E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Non-Muscle Invasive Bladder Cancer (NMIBC) |
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E.1.1.1 | Medical condition in easily understood language |
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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 | PT |
E.1.2 | Classification code | 10005003 |
E.1.2 | Term | Bladder cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
In:
Cohort A - Subjects with CIS at baseline (CIS only, Ta+CIS, or T1+CIS)
And
Cohort B - Subjects without CIS at baseline (High Grade Ta or Any Grade T1)
To evaluate anti-tumor activity of pembrolizumab (MK-3475) by evaluating the absence of high risk NMIBC or progressive disease, as determined by cystoscopy, cytology, biopsy (if applicable), and radiologic imaging by central pathology and radiology review. |
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E.2.2 | Secondary objectives of the trial |
To evaluate anti-tumor activity of MK-3475:
Cohort A -CIS at baseline
1. by CR rate of any disease
2. by DOR of high risk NMIBC and any disease (responders only)
3. in PD-L1+ subjects by CR rate of high risk NMIBC and any disease
4. in PD-L1+ subjects by DOR of high risk NMIBC and any disease (responders only)
5. in the study population and in PD-L1+ subjects by:
a. DOR rate at specific time points of both high risk NMIBC and any disease (responders only)
b. PFS, to worsening of grade or stage or death
c. PFS, to muscle invasive or metastatic disease or death
d. OS
Cohort B -no CIS at baseline
1. by DFS rate of any disease
2. in PD-L1 + subjects by 12-month DFS rate of high risk NMIBC and any disease
3. in the study population and in PD-L1+ subjects by:
a. Overall DFS and 3-month/6-month DFS rates of high risk NMIBC and any disease
b. PFS, to worsening of grade or stage or death
c. PFS, to muscle invasive or metastatic disease or death
d. OS |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Have a histologically-confirmed diagnosis of high risk non-muscle-invasive (T1, High Grade Ta and/or CIS) transitional cell carcinoma of the bladder.
2. In subjects who have papillary tumors (Ta and T1), a complete TURBT must have been performed, as characterized by: attainment of a visually complete resection of all papillary tumors (Ta and T1). Residual CIS not amenable to complete transurethral resection is acceptable. The most recent cystoscopy/TURBT must have been performed within 12 weeks of first dose of trial treatment.
3. Have been treated with adequate BCG therapy and have developed high risk NMIBC that is unresponsive to BCG therapy.
4. Have elected not to undergo, or are considered ineligible for radical cystectomy, as determined by the treating surgeon.
5. Have provided tissue for biomarker analysis from the most recent cystoscopy/TURBT procedures from which tumor sample is available.
6. Have a performance status of 0, 1 or 2 on the Eastern Cooperative Oncology Group (ECOG)
Performance Scale. (Max of 5% ECOG of 2.)
7. Demonstrate adequate organ function.
8. Female subjects of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication and be willing to use contraception in accordance with the Protocol.
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E.4 | Principal exclusion criteria |
1. Has muscle invasive (i.e. T2, T3, T4) locally advanced non-resectable or metastatic urothelial carcinoma.
2. Has concurrent extra-vesical (i.e. urethra, ureter or renal pelvis) non-muscle invasive transitional cell carcinoma of the urothelium.
3. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
4. Has undergone any intervening intravesical chemotherapy or immunotherapy from the time of the most recent cystoscopy/TURBT to starting trial treatment.
5. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to Cycle 1, Day 1 or who has not recovered (ie, ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.
6. Has a known additional malignancy that is progressing or requires active treatment.
7. Has an active autoimmune disease that has required systemic treatment in past 2 years.
8. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the planned first dose of the study. The use of physiologic doses of corticosteroids may be approved after consultation with the sponsor.
9. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
10. Has an active infection requiring systemic therapy, including active or intractable urinary tract infection (UTI) in the last month.
11. Is pregnant or breastfeeding, or expecting to conceive within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment.
12. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2 agent, or with an agent directed to another co-inhibitory T-cell receptor (e.g. CTLA-4, OX-40, CD137).
13. Has a known history of Human Immunodeficiency Virus (HIV) (HIV-1/2 antibodies).
14. Has known active Hepatitis B or Hepatitis C.
15. Has received a live virus vaccine within 30 days of planned start of trial treatment.
16. Has had an allogenic tissue/solid organ transplant. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Cohort A: CR rate of high risk NMIBC in the overall population.
Cohort B: 12-month DFS rate of high risk NMIBC in the overall population.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Interim Analysis Proof of Concept (IA POC) = 20 Cohort A subjects @ 12 weeks
Interim Analysis II (IA 2) = 50 Cohort A subjects @ 24 weeks
Final Analysis = Full Enrollment plus 9 months
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E.5.2 | Secondary end point(s) |
Cohort A: CR rate of any disease in the overall population; DOR of high risk NMIBC and any disease.
Cohort B: 12-month DFS rate of any disease in the overall population.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Interim Analysis Proof of Concept (IA POC) = 20 Cohort A subjects @ 12 weeks
Interim Analysis II (IA 2) = 50 Cohort A subjects @ 24 weeks
Final Analysis = Full Enrollment plus 9 months
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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 | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
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 | No |
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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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 | 11 |
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 |
Australia |
Brazil |
Canada |
Japan |
Korea, Republic of |
United States |
Russian Federation |
Turkey |
Finland |
France |
Greece |
Ireland |
Italy |
Netherlands |
Sweden |
United Kingdom |
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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 | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |