Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Symptoms and General Pathology

Prostatic Neoplasms

Adenocarcinoma

Recurrence

Carcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Arm 2 (experimental): (SRT) Salvage radiation therapy (Three dimensional conformal radiation therapy (3D-CRT)/IMRT \[Intensity-modulated radiation therapy\]) 66.6-70.2 Gy as 1.8 Gy M-F for 37-39 fx PLUS Enzalutamide (MDV3100) 160 mg PO once daily for 6 months (2 months prior to SRT, 2 months during SRT and 2 months following SRT)

Arm 1 (control): Salvage radiation therapy (3D-CRT (Three dimensional conformal radiation therapy)/IMRT (Intensity-modulated radiation therapy)) 66.6-70.2 Gy given 1.8 Gy M-F for 37 -39 fx PLUS Placebo PO daily for 6 months (2 months prior to SRT, 2 months during SRT and 2 months following SRT)

Enzalutamide (MDV3100) 160 mg PO once daily for 6 months (2 months prior to SRT, 2 months during SRT and 2 months following SRT)

Enzalutamide

Salvage radiation therapy (3D-CRT (Three dimensional conformal radiation therapy)/IMRT) 66.6-70.2 Gy given 1.8 Gy M-F for 37 -39 fx

Phuoc Tran, M.D.

The primary hypothesis of this study is that outcomes for patients with biochemically recurrent prostate cancer following radical prostatectomy will be improved by the addition of enzalutamide for 6-months compared to standard-of-care salvage radiation therapy to allow for further study in the definitive phase III setting. This study builds on the prior success of high-dose bicalutamide (for 24 months) when combined with salvage external radiation therapy (XRT), while using a newer more potent anti-androgen for a shorter duration of time (6 months) in an effort to minimize adverse effects.

Enzalutamide is a second-generation androgen receptor signaling inhibitor that significantly prolongs survival in patients with metastatic castration-resistant prostate cancer who have received prior docetaxel chemotherapy 35,36. Enzalutamide has demonstrated activity in cells that overexpress the androgen receptor. Unlike previous androgen receptor blocker (ARB) agents, Enzalutamide does not display any agonist properties and blocks translocation of the ligand-receptor complex into the nucleus preventing DNA binding 33. Enzalutamide is an oral agent that is generally well tolerated and does not require concurrent steroid administration, which makes it an ideal candidate for combination with salvage radiation therapy (SRT).

Finally, provocative preliminary Phase II data presented at the American Society of Clinical Oncology (ASCO) 2013 by M. Smith and colleagues assessed the efficacy and safety of 25-weeks (\~6-mos) of enzalutamide alone in prostate cancer of all stages who had never received hormone therapy; presenting with non-castrate testosterone levels ( 230 ng/dL). Enzalutamide alone for 6-mos achieved a high PSA response rate with efficacy similar to castration, but .in contrast to castration, bone mineral density (BMD) remained stable and metabolic variables were not substantially impacted.

The trial described here differs from Radiation Therapy Oncology Group (RTOG) 96-01, RTOG 05-34 and RADICALS in several ways. First, the eligibility criteria are stricter; less favorable patients have been selected. Second, short-term ARB is being tested, while in RTOG 96-01 and RADICALS long-term ARB of 2-years was examined. Finally, and most importantly, we are testing the second generation ARB agent, enzalutamide, alone in combination with SRT as opposed to RTOG 05-34 and RADICALS which use androgen deprivation (AD).

This trial is not intended to address the efficacy of SRT alone over observation. The complete response rate (a drop in PSA to undetectable levels) after SRT is 70%-80% and durable responses are observed in 30%-40% of patients. For these reasons, it is not feasible or appropriate to randomize men between observation and SRT. The more important issue is whether the proportion of durable responses is increased by altering the therapeutic approach, such as the use of enhanced ARB using enzalutamide.

Randomized Salvage Radiation Therapy Plus Enzalutamide Post Prostatectomy

Phase II Randomized Placebo-Controlled Double-Blind Study of Salvage Radiation Therapy (SRT) Plus Placebo Versus SRT Plus Enzalutamide in Men With High-Risk PSA-Recurrent Prostate Cancer After Radical Prostatectomy

The primary efficacy endpoint is the rate of Freedom-from-PSA-progression (FFPP) at 2-years. FFPP is defined as the time from randomization to the date of PSA progression. A subject who does not have PSA progression at the time of the analysis will be censored at the last date of PSA measurement.

