus best supportive care (BSC) with BSC alone as second-line therapy. In the eligible population, the median overall survival was significantly longer for VFL + BSC than BSC (6.9 versus 4.3 months, respectively). As a result of this study, VFL was the first agent to be approved in Europe for second-line treatment in UC.21,22

Doxorubicin, a DNA-intercalating antibiotic, has been used alone, as first-line therapy in advanced UC patients, and in combination with other agents as second-line therapy, with a 17 % response rate.3–6 Zoptarelin doxorubicin, an LHRH-cytotoxic hybrid drug whose rational design covalently couples the carrier D-Lys6-LHRH (an LHRH agonist) to the doxorubicin radical, employs the doxorubicin molecule as its cytotoxic agent. The structure of zoptarelin doxorubicin fully preserves the cytotoxicity of doxorubicin while maintaining the binding affinity of the LHRH carrier.11 As receptors for LHRH are not expressed in high concentrations in most normal tissues, serious targeting related side effects are not expected after treatment with zoptarelin doxorubicin.23–25 LHRH-Rs have been reported in UC7,26 – zoptarelin doxorubicin powerfully inhibited growth of bladder cancer in nude mice.

Zoptarelin doxorubicin exerted a greater effect than doxorubicin alone but with less toxicity.26 Clinical activity and favourable safety have been obtained in patients with LHRH-R positive ovarian, endometrial cancer and prostate cancer.11–14 Ours is the first patient with LHRH-R-positive UC treated with zoptarelin doxorubicin that has been reported.27 Despite failing multiple prior chemotherapies this patient had a CR with a long progression-free survival. Patient is still free of disease at 30 months. The phase I study is completed and closed to accrual28 (ClinicalTrials.gov identifier: NCT01234519, Study ID Number: AEZS-108-046).

Conclusion

Considering the usually poor outcome of progressive UC and the short survival of these patients the effects of zoptarelin doxorubicin in this patient has been remarkable.

2

References

1. International Agency for Research on Cancer, GLOBOCAN
2012: Estimated cancer incidence, mortality and prevalence
worldwide in 2012, Available at: https://globocan.iarc.fr/Pages/
fact_sheets_population.aspx (accessed 18 December 2014)
2. Gallagher DJ, Milowsky MI, Bajorin DF, Advanced bladder
cancer: Status of first-line chemotherapy and the search
for active agents in the second-line setting, Cancer,
2008;113:1284–93.
3. Yagoda A, Phase-II trials in patients with urothelial tract
tumors. Memorial Sloan-Kettering Cancer Center, Cancer
Chemother Pharmacol, 1983;(Suppl. 11):S9–12.
4. Yagoda A, Chemotherapy of urothelial tract tumors, Cancer,
1987;60(Suppl. 3):574–85.
5. Yagoda A, Watson RC, Whitmore WF, et al., Adriamycin in
advanced urinary tract cancer: experience in 42 patients and
review of the literature, Cancer, 1977;39:279–85.
6. O’Bryan RM, Baker LH, Gottlieb JE, et al., Dose response
evaluation of adriamycin in human neoplasia, Cancer,
1977;39:1940–8.
7. Bahk JY, Kim MO, Park MS, et al., Gonadotropin-releasing
hormone (GnRH) and GnRH receptor in bladder cancer
epithelia and GnRH effect on bladder cancer cell proliferation,
Urol Int, 2008;80:431–8.
8. Nagy A, Schally AV, Targeting of cytotoxic luteinizing hormonereleasing
hormone analogs to breast, ovarian, endometrial,
and prostate cancers, Biol Reprod, 2005;73:851–9.
9. Nagy A, Schally AV, Armatis K, et al., Cytotoxic analogs of
luteinizing hormone-releasing hormone containing doxorubicin
or 2-pyrrolinodoxorubicin, a derivative 500–1000 times more
potent, Proc Natl Acad Sci U S A, 1996;93:7269–73.
10. Westphalen S, Kotulla G, Kaiser F, et al., Receptor mediated
antiproliferative effects of the cytotoxic LHRH agonist AN-152
in human ovarian and endometrial cancer cell lines, Int J
Oncol, 2000;17:1063–9.
11. Emons G, Kaufmann M, Gorchev G, et al., Dose escalation
and pharmacokinetic study of AEZS- 108 (AN-152), an LHRH
agonist linked to doxorubicin, in women with LHRH receptor
positive tumors, Gynecol Oncol, 2010;119:457–61.
12. Emons G, Gorchev G, Sehouli J, et al., Efficacy and safety
of AEZS-108 (INN: Zoptarelin Doxorubicin Acetate) anLHRH
agonist linked to doxorubicin in women with platinum
refractory or resistant ovarian cancer expressing LHRH
receptors: A multicenter Phase II trial of the ago-study group
(AGO GYN 5), Gynecol Oncol, 2014;133:427–32.
13. Emons G, Gorchev G, Harter P, et al., Efficacy and safety of
AEZS-108 (LHRH Agonist Linked to Doxorubicin) in women
with advanced or recurrent endometrial cancer expressing
lhrh receptors. a multicenter phase 2 trial (AGO-GYN5),
Int J Oncol, 2014;24:260–5.
14. Liu SV, Tsao-Wei DD, Xiong S, et al., Phase I, Dose-escalation
study of the targeted cytotoxic LHRH analog AEZS-108 in
patients with castration- and taxane-resistant prostate
cancer, Clin Cancer Res, 2014;20:6277–83.
15. von der Maase H, Hansen SW, Roberts JT, et al., Gemcitabine
and cisplatin versus methotrexate, vinblastine, doxorubicin,
and cisplatin in advanced or metastatic bladder cancer:
results of a large, randomized, multinational, multicenter,
phase III study, J Clin Oncol, 2000;18:3068–77.
16. von der Maase H, Sengelov L, Roberts JT, et al., Long-term
survival results of a randomized trial comparing gemcitabine
plus cisplatin, with methotrexate, vinblastine, doxorubicin,
plus cisplatin in patients with bladder cancer, J Clin Oncol,
2005;23:4602–8.
17. Sio TT, Ko J, Gudena VK, et al., Chemotherapeutic and
targeted biological agents for metastatic bladder cancer: A
comprehensive review, Int J Urol, 2014;21:630–7.
18. Kouno T, Ando M, Yonemori K, et al., Weekly paclitaxel and
carboplatin against advanced transitional cell cancer after
failure of a platinum-based regimen, Eur Urol, 2007;52:1115–22.
19. Vaughn DJ, Broome CM, Hussain M, et al., Phase II trial of
weekly paclitaxel in patients with previously treated advanced
urothelial cancer, J Clin Oncol, 2002;20:937–40.
20. Sonpavde G, Sternberg CN, Rosenberg JE, et al., Secondline
systemic therapy and emerging drugs for metastatic
transitional-cell carcinoma of the urothelium, Lancet Oncol,
2010;11:861–70.
21. Bellmunt, J, Théodore C, Demkov T, et al., Phase III trial of
vinflunine plus best supportive care compared with best
supportive care alone after a platinum-containing regimen
in patients with advanced transitional cell carcinoma of the
urothelial tract, J Clin Oncol, 2009 27:4454–61.
22. Bellmunt J, Fougeray R, Rosenberg JE, et al., Long-term
survival results of a randomized phase III trial of vinflunine
plus best supportive care versus best supportive care alone
in advanced urothelial carcinoma patients after failure of
platinum-based chemotherapy, Ann Oncol, 2013;24:1466–72.
23. Schally AV, Nagy A, New approaches to treatment of various
cancers based on cytotoxic analogs of LHRH, somatostatin
and bombesin, Life Sci, 2003;72:2305–20.
24. Emons G, Sindermann H, Engel J, et al., Luteinizing hormonereleasing
hormone receptor-targeted chemotherapy using
AN-152, Neuroendocrinology, 2009;90:15–8.
25. Grundker C, Volker F, Griesinger A, et al., Antitumor effects
of the cytotoxic luteinizing hormone-releasing hormone
analog AN-152 on human endometrial and ovarian
cancers xenografted into nude mice, Am J Obstet Gynecol,
2002;187:528–37.
26. Szepeshazi K, Schally A, Keller G, et al., Receptor-targeted
therapy of human experimental urinary bladder cancers
with cytotoxic LH-RH analog AN-152 (AEZS- 108), Oncotarget,
2012;3:686–99.
27. Fernandez-Castro G, Schally AV, Koru-Sengul T, et al., Longterm
response in a patient with urothelial cancer (UC) treated
with AEZS-108, J Clin Oncol, 2013;(Suppl. 31):Abstr. e155962.
28. Fernandez-Castro G, Schally AV, Koru-Sengul T, et al., A phase
I/II trial of AEZS-108 in locally advanced unresectable or
metastatic Luteinizing Hormone-Releasing Hormone (LHRH)
positive urothelial carcinoma (UC) patients who failed platinum
based chemotherapy. Presented for the Trials in Progress
Poster Session at 2011 American Society for Clinical Oncology
(ASCO) Annual Meeting, Chicago, Illinois (3–7 June 2011).

3

Article Information

Disclosure

Andrew V Schally is listed as co-inventor on the Tulane University patents on AN-152 (AEZS-108). Gustavo Fernandez-Castro, Tulay Koru-Sengul, Merce Jorda, Jaime R Merchan, Aurea M Flores and Maria Restrepo have no conflicts of interest to declare. Norman L Block has stock ownership at Aeterna Zentaris. No funding was received in the publication of this article.

Correspondence

Gustavo Fernandez-Castro, Division of Hematology/Oncology, Department of Medicine, University of Miami Miller School of Medicine, 1475 NW 12th Avenue, Miami, Florida, 33136 US. E: gfernandez3@med.miami.edu

Compliance with Ethics Guidelines: All procedures were followed in accordance with the responsible committee on human experimentation and with the Helsinki Declaration of 1975 and subsequent revisions. Informed consent was received from the patient involved in this case study.

Received

2014-08-26T00:00:00

4

Further Resources

Share
Facebook
X (formerly Twitter)
LinkedIn
Via Email
Mark CompleteCompleted
BookmarkBookmarked
Copy LinkLink Copied
Download as PDF

This Functionality is for
Members Only

Explore the latest in medical education and stay current in your field. Create a free account to track your learning.

Close Popup