A Phase III, Single-arm Study to Evaluate the Efficacy and Safety of ONCOFID-P-B (Paclitaxel-hyaluronic Acid Conjugate) Administered Intravesically to Patients With BCG-unresponsive Carcinoma in Situ of the Bladder With or Without Ta-T1 Papillary Disease (Orion-BC)
This is a phase III, single-arm, multicenter, international study to assess the efficacy and safety of ONCOFID-P-B following intravesical instillation in adult patients with histologically and cytologically confirmed CIS, with or without concomitant Ta-T1, who are unresponsive to BCG therapy and unwilling or unfit to undergo radical cystectomy. After providing written informed consent (in presence of an Independent Witness, if applicable), patients will receive an induction therapy consisting of 12 weekly intravesical instillations of ONCOFID-P-B (induction phase). Patients with residual CIS at the end of induction treatment are eligible to enter a re-induction course of therapy (reinduction phase). Patients with stable disease by Investigator assessment defined as neither increased or decreased in extent or severity compared to baseline, are not eligible for re-induction therapy. Patients who achieve a complete resonde (CR) at the end of the induction or re-induction phase enter in the maintenance phase and receive monthly intravesical instillations of ONCOFID-P-B for an additional 12 monsthe or untile recurrence of CIS/HG Ta-T1 or progression to MIBC or extravesical disease. Patients who do not achieve a CR at the end of induction or re-induction phase, will discontinue investigational treatement and are followed up until month 48 from induction or re-induction start, or until a new antitumor therapy is initiated, wichever occurs first. Tumor response is evaluated by cystoscopy, cytology and biopsy at the end of the induction and re-induction phases and at Safety Follow Up Visit (SFUV). During the maintenance/follow-up period, tumorresponse is evaluated by cystoscopy and cytology every 3 months for up to 24 months from induction or re-induction start, and then every 6 months for an additional 2 years (long-term follow-up). Tumor biopsies are performed in case of of positive cystoscopy and/or cytology. Random biopsies are to be performed at 6, 12 and 18 months after the end of the induction or re-induction phase in responding patients (i.e. at 9, 15 and 21 months after induction or re-induction start.
• Willing and able to freely provide written informed consent (in presence of an Independent Witness if applicable) prior to performing study procedures.
• Age 18 years or older, male or female.
• Persistent or recurrent histologically confirmed CIS of the bladder with or without concomitant recurrent HG Ta-T1 and with no evidence of metastases demonstrated by abdominal CT scan or MRI.
• BCG unresponsive patients who refuse radical cystectomy or are not clinically suitable for cystectomy. BCG unresponsive disease is defined as persistent or recurrent CIS alone or with recurrent HG Ta-T1 within 12 months of completion of adequate BCG therapy.
• Adequate BCG therapy is defined as at least one of the following:
⁃ At least five of six doses of an initial induction course plus at least two of three doses of maintenance therapy.
⁃ At least five of six doses of an initial induction course plus at least two of six doses of a second induction course.
• Complete resection of Ta-T1 papillary lesions before entering the trial in patients with concomitant CIS and papillary tumors (residual CIS acceptable, obvious areas of CIS should also be fulgurated).
∙ In patients with T1 papillary lesions undergoing resection of the base of the lesion, the biopsy should contain muscle fibers.
‣ In patients undergoing transurethal resection of their bladder tumors, absence of locally advanced disease should be confirmed by pelvic examination under anesthesia.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
• Adequate organ function:
‣ absolute neutrophil count ≥ 1,500/mm3,
⁃ platelets ≥ 100,000/mm3,
⁃ hemoglobin ≥ 8.5 g/dL,
⁃ ALT/AST ≤1. 5 x upper limit of normal (ULN),
⁃ alkaline phosphatase ≤ 5 x ULN,
⁃ total serum bilirubin ≤ 1.5 x ULN, for patients with Gilbert's ≤ 3 X ULN,
⁃ serum creatinine ≤ 2.2 mg/dL.
• Women in non-reproductive years (defined as surgically sterile or one year postmenopausal). Women of childbearing potential (WOCBP) must have a negative serum pregnancy test upon entry into this study and agree to use highly effective contraceptive methods, i.e. methods that can achieve a failure rate of less than 1% per year when used consistently and correctly. Such methods include:
‣ combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation:
• oral
∙ intravaginal
∙ transdermal
⁃ progestogen-only hormonal contraception associated with inhibition of ovulation:
• oral
∙ injectable
∙ implantable
⁃ intrauterine device (IUD)
⁃ intrauterine hormone-releasing system (IUS)
⁃ bilateral tubal occlusion
⁃ vasectomised partner (\*)
⁃ sexual abstinence (\*\*)
• Male patients with WOCBP partners must agree to use effective contraceptive methods, i.e.:
‣ condom;
⁃ consider contraception for non-pregnant WOCBP partner.
⁃ Able and willing to comply with the scheduled visits, therapy plans, and laboratory tests required in this protocol.
⁃ (\*) Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual partner of the WOCBP trial participant and that the vasectomised partner has received medical assessment of the surgical success.
⁃ (\*\*) Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated to the study treatment. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject.