To estimate the objective response rate (ORR) by RECIST 1.1 in subjects with measurable disease assessed by central imaging vendor in Cohorts 1 and 2 combined, Cohort 1, Cohort 2 and Cohort 4.
ID
Source
Brief title
Condition
- Reproductive neoplasms male malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Cohorts 1, 2, and 4 - Objective Response Rate (ORR) - per RECIST 1.1 assessed
by central imaging vendor: Proportion of subjects int he analysis population
who have complete response (CR) or partial response (PR) where responses are
determined by RECIST 1.1 assessed by central imaging vendor.
Secondary outcome
1.Duration of Response (DOR) per PCWG3-modified RECIST 1.1 assessed by central
imaging vendor.
For subjects who demonstrated CR or PR, DOR is defined as the time from first
documented evidence of CR of PR until disease progression assessed by central
imaging vendor where progressive disease (PD) in bone-only tumors will be
determined by radionuclide bone scan using RECIST 1.1/PCWG3 criteria and PD for
all other tumors will be determined using RECIST 1.1 or death due to any cause,
whichever occurs first
2.Duration of Response (DOR) - per RECIST 1.1 assessed by central imaging
vendor.
For subjects who demonstrated CR or PR, DOR is defined as the time from first
documented evidence of CR of PR until progressive disease (PD) assessed by
central imaging using RECIST 1.1 or death due to any cause, whichever occurs
first.
3. Disease Control Rate (DCR) - assessed by central imaging vendor
Proportion of subjects in the analysis population who have CR or PR or stable
disease (SD) for at least 6 months, by central imaging vendor where progressive
disease (PD) in bone-only tumors will be determined by radionuclide bone scan
using PCWG3 criteria and PD for all other tumors will be determined using
RECIST 1.1
4. PSA Response Rate
Proportion of subjects in the analysis population who have PSA response defined
as more than 50% decline from baseline measured twice at least 3 weeks apart.
5. Time to PSA Progression, defined as the time from first day of study
treatment to the date of PSA progression. Subjects without PSA progression will
be censored at the last PSA assessment date. PSA progression is defined as the
date that an increase of 25% or more and an absolute increase of 2 ng/mL or
more from the nadir are documented. For subjects who had an initial PSA decline
during treatment, this must be confirmed by a second value 3 or more weeks
later.
6. Radiographic progression-free survival (rPFS) - per PCWG3-modified RECIST
1.1 assessed by central imaging vendor. It is defined as the time from first
day of study treatment to the documented disease progression by central imaging
vendor where progressive disease (PD) in bone-only tumors will be determined by
radionuclide bone scan using PCWG3 criteria and PD for all other tumors will be
determined using RECIST 1.1 or death due to any cause, whichever occurs first.
7. Overall Survival (OS)
Overall survival (OS) is defined as the time from first day of study treatment
to the time of death.
8. Duration of PSA response (Cohorts 4 and 5 only)
Duration of PSA response is defined as the time from PSA response, when the PSA
value first declines by at least 50% of the baseline (must be confirmed y a
second value), to the date of PSA progression at which there is an increase of
25% or more from the nadir PSA, provided the absolute increase from the nadir
PDA is at least 2 ng/mL.
9. Time to initiation of cytotoxic chemotherapy (Cohorts 4 and 5 only)
Time to initiation of cytotoxic chemotherapy is defined as the time from first
day of study treatment to the time of initiation of cytotoxic chemotherapy for
prostate cancer.
10. Time to new-anticancer therapy (Cohorts 4 and 5 only)
Time to new-anticancer therapy is defined as the time from first day of study
treatment to the time of new-anticancer therapy for prostate cancer
11. Time to first skeletal-related event (Cohorts 4 and 5 only)
Time to initiation of first skeletal-related event is defined as the time from
first day of study treatment to the first skeletal-related event, which is
defined as radiation therapy or surgery to bone, pathologic bone fracture,
spinal cord compression, or change or antineoplastic therapy to treat bone
pain. See Section 8.6.1 for censoring rules.
