| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Muscle invasive non-metastatic bladder cancer |
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| E.1.1.1 | Medical condition in easily understood language |
| Muscle invasive non-metastatic bladder cancer |
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| 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 |
The primary objectives are:
*In the phase Ib study: to assess the feasibility and safety of the addition of nivolumab and/or ipilimumab to MMC/capecitabine chemoradiation of the bladder.
*In the phase II study: to assess the impact of the addition of the addition of nivolumab and/or ipilimumab to MMC/capecitabine chemoradiation of the bladder on disease free survival (DFS) and disease free survival rate (DFS-rate).
*to assess toxicity
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| E.2.2 | Secondary objectives of the trial |
The Secondary Objectives are: (both in the phase Ib and phase II study):
*to assess overall survival (OS)
*to assess overall survival-rate (OS-rate)
*to assess response rate (RR)
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
In order to be eligible for participation in this trial, the participant must:
1 Be willing and able to provide written informed consent for the trial.
2 Be ≥ 18 years of age on day of signing informed consent.
3 Must have undergone transurethral biopsy of the bladder tumor, within 35 days of planned treatment commencement. The patient should have a histologically-confirmed diagnosis of muscle-invasive T2-T4a, N0-1M0 urothelial cell carcinoma of the bladder.
4 Must have undergone maximal transurethral resection of the bladder tumour, to an extent that is judged as safe by the urologist performing the resection, within 35 days of planned treatment commencement.
5 Subjects with tumors of mixed urothelial/non-urothelial cell histology are allowed, but urothelial cell carcinoma must be the predominant histology (>50%). Subjects with predominant or exclusively non-urothelial cell histology are not allowed.
6 Have planned for chemoradiotherapy as definitive treatment.
7 Have a performance status of 0 or 1 on the ECOG Performance Scale
8 Have a bladder function that is accessible for cystoscopical follow up.
9 Demonstrate adequate organ function as defined below. All screening labs should be performed within 28 days of registering the patient on the trial. Screening laboratory values must meet the following criteria:
10 Female participants of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to registering the patient. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
11 Female participants of childbearing potential should be willing to one highly effective method use two methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days5 month after the last dose of study medication Participants of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.
12 Male participants should agree to use an adequate method of contraceptioncondoms starting with the first dose of study therapy through 120 7 monthdays after the last dose of study therapy.
13 Willing to consent to the use of their collected tumor specimen, blood and urine as detailed in the protocol for future scientific research including but not limited to DNA, RNA and protein based biomarker detection.
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| E.4 | Principal exclusion criteria |
The participant must be excluded from participating in the trial if the participant:
1 Has concurrent extra-vesical (i.e. urethra, ureter or renal pelvis) urothelial cell carcinoma of the urothelium. Patients who have involvement of the prostatic urethra with urothelial cell cancer may be included if the location can be safely incorporated in the radiation field.
2 Extensive or multifocal bladder carcinoma in situ (CIS) precluding curative chemoradiotherapy.
3 Evidence of distant metastatic disease on a CT or FDG PET/CT chest/abdomen/pelvis performed within 28 days prior to study entry. Up to 3 metastatic lymphnodes in the pelvis (below the common iliac arteries) are allowed, if these can be incorporated in the radiotherapy field.
4 Prior pelvic radiotherapy
5 Has had prior intravenous chemotherapy, targeted small molecule therapy, or radiation therapy for treatment of bladder cancer. Prior intravesical use of BCG and MMC is permissible.
6 Unsuitable for concurrent MMC / capecitabine based ChRT based on pre-existing medical conditions.
7 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 prior to the first dose of treatment.
8 Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to registering the patient. Patients with adrenal insufficiency receiving replacement dose steroids are allowed on the trial.
9 Has a known history of active TB (Bacillus Tuberculosis)
10 Hypersensitivity to nivolumab and/or ipilimumab or any of its excipients.
11 Prior or concurrent known additional malignancy of any site unless disease free for 5 years. 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, Stage T1a well differentiated prostatic carcinoma in men (Gleason = 3+3, PSA <5)
12 Has any history of active autoimmune disease, Stevens-Johnson syndrome or Guillain-Barre. Exceptions to this are:
a. Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone
b. Patients with controlled Type I diabetes mellitus on a stable dose of insulin regimen who are also be eligible for this study
13 Has known history of, or any evidence of active, non-infectious pneumonitis.
14 Has an active infection requiring systemic therapy.
15 Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient’s participation for the full duration of the trial, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
16 Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
17 Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
18 Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
19 Has an Human Immunodeficiency Virus (HIV) infection with a PCR detectable viral load.
Note: HIV 1/2 seropositivity without a PCR detectable viral load is no exclusion criterion27,28.
20 Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
21 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.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoints are:
In the phase Ib study: toxicity scored with CTCAE v 4.0*; incidence of dose limiting toxicity (DLT) during the first 6 weeks after start of the immuno-chemoradiotherapy
In the phase II study: disease free survival (DFS) and disease free survival-rate (DFS-rate)
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| the first 6 weeks after start of the immuno-chemoradiotherapy. |
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| E.5.2 | Secondary end point(s) |
The secondary objectives are (both in the phase Ib and phase II study):
to assess overall survival (OS)
to assess overall survival-rate (OS-rate)
to assess response rate (RR)
to assess toxicity
to assess quality of life (QoL)
to assess HPV positivity in relation to PFS/OS/response
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Up to 8 years after start of the study |
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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 | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| regimen finding / dose finding |
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| 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 | 3 |
| 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
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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 | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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