To determine the tolerability, pharmacokinetics and pharmacodynamics of liposomal dexamethasone (Oncocort*) in patients with metastatic prostate cancer.
ID
Source
Brief title
Condition
- Reproductive neoplasms male malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety and tolerability
Assessed using adverse event reporting, standard clinical measures (vital
signs, ECG), routine laboratory assessments and activation of complement during
infusion.
Pharmacokinetic endpoints
Extensive PK sampling will be performed in each of the 10 patients after the
first dose of 10 mg and after the first dose of 20 mg. Optionally, additional
PK sampling will be performed, guided by PK data obtained in part I.
A validated bioanalytical assay will be used to determine the concentrations of
liposomal and free dexamethasone in plasma after Oncocort administration. The
following pharmacokinetic variables will be calculated, if possible:
- Area under the plasma concentration-time curve (AUC) from time 0 to the time
of the last quantifiable concentration (AUC0-t) and from time 0 extrapolated to
infinity (AUC0-inf);
- Maximal observed plasma drug concentration (Cmax);
- Time to maximum observed plasma drug concentration (tmax);
- Half-life (t *);
- Volume of distribution (Vd);
- Clearance.
Pharmacodynamic effect endpoints
- PSA;
- Bone marker: alkaline phosphatase;
- Cortisole;
- Sex steroids (testosterone, estradiol, FSH, LH and SHBG);
- Fasting blood glucose;
- Lymphocyte count;
- Activation of complement; AP and CP
- Comprehensiveness of bone metastases, as assessed in Scintigraphy/CT/MRI;
Secondary outcome
N/A
Background summary
Glucocorticoids are steroid hormones with anti-inflammatory and
immunosuppressive activities. For over 30 years corticosteroids have been used
in the management of castration resistant prostate cancer (CRPC). Initially,
single agent prednisone 7.5*10 mg daily was used in the management of
metastatic CRPC patients (mCRPC) and subsequent studies showed clinical benefit
in these patients. In phase 3 trials the response rate of prostate-specific
antigen (PSA) to prednisolone ranged from 9% to 33%, and the median time to PSA
progression has ranged from 2 to 6.6 months.
Until recently, dexamethasone has been less well studied in the treatment of
CRPC. Phase 2 studies of low-dose, daily dexamethasone have reported somewhat
higher PSA response rates (50*60%), with median time to PSA progression of 7-8
months. The two largest studies, including a combined total of 237 patients
treated with dexamethasone as a single agent, reported PSA response rates
around 50%. In a recently reported trial, the group of Parker and De Bono
reported a single-center randomised phase 2 trial comparing dexamethasone and
prednisolone to explore the hypothesis that dexamethasone may be more active
than prednisolone in the treatment of CRPC. Intention to treat analysis showed
a confirmed PSA response in 41% of the patients for daily dexamethasone
treatment versus 22% for daily prednisolone (p=0.08). In evaluable patients,
the PSA response rates were 47% versus 24% for dexamethasone and prednisolone,
respectively (p=0.05). Median time to PSA progression was 9.7 months on
dexamethasone versus 5.1 months on prednisolone (hazard ratio: 1.6; 95%
confidence interval, 0.9-2.8). In 43 patients with measurable disease, the
response rate by RECIST was 15% and 6% for dexamethasone and prednisolone,
respectively (p=0.6). Of 23 patients who crossed over at PSA progression on
prednisolone, 7 of the 19 evaluable (37%) had a confirmed PSA response to
dexamethasone. Clinically significant toxicities were rare. These data suggest
that dexamethasone is more effective with a similar side-effect profile and may
be the most efficacious corticosteroid monotherapy in CRPC patients. The higher
antitumor activity for dexamethasone supports its use in the clinic in mCRPC
patients and daily doses of 0.5 mg dexamethasone are regarded as standard for
CRPC patients who require corticosteroid monotherapy.
The explanation for the superior activity of dexamethasone remains uncertain.
However, it is plausible that differential anti-inflammatory activity and/or
superior suppression of tumour-associated macrophages play a role. The
inflammatory tumour microenvironment, and more specifically the
tumour-associated macrophages, plays an essential role in the development and
progression of prostate cancer towards metastatic bone disease. This may be
further exploited by using liposomal formulations that utilize the so-called
enhanced permeability and retention (EPR)-effect. Tumours are often
characterized by a leaky vasculature, which - combined with the prolonged
circulation time of liposomes - leads to efficient tumour localization of these
drug carriers, via the so-called enhanced permeability and retention
(EPR)-effect. Over the last few decades, tumour-targeted liposomal drug
delivery has become an emerging therapeutic strategy. For specifically designed
long-circulating liposomes it has been shown that intravenous administration
results in accumulation in tumour tissue due to the EPR-effect.
The anti-cancer activity and utility of liposomal encapsulated dexamethasone
versus free dexamethasone was studied in a preclinical model of human prostate
cancer metastatic to the bone. Intravenously administered liposomes were shown
to localize efficiently to bone metastases in vivo and treatment of established
bone metastases with (liposomal) dexamethasone resulted in a significant
inhibition of tumour growth up to 26 days after initiation of treatment.
Furthermore, 1.0*mg/kg liposomal dexamethasone significantly outperformed 1.0*
mg/kg free dexamethasone, and was found to be well-tolerated at
clinically-relevant dosages that display potent anti-tumour efficacy. Liposomal
delivery of the dexamethasone inhibits the growth of malignant bone lesions and
offers a promising new treatment option for advanced, metastatic prostate
cancer which supports further clinical evaluation.
Study objective
To determine the tolerability, pharmacokinetics and pharmacodynamics of
liposomal dexamethasone (Oncocort*) in patients with metastatic prostate
cancer.
Study design
This exploratory, non-comperative, monocentre, open label, prospective stage
I-IIa, dose escalating study of intravenous pegylated liposomal dexamethasone
sodium phosphate (Oncocort*) monotherapy in patients with metastatic prostate
cancer with the objective to assess safety, tolerability, pharmacokinetics, and
pharmacodynamics after short-term treatment with repeated infusions.
We aim to treat ten mCRPC patients with bone metastases with a single dose of
10mg and 5 doses of liposomal Dexamethasone 20 mg (approximately equivalent to
therapeutic dose of 0.5 mg oral dexamethasone daily), administered in
two-weekly invervals.
Intervention
Oncocort*
Study burden and risks
The risks associated with the administration of Oncocort to humans have not yet
been identified, because this compound has not yet been studied in humans. On
the basis of data collected from preclinical investigations, the main target
organ toxicity of Oncocort is considered to be related to the thyroid. Humans
are much less sensitive to changes in thyroid hormones because their higher
levels of thyroxine-binding proteins lead to slower hormone metabolism. As a
safety measure thyroid hormones will be monitored in this study.
St. Annastraat 38a
Naarden 1411PH
NL
St. Annastraat 38a
Naarden 1411PH
NL
Listed location countries
Age
Inclusion criteria
1. Adult patients with mCRPC and one or more metastases in the bone, confirmed by bone scintigraphy, MRI or CT-scan within 6 weeks before first dosage;
2. Able to participate, and willing to give written informed consent and to comply with the study restrictions;
3. Body mass index (BMI) of 18 kg/m2 or higher (inclusive) and a minimum weight of 50 kg;
4. Not yet, or no longer being eligable for other, registered therapy other than corticosteroids.
5. Live expectancy in good clinical condition (WHO 0-1) and live expectancy of more than 3 months.
Exclusion criteria
1. Concomitant disease or condition that could interfere with, or for which the treatment might interfere with, the conduct of the study, or that would, in the opinion of the investigator, pose an unacceptable risk to the subject in this study.
2. Contraindication for glucocorticoids as judged by investigator
3. Use of systemic glucocorticosteroids within 4 weeks before first dosage, with exception of topical and inhalation steroids.
4. Any confirmed and clinically significant allergic reactions (urticaria or anaphylaxis; non-active hay fever is acceptable). Allergy or hypersensitivity against any drug, including any component of the study drug, biologic therapy or IV radiocontrast agent.
5. Clinically significant abnormalities, as judged by the investigator, following a detailed medical history, a physical examination including vital signs, 12-lead ECG and laboratory test results (including hepatic and renal panels, complete blood count, chemistry panel and urinalysis). In the case of uncertain or questionable results, tests performed during screening may be repeated before randomization to confirm eligibility or judged to be clinically irrelevant.
6. History or symptoms of any significant disease including (but not limited to), neurological, psychiatric, endocrine, cardiovascular, respiratory, gastrointestinal, hepatic, or renal disorder that may aggravate due to study participation and jeopardize the health status of the patient.
7. Any infection within 1 month prior to the anticipated dosing day.
8. Positive Hepatitis B surface antigen (HBsAg), Hepatitis C antibody (HCV Ab), or human immunodeficiency virus antibody (HIV Ab) at screening.
9. History of alcohol or substance abuse
10. Use of CYP3A4-inhibiting drugs or food (grapefruit, grapefruit juice, grapefruit-containing products, Seville oranges, or pomelo-containing products, and quinine containing drinks within 11 days prior to day of dosing.
11. Participation in an investigational drug or device study within 3 months prior to screening.
12. Donation of blood over 500 mL within three months prior to screening.
13. Vaccination within 6 weeks prior to start of treatment or planned vaccination up to 90 days after the final dose.
14. Unwillingness or inability to comply with the study protocol for any other reason.
15. Expected fulminant progression of disease
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-003121-42-NL |
| CCMO | NL58731.056.16 |