Studienregister der Deutschen Gesellschaft für Urologie e.V.



A Phase III Randomized, Controlled Clinical Trial of Pembrolizumab with or without Platinum-Based Combination Chemotherapy versus Chemotherapy in Subjects with Advanced or Metastatic Urothelial Carcinoma

Status: Active (Recruitment Closed)

Purpose / Objectives

Primary Outcome

To compare PFS using RECIST 1.1 as assessed by BICR and OS in PD-L1

positive subjects and all subjects between the following treatment comparisons:

(a) Pembrolizumab + chemotherapy versus chemotherapy

(b) Pembrolizumab versus chemotherapy

Secondary Outcomes

To evaluate the safety and tolerability profile in all subjects (PD-L1

positive and negative) in the following treatment groups:

(a) Pembrolizumab

(b) Pembrolizumab + chemotherapy

(c) Chemotherapy


Treatment of subjects with advanced or metastatic urothelial


Patient attributes


metastatic UCC



Inclusion criteria

1. Have a histologically or cytologically confirmed diagnosis of advanced/ unresectable (inoperable) or metastatic urothelial carcinoma of the renal pelvis, ureter [upper urinary track], bladder, or urethra. Both transitional cell and mixed transitional/nontransitional cell histologies are allowed, but transitional cell carcinoma must be the predominant histology.

2. Have measurable disease based on RECIST 1.1 as determined by the local site investigator/radiology assessment. Target lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.

3. Voluntarily agree to participate by providing written informed consent/ assent for the trial. The subject may also provide consent for Future Biomedical Research. However, the subject may participate in the main trial without participatin g in Future Biomedical Research.

4. Be ≥18 years of age on the day of signing informed consent.

5. Have received no prior systemic chemotherapy for advanced or metastatic urothelial carcinoma, with the following exceptions:

a. Neoadjuvant platinum-based chemotherapy with recurrence >12 months from completion of therapy is permitted.

b. Adjuvant platinum-based chemotherapy following radical cystectomy with recurrence >12 months from completion of therapy is permitted.

Note: Low-dose chemotherapy (e.g., low-dose cisplatin, cisplatin plus 5-FU, mitomycin plus 5-FU, or cisplatin plus paclitaxel) given concurrently with

Radiation to the primary tumor site is not considered systemic therapy. In the

clinical setting, chemotherapy is given with the sole purpose of sensitizing the

tumor to local radiation. It is not administered at doses with any systemic

efficacy. Surgery is not considered first-line therapy following diagnosis of

advanced/metastatic disease.

6. Have provided tissue for biomarker analysis from an archival tissue sample

or newly obtained core or excisional biopsy of a tumor lesion not previously

irradiated. A newly obtained biopsy is strongly preferred but not required if

archival tissue is adequate for analysis. Submit an evaluable sample for

analysis. If submitting unstained cut slides, freshly cut slides should be

submitted to the testing laboratory within 14 days from when the slides are

cut. Refer to Section in protocol for an explanation. Adequacy of the

archived or freshly-obtained biopsy specimen must be confirmed by the

central laboratory during the screening period prior to enrollment.

7. Have an ECOG PS of 0, 1, or 2.

8. Demonstrate adequate organ function as defined in Table 3. (All screening labs

should be performed within 2 weeks prior to treatment initiation.)

9. Female subjects of childbearing potential must have a negative urine or

Serum pregnancy test within 72 hours prior to receiving the first dose of trial

medication. If the urine test is positive or cannot be confirmed as negative, a

serum pregnancy test will be required.

10. Female subjects of childbearing potential (Section 5.7.2) must be willing to

use an adequate method of contraception as outlined in Section 5.7.2 –

Contraception, for the course of the trial through 120 days after the last dose

of pembrolizumab or´180 days after chemotherapy treatment.

Note: Abstinence is acceptable if this is the usual lifestyle and preferred

contraception for the subject.

11. Male subjects of childbearing potential (Section 5.7.2) must agree to use

an adequate method of contraception as outlined in Section 5.7.2 –

Contraception, starting with the first dose of trial therapy through 120 days

after the last dose of pembrolizumab or 180 days after chemotherapy.

Note: Abstinence is acceptable if this is the usual lifestyle and preferred

contraception for the subject.


Exclusion criteria

Has disease that is suitable for local therapy administered with curative

intent . An example of local therapy with curative intent is treatment with

chemotherapy and radiation for Stage 3 disease. A subject with non-urothelial

carcinoma of the urinary tract is also ineligible.

