| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| advanced urothelial cancer |
| gevorderde urotheelcelcarcinoom |
|
| E.1.1.1 | Medical condition in easily understood language |
| advanced urothelial cancer |
| gevorderde urotheelcelkanker |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 identify potential biomarkers for early identification of clinical benefit during pembrolizumab treatment in patients with advanced urothelial cancer
|
| Identificeren van potentiële biomarkers die vroeg kunnen voorspellen of behandeling met pembrolizumab klinisch voordelig zal zijn in patiënten met gevorderde urotheelcelcarcinoom |
|
| E.2.2 | Secondary objectives of the trial |
- To identify potential mechanisms of primary and acquired resistance to pembrolizumab.
- To assess potential correlations between biomarkers and clinical activity according to different definitions and response evaluation criteria.
- To collect tissue, blood and urine samples for future translational experiments. |
- Identificeren van potentiële mechanismes die leiden tot pembrolizumab resistentie (primair en verworven)
- Beoordelen van potentiële correlaties tussen biomarkers en klinische activiteit aan de hand van verschillende definities en response evaluatie criteria
- Verzamelen van weefsel-, bloed-, en urinemonsters voor toekomstig onderzoek |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
In order to be eligible to participate in this study, a subject must meet all of the following criteria:
1. Should have signed informed consent for CPCT-02.
Note: when a safe biopsy of a metastatic or locally advanced lesion is not deemed possible by the treating investigator, subject may be included in the trial without participation in the CPCT-02 trial only upon approval by the central principal investigator.
2. Be willing and able to provide written informed consent for the trial.
3. Be 18 years of age on day of signing informed consent.
4. Have histologically or cytologically-confirmed urothelial cancer that is not
amenable to curative treatment with local and/or systemic therapies.
5. Second-line treatment: have progressive disease after platinum containing chemotherapy as defined by:
- Disease progression after treatment with a platinum-containing regimen for recurrent (disease not amenable to curative treatment)/metastatic disease
- Recurrence/progression within 12 months of prior therapy containing platinum
OR
First-line treatment: have received no prior systemic chemotherapy for advanced/unresectable (inoperable) or metastatic urothelial
a. Adjuvant platinum based chemotherapy, following radial cystectomy, with recurrence > 12 months from completion of therapy is permitted
b. Neoadjuvant platinum based chemotherapy, with recurrence > 12 months since completion of therapy is permitted.
Note: Low-dose chemotherapy (e.g., low dose cisplatin, cisplatin+5FU, mytomycin+5FU, or cisplatin+paclitaxel) given concurrent with radiation to the primary tumor site is not considered as systemic therapy.
And subject must be considered ineligible to receive cisplatin-based combination therapy, based on having at least one of the following criteria:
a. Creatinine clearance (calculated or measured) < 60 mL/min but >30 mL/min
Note: Subjects with a creatinine clearance (calculated or measured) < 30 mL/min or on dialysis are excluded from the trial.
b. CTCAE v.4, Grade >2 audiometric hearing loss (25dB in two consecutive wave ranges)
c. CTCAE v.4, Grade >2 peripheral neuropathy
d. NYHA Class III heart failure (Appendix 13.1)
6. Cisplatin-unfit patients should have a PD-L1 CPS of 10, determined with the use of the commercially available PD-L1 IHC 22C3 pharmDx assay on a DAKO stainer.
PD-L1 expression may be determined prior to enrollment or during the screening phase.
7. Have measurable disease based on RECIST 1.1. Tumor lesions located in a previously irradiated area are considered measurable if progression has been demonstrated in these lesions.
8. Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion. Newly
8.- Note: newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to initiation of treatment on Day 1. Subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen only upon agreement from the Sponsor.
- Note: when a safe biopsy of a metastatic or locally advanced lesion is not deemed possible by the treating investigator, subject may be included in the trial without providing a new core or excisional biopsy of a tumor lesion only upon approval of the central principal investigator.
9. Have a performance status of 0 or 1 on the ECOG Performance Scale.
10. Demonstrate adequate organ function as defined in Table 1, all screening labs should be performed within 10 days of treatment initiation.
11. Female subject of childbearing potential should have a negative urine or serum pregnancy 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.
12. Female subjects of childbearing potential (Section 5.5.2) must be willing to use an adequate method of contraception as outlined in Section 5.5.2 Contraception, for the course of the study through 120 days after the last dose of study medication.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
13. Male subjects of childbearing potential (Section 5.5.2) must agree to use an adequate method of contraception as outlined in Section 5.5.2- Contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy.
|
|
| E.4 | Principal exclusion criteria |
1. Treamtent with an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
2. Has a diagnosis of immunodeficiency or is receiving high dose systemic steroid therapy (defined as > 20 mg prednisone or equivalent per day) or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
3. Has a known history of active TB (Bacillus Tuberculosis).
4. Hypersensitivity to pembrolizumab or any of its excipients.
5. Has had a prior anti-cancer monoclonal antibody (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.
6. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.
- Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
- Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
- Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be allowed at the investigator’s discretion
7. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or
squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
Diagnosis of prostate carcinoma in cystectomy material is not an exclusion criterium.
8. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain
metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose
of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and
are not using high dose steroids (defined as > 20 mg prednisone or equivalent per day) for at least 7 days prior to trial treatment. This
exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
9. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents,
corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
10. Has known history of, or any evidence of active, (non-infectious) pneumonitis that required steroids, evidence of interstitial lung disease or active, non-infectious pneumonitis.
11. Has an active infection requiring systemic therapy.
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.
14. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the prescreening
or screening visit through 120 days after the last dose of trial treatment.
15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti- PD-L2 agent.
16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
17. Has a known history of or is positive for hepatitis B (hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (hepatitis C virus [HCV]
RNA [qualitative] is detected). Note: Without known history, testing needs to be performed to determine eligibility. Hepatitis C antibody (Ab)
testing is allowed for screening purposes in countries where HCV RNA is not part of standard of care.
18. Has received a live vaccine within 30 days of planned start of study therapy.
Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
To identify potential biomarkers for early identification of clinical benefit
during pembrolizumab treatment in patients with advanced urothelial
cancer after first-line chemotherapy |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Clinical benefit and disease progression will be measured according to
modified RECIST 1.1 at any time during the study, while assessment of
the biomarkers will take place at end of the study which will be
approximately 2 years after inclusion of the first patient. |
|
| E.5.2 | Secondary end point(s) |
- To identify potential mechanisms of primary and acquired resistance to
pembrolizumab.
- To assess potential correlations between biomarkers and clinical
activity according to different definitions and response evaluation
criteria.
- To collect tissue, blood and urine samples for future translational
experiments. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Clinical benefit and disease progression will be measured according to
modified RECIST 1.1 at any time during the study, while assessment of
the biomarkers will take place at end of the study which will be
approximately 2 years after inclusion of the first patient.
Collection of samples will be done throughout the study, with time
moments as described in protocol |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| 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 | Yes |
| 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 | No |
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
LVLS. The trial will end when the last subject completes the last visit,
discontinues from the trial or is lost to follow -up. |
|
| 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 | |
| E.8.9.1 | In the Member State concerned days | |
Print
