Sequential Combination Therapy in Bladder Cancer

Methods:

A consecutive series of patients with High Risk Non-Muscle Invasive Bladder Cancer will be enrolled in several centres

Clinical evaluation:

Patients with High Risk Non-Muscle Invasive Bladder Cancer will be enrolled. For each patients we evaluate the following parameters:

• Age
• Sex
• Occupational status
• Smoker Status
• Co-morbidities
• Concomitant medications or treatment
• Height, Weight, BMI
• Urinary symptoms evaluation:
• Presence of Haematuria at the diagnosis
• International Prostatic Symptoms Score
• Laboratories Analyses
• Hemoglobin serum level
• Creatinine
• EORTC/EAU risk stratification
• Endoscopic bladder evaluation (video-recorded and centrally evaluated)
• Number of Tumors
• Diameter of Tumors (<3 cm or > 3 cm)
• Location of Bladder Tumors
• TURB (video recorded) + histological examination
• Re-TURB showing no evidence of neoplasms
• Follow-up
• Cystoscopy (video will be recorded and centrally re-evaluated for recurrence) and cytology every three months later
• Recurrence Rate
• Number of Recurrence Rate
• Number of Tumors
• Diameter of Tumors
• Location of Bladder Tumors
• Urethral Stricture
• Bladder mapping at 6 months
• Uro Tomography Computerized yearly

Intervention:

The subjects will be assessed for eligibility at the screening visit (Visit 1) three weeks after TURB and re-TURB prior to randomization and only subjects who fulfil the inclusion criteria will be included: patients with a diagnosis of High risk Non Muscle Invasive Bladder Cancer (NMIBC): T1 tumor, G3, Carcinoma in Situ (CIS), or multiple and recurrent and large (>3 cm) Ta or patients in the last EAU recurrence category (EAU/EORTC recurrence score >/=10). Patients selected for the study, are centrally randomized (randomization is performed at the Sant'Andrea Hospital) to receive BCG induction treatment according to the standard protocol (an instillation once a week for six weeks) with Immucyst (81 mg Connaught strain BCG). Patients in group two received BCG treatment with the same protocol with a 40 mg mitomycin instillation the day before .

Adverse Events All the adverse events that will occur in the study will be recorded in the case report form (CRF).

An adverse event (AE) is defined as a harmful clinical event occurring in a patient or a human volunteer involved in a clinical experimentation who received a drug that does not necessarily have a relationship with the treatment given. It is considered AE any medical occurrence including undesirable signs or symptoms or abnormal lab finding.

A Serious Adverse Event (SAE) is an AE that, independently from the dosage of the drug used, had one of the following characteristic:

1. Results in death
2. It's life threatening (i.e. the subject was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe)
3. It's cause of hospital admission or increase the time of hospitalization
4. It's cause of congenital abnormalities at birth
5. It's cause of disability or severe and long lasting inability Treatment Emergent Adverse Events (TEAE) is defined as any event not present prior to the initiation of the treatments or any event already present that worsens in the either intensity or frequency following exposure to the treatments.

A Suspected Unexpected Serious Adverse Reaction (SUSAR) is the term used to refer to an adverse event that occurs in a clinical trial subject, which is assessed as being unexpected, serious and as having a reasonable possibility of a causal relationship with the study drug. It is defined as an untoward and unintended response to a study drug, at any dose, which is not listed in the product information, and meets one of the above mentioned serious characteristics.

Generally AEs are collected after signing the informed consent form and could be related or unrelated to the study drug.

For any AE/SAE recorded during the study a causal relationship with the drug used will be assessed as follows:

• Very likely: the AE/SAE is temporally associated to the drug administration, cannot be explained by other clinical conditions and/or concomitant treatments, disappears with drug withdrawal and recurs after drug reintroduction;
• Likely: the AE/SAE is temporally associated to the drug administration, cannot be explained by other clinical conditions and/or concomitant treatments, disappears with the drug withdrawal. There is no information on drug reintroduction;
• Possible: the AE/SAE is temporally associated to the drug administration, cannot be explained by other clinical conditions and/or concomitant treatments, disappears with drug. There is no information available on the drug withdrawal and reintroduction;
• Doubtful: the AE/SAE could be temporally associated to the drug administration, but can be explained by other clinical conditions and/or concomitant treatments;
• Not correlated: the AE/SAE is not temporally associated to the drug administration and/or can be explained by other clinical conditions and/or concomitant treatments.
• An AE/SAE with causal relationship very likely, likely possible with the drug is considered correlated with it and is defined Adverse Reaction (ADR).

World Health Organization (WHO) defines ADR as "a response to a drug which is noxious \& unintended and which occurs at doses normally used for prophylaxis diagnosis or therapy of a disease or for modification of a physiological function".

The difference between AE and ADR is that AE event does not imply causality but not for ADR, a causal rule is suspected.

An ADR unexpected is defined an ADR that for nature and severity is not listed in the product information (Reference Safety Information (RSI)/Investigator's Brochure (IB)).

Toxicity evaluation Urine culture is performed 3 days before each bladder instillation to check urine sterility (mandatory before the first course, optional before the following instillations). Treatment related adverse events are recorded by the patients on a diary.

Outcome analysis: adverse events are self-recorded by the patients after each instillation and classified by the investigator according to a classification grid considering account duration and intensity as proposed by Saint et al. Thus, toxicity is classified as systemic or local and class I (mild) up to class III (severe). The baseline symptoms are also assessed. Local toxicity included bacterial cystitis, BCG induced cystitis, frequency, macroscopic hematuria and "other". Bacterial cystitis is defined as the occurrence of culture proven (not BCG) bacterial cystitis. Irritative bladder symptoms with negative urine culture are classified as BCG induced (chemical) cystitis. "Other" local side effects include granulomatous prostatitis, epididymitis, ureteral obstruction and contracted bladder. Systemic side effects are classified as fever (≥39 °C), influenza like symptoms including general malaise and chills, BCG induced lung infection, liver toxicity, and BCG sepsis. Skin rash, arthralgia and arthritis are classified as possible allergic reactions. Based on the severity of adverse events experienced by the patient, one of the investigator, who is blind to the given therapy, decides whether the next instillation is to be done, postponed, deleted or whether the patient should receive specific anti-tuberculosis therapy. Dose reduction is not allowed in either group. Patients will also complete flow-volume charts for three days after BCG instillations and two questionaries to assess urinary symptoms and patient's perception of bladder pain as the chronic prostatitis symptoms index (NIH-CPSI) and the pelvic pain and urgency/frequency questionaire (PUF). The efficacy of both treatments is assessed at 3, 6,9,12 months with flexible cystoscopy, urinary cytology and bladder biopsy if needed.

STATISTYCAL ANALYSIS Using type I error, and a power of 2.5% and 81% respectively, and by proposing the hypothesis that Immucyst induced a recurrence in about 60% of cases (EORTC risk score 10) and its combination with mitomycin decreases this percent by 30%, it was calculated that 66 subjects per group were necessary to detect this difference using the adjusted chi-square method and Statistical Solution calculator. Student's T test was used for continuous variables. Two-sided p values were calculated.