| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced or Metastatic Urothelial Carcinoma |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10064467 |
| E.1.2 | Term | Urothelial carcinoma |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare PFS using RECIST 1.1 as assessed by BICR in the all -subject population for combo vs chemo only, and to compare OS for combo vs chemo only in the all-subject population and for pembro only vs chemo only in the PD-L1 CPS ≥10% and all-subject population. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the safety and tolerability profile in all subjects (PD-L1 CPS ≥10% and CPS <10%) in the following treatment groups:
a) Pembro only
b) Combo
c) Chemo only
2. To compare the ORR using RECIST 1.1 as assessed by BICR between the following treatment comparisons:
a) Combo versus chemo only
b) Pembro only versus chemo only
3. To evaluate the DOR in all subjects (PD-L1 CPS ≥10% and CPS <10%) using RECIST 1.1 as assessed by BICR in the following treatment groups:
a) Pembro only
b) Combo
c) Chemo only
4. To evaluate the disease control rate (DCR = combined complete response, partial response, and stable disease rates) in all subjects (PDL1 CPS ≥10% and CPS <10%) using RECIST 1.1 as assessed by BICR in the following treatment groups:
a) Pembro only
b) Combo
c) Chemo only
For a full list of secondary objectives, see protocol. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Have a histologically or cytologically confirmed diagnosis of advanced/unresectable or metastatic urothelial carcinoma of the renal pelvis, ureter [upper urinary tract], 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 participating 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.
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 from a muscle invasive urothelial carcinoma or a metastatic biopsy, originating from the original tumor. A newly obtained biopsy is strongly preferred but not required if archival tissue is evaluable. 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 7.1.2.12 in the protocol for an explanation. PDL1 status (CPS ≥10% or CPS <10%) must be determined 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 the protocol
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 and male subjects of childbearing potential must be willing to use an adequate method of contraception for the course of the trial through 120 days after the last dose of pembrolizumab or 180 days after chemotherapy treatment.
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.
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|
| E.4 | Principal exclusion criteria |
1. Has disease that is suitable for local therapy administered with curative intent.
2. Is currently participating and receiving study therapy.
3. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to randomization.
4. Has an active autoimmune disease that has required systemic treatment in the past 2 years.
5. Has had a prior anticancer mAb for direct antineoplastic treatment within 4 weeks prior to the first dose of trial treatment (6 weeks for nitrosoureas or mitomycin C) or who has not recovered (ie, ≤Grade 1 or at baseline) from AEs due to mAbs administered more than 4 weeks earlier.
6. Has not recovered from AEs due to a previously administered agent.
7. Has a known additional malignancy that is progressing or requires active treatment within the past 5 years.
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 to pembrolizumab, gemcitabine, carboplatin, or cisplatin or their analogs, and / or to any of their excipients.
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.
13. Has known psychiatric or substance abuse disorders.
14. Is pregnant or breastfeeding, or expecting to conceive or father children.
15. Has received prior therapy with an anti-PD-1, or anti-PD-L1, or anti-PD-L2 agent.
16. Has a known history of human immunodeficiency virus.
17. Has known active hepatitis B /C.
18. Has received a live virus vaccine within 30 days of planned start of trial therapy.
19. Has known active CNS metastases and/or carcinomatous meningitis.
20. Has symptomatic ascites or pleural effusion.
21. Has had a prior allogeneic stem cell or bone marrow transplant.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
progression-free survival (PFS) for combo vs chemo only in the all subject population using a blinded independent central review (BICR)
and RECIST 1.1 to determine disease progression, and overall survival (OS) for combo vs chemo only in the all-subject population and OS for pembrolizumab only vs chemo only in the PD-L1 CPS ≥10% and all subject population. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
This evaluation will occur when:
1) all subjects are enrolled
2) the information fraction (IF) of OS events observed in PD-L1 positive subjects is at least 0.5 (148 events)
3) the IF of OS events observed in all subjects is at least 0.5 (229 events)
4) the IF of PFS events observed in PD-L1 positive subjects is at least 0.5 (207 events)
5) And IF of PFS events observed in all subjects is at least 0.5 (318 events)
This is projected to happen approximately 19 months after the first patient enters this trial. |
|
| E.5.2 | Secondary end point(s) |
Objective Response Rate – RECIST 1.1 by blinded central radiology review
Objective response rate is defined as the proportion of the subjects in the analysis population who have a CR or PR. Responses are based upon blinded central radiology review per RECIST 1.1. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) Final analysis – after Last Patient Last Visit (LPLV)
2) In addition, if the decision is filing at the interim analysis after the DMC review, we need to provide results for secondary endpoints as well.
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|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 48 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Brazil |
| Canada |
| Chile |
| Israel |
| Japan |
| Korea, Republic of |
| South Africa |
| Taiwan |
| Thailand |
| United States |
| France |
| Spain |
| Germany |
| Italy |
| Belgium |
| Hungary |
| Ireland |
| Russian Federation |
| Turkey |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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