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A Double-Blind, Randomised, Placebo-Controlled Study of the Effect of Transdermal Nitroglycerin (Glyceryl Trinitrate; GTN) Therapy on Biomarkers of Immune Escape in Men With Biochemical Recurrence of Prostate Cancer After Primary Therapy

Phase 3
18 Years
90 Years
Open (Enrolling)
Prostate Cancer

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Trial Information

A Double-Blind, Randomised, Placebo-Controlled Study of the Effect of Transdermal Nitroglycerin (Glyceryl Trinitrate; GTN) Therapy on Biomarkers of Immune Escape in Men With Biochemical Recurrence of Prostate Cancer After Primary Therapy

Researcher's pre-clinical research has demonstrated that hypoxia-induced tumor cell
invasiveness, metastatic ability, resistance to chemotherapeutic agents and evasion of
immune cell recognition are inhibited by molecules that activate the NO signalling pathway
involving cGMP generation (such as glyceryl trinitrate, GTN), and that pharmacological
inhibition of NO signalling results in phenotypes similar to those induced by exposure to

Based on pre-clinical data described above the researchers have recently completed and
published a phase 2 trial in patients with recurrent prostate cancer using a low-dose,
sustained release trasndermal patch of GTN. The GTN was supplied as Minitran™
(nitroglycerin) transdermal delivery system (3M Company, St. Paul, Minnesota) in an open
label, non-blinded fashion. GTN is a nitrodonor that has been used in the management of
angina for over 100 years with a well-documented safety and tolerability record and has
never been associated with carcinogenesis. Their pre-clinical studies have demonstrated
that very low molar concentrations of nitric oxide donors are required to attenuate
hypoxia-induced malignant phenotypes.

Our results suggest a significant inhibition of progressive disease given the effect on PSA
doubling time with GTN treatment compared to their doubling time prior to initiating the
trial. Within 12 months of the trial, 17 of 24 patients had doubling times in the slow
category or even stable/declining PSA levels. The mean doubling time of the entire cohort
increased to 31.8 months from 13.2 months prior to starting treatment. When compared to a
matched control group of patients with PSA recurrence that did not receive any treatment, a
similar significant difference in PSA doubling time was observed. There were no adverse
effects reported in this trial.

This was the first report of the clinical use of nitric oxide donors in the treatment of
prostate cancer. The role of nitric oxide in malignant progression has been a subject of
controversy, with studies showing either tumor-promoting or tumor-inhibitory roles. These
apparently contradictory effects of NO may be explained by the fact that this molecule can
regulate phenotypes through a variety of mechanisms depending on local concentrations and
the redox state of the cell. Based on our previous findings, the investigators propose that
the observed effect of GTN on the PSA of this patient cohort is related to the 'low
concentration' effects of NO.

The investigators have identified several possible beneficial mechanisms of effect of
low-dose NO donors for cancer management. We have recently published the positive effect of
effect of NO signalling (with GTN as the effector molecule) on cancer immune surveillance.
The major histocompatibility complex class I chain-related (MIC) molecules, MICA and MICB,
play important roles in tumor surveillance by NK cells, lymphokine-activated killer (LAK)
cells, and cytotoxic T cells. While MICA is absent from most normal tissues, they can be
induced by cellular stresses, such as exposure to carcinogens and infection, and are
expressed in a broad range of carcinomas and some haematopoietic malignancies. In humans,
the interaction of cell surface MIC molecules with the C-type lectin-like NKG2D receptor on
NK, LAK and effector T cells leads to the activation of innate and adaptive immune responses
with the subsequent lysis of the tumor cells. Thus, it has been proposed that MIC-NKG2D
interactions are critical to the immune surveillance function of NK, LAK and cytotoxic T

The investigators have shown that hypoxia contributes to tumor cell shedding of MIC through
a mechanism involving impaired nitric oxide (NO) signalling. While hypoxia increased MIC
shedding in human prostate cancer cells, activation of NO signalling inhibited
hypoxia-mediated MIC shedding. Similar to incubation in hypoxia, pharmacological inhibition
of endogenous NO signalling increased MIC shedding. These findings suggest that the hypoxic
tumor microenvironment contributes to impaired immune surveillance and that activation of NO
signalling is of potential use in cancer immunotherapy.

Based on previous studies it is investigator's hypothesis that low-dose transdermal GTN
will have positive effects on cancer immune surveillance that may translate to therapeutic
benefit. In order to establish proof-of-concept, they propose to initiate the correlative
study described in this protocol, to determine the effect of the GTN treatment on biomarkers
of immune activity in patients with prostate cancer.

Inclusion Criteria:

- Males;

- Legal age of consent (18 years of age);

- Histological evidence of adenocarcinoma of the prostate;

- Patients have chosen watchful waiting or active surveillance as preferred management;

- Patients have biochemical failure (defined below) after primary cancer treatment and
prefer deferred cancer management:

- Patients with an increasing PSA at least 3 months after surgery (at least two
values above PSA 0.2 ng/mL);

- Patients with a PSA 2 ng/ml above their nadir PSA after radiation therapy.

Exclusion Criteria:

- Inability to provide an informed consent;

- Inability to adhere to the study protocol for any reason;

- Receiving any other adjuvant therapies for prostate cancer less than 6 months prior
to study entry;

- Any contraindication to GTN (including concomitant use of nitroglycerin formulations
or phosphodiesterase inhibitors).

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Basic Science

Outcome Measure:

Change in the following biomarkers: inflammatory/immune markers uPAR, PAI-1, ULBP2, B7-H1, MIF, TGF-β; and PSA compared to placebo.

Outcome Description:

All assessments are as per standard of care. The only additional intervention is a 5 mL peripheral vein phlebotomy at each visit. Patients will be followed at 3, 6, 9 and 12 months after initiation of the trial. Clinic visits will assess side effects of drug and include routine follow-up for prostate cancer management. Serum samples for the above-described makers of immune activity will be obtained at the month 3, 6, 9 and 12 visit.

Outcome Time Frame:

12 months

Safety Issue:


Principal Investigator

D. Robert Siemens, MD FRCSC

Investigator Role:

Principal Investigator

Investigator Affiliation:

Queen's University


Canada: Health Canada

Study ID:

Protocol # CAUR 09



Start Date:

April 2012

Completion Date:

December 2013

Related Keywords:

  • Prostate Cancer
  • biochemical
  • recurrence
  • prostate
  • cancer
  • active
  • surveillence
  • Prostatic Neoplasms
  • Recurrence