Primary:• To evaluate the ability of relugolix to achieve and maintain serum testosterone suppression to castrate levels (
ID
Source
Brief title
Condition
- Reproductive neoplasms male malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Sustained castration rate defined as the cumulative probability of testosterone
suppression to <= 50 ng/dL (1.7 nmol/L) while on study treatment from Week 5 Day
1 (Study Day 29) through Week 49 Day 1 (Study Day 337).
Secondary outcome
Secondary Endpoints
• Describe effects on serum testosterone:
o Castration rate defined as the cumulative probability of testosterone
suppression to <= 50 ng/dL (1.7 nmol/L) prior to dosing on Week 1 Day 4 and
prior to dosing on Week 3 Day 1;
o Profound castration rate defined as the cumulative probability of
testosterone suppression to <= 20 ng/dL (0.7 nmol/L) while on study treatment
from Week 25 Day 1 through Week 49 Day 1;
o Time to testosterone recovery in approximately100 patients randomized to
relugolix and approximately 50 patients randomized to leuprolide acetate who
complete 48 weeks of treatment and who do not plan to start alternative
androgen deprivation therapy within the following 12 weeks (or within 24 weeks
following the last injection of leuprolide acetate 3-M depot);
• Describe effects on PSA:
o Proportion of patients with confirmed PSA response by Prostate Cancer
Clinical Trials Working Group 3 guidelines at the Week 5 visits [Scher, 2016];
o Proportion of patients with PSA concentration < 0.2 ng/mL (0.2 µg/L) at the
Week 25 visit;
• Absolute values and changes from baseline in the scores of the EORTC-QLQ-C30
global health domain, and the EORTC-QLQ-PR25 sexual activity and
hormonal-treatment-related symptom subdomains, at regular intervals during
treatment, and as applicable during the Follow-up and/or at End of Treatment
visits;
• Absolute values and changes from baseline of the remaining domains in the
EORTC QLQ-C30 and EORTC QLQ-PR25, as well as the EuroQol EQ-5D-5L
questionnaire, at regular intervals during treatment, and as applicable during
the Follow-up visits;
• Incidence of adverse events;
• Incidence of abnormalities in clinical laboratory data;
• Endocrine marker effects of relugolix and leuprolide acetate as measured as
absolute value and change from baseline for:
o LH at the Day 4, Week 5, Week 25 and Week 49 visits;
o FSH at the Day 4, Week 5, Week 25 and Week 49 visits;
o Dihydrotestosterone at the Week 5, Week 25 and Week 49 visits; and
o Sex hormone binding globulin at the Week 5, Week 25, and Week 49 visits;
• Predose relugolix plasma concentrations;
• Single and repeat-dose plasma relugolix PK parameters such as maximum plasma
concentration (Cmax), area under the concentration-time curve from time 0 to
the end of the dosing interval (AUC0-*), and time to maximum plasma
concentration (tmax) in a subset of patients from China (if enrolled) and Japan
during the Day 1 visit.
• Time to PSA progression;
• Proportion of patients with confirmed PSA progression among those who have
achieved sustained testosterone suppression during the 48-week treatment
Exploratory Endpoints
• Overall survival defined as time from randomization to date of death prior to
data cutoff date; and
• The presence of polymorphisms in germline genes related to the
hypothalamic-pituitary-androgen pathway, prostate cancer risk, or to drug
metabolizing enzymes and transporter proteins that might be implicated in the
drug disposition, safety, or efficacy of relugolix. These will be evaluated in
a subset of patients.
Background summary
Prostate cancer is the most prevalent form of cancer in men and the second
leading cause of death due to cancer in men in the US and Europe. The median
age of diagnosis is 70 years, and diagnosis before the age of 40 years is
rare. In Japanese men, prostate cancer was the fourth leading cancer diagnosis
in 2007. The incidence of invasive prostate cancer increases with age; a clear
increase is seen among men aged 60 years or older.