Local recurrence within the radiation field (confirmed pathologically) at 2-years

Metastasis-free survival (MFS) rates at 2 years. Metastasis-free survival will be defined as the time from the date of registration to date of evidence of systemic disease on bone scan or cross sectional imaging or death, which occurs first.

Safety as assessed by NCI Common Toxicity Scales (v4.0)

Quality of life (QoL) tools to be used to determine participant tolerability of treatment will include FACT-P, European Organization for the Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ) -C30/QLQ-PR25, and SHIM.

Compare anticipated accrual versus actual.

Astellas Pharma Inc

Medivation, Inc.

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Urologic Neoplasms

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

Disease Attributes

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Urologic Diseases

Antineoplastic Agents

All Drugs and Chemicals

Pembrolizumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Pembrolizumab 200mg i.v. three-weekly in combination with salvage radiation therapy (SRT) according to standard of care

Up to 17 cycles of pembrolizumab until disease progression, toxicity, death, or withdrawal of IC (whichever occurs first)

Pembrolizumab Injection [Keytruda]

SRT according to standard of care (SRT with at least 66 Gy)

Salvage Radiation Therapy (SRT)

Markus T Grabbert, Dr.

Anika Josef, Dr.

Markus T Grabbert, Dr. med.

Anika Josef, Dr. phil.

Christian Gratzke, Prof. Dr.

To evaluate the efficacy and safety of a pembrolizumab therapy of pembrolizumab in combination with standard salvage radiation therapy (SRT) in patients with biochemical recurrence (BCR) of prostate-specific antigen (PSA) persistence after radical prostatectomy (RP).

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.

The trial is designed as a phase II, open-label, monocentric, single-arm trial evaluating a combination therapy of pembrolizumab and salvage radiation therapy (SRT) in patients with biochemical recurrence (BCR) or persisting prostate-specific antigen (PSA) after radical prostatectomy (RP).

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

Radiotherapy in Combination With Pembrolizumab in Patients With PSA Persistence or Biochemical Recurrence After Radical Prostatectomy Due to Prostate Cancer

The PSA-nadir is defined as the lowest PSA-level measured after start of pembrolizumab administration.

The time to PSA-nadir is defined as the time from start of pembrolizumab administration to this time point.

Number of administered pembrolizumab cycles.

Cumulative dose as sum of all pembrolizumab doses given.

Cumulative dose as sum of all pembrolizumab doses given divided by the time under pembrolizumab treatment (last date minus first date of administration).

Number of patients with dose change of pembrolizumab along with reasons for dose change.

Number of patients with interruptions of pembrolizumab administration along with reasons for dose interruptions.

Cumulative dose of ADT after month 6 after start of pembrolizumab administration.

Time from month 6 after start of pembrolizumab administration to start of ADT.

Cumulative dose of ADT after start of pembrolizumab administration.

Time from start of pembrolizumab administration to start of ADT.

Quality of life of patients will be evaluated using the Functional assessment of cancer therapy - prostate cancer (FACT-P questionnaire. The scoring and the analysis of the total score and the subscale scores will be performed according to the scoring manual available from www.facit.org.

Minimum value: 0, Maximum value (FACT-P Trial Outcome Index, TOI): 104, Maximum value (FACT-G total score): 108, Maximum value (FACT-P total score): 156, High score indicates better outcome.

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).

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Randomized Salvage Radiation Therapy Plus Enzalutamide Post Prostatectomy	NCT02203695	Adenocarcinoma ...	Enzalutamide SRT	18 Years - 100 Years	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Randomized Salvage Radiation Therapy Plus Enzalutamide Post Prostatectomy	NCT02203695	Adenocarcinoma ...	Enzalutamide SRT	18 Years - 100 Years	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
SRT in Combination With Pembrolizumab in Patients With Recurrent Prostate Cancer After Radical Prostatectomy	NCT04931979	Urologic Cancer Biochemical Rec...	Pembrolizumab I... Salvage Radiati...	18 Years -	University Hospital Freiburg

Spots Global Cancer Trial Database for salvage radiation therapy (srt)