Telmisartan in Prostate Cancer

Prostate Cancer Clinical Trial

Official title:

Phase I Non-Randomized, Unblinded, Single-Center Trial of Oral Telmisartan Alone or Combined With Selected Standard of Care Therapies for Prostate Cancer

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06168487
• Other study ID #: STUDY02002057
• Status: Not yet recruiting
• Phase: Early Phase 1
• Start date: June 1, 2024
• Est. completion date: April 1, 2027

Study information

• Verified date: November 2023
• Source: Dartmouth-Hitchcock Medical Center
• Contact: Kayla Fay
• Phone: 603-650-5000
• Email: kayla.a.fay[@]hitchcock.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The goal of this clinical trial is to learn about the tolerability of telmisartan in patients with prostate cancer.

Description:

The primary objective of this study is to test the tolerability of oral telmisartan given as a single agent or combined with specific standard of care agents in selected participants with PC. Patients will be defined as tolerating telmisartan if they maintain systolic blood pressure >110 mm Hg and are without greater than grade 2 toxicities as defined in the Common Terminology Criteria for Adverse Events v5.1 for at least 60 days total telmisartan treatment.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 42
• Est. completion date: April 1, 2027
• Est. primary completion date: April 1, 2026
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Participants must be =18 years of age.
• Participants must be able and willing to provide informed consent or have a surrogate capable of providing same.
• Participants must not require immediate change in SOC treatment, i.e., patients with stable PSA (do not meet PCWG310 criteria for PSA progression), or with rising PSA but they remain on SOC treatment (defined as having met PCWG3 criteria for PSA progression, but do not have clinical/radiographic progression and have not met criteria for an immediate change in therapy based on PSA doubling time) as determined by their primary oncologist
• Participants must be receiving or likely to receive one of the following SOC agents for PC: cabazitaxel, docetaxel (alone or plus abiraterone) olaparib, rucaparib, or talazoparib plus enzalutamide
• Participants who are not receiving one of the above agents must have
• ECOG performance status of 0-2
• Adequate hepatic (SCOT =3x ULN) and renal function (serum creatinine =2.5 or estimated GFR >30 cc/min)
• All participants must have a systolic blood pressure >110 mm Hg during study enrollment assessment and throughout the study
• If participants are concurrently treated for hypertension, they must be able to allow telmisartan in addition to, or replacing their antihypertensive regimen
• Participants must be able to withstand planned research phlebotomies (Hb >10 gm/dl).
• Participants must have a blood prostate specific antigen > 1 ng/ml at study entry using the Roche Cobas immunoassay.
• Participants must be able to take or have taken their own blood pressure per the study protocol (daily during telmisartan escalation and for two weeks after the final escalation and weekly thereafter for the following month and then monthly) if normotensive at enrollment. Exclusion Criteria: Participants who fall into one of the following categories will NOT be eligible for this

study:

• Adults who are unable to provide informed consent.
• Angiotensin l receptor blocker use currently or within the 30 days prior to day 1, cycle 1.
• Patients unwilling or unable to have SOC PC agent(s) added to telmisartan if telmisartan is started per protocol before SOC PC treatment is administered.
• Inadequately treated or uncontrolled hypertension.
• Patients who are incarcerated, homeless, or have active substance drug/alcohol dependence or abuse history.
• Patients who are receiving PC-specific treatment aside from cabazitaxel, docetaxel, olaparib, rucaparib, abiraterone or talazoparib plus enzalutamide or have plans to undergo the same during the study period, except local irradiation therapy to PC lesions.
• Patients on lithium therapy in any form
• Patients who received rituximab or amifostine within 30 days prior to first telmisartan dose on this study
• Patients on ramapril
• Patients on digoxin who do not consent to monthly digoxin blood level testing

Related Conditions & MeSH terms

• Prostate Cancer
• Prostatic Neoplasms

Intervention

Drug:
• Telmisartan
Patients will be given telmisartan alone or with standard of care chemotherapy.