If prostate cancer is diagnosed at a stage where it is confined to the prostate
gland and immediate surroundings, it is generally treated by surgical removal
of the prostate gland, or prostatectomy, or with radiation. Often, these
procedures are successful in curing men of their disease. Men whose disease
progresses after prostatectomy or radiation are said to have advanced prostate
cancer. Advanced prostate cancer is defined as either: PSA biochemical
relapse following primary surgical or radiation therapy of curative intent;
newly diagnosed metastatic prostate cancer; or advanced localized disease for
which immediate radiation or surgical therapy is not indicated. The cure rate
following surgery, depending on the stage of the cancer, is about 70% overall
and, following radiation, about 50% to 60%.
Approximately 25% to 30% of men will, therefore, progress to advanced disease,
excluding those with metastatic disease at the time of diagnosis. Androgens,
such as testosterone and its more potent metabolite dihydrotestosterone, are
strong tumor promoters for prostate cancer. Through the androgen receptor,
they synergistically augment the effect of other tumor promoters or
carcinogens. Although prostate cancer is driven by presumed mutations in other
tumor promoting pathways and/or by translocations leading to aberrant
activation of the androgen receptor pathway, most early-stage prostate cancer
cells remain either sensitive to or dependent upon circulating androgens.
Thus, for more than 60 years, androgen deprivation therapy with surgical or
medical castration has been the foundational therapy for either advanced
inoperable or metastatic cancer. Increasingly, androgen deprivation therapy is
used earlier as a neoadjuvant/adjuvant treatment to radiation therapy or for
biochemical or clinical relapse after local therapies of curative or palliative
intent. More than 80% of men with progressive or advanced disease initially
respond to androgen deprivation therapy with varying degrees of tumor
regression or stabilization. The duration and depth of response to androgen
deprivation therapy is presumably dependent on the underlying tumor biology and
burden. Thus, patients with metastases respond for an average of 2 years
before any biochemical evidence of castration resistance occurs. By contrast,
patients with biochemical-only evidence of progressive disease may respond to
androgen deprivation therapy for 5 years or more.
Currently, most patients in developed countries receive medical rather than
surgical castration. GnRH (or LH-releasing hormone) agonists (ie, long-acting
leuprolide acetate depot injections) are the current mainstay of medical
castration, causing long-term desensitization and down regulation of the
hypothalamic-pituitary gonadal axis. One disadvantage of the agonist form of
GnRH is the initial stimulation of the axis lasting 1 to 3 weeks that occurs
prior to desensitization. This results in a rise in LH and testosterone levels
and an increase in clinical symptoms. In addition, at the time of repeat
injection of GnRH agonist depot, microsurges of LH and testosterone may occur,
although the apparent incidence is low. The initial flare response may be
managed with simultaneous antiandrogen administration, such as with
bicalutamide.
Recently, GnRH antagonists, in particular degarelix, have become available as
an alternative form of medical castration. Degarelix, an injectable peptide,
has been approved in some countries for the treatment of patients with advanced
prostate cancer. As a GnRH antagonist, degarelix achieves medical castration
and PSA response with no initial agonist activity within the first 1 to 2 weeks
of administration, and effectively can obviate the need for concomitant
antiandrogen treatment. Post-hoc analyses of degarelix trials suggest that it
may have additional advantages regarding disease response or secondary relapse;
however, such differences require confirmation in prospective studies. Because
of the need for monthly depot injections, with large volumes and accompanying
local reactions, the use of degarelix in clinical practice has remained low.
Relugolix, previously known as TAK-385, is a potent and highly selective oral
small molecule antagonist for the human GnRH receptor. For patients, relugolix
may offer the advantages conferred by a direct receptor antagonist, including a
more rapid onset of action and the absence of clinical flare or worsening of
symptoms from the initial rise in androgens caused by GnRH agonists, as well as
having the added convenience and relative comfort of oral dosing.
Study objective
Primary:
• To evaluate the ability of relugolix to achieve and maintain serum
testosterone suppression to castrate levels (<= 50 ng/dL [1.7 nmol/L]) in men
with androgen-sensitive advanced prostate cancer.
