| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic or locally advanced/unresectable urothelial cancer that has recurred or progressed following platinum-based chemotherapy |
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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 | LLT |
| E.1.2 | Classification code | 10046714 |
| E.1.2 | Term | Urothelial carcinoma bladder |
| E.1.2 | System Organ Class | 100000004864 |
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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 |
-Evaluate PFS per RECIST 1.1 by blinded independent radiologists’ review of all subjects with recurrent/progressive metastatic urothelial cancer treated with pembrolizumab (MK-3475) compared to paclitaxel, docetaxel or vinflunine.
-Evaluate the OS of all subjects with metastatic or locally advanced/unresectable urothelial cancer that has recurred or progressed following platinum-based chemotherapy (recurrent/progressive metastatic urothelial cancer), when treated with MK-3475 compared to paclitaxel, docetaxel or vinflunine.
-Evaluate the PFS per RECIST 1.1 by blinded independent radiologists’ review of subjects with platinum-refractory recurrent/progressive metastatic PD-L1 positive urothelial cancer treated with MK-3475 compared to paclitaxel, docetaxel or vinflunine.
-Evaluate the OS of subjects with platinum-refractory metastatic or locally advanced/unresectable PD-L1 positive urothelial cancer, when treated with MK-3475 compared to paclitaxel, docetaxel or vinflunine.
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| E.2.2 | Secondary objectives of the trial |
-Evaluate the safety and tolerability profile of MK- 3475 in subjects with recurrent/progressive metastatic urothelial cancer.
- Evaluate the ORR per RECIST 1.1. by independent radiologists’ review in PD-L1 strongly positive, PD-L1 positive and all subjects with recurrent/progressive metastatic urothelial cancer treated with MK-3475 compared to paclitaxel, docetaxel or vinflunine.
-Evaluate PFS per modified RECIST by independent radiologists’ review of PD-L1 strongly positive, PD-L1 positive, and all subjects with recurrent/progressive metastatic urothelial cancer treated with MK-3475 compared to paclitaxel, docetaxel or vinflunine.
-Evaluate the objective response rate (ORR) per modified RECIST by independent radiologists’ review in PD-L1 strongly positive, PD-L1 positive and all subjects with recurrent/progressive metastatic urothelial cancer treated with MK-3475 compared to paclitaxel, docetaxel or vinflunine.
Refer to protocol for complete list |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Merck will conduct Future Biomedical Research on DNA (blood and tissue) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time. |
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| E.3 | Principal inclusion criteria |
Male and Female subjects with recurrent/progressive metastatic urothelial cancer will be enrolled in this trial.
1. Be willing and able to provide written informed consent/assent for the trial. The subject may also provide consent/assent for FBR. However, the subject may participate in the main trial without participating in Future Biomedical Research.
2. Be ≥18 years of age on day of signing informed consent.
3. Have histologically or cytologically-confirmed diagnosis of urothelial cancer of the renal pelvis, ureter, bladder, or urethra. Both transitional cell and mixed transitional/non-transitional cell histologies are allowed, but transitional cell carcinoma must be the predominant histology. Subjects with non-urothelial cancer of the urinary tract are not allowed.
4. Have had progression or recurrence of urothelial cancer following receipt of a first-line platinum-containing regimen (e. g cisplatin, carboplatin):
a. Received a first-line platinum-containing regimen in the metastatic setting or for inoperable locally advanced disease
or
b. Received adjuvant platinum-containing therapy following cystectomy for localized muscle-invasive urothelial cancer, with recurrence/progression ≤12 months following completion of therapy.
or
c. Received neoadjuvant platinum-containing therapy prior to cystectomy for localized muscle-invasive urothelial cancer, with recurrence ≤12 months following completion of therapy.
5. Have received no more than two prior lines of systemic chemotherapy for metastatic urothelial cancer. Subjects for whom the most recent therapy has been a non-platinum-based regimen following progression/recurrence on platinum-based therapy (i.e. third-line patients) are eligible if they have progressed/recurred on their most recent therapy.
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. 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 measureable disease based on RECIST 1.1 as assessed by the investigator/site radiologist. Tumor lesions situated in a previously irradiated area are considered measureable if progression has been demonstrated in such lesions.
8. Have a performance status of 0, 1 or 2 on the ECOG Performance Scale, as assessed within 10 days prior to treatment initiation. Subjects with an ECOG performance status of 2 must have a hemoglobin ≥10 g/dL, must not have liver metastases, and must have received the last dose of their last prior chemotherapy regimen ≥3 months (90 days) prior to enrollment.
9. Demonstrate adequate organ function as defined in Table 1 of the protocol, all screening labs should be performed within 10 days of treatment initiation
10. 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. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
11. Female subjects of childbearing potential must be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through120 days after the last dose of pembrolizumab or 180 days after the last dose of paclitaxel, docetaxel or vinflunine. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for >1 year.
12. Male subjects must agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of pembrolizumab (MK-3475) or 180 days after the last dose of paclitaxel, docetaxel or vinflunine.
Crossover from Control Arm to Pembrolizumab
•Have been randomized to the control arm, taken at least one dose and subsequently discontinued treatment with paclitaxel, docetaxel or vinflunine.
•Experienced an investigator-determined confirmed radiographic disease progression per RECIST 1.1 after stopping their initial treatment.
•A scan must be performed within 30 days prior to starting treatment with pembrolizumab.
•Did not receive any anti-PD1/PD-L1, anti-CTLA4 or other checkpoint inhibitor since the last dose of chemotherapy.
•Have a performance status of 0 to 2 on the ECOG Performance Scale.
•Subjects with known and treated brain metastasis are eligible provided they are clinically stable, and brain metastases have been treated.
•Have adequately recovered from adverse events of previous anti-cancer therapy.
•Female and male subjects should agree to use adequate methods of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.
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| E.4 | Principal exclusion criteria |
1.Has disease that is suitable for local therapy administered with curative intent.
2.Currently participating/ has participated in a study of an investigational agent or using an investigational device within 4 weeks prior to the first dose.
3.Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose. The use of physiologic doses of corticosteroids may be approved.
4.Has had a prior anti-cancer mAb within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
5.Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered from adverse events due to a previously administered agent.
6.Has a known additional malignancy that is progressing or requires active treatment. 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. 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 ≤ 6, PSA undetectable.
7.Has known active CNS metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable, have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
8.Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic or immunosuppressive agents. Subjects with vitiligo, diabetes Type I, or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators, inhaled steroids, or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjøgren’s syndrome will not be excluded from the study.
9.Has active cardiac disease, defined as:
a. Myocardial infarction or unstable angina pectoris within 6 months of the first date of study therapy
b. History of serious ventricular arrhythmia, high-grade AV block, or other cardiac arrhythmias requiring anti-arrhythmic medications (except for atrial fibrillation that is well controlled); history of QT interval prolongation
c. NYHA Class III or greater congestive heart failure, or left ventricular ejection fraction of < 40%
10.Has evidence of interstitial lung disease or active non-infectious pneumonitis.
11.Has an active infection requiring systemic therapy.
12.Has a history of severe hypersensitivity reaction to paclitaxel or to other drugs formulated with polyoxyethylated castor oil, to docetaxel or other drugs formulated with polysorbate 80,or to vinflunine or other vinca alkaloids.
13.Requires ongoing therapy with a medication that is a strong inhibitor or inducer of the CYP3A4 enzymes.
14.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.
15.Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
16.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.
17.Has received prior therapy with an anti-PD-1 or anti-PD-L1 agent, or with an agent directed to another co-inhibitory T-cell receptor (e.g. CTLA-4, OX-40, CD137).
18.Has received prior chemotherapy for urothelial cancer with all available study therapies in the control arm (i.e both prior paclitaxel and docetaxel in regions where vinflunine is not an approved therapy, or prior paclitaxel, docetaxel and vinflunine in regions where vinflunine is an approved therapy).
19.Has a known history of HIV.
20.Has known active Hepatitis B or C.
21.Has received a live virus vaccine within 30 days of planned start of trial treatment.
22.Is/ has an immediate family member who is investigational site or sponsor staff directly involved with this trial.
Crossover from Control Arm to Pembrolizumab
• Has discontinued from study MK-3475-045.
• Has active pneumonitis of Grade 2 or greater or history of pneumonitis requiring systemic steroid therapy.
• Has received thoracic radiation therapy of > 30 Gy within 6 months have active and untreated brain metastasis.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoints are progression-free-survival (PFS) and overall survival (OS) in PD-L1 strongly positive, PD-L1 positive, and all subjects. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| OS: The time from randomization to death due to any cause. Patients without documented death at the time of the final analysis will be censored at the date of the last follow-up. PFS: The time from randomization to the first documented disease progression per RECIST 1.1 based on blinded independent radiologists’ review or death due to any cause, whichever occurs first. |
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| E.5.2 | Secondary end point(s) |
-Objective Response Rate (ORR)
-PFS/ORR
-Response Duration |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
ORR: When the proportion of the subjects in the analysis population who have a complete response (CR) or partial response (PR). Responses are based upon blinded central radiologists' review per RECIST 1.1. A supportive analysis of ORR will be conducted using site radiology review as defined in the Imaging Review Charter.
PFS and ORR : When modified RECIST by blinded independent
radiologists' review Response Duration: The time from first documented evidence of CR or PR until disease progression or death. Response duration will be calculated for RECIST 1.1 based on blinded independent radiologists' review and site review. |
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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 | No |
| 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 | No |
| E.8.1.6 | Cross over | Yes |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| Paclitaxel, Docetaxel and Vinflunine |
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| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 60 |
| 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 |
| Austria |
| Belgium |
| Canada |
| Chile |
| Denmark |
| France |
| Germany |
| Hungary |
| Ireland |
| Israel |
| Italy |
| Korea, Republic of |
| Netherlands |
| New Zealand |
| Norway |
| Peru |
| Poland |
| Portugal |
| Puerto Rico |
| Romania |
| Singapore |
| Spain |
| Sweden |
| Taiwan |
| Turkey |
| United Kingdom |
| United States |
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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
|
| The overall trial ends when the last subject completes the last study-related phone call or visit, discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by the investigator). |
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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 | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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