12. Safety endpoints: Safety will be assessed by quantifying the toxicities and
grades experienced by subjects who have received pembrolizumab, including
serious adverse events (SAEs) and events of clinical interest (ECIs). Safety
will be assessed by reported adverse experiences using CTCAE, Version 4.0.
Background summary
Prostate cancer represents the second most common malignancy
diagnosed in men worldwide where the annual incidence has been estimated to
be over 1 million and over 300,000 deaths are expected annually. In the US,
approximately one in every six men will be diagnosed with prostate cancer in
his lifetime.
While many men are diagnosed with locally confined disease and may be treated
definitively with radiation or surgery, men who go on to develop or are
diagnosed with metastatic prostate cancer, an incurable entity, are typically
treated first with androgen deprivation therapy (ADT), usually with a GnRH
agonist or antagonist that results in suppression of testosterone production in
the testes. This alone often succeeds in controlling disease for some time,
years in many cases. However, prostate cancer progresses invariably and
requires additional systemic therapies to reestablish control of disease. The
point at which prostate cancer progresses in spite of ADT alone is referred to
as castrate resistance, and the disease at this point is known as (metastatic)
castrate-resistant prostate cancer (mCRPC).
A number of important systemic therapies have been developed to treat mCRPC and
have received regulatory approval and now comprise the current therapeutic
landscape. Docetaxel became the first systemic therapy to improve survival for
men with mCRPC in a randomized study with docetaxel demonstrating superior
survival of median 18.9 months versus 16.5 for mitoxantrone. Cabazitaxel, a
second taxane was studied versus mitoxantrone in patients after docetaxel, and
it too was found to be associated with superior survival * median 15.1 months
versus 12.7 with mitoxantrone. Finally, the targeted endocrine therapies,
enzalutamide and abiraterone, were examined in randomized clinical trials in
patients with mCRPC before treatment with chemotherapy and found to have
superior overall survival versus control therapy (placebo and prednisone,
respectively).
Cabazitaxel can be a toxic therapy. Deaths occurred on study due to
treatment-related neutropenia, and mortality has been reported due to
treatment-related diarrhea. Its label contains a black box warning regarding
risks from neutropenia, severe hypersensitivity, and other label warnings and
precautions pertain to diarrhea, renal failure, prohibitive risk in elderly
patients * 65, and hepatic impairment. Consequently, cabazitaxel is not well
utilized and consensus guidelines, such as NCCN, recommend that men with mCRPC
after docetaxel should be encouraged to participate in clinical trials. Thus,
an unmet medical need remains for patients after treatment in the mCRPC setting
with targeted endocrine therapy and docetaxel.
Study objective
To estimate the objective response rate (ORR) by RECIST 1.1 in subjects with
measurable disease assessed by central imaging vendor in Cohorts 1 and 2
combined, Cohort 1, Cohort 2 and Cohort 4.
Study design
This is a nonrandomized, multinational, open-label trial of pembrolizumab
(MK-3475) in subjects with metastatic castration-resistant prostate cancer
(mCRPC) previously treated with docetaxel-based chemotherapy.
Intervention
Intervention with medicine, for a description of the concerned medicine, see
C16.
Study burden and risks
Treatment cycles will take three weeks, of which pembrolizumab will be
administered on day 1. At every visit, a physical examination will be
performed, vital signs will be measured, ECGs made and blood samples will be
collected.
The subjects will also be asked to complete questionnaires on their health and
symptoms.
There will be a tumor biopsy at screening (this can be omitted in case there is
adequeate tumor tissue available).
Trial subjects may experience physical and/or psychological discomfort with
some of the study procedures, such as blood sampling, administration of the IV
line ECGs, CT/MRI/bone scans, and tumor biopsy.
The main side effects reported with the trial medication include fatigue,
itching, rash, frequent or irregular bowel movements, pain in joints, muscles,
or bones, stomach ache and nausea.