Secondary:
• To evaluate the time course and change in serum testosterone during treatment
with relugolix;
• To evaluate the time course and magnitude of prostate-specific antigen (PSA)
reduction during treatment with relugolix;
• To evaluate testosterone recovery following discontinuation of relugolix;
• To evaluate quality of life using validated patient-reported outcome
instruments;
• To evaluate the safety of relugolix 120 mg once daily in men with
androgen-sensitive advanced prostate cancer;
• To evaluate the effect of relugolix and leuprolide acetate on endocrine
pharmacodynamic parameters;
• To collect relugolix plasma concentration data to further evaluate relugolix
population pharmacokinetics (PK) and the relationship between relugolix
exposure and serum testosterone; and
• To characterize the relugolix plasma PK parameters in a subset of patients
from China (if enrolled) and Japan: and
• To describe the time course and magnitude of PSA progression and development
of castration resistant prostate cancer during treatment with relugolix.
Exploratory:
• To explore the overall survival of patients treated with relugolix; and
• To explore the contribution of genetic variance on drug response.
Study design
The HERO study is a phase 3 multinational randomized, open-label,
parallel-group study to evaluate the safety and efficacy of relugolix in
patients with androgen-sensitive advanced prostate cancer who require at least
1 year of continuous androgen deprivation therapy. Relugolix is an oral
gonadotropin-releasing hormone (GnRH) receptor antagonist that lowers
testosterone by inhibiting pituitary release of follicle-stimulating hormone
(FSH) and luteinizing hormone (LH). Relugolix 120 mg orally once daily or
leuprolide acetate depot suspension, 22.5 mg (or 11.25 mg in Japan, Taiwan, and
China), every 3-months (3-M) by subcutaneous or intramuscular injection will be
administered to patients with prostate cancer who require androgen deprivation
therapy. This study will evaluate the ability of relugolix to achieve and
maintain serum testosterone suppression to castrate levels (<= 50 ng/dL [1.7
nmol/L]) for 48 weeks in patients with androgen-sensitive advanced prostate
cancer.
To be eligible for the study, a patient must be, in the opinion of the
investigator, a candidate for at least 1 year of continuous androgen
deprivation therapy for the management of androgen-sensitive advanced prostate
cancer and must not be a candidate for surgical therapy. Eligible patients
include those with evidence of biochemical relapse (rising PSA) following local
primary intervention with curative intent, newly diagnosed metastatic disease
(excluding metastases to the brain), and/or advanced localized disease.
Patients may receive radiotherapy, cryotherapy or high frequency ultrasound no
sooner than 2 months after initiation of androgen deprivation therapy.
Patients may be included if they have not previously received androgen
deprivation therapy for more than 18 months, and if the androgen deprivation
therapy was completed at least 3 months prior to the baseline visit. If the
dosing interval of the depot is longer than 3 months, then the prior androgen
deprivation therapy must have been completed at least as long as the dosing
interval of the depot. Patients previously treated with taxanes or expected to
receive taxanes after initiation of androgen deprivation therapy are excluded,
as are patients receiving androgen deprivation therapy adjuvant or neoadjuvant
to radiotherapy as primary definitive therapy. Baseline serum testosterone
must be >= 150 ng/dL (1.50 ng/mL or 5.2 nmol/L) to be enrolled.
Patients enrolled in this study will be randomized 2:1 to receive oral
relugolix 120 mg once daily following a loading dose of 360 mg on Day 1 or 3-M
depot of leuprolide acetate 22.5 mg (or 11.25 mg in Japan, Taiwan and China)
After randomization, patients on the leuprolide acetate arm may receive an
antiandrogen for the first 4 weeks or longer if indicated in the opinion of the
investigator. Randomization will be stratified by geographic region, presence
of metastatic disease, and age.
Approximately 915 patients will be enrolled in this study from approximately
200 study centers in North and South America, Europe, and the Asia-Pacific
region. The study includes a Screening Period of up to 28 days, a Treatment
Period of 48 weeks, and a Follow-up Period of up to 90 days. Additionally,
unscheduled follow-up visit(s) may be arranged for patients with study-related
safety concerns as needed. Eligible patients will receive study treatment for
48 weeks. During that time, testosterone and PSA will be assessed monthly and
patient-reported outcomes (European Organisation of Research and Treatment of
Cancer [EORTC] QLQ-C30, European Quality of Life 5-Dimesion 5-Level
questionnaire [EuroQol EQ-5D-5L]) will be assessed approximately every 3 months
during the Treatment Period and more frequently during the Follow-up Period.
