SRT in Combination With Pembrolizumab in Patients With Recurrent Prostate Cancer After Radical Prostatectomy

Studien-Informationen Einschlusskriterien Studien-Rationale Geprüfte Regime

Rekrutierend

NCT-Nummer:
NCT04931979

Studienbeginn:
Oktober 2022

Letztes Update:
01.03.2023

Wirkstoff:
Pembrolizumab Injection [Keytruda]

Indikation (Clinical Trials):
Prostatic Neoplasms, Neoplasms, Urologic Neoplasms, Recurrence

Geschlecht:
Männer

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 2

Sponsor:
Prof. Dr. med. Christian Gratzke

Collaborator:
Merck Sharp & Dohme LLC

Studienleiter

Christian Gratzke, Prof. Dr.
Principal Investigator
University Medical Center - University of Freiburg, Clinical of Urology

Kontakt

Markus T Grabbert, Dr.
Kontakt:
Phone: +49 761 270 28930
E-Mail: markus.grabbert@uniklinik-freiburg.de» Kontaktdaten anzeigen

Anika Josef, Dr.
Kontakt:
Phone: +49 761 270 77110
E-Mail: anika.josef@uniklinik-freiburg.de» Kontaktdaten anzeigen

Studienlocations
(1 von 1)

Clinic of Urology, Medical Center - University of Freiburg
79106 Freiburg
(Baden-Württemberg)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Markus T Grabbert, Dr. med.
Phone: +49 761 270 28930
E-Mail: markus.grabbert@uniklinik-freiburg.de

Anika Josef, Dr. phil.
Phone: +49 761 270 77110
E-Mail: anika.josef@uniklinik-freiburg.de» Ansprechpartner anzeigen

Studien-Informationen

Detailed Description:

Current guidelines recommend a salvage radiation therapy (SRT) with at least 66 Gy as

preferred treatment option in patients with biochemical recurrence (BCR) resp. PSA

(prostate-specific antigen) persistence after radical prostatectomy (RP). The guideline

recommendation is based on two non-randomized controlled trials that showed an improved

cancer-specific survival and a better local tumor control. The optimal timing for a radiation

therapy cannot be clearly defined by the available literature. A radiation therapy as early

as possible with a PSA level <0,5 ng/ml seems to be beneficial. The guideline recommendation

is based on two non-randomized controlled trials that showed an improved cancer-specific

survival and a better local tumor control. A complete biochemical response is to be expected

in approx. 60-70% of patients after 12 months.

The established imaging modality in patients with BCR used to be computed tomography of the

abdomen and bone scintigraphy for the detection of skeletal lesions. The introduction of PSMA

PET/CT (prostate-specific membrane antigen positron emission tomography combined with CT) has

changed the imaging in patients with recurrent prostate cancer and several studies could show

improved oncological results compared to patients undergoing standard treatment without

positron emission tomography (PET) positive lesions with a 10% improvement in biochemical

recurrence-free survival after 2 years.

Immunotherapy alone has not yet proven to be efficacious in prostate cancer as a monotherapy

in smaller studies. Several trials could show that the combination of the immunotherapy and

radiation therapy has the potential to provide a synergistic effect in treating genitourinary

malignancies, whereas more studies are needed to uncover the exact underlying mechanism. In

brief, radiation therapy of the location of recurrence increases the tumor´s immunogenic

potential and a systemic immunological reaction is initiated that leads to an increased

activity of the immune system against tumor tissue (abscopal effect). Lately several trials

have been evaluating a possible synergistic effect with tolerable side-effects. A trial

combining those two treatment regimens in the early treatment of prostate cancer recurrence

is not available up to date.

The clinical benefit of concomitant androgen deprivation therapy (ADT) is controversial and

literature failed to show a clear overall survival benefit for all patients. Several

retrospective trials have been evaluating a concomitant ADT and for patients with risk

factors like suspicious lymph-nodes in staging diagnostics. Several studies have been

evaluating the effect of concomitant ADT though. Shipley et al. could show the addition of 24

months of bicalutamide to SRT resulted in significantly higher rates of long-term overall

survival. However, sub-group analyses revealed that this effect counts mainly for patients

with PSA of >0.7 ng/ml before SRT. The GETUG-AFU trial did not find any survival benefit for

short term (6 months) ADT additionally to SRT. However, a significant benefit in

progression-free survival after 120 months of follow-up time was reported. A combination

therapy of pembrolizumab and radiation therapy has not been evaluated before in this patient

population. The investigators hypothesize that this combination is more effective than

radiation therapy alone due to a radiogenic triggered immunomodulation which increases the

anti-tumor effect of pembrolizumab. For patients with BCR or PSA persistence after RP no such

treatment regimen has been tested yet.