Other:
• Standard of Care Regimen
Standard of Care Regimen

Locations

Country	Name	City	State
United States	Dartmouth Health	Lebanon	New Hampshire

Sponsors (1)

Lead Sponsor	Collaborator
Tyler J Curiel

Country where clinical trial is conducted

United States, 

References & Publications (48)

Asim M, Tarish F, Zecchini HI, Sanjiv K, Gelali E, Massie CE, Baridi A, Warren AY, Zhao W, Ogris C, McDuffus LA, Mascalchi P, Shaw G, Dev H, Wadhwa K, Wijnhoven P, Forment JV, Lyons SR, Lynch AG, O'Neill C, Zecchini VR, Rennie PS, Baniahmad A, Tavare S, M — View Citation

Cernes R, Mashavi M, Zimlichman R. Differential clinical profile of candesartan compared to other angiotensin receptor blockers. Vasc Health Risk Manag. 2011;7:749-59. doi: 10.2147/VHRM.S22591. Epub 2011 Dec 12. — View Citation

Chen K, O'Brien J, McVey A, Jenjitranant P, Kelly BD, Kasivisvanathan V, Lawrentschuk N, Murphy DG, Azad AA. Combination treatment in metastatic prostate cancer: is the bar too high or have we fallen short? Nat Rev Urol. 2023 Feb;20(2):116-123. doi: 10.10 — View Citation

Daniel B, Nagy G, Czimmerer Z, Horvath A, Hammers DW, Cuaranta-Monroy I, Poliska S, Tzerpos P, Kolostyak Z, Hays TT, Patsalos A, Houtman R, Sauer S, Francois-Deleuze J, Rastinejad F, Balint BL, Sweeney HL, Nagy L. The Nuclear Receptor PPARgamma Controls P — View Citation

de Araujo Junior RF, Leitao Oliveira AL, de Melo Silveira RF, de Oliveira Rocha HA, de Franca Cavalcanti P, de Araujo AA. Telmisartan induces apoptosis and regulates Bcl-2 in human renal cancer cells. Exp Biol Med (Maywood). 2015 Jan;240(1):34-44. doi: 10 — View Citation

Fang T, Zhang J, Zuo T, Wu G, Xu Y, Yang Y, Yang J, Shen Q. Chemo-Photothermal Combination Cancer Therapy with ROS Scavenging, Extracellular Matrix Depletion, and Tumor Immune Activation by Telmisartan and Diselenide-Paclitaxel Prodrug Loaded Nanoparticle — View Citation

Fujihara S, Morishita A, Ogawa K, Tadokoro T, Chiyo T, Kato K, Kobara H, Mori H, Iwama H, Masaki T. The angiotensin II type 1 receptor antagonist telmisartan inhibits cell proliferation and tumor growth of esophageal adenocarcinoma via the AMPKalpha/mTOR — View Citation

Fujita N, Fujita K, Iwama H, Kobara H, Fujihara S, Chiyo T, Namima D, Yamana H, Kono T, Takuma K, Hirata M, Kobayashi K, Kato K, Kamada H, Morishita A, Tsutsui K, Himoto T, Okano K, Suzuki Y, Masaki T. Antihypertensive drug telmisartan suppresses the prol — View Citation

Funao K, Matsuyama M, Kawahito Y, Sano H, Chargui J, Touraine JL, Nakatani T, Yoshimura R. Telmisartan is a potent target for prevention and treatment in human prostate cancer. Oncol Rep. 2008 Aug;20(2):295-300. — View Citation

Galle J. Reduction of proteinuria with angiotensin receptor blockers. Nat Clin Pract Cardiovasc Med. 2008 Jul;5 Suppl 1:S36-43. doi: 10.1038/ncpcardio0806. — View Citation

Grahovac J, Srdic-Rajic T, Francisco Santibanez J, Pavlovic M, Cavic M, Radulovic S. Telmisartan induces melanoma cell apoptosis and synergizes with vemurafenib in vitro by altering cell bioenergetics. Cancer Biol Med. 2019 May;16(2):247-263. doi: 10.2089 — View Citation

Green R, Howell M, Khalil R, Nair R, Yan J, Foran E, Katiri S, Banerjee J, Singh M, Bharadwaj S, Mohapatra SS, Mohapatra S. Actinomycin D and Telmisartan Combination Targets Lung Cancer Stem Cells Through the Wnt/Beta Catenin Pathway. Sci Rep. 2019 Dec 3; — View Citation