Additional serum endocrine evaluations will include: LH, FSH,
dihydrotestosterone, and sex hormone binding globulin. Relugolix PK samples
will be collected throughout the study. Full PK profiles will be determined in
a subset of patients in China (if enrolled) and Japan. Safety assessments will
include treatment-emergent adverse events, vital signs, physical examinations,
clinical laboratory tests, 12-lead electrocardiograms (ECG), and visual acuity
tests.
Patients with disease progression during the treatment period, in the setting
of testosterone suppression to castrate levels (testosterone level <= 50 ng/dL
[1.7 nmol/L]), should remain on study and may receive additional oral therapy,
systemic antineoplastic, and/or radiotherapy as prescribed by the investigator.
In the setting of rising PSA patients may also receive enzalutamide. For
patients requiring other systemic antineoplastic therapy during the treatment
period, the investigator should contact the medical monitor.
Intervention
Test Product
Relugolix 120 mg tablet strength will be available as immediate-release
film-coated tablets, and 1 tablet (120 mg) will be administered once daily
following an oral loading dose of 360 mg (three 120-mg tablets) on Day 1.
These tablets will be presented in 45-tablet bottles and dispensed to patients
every 4 weeks at scheduled study visits.
All protocol-specific inclusion criteria and none of the exclusion criteria
must be met and documented prior to study drug administration. Study drug will
be dispensed only to eligible patients who are under the supervision of the
investigator or identified subinvestigator(s).
Reference Product
Leuprolide acetate, 22.5 mg (or 11.25 mg in some Asian countries), 3 M depot
subcutaneous or intramuscular injection will be administered per the approved
dose and method of dosing in the region where the patient is enrolled.
Leuprolide acetate 3-M depot injection will be administered on Day 1 (with an
antiandrogen of choice, if indicated according to the investigator, for the
first 4 weeks or longer), then at 12-week intervals thereafter for 48 weeks.
Preparation of the depot injection should follow the instructions provided by
the manufacturer.
Study burden and risks
The following risks and possible side effects happened in 5% or more of men
with prostate cancer treated with relugolix.
• Hot flush (59%)
• Feeling tired (26%)
• Cataract (17%; note: eye doctors did special eye checks during these studies)
• Diarrhea (10%)
• Joint pain (10%)
• Infection or inflammation of the nose and throat (7%)
• Constipation (7%)
• Liver test increase [abnormal] (6%)
• Frequent urination (6%)
• Urination during the night (5%)
• Headache (6%)
• Dizziness (6%)
• Back pain (5%)
• Increase in weight 5%)
• Infection or inflammation of the sinuses (5%)
• Nausea (5%)
• Pain in arms or legs (5%)
• Sharpness of vision decreased (5%)
• Urine infection (5%)
• Increase in male breast tissue (2.9%); included because it is a known side
effect though <5%
• Night sweats (2.3%); included because it is a known side effect though <5%
The following side effects have been reported in patients taking leuprolide
acetate:
Very common side effects (may affect more than 1 in 10 people)
• Hot flashes
• Spontaneous bleeding in skin or mucous membrane, redness of the skin
• Fatigue, injection-related side effects (see also local side effects above)
Common side effects (may affect up to 1 in 10 people)
• Nasopharyngitis (symptoms of common cold)
• Nausea, malaise, diarrhoea, inflammation of the stomach and intestines
(gastroenteritis/ colitis)
• Itching, nightly sweating
• Pain in the joints,
• Irregular trips to the toilet to pass water (also at night), difficulty in
starting to pass water, painful urination, reduced urine output
• Breast tenderness, swelling of the breast, shrinking of testicles, testicular
pain, infertility, erectile dysfunction, reduced penis size
• Rigors (episodes of exaggerated shaking with high fevers), weakness
• Prolonged bleeding time, changes in blood values, decreased red blood
cells/low red blood cell count
Uncommon side effects (may affect up to 1 in 100 people)
• Urinary tract infection, local skin infection
• Worsening of diabetes mellitus
• Abnormal dreams, depression, decreased libido
• Dizziness, headache, an alteration in the skin sensation, insomnia, taste
disturbance, smell disturbance
• Hypertension (increased blood pressure), hypotension (decreased blood
pressure)
• Shortness of breath
• Constipation, dry mouth, Dyspepsia (disturbed digestion, with symptoms as
full stomach, pain in the stomach, belching, nausea, vomiting, burning feeling
in the stomach), vomiting
• Clamminess, increased sweating
• Back pain, muscles cramps