2. 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 treatment

3. Has a diagnosis of immunodeficiency or is receiving systemic steroid

therapy or any other form of immunosuppressive therapy within 7 days prior to


4. Has an active autoimmune disease that has required systemic treatment in

the past

2years (ie, 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


etc.) is not considered a form of systemic treatment.

a. Brief (<7 days) use of systemic corticosteroids is allowed when use is

considered SOC.

b. Subjects with vitiligo, diabetes Type I, hypothyroidism, or resolved

childhood asthma/atopy would be an exception to this rule.

c. Subjects who require intermittent use of bronchodilators, inhaled steroids,

or local steroid injections would not be excluded from the trial.

d. Subjects with hypothyroidism stable on hormone replacement or Sjøgren’s

syndrome will not be excluded from the trial.

e. If a subject is on a stable dose of steroids for central nervous system (CNS)

metastases at screening, the subject will need to stop steroids 7 days prior to

first dose in order to qualify for the trial.

5. Has had a prior anti-cancer mAb for direct anti-neoplastic treatment within 4

weeks prior to the first dose of trial treatment (6 weeks for nitrosoureas or


C) or who has not recovered (ie, ≤rade 1 or at baseline) from AEs due to

mAbs administered more than 4 weeks earlier. Subjects previously treated

with a mAb will be eligible to participate after a 28-day washout period.

6. Has not recovered (ie, AE ≤rade 1 or at baseline) from AEs due to a

previously administered agent.

a. Subjects with ≤rade 2 neuropathy or ≤rade 2 alopecia are an exception to

this criterion and may qualify for the trial.

b. If subjects received major surgery they must have recovered adequately

from the toxicity and/or complications from the intervention prior to starting

trial therapy.

7. Has a known additional malignancy that is progressing or requires active


a. Exceptions include basal cell carcinoma of the skin, squamous cell

carcinoma of the skin that has undergone potentially curative therapy or in situ

cervical cancer.

b. A history of prostate cancer that was identified incidentally following

cystoprostatectomy for bladder cancer is acceptable, provided that the

following criteria are met: Stage T2N0M0 or lower; Gleason score ≤; prostate-

specific antigen (PSA) undetectable.

8. Has a history of (non-infectious) pneumonitis that required steroids or

current pneumonitis.

9. Has a known history of active tuberculosis (TB) (Bacillus tuberculosis).

10. Has an active infection requiring systemic therapy.

11. Has a history of severe hypersensitivity reaction (e.g., generalized

rash/erythema, hypotension, bronchospasm, angioedema or anaphylaxis) to

gemcitabine, carboplatin, or cisplatin or their analogs.

12. 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.

13. Has known psychiatric or substance abuse disorders that would interfere

with cooperation with the requirements of the trial. At the time of signing

informed consent is a known regular user (including "recreational use") of any

illicit drug(s) or had a recent history (within the last year) of drug or alcohol


14. Is pregnant or breastfeeding, or expecting to conceive or father children

within the projected duration of the trial, starting with the screening visit

through 120 days after the last dose of pembrolizumab or 180 days after the

last dose of chemotherapy treatment.

15. Has received prior therapy with an anti-PD-1, or anti-PD-L1, or anti-PD-L2

agent or with an agent directed to another co-inhibitory T-cell receptor (eg,

CTLA-4, OX-40, CD137).

16. Has a known history of human immunodeficiency virus (HIV) (HIV 1/2


17. Has known active hepatitis B (eg, HBsAg reactive) or hepatitis C (eg, HCV

RNA [qualitative] is detected).

18. Has received a live virus vaccine within 30 days of planned start of trial


19. Has known active CNS metastases and/or carcinomatous meningitis.

Subjects with previously treated brain metastases may participate provided

they have stable brain metastases (stability is normally defined as a period of

1 to 3 months in which there is no evidence of new or enlarging CNS


20. Has symptomatic ascites or pleural effusion; a subject who is clinically

stable following treatment for these conditions is eligible.

21. Has had a prior allogeneic stem cell or bone marrow transplant.





Trial design

  • Phase III
  • Multicenter
  • Randomized
  • Three-arm
  • Open Label



1. Pembrolizumab (MK-3475)

2. Pembrolizumab in combination with chemotherapy (Cisplatin orCarboplatin plus Gemcitabin)

3. Chemotherapy

Documents (password protected)

Responsibilities in overall trial

Merck Sharp & Dohme Corp.

  • Tel. +1 (908) 740-4000

National Coordinating Investigator

Prof. Dr. med. Margitta Retz

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