Waarderweg 39
Haarlem 2031 BN
NL
Waarderweg 39
Haarlem 2031 BN
NL
Listed location countries
Age
Inclusion criteria
1. Be willing and able to provide written informed consent for the trial. The
subject may also provide consent for Future Biomedical Research. However, the
subject may participate in the main trial without participating in Future
Biomedical Research.
2. Be *18 years of age on day of signing informed consent.
3. Have histologically- or cytologically-confirmed adenocarcinoma of the
prostate without small cell histology. Diagnosis must be stated in a pathology
report and confirmed by the Investigator.
4. Have RECIST 1.1-measurable prostate cancer on computed tomography (CT) or
magnetic resonance imaging (MRI) scans (Cohorts 1, 2 and 4) or detectable bone
metastases by whole body bone scintigraphy and no RECIST 1.1-measurable tumors
(Cohorts 3 and 5), as determined by central review. Disease must be either
metastatic or locally confined inoperable disease that cannot be treated with
definitive intent.
5. Have supplied tumor tissue from a newly obtained biopsy or provided a tumor
tissue specimen *12 months prior to the screening date and an archival
specimen, if available, from a site not previously irradiated (tumors
progressing in a prior site of radiation are allowed for PD-L1
characterization; other exceptions may be considered after Sponsor
consultation). Adequacy of these specimens for PD-L1 biomarker analysis will be
required by a central laboratory prior to enrollment. Subjects in Cohorts 1, 2
and 4 with visceral / measurable lesions must provide a newly obtained biopsy
performed after the last line of systemic therapy where safely available or a
specimen obtained *12 months prior to the screening date and an archival
specimen, if available. Subjects in Cohort 3 and 5 must at least provide an
archival specimen.
For Cohorts 1, 2, and 3 only:
6. Have been treated with:
a. At least one targeted endocrine therapy (defined as second generation
antiandrogen therapies that include but are not limited to abiraterone acetate
with prednisone, enzalutamide, and next generation targeted agents such as
ARN-509).
b. At least one regimen / line of chemotherapy that contained docetaxel.
c. No more than two chemotherapy regimens.
d. No more than three regimens / lines of the aforementioned treatments (having
failed / progressed on chemotherapy and targeted endocrine therapy).
For Cohorts 4 and 5 only:
7. For chemotherapy-naive subjects with mCRPC either having failed or showing
early signs of failing on enzalutamide treatment as defined by PCWG3-
guidelines (eg, signs of clinical progression, increased alkaline phosphatase,
PSA increase, or positive imaging assessments). Subjects can have failed prior
abiraterone treatment before current enzalutamide treatment. Subjects must have
had a clinically meaningful response to enzalutamide treatment. Enzalutamide
must have been initiated no less than 4 weeks prior to the first dose of trial
treatment and be continued throughout the study.
All Cohorts:
8. Have documented prostate cancer progression within 6 months prior to
screening, as determined by the Investigator, by means of one of the following:
a. PSA progression as defined by a minimum of 3 rising PSA levels with an
interval of * 1 week between each assessment where the PSA value at screening
should be * 2 ng/mL.
b. Radiographic disease progression in soft tissue or bone with or without PSA
progression
9. Have ongoing androgen deprivation with total serum testosterone < 50 ng/dL
(< 2.0 nM). If the subject is currently being treated with LHRH agonists
(subjects who have not undergone an orchiectomy), this therapy must have been
initiated at least 4 weeks prior to first dose of trial treatment. This
treatment must be continued throughout the study.
10. Subjects receiving bone resorptive therapy (including but not limited to
bisphosphonate or RANK-L inhibitor) must have been on stable doses for * 4
weeks prior to first dose of trial treatment.
11. Have a performance status of 0, 1 or 2 on the Eastern Cooperative Oncology
Group (ECOG) Performance Scale.
12. Subjects are eligible to participate if they agree to the following during
the intervention period and for at least the time needed to eliminate each
study intervention after the last dose of study intervention. The length of
time required to continue contraception after the last dose of enzalutamide is
30 days.
- Be abstinent from heterosexual intercourse as their preferred and usual
lifestyle and agree to remain abstinent.