• HamaturiaHematuria (blood in the urine)
• Bladder spasm, more trips to the toilet to pass water than usual, unable to
pass water
• Enlargement of male breast tissue, impotence
• Lethargy (sleepiness), pain, fever
• Increased weight
• Loss of balance, light-headedness
• Muscle wasting/loss of muscle tissue after prolonged use
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US
Listed location countries
Age
Inclusion criteria
1. Has voluntarily signed and dated the informed consent form prior to
initiation of any screening or study-specific procedures;
2. Is a male aged 18 years or older on the day of signing and dating the
informed consent form;
3. Has histologically or cytologically confirmed diagnosis of
adenocarcinoma of the prostate;
4. Is a candidate for, in the opinion of the investigator, at least 1 year of
continuous androgen deprivation therapy for the management of
androgen-sensitive advanced prostate cancer with one of the following
clinical disease state presentations:
a. Evidence of biochemical (PSA) or clinical relapse following local
primary intervention with curative intent, such as surgery, radiation
therapy, cryotherapy, or high-frequency ultrasound and not a candidate
for salvage treatment by surgery (radiotherapy, cryotherapy, or high
frequency ultrasound are allowed after 2 months of androgen
deprivation therapy); or b. Newly diagnosed androgen-sensitive
metastatic disease; or c. Advanced localized disease unlikely to be cured by -
local
primary surgical intervention with either surgery or radiation with curative
intent (radiotherapy,
cryotherapy, or high frequency ultrasound are allowed
after 2 months of androgen deprivation therapy);
5. Has a serum testosterone at the Screening visit of >= 150 ng/dL (1.5 ng/mL of
5.2
nmol/L);
6. Has a serum PSA concentration at the Screening visit of > 2.0 ng/mL
(2.0 µg/L), or, when applicable, post radical prostatectomy of > 0.2
ng/mL (0.2 µg/L) or post radiotherapy, cryotherapy, or high frequency
ultrasound > 2.0 ng/mL (2.0 µg/L) above the post interventional nadir;
7. Has an Eastern Cooperative Oncology Group (ECOG) performance
status of 0 or 1 at initial screening and at baseline;
8. Is a male patient who, even if surgically sterilized (ie, status post
vasectomy): a. Agrees to use a male condom if having sex with a woman
of childbearing potential or a pregnant woman, during the entire study
Treatment Period and through 4 months after the last dose of study
drug; or b. Agrees to practice true abstinence, when this is in line with
the preferred and usual lifestyle of the patient. Periodic abstinence (eg,
calendar, ovulation, symptothermal, postovulation methods for the
female partner) and withdrawal are not acceptable
methods of contraception;
9. Must agree not to donate sperm from first dose of study drug through
4 months after the last
dose of study drug;
10. A randomization authorization form has been signed by a study
medical monitor approving the patient for randomization into the trial.
Exclusion criteria
1. In the investigator's opinion, is likely to require chemotherapy or
surgical therapy for symptomatic disease management within 2 months
of initiating androgen deprivation therapy;
2. Previously received GnRH analog or other form of androgen
deprivation therapy (estrogen or antiandrogen) for > 18 months total
duration. If androgen deprivation therapy was received for <= 18 months
total duration, then that therapy must have been completed at least 3
months prior to baseline. If the dosing interval of the depot is longer than 3
months, then the prior ADT must have been completed at least as long as the
dosing interval of the depot;
3. Previous systemic cytotoxic treatment for prostate cancer (e.g. taxane-based
regimen);
4. Metastases to brain per prior clinical evaluation;
5. Scheduled for major surgery after baseline;
6. History of surgical castration;
7. Active malignancy beyond prostate cancer with the exception of any
of the following: adequately treated basal cell carcinoma, squamous cell
carcinoma, or in situ carcinoma of any type; adequately treated Stage I
cancer from which the subject is currently in remission and has been in
remission for >= 2 years; any other cancer from which the subject has
been disease-free for >= 5 years;
8. Abnormal laboratory values at the Screening visit that suggest a
clinically unstable underlying disease, or the following laboratory values:
a. Serum gamma-glutamyl transferase > 2.0 x upper limit of normal
(ULN); b. Serum ALT and/or AST > 1.0 x ULN; c. Total Bil. > 1.0 x ULN
(unless secondary to Gilbert's syndrome or the pattern is consistent with
a diagnosis of Gilbert's syndrome) or; d. Serum creatinine > 2.0 mg/dL (176.8
µmol/L); e.
Platelets < 100 x 103/µL or history of bleeding disorder; f. Hemoglobin
< 10.0 g/dL (100 g/L); g. WBC < 3 x 103/µL (3 GI/L); h. Absolute
neutrophil count<1.5 x 103/µL(1.5 GI/L);;
9. HbA1c > 10% in patients previously diagnosed with diabetes. HbA1c > 8% in
patients whose diabetes is previously undiagnosed. (Excluded patients
may be rescreened after referral and evidence of improved control of
their condition);
10. Has jaundice or known current active liver disease from any cause,
including hep. A (hep. A virus IgM positive), hep. B (hep. B virus surface
antigen [HBsAg] positive), or hep. C (hep. C virus [HCV] antibody
positive, confirmed by HCV ribonucleic acid);
11. Known human HIV infection;
12. Any of the following within 6 months before Baseline Day1: a. myocardial
infarction b.
unstable angina c. unstable symptomatic ischemic heart disease d. NYHA class 3
or 4 heart failure e. Thromboembolic events (deep vein thrombosis, pulmonary
embolism, symptomatic cerebrovascular events) f. Any other significant cardiac
condition (pericardial effusion, restrictive cardiomyopathy, severe untreated
valvular stenosis, severe congenital heart disease);
13. These ECG abnormalities are excluded: a. ECG evidence of ischaemia
b. Q-wave infarction, unless identified 6 or more months before the
Screen visit; c. QTc > 470 msec, measured by Fridericia's formula [QTcF
= QT/(RR^0.33)]. If the QTc is prolonged in a patient with a pacemaker,
the patient may be enrolled in the study if confirmed by the medical
monitor. d. Congenital long QT syndrome. e. Active conduction system
abnormalities, e.g.,
• Mobitz II second degree heart block without a permanent pacemaker
in place;
• Third degree heart block without permanent pacemaker in place;
• Untreated supraventricular tachycardia (heart rate >= 120 beats per
minute);
• Clinically significant ventricular arrhythmias such as ventricular
tachycardia, ventricular fibrillation, or torsades de pointes;
• Uncontrolled atrial fibrillation (patients with chronic stable atrial
fibrillation on stable anticoagulant therapy or patients with stable
cardiac rhythm controlled by a pacemaker are allowed);
14. Uncontrolled hypertension despite appropriate medical therapy
(sitting blood pressure of greater than 160 mmHg systolic and/or 100
mmHg diastolic at 2 separate measurements no more than 45 minutes
apart during the Screening visit). Patients may be re-screened after
referral and further management of hypertension;
15. Hypotension indicated by systolic blood pressure< 84 mmHg on 2
repeat measures at least 15 minutes apart, or treated ongoing
symptomatic orthostatic hypotension with > 20 mmHg decrease in
systolic blood pressure one minute or more after assuming upright
position;
16. Bradycardia as indicated by a heart rate of < 45 beats per minute on
the ECG at the Screening or Baseline Day 1 visit;
17. Treatment with any investigational product within 28 days or 5 half lives,
whichever is longer;
18. Previous treatment with relugolix in a clinical study;
19. Patient is a study site employee or is primary family member
(spouse, parent, child, or sibling) of a site employee involved in the
conduct of the study;, Please refer to protocol amendment 2 for remaining list
of exclusion criteria
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 | EUCTR2017-000160-15-NL |
| ClinicalTrials.gov | NCT03085095 |
| CCMO | NL61318.028.17 |