Ein-/Ausschlusskriterien

Inclusion criteria:

1. Male patients who are at least 18 years of age on the day of signing informed consent

2. Histologically confirmed diagnosis of an adenocarcinoma of the prostate and a BCR or

PSA persistence after RP

3. Histology of the RP specimen needs to fulfill the following criteria: adenocarcinoma

of the prostate, Gleason score 7-10; pNX or pN0 or pN1 (max. 2 lymph nodes involved)

4. Imaging within 50 days prior to study inclusion is mandatory (patient registration)

([68Ga] or [18F] PSMA PET-CT as standard imaging modality, alternatively CT abdomen

and full-body bone scan)

5. PSA value between ≥0.2 and ≤1.0 ng/ml measured at least six weeks postoperatively

6. The patients agree not to undergo testicular sperm extraction for at least 90 days

after the last administration of pembrolizumab. (Due to prior surgical removal of the

prostate no contraception is necessary.)

7. Written informed consent obtained according to international guidelines and local law

8. Patients further having an Eastern Cooperative Oncology Group (ECOG) performance

status of 0 to 1.

9. Patients with adequate organ function as defined in clinical trial protocol (CTP)

(Section 4)

Exclusion criteria:

1. Prior-therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent

directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40,

CD137).

2. Prior systemic anti-cancer therapy including investigational agents within 4 weeks

prior to registration (like neo-adjuvant androgen deprivation therapy (ADT), secondary

hormone ablation or taxan-based chemotherapy).

3. Prior radiotherapy within 4 weeks before start of study medication. Patients must have

recovered from all radiation-related toxicities, not require corticosteroids, and not

have had radiation pneumonitis.

4. Distant metastases or suspicious lymph nodes outside the lower pelvis in imaging with

PSMA PET-CT are to be excluded (patients with PET positive bone lesions that are

morphologically not clearly suspicious of metastases and would not change clinical

practice can be included).

5. Adverse histology of RP specimen (e.g. neuroendocrine or small cell)

6. Any vaccination with live vaccine or live-attenuated vaccine within 30 days prior to

the first dose of study medication. Administration of killed vaccines is allowed.

7. Currently or previously participating in a study of an investigational product within

4 weeks prior to the first dose of study medication.

8. Diagnosis of immunodeficiency, chronic systemic steroid therapy (in dosing exceeding

10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy

within 7 days prior to the first dose of study medication.

9. History of a second malignancy, unless potentially curative treatment has been

completed with no evidence of malignancy for 2 years.

10. Known active central nervous system (CNS) metastases and/or carcinomatous meningitis.

11. Severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.

12. Active autoimmune disease that required systemic treatment in the 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 and is allowed.

13. History of (non-infectious) pneumonitis/interstitial lung disease that required

steroids or currently pneumonitis/ interstitial lung disease

14. Active infection requiring systemic therapy.

15. History of Human Immunodeficiency Virus (HIV) infection.

16. History of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or

known active Hepatitis C virus (defined as Hepatitis C virus (HCV) RNA is detected)

infection. No testing is required.

17. History of active TB (Bacillus Tuberculosis).

18. History or current evidence of any condition, therapy, or laboratory abnormality that

might confound the results of the study, interfere with the subject's participation

for the full duration of the study, or is not in the best interest of the subject to

participate, in the opinion of the investigator.

19. Known psychiatric or substance abuse disorders that would interfere with cooperation

with the requirements of the trial.

20. History of allogeneic tissue/solid organ transplantation.

Studien-Rationale

Primary outcome:

1. Complete biochemical response (Time Frame - at week 60 (+/- weeks) after start of treatment):
number of patients with complete biochemical response defined as a PSA level below limit of detection. Patients will be counted as a responder with respect to the primary endpoint, if the PSA level is below the limit of detection at week 60 (± 2 weeks) after start of trial treatment. Patients will be counted as a non-responder with respect to the primary endpoint, if the PSA level is above the limit of detection at week 60 (± 2 weeks).

Secondary outcome:

1. Radiographic progression-free survival (Time Frame - at week 60 (+/- 2 weeks) after start of treatment):
The probability of radiographic progession-free survival at week 60 (+/- 2 weeks) after start of treatment will be estimated as the number of patients who are alive and progression-free divided by the total number of treated patients.

Geprüfte Regime

Pembrolizumab Injection [Keytruda]:
Up to 17 cycles of pembrolizumab until disease progression, toxicity, death, or withdrawal of IC (whichever occurs first)
Salvage Radiation Therapy (SRT):
SRT according to standard of care (SRT with at least 66 Gy)

Quelle: ClinicalTrials.gov

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