OR
- Must agree to use contraception unless confirmed to be azoospermic, as
detailed below:
- Agree to use a male condom plus partner use of an additional contraceptive
method when having penile-vaginal intercourse with a WOBCP who is not currently
pregnant.
- Contraceptive use by men should be consistent with local regulation. If the
contraception requirements in the local label for any of the study
interventions is more stringent.
13. Demonstrate adequate organ function as defined in protocol
Exclusion criteria
1. Is currently participating and receiving study therapy or has participated
in a study of an investigational agent and received study therapy or used an
investigation device within 4 weeks of the first dose of trial treatment.
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy
or any other form of immunosuppressive therapy within 7 days prior to the first
dose of trial treatment. The use of physiologic doses of corticosteroids may be
approved after consultation with the Sponsor (replacement therapy for adrenal
insufficiency is permitted).
3. Has had a prior anti-cancer mAb within 4 weeks prior to the first dose of
trial treatment or who has not recovered (i.e., * Grade 1 or at baseline) from
AEs due to mAbs administered more than 4 weeks earlier.
4. Has had prior chemotherapy, targeted small molecule therapy, or external
beam radiation therapy within 4 weeks prior to the first dose of trial
treatment or who has not recovered (i.e., * Grade 1 or at baseline) from AEs
due to a previously administered agent. Treatment with Radium-223 is allowed as
long as the last dose has been administered no less than 4 weeks prior to the
first dose.
5. Has a known additional malignancy that has had progression or has required
active treatment in the last 3 years. Exceptions include basal cell carcinoma
of the skin, and squamous cell carcinoma of the skin that has undergone
potentially curative therapy or in situ cervical cancer.
6. Has known active central nervous system (CNS) metastases and/or
carcinomatous meningitis. Subjects with previously treated brain metastases may
participate provided they are stable (without evidence of progression by
imaging for at least 4 weeks prior to the first dose of trial treatment and any
neurologic symptoms have returned to baseline), have no evidence of new or
enlarging brain metastases, and are not using steroids for at least 7 days
prior to the first dose of trial treatment. This exception does not include
carcinomatous meningitis which is excluded regardless of clinical stability.
7. Has an active autoimmune disease that has required systemic treatment in
past 2 years (i.e., with use of disease modifying agents, corticosteroids or
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary
insufficiency, etc.) is not considered a form of systemic treatment.
8. Has evidence of interstitial lung disease and / or a history of
(non-infectious) pneumonitis that required steroids, or current pneumonitis.
9. Has an active infection requiring systemic therapy.
10. Has a history or current evidence of any condition, therapy, or laboratory
abnormality that might confound the results of the trial, interfere with the
subject*s participation for the full duration of the trial, or is not in the
best interest of the subject to participate, in the opinion of the treating
Investigator.
11. Has known psychiatric or substance abuse disorders that would interfere
with cooperation with the requirements of the trial.
12. Has previously participated in any other pembrolizumab (MK-3475) trial, or
received prior therapy with an anti-PD-1, anti-PD-L1, and anti-PD-L2 (including
ipilimumab or any other antibody or drug specifically targeting T-cell
co-stimulation or checkpoint pathways).
13. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2
antibodies).
14. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g.,
HCV RNA [qualitative] is detected).
15. Has received a live vaccine within 30 days of planned start of study
therapy. Any licensed COVID-19 vaccine (including for Emergency use)
in a particular country is allowed in the study as long as they are mRNA
vaccines, adenoviral vaccines, or inactivated vaccines. Investigational
vaccines (ie, those not licensed or approved for Emergency Use) are not allowed.
Additionally, the following apply to Cohorts 4 and 5 only:
16. Has received prior chemotherapy (e.g., docetaxel) for mCRPC.
17. Has any condition (cardiac, neurologic, absorption) other than clinically
failing or showing early signs of failing on enzalutamide treatment that would
require imminent discontinuation of enzalutamide treatment
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 | EUCTR2015-003644-40-NL |
| CCMO | NL57447.056.16 |