Hartley A, Ahmad I. The role of PPARgamma in prostate cancer development and progression. Br J Cancer. 2023 Apr;128(6):940-945. doi: 10.1038/s41416-022-02096-8. Epub 2022 Dec 12. — View Citation

Jensterle M, Janez A, Vrtovec B, Meden-Vrtovec H, Pfeifer M, Prezelj J, Kocjan T. Decreased androgen levels and improved menstrual pattern after angiotensin II receptor antagonist telmisartan treatment in four hypertensive patients with polycystic ovary s — View Citation

Khorsand M, Khajeh S, Eslami M, Nezafat N, Ghasemi Y, Razban V, Mostafavi-Pour Z. Telmisartan anti-cancer activities mechanism through targeting N-cadherin by mimicking ADH-1 function. J Cell Mol Med. 2022 Apr;26(8):2392-2403. doi: 10.1111/jcmm.17259. Epu — View Citation

Kobara H, Fujihara S, Iwama H, Matsui T, Fujimori A, Chiyo T, Tingting S, Kobayashi N, Nishiyama N, Yachida T, Tadokoro T, Oura K, Tani J, Fujita K, Nomura T, Yoneyama H, Morishita A, Okano K, Suzuki Y, Mori H, Masaki T. Antihypertensive drug telmisartan — View Citation

Kornepati AVR, Boyd JT, Murray CE, Saifetiarova J, de la Pena Avalos B, Rogers CM, Bai H, Padron AS, Liao Y, Ontiveros C, Svatek RS, Hromas R, Li R, Hu Y, Conejo-Garcia JR, Vadlamudi RK, Zhao W, Dray E, Sung P, Curiel TJ. Tumor Intrinsic PD-L1 Promotes DN — View Citation

Kornepati AVR, Rogers CM, Sung P, Curiel TJ. The complementarity of DDR, nucleic acids and anti-tumour immunity. Nature. 2023 Jul;619(7970):475-486. doi: 10.1038/s41586-023-06069-6. Epub 2023 Jul 19. — View Citation

Koyama N, Nishida Y, Ishii T, Yoshida T, Furukawa Y, Narahara H. Telmisartan induces growth inhibition, DNA double-strand breaks and apoptosis in human endometrial cancer cells. PLoS One. 2014 Mar 25;9(3):e93050. doi: 10.1371/journal.pone.0093050. eCollec — View Citation

LaFargue CJ, Dal Molin GZ, Sood AK, Coleman RL. Exploring and comparing adverse events between PARP inhibitors. Lancet Oncol. 2019 Jan;20(1):e15-e28. doi: 10.1016/S1470-2045(18)30786-1. — View Citation

Mariniello M, Petruzzelli R, Wanderlingh LG, La Montagna R, Carissimo A, Pane F, Amoresano A, Ilyechova EY, Galagudza MM, Catalano F, Crispino R, Puchkova LV, Medina DL, Polishchuk RS. Synthetic Lethality Screening Identifies FDA-Approved Drugs that Overc — View Citation

McAlister FA; Renin Angiotension System Modulator Meta-Analysis Investigators. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are beneficial in normotensive atherosclerotic patients: a collaborative meta-analysis of randomized t — View Citation

Murray C, Bai H, Ontiveros CO, et al. Pharmacologic tumor PDL1 depletion as a novel approach to overcome treatment resistance. The Journal of Immunology. 2023;210(1_Supplement):230.08-230.08. doi:10.4049/jimmunol.210.Supp.230.08

Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm. 2016 Mar;7(2):27-31. doi: 10.4103/0976-0105.177703. — View Citation

Oura K, Tadokoro T, Fujihara S, Morishita A, Chiyo T, Samukawa E, Yamana Y, Fujita K, Sakamoto T, Nomura T, Yoneyama H, Kobara H, Mori H, Iwama H, Okano K, Suzuki Y, Masaki T. Telmisartan inhibits hepatocellular carcinoma cell proliferation in vitro by in — View Citation

Ozeki K, Tanida S, Morimoto C, Inoue Y, Mizoshita T, Tsukamoto H, Shimura T, Kataoka H, Kamiya T, Nishiwaki E, Ishiguro H, Higashiyama S, Joh T. Telmisartan inhibits cell proliferation by blocking nuclear translocation of ProHB-EGF C-terminal fragment in — View Citation

Pu Z, Zhu M, Kong F. Telmisartan prevents proliferation and promotes apoptosis of human ovarian cancer cells through upregulating PPARgamma and downregulating MMP-9 expression. Mol Med Rep. 2016 Jan;13(1):555-9. doi: 10.3892/mmr.2015.4512. Epub 2015 Nov 6 — View Citation

Qaisar R, Kamli H, Karim A, Muhammad T, Ahmad F, Shaikh A. Angiotensin Receptor Blockers Restore Skeletal Muscle in Patients with Chronic Obstructive Pulmonary Disease. Arch Med Res. 2023 Nov;54(7):102890. doi: 10.1016/j.arcmed.2023.102890. Epub 2023 Sep — View Citation

Rasheduzzaman M, Moon JH, Lee JH, Nazim UM, Park SY. Telmisartan generates ROS-dependent upregulation of death receptor 5 to sensitize TRAIL in lung cancer via inhibition of autophagy flux. Int J Biochem Cell Biol. 2018 Sep;102:20-30. doi: 10.1016/j.bioce — View Citation

Rudolph J, Jung K, Luger K. Inhibitors of PARP: Number crunching and structure gazing. Proc Natl Acad Sci U S A. 2022 Mar 15;119(11):e2121979119. doi: 10.1073/pnas.2121979119. Epub 2022 Mar 8. — View Citation

Saad F, Clarke NW, Oya M, Shore N, Procopio G, Guedes JD, Arslan C, Mehra N, Parnis F, Brown E, Schlurmann F, Joung JY, Sugimoto M, Sartor O, Liu YZ, Poehlein C, Barker L, Del Rosario PM, Armstrong AJ. Olaparib plus abiraterone versus placebo plus abirate — View Citation

Samukawa E, Fujihara S, Oura K, Iwama H, Yamana Y, Tadokoro T, Chiyo T, Kobayashi K, Morishita A, Nakahara M, Kobara H, Mori H, Okano K, Suzuki Y, Himoto T, Masaki T. Angiotensin receptor blocker telmisartan inhibits cell proliferation and tumor growth of — View Citation

Sayegh N, Swami U, Agarwal N. Recent Advances in the Management of Metastatic Prostate Cancer. JCO Oncol Pract. 2022 Jan;18(1):45-55. doi: 10.1200/OP.21.00206. Epub 2021 Sep 2. — View Citation

Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K, Antonarakis ES, Beer TM, Carducci MA, Chi KN, Corn PG, de Bono JS, Dreicer R, George DJ, Heath EI, Hussain M, Kelly WK, Liu G, Logothetis C, Nanus D, Stein MN, Rathkopf DE, Slovin SF, Ryan CJ, — View Citation

SEER*Explorer: An interactive website for SEER cancer statistics [Internet]. Surveillance Research Program, National Cancer Institute; 2023 Apr 19. Available from: https://seer.cancer.gov/statistics-network/explorer/. Data source(s): SEER Incidence Data,

Smith MR, Saad F, Rathkopf DE, Mulders PFA, de Bono JS, Small EJ, Shore ND, Fizazi K, Kheoh T, Li J, De Porre P, Todd MB, Yu MK, Ryan CJ. Clinical Outcomes from Androgen Signaling-directed Therapy after Treatment with Abiraterone Acetate and Prednisone in — View Citation

Takahashi S, Uemura H, Seeni A, Tang M, Komiya M, Long N, Ishiguro H, Kubota Y, Shirai T. Therapeutic targeting of angiotensin II receptor type 1 to regulate androgen receptor in prostate cancer. Prostate. 2012 Oct 1;72(14):1559-72. doi: 10.1002/pros.2250 — View Citation

Tascilar K, Azoulay L, Dell'Aniello S, Bartels DB, Suissa S. The Use of Telmisartan and the Incidence of Cancer. Am J Hypertens. 2016 Dec 1;29(12):1358-1365. doi: 10.1093/ajh/hpw095. — View Citation

Torika N, Asraf K, Danon A, Apte RN, Fleisher-Berkovich S. Telmisartan Modulates Glial Activation: In Vitro and In Vivo Studies. PLoS One. 2016 May 17;11(5):e0155823. doi: 10.1371/journal.pone.0155823. eCollection 2016. — View Citation

Uemura H, Hasumi H, Kawahara T, Sugiura S, Miyoshi Y, Nakaigawa N, Teranishi J, Noguchi K, Ishiguro H, Kubota Y. Pilot study of angiotensin II receptor blocker in advanced hormone-refractory prostate cancer. Int J Clin Oncol. 2005 Dec;10(6):405-10. doi: 1 — View Citation

Uemura H, Ishiguro H, Nakaigawa N, Nagashima Y, Miyoshi Y, Fujinami K, Sakaguchi A, Kubota Y. Angiotensin II receptor blocker shows antiproliferative activity in prostate cancer cells: a possibility of tyrosine kinase inhibitor of growth factor. Mol Cance — View Citation

Uemura H, Kubota Y. [Application of angiotensin II receptor blocker in prostate cancer]. Nihon Rinsho. 2009 Apr;67(4):807-11. Japanese. — View Citation

Uemura H, Miyoshi Y, Ishiguro H, Nakaigawa N, Noguchi K, Kubota Y. Effectiveness of angionten II receptor blocker (ARB), candesartan, in the treatment of hormone refractory prostate cancer (HRPC). presented at: 2004 ASCO Annual Meeting; 2004

Wang C, Wang WB. Telmisartan Induces Osteosarcoma Cells Growth Inhibition and Apoptosis Via Suppressing mTOR Pathway. Open Life Sci. 2018 Jul 5;13:242-249. doi: 10.1515/biol-2018-0029. eCollection 2018 Jan. — View Citation

Washida K, Ihara M, Nishio K, Fujita Y, Maki T, Yamada M, Takahashi J, Wu X, Kihara T, Ito H, Tomimoto H, Takahashi R. Nonhypotensive dose of telmisartan attenuates cognitive impairment partially due to peroxisome proliferator-activated receptor-gamma act — View Citation

Wilk M, Wasko-Grabowska A, Skoneczna I, Szmit S. Angiotensin System Inhibitors May Improve Outcomes of Patients With Castration-Resistant Prostate Cancer During Abiraterone Acetate Treatment-A Cardio-Oncology Study. Front Oncol. 2021 Apr 1;11:664741. doi: — View Citation

Wu TT, Niu HS, Chen LJ, Cheng JT, Tong YC. Increase of human prostate cancer cell (DU145) apoptosis by telmisartan through PPAR-delta pathway. Eur J Pharmacol. 2016 Mar 15;775:35-42. doi: 10.1016/j.ejphar.2016.02.017. Epub 2016 Feb 4. — View Citation

Zhu Y, Yu F, Tan Y, Hong Y, Meng T, Liu Y, Dai S, Qiu G, Yuan H, Hu F. Reversing activity of cancer associated fibroblast for staged glycolipid micelles against internal breast tumor cells. Theranostics. 2019 Sep 19;9(23):6764-6779. doi: 10.7150/thno.3633 — View Citation

* Note: There are 48 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Reduction of blood prostate specific antigen	This exploratory objective is to determine whether telmisartan when given alone or combined with selected standard of care therapies can reduce blood prostate specific antigen or slow its rise in selected patients with prostate cancer as determined by Roche Cobas immunoassay in ng/mL blood	24 months
Primary	Tolerability of oral telmisartan	Ability of the participant to tolerate telmisartan alone or with standard of care agents as defined by maintaining a systolic blood pressure >110mmHG and are without greater than grade 2 toxicities	12 months
Secondary	Increase in tumor DNA damage	Determine if telmisartan increases tumor DNA damage or alters immunity in ways consistent with anti-tumor activity when given alone or with selected standard of care treatments in selected patients with prostate cancer as determined by counting gamma-H2AX foci in tissue sections and peripheral blood mononuclear cells	24 months