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)
Overview
- Phase
- Phase 3
- Intervention
- ONCOFID P-B (PACLITAXEL-HYALURONIC ACID)
- Conditions
- Bladder Carcinoma in Situ (CIS)
- Sponsor
- Fidia Farmaceutici s.p.a.
- Enrollment
- 112
- Locations
- 47
- Primary Endpoint
- Centrally assessed Complete Response Rate (CRR) at any time
- Status
- Recruiting
- Last Updated
- 4 months ago
Overview
Brief Summary
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •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.
Exclusion Criteria
- •Current or previous muscle-invasive disease (T2-T4) or metastatic urothelial carcinoma.
- •Patients with more than 12 months between inclusion and the last BCG instillation
- •Suspected hypersensitivity to paclitaxel or to any of the Oncofid-P-B constituents.
- •Previous or concomitant cancer of the upper urinary tract or the prostatic urethra. Freedom from upper tract disease must be demonstrated by intravenous pyelogram, retrograde pyelogram, CT scan or MRI.
- •Current or prior systemic therapy for bladder cancer.
- •Intravesical therapy within 4 weeks prior to beginning study treatment with the exception of cytotoxic agents (e.g. mitomycin C, doxorubicin and epirubicin) when administered as a single instillation immediately following a TURBT procedure between 14 to 60 days prior to beginning study treatment.
- •Symptomatic urinary tract infection or bacterial cystitis. Once successfully treated (negative urine culture), patients may enter the study.
- •Major surgery, other than diagnostic, within 4 weeks prior to treatment.
- •Patients who have previous or concurrent malignancies that require treatment and are not clinically stable; examples of permitted concurrent recent second malignancies are: adequately treated basal cell or squamous cell skin cancer, in situ carcinoma of the cervix or prostate cancer on active surveillance at low risk for progression, defined as prostate-specific antigen (PSA) \<10 ng/dL, Gleason score 6 or less and cT
- •Subjects who, in the opinion of the Investigator, cannot tolerate intravesical administration or intravesical surgical manipulation (cystoscopy, biopsy) due to the presence of serious comorbid condition(s) (e.g., uncontrolled cardiac or respiratory disorders).
Arms & Interventions
ONCOFID P-B (PACLITAXEL-HYALURONIC ACID)
Intervention: ONCOFID P-B (PACLITAXEL-HYALURONIC ACID)
Outcomes
Primary Outcomes
Centrally assessed Complete Response Rate (CRR) at any time
Time Frame: CRR will be evaluated at any time
CRR calculated as the proportion of patients achieving a CR at any time. CRR will be based on central assessment of response
Secondary Outcomes
- Duration of Response (DoR) rate(DoR rates will be evaluated at 6, 9, 12, 15, 18, 21, 30, 36, 42 and 48 after induction or re-induction start)
- Centrally assessed CRR(CRR will be evaluated at 6, 9, 12, 15, 18, 21, 24, 30, 36, 42 and 48 months after induction or re-induction)
- Rate of patients undergoing cystectomy(Rate of patients undergoing cystectomy will be evaluated at EOIT/EROIT, 9, 15, 24, 24 and 48 months after induction or re-induction start.)
- Time to cystectomy defined as time from start of treatment to the date of cystectomy(from start of treatment to date of cystectomy)
- event-free survival (EFS)(Event-free survival (EFS) will be evaluated at any time during the study up to 48 months after treatment start)
- Duration of Response (DoR)(DoR will be evaluated at 6, 9, 12, 15, 18, 21, 24, 30, 36, 42 and 48 months after induction or re-inductiononths after treatment start)
- Progression rate(Progression rate will be evaluated at EOIT/EROIT, 15, 24 and 48 months after induction or re-inductionstart)
- Time to progression(Time to progression will be evaluated at 15, 24 and 48 months after induction or re-induction start)
- Treatment time of retention (tolerability)(Tolerability will be evaluated up to study month 16)
- Overall survival (OS)(overall survival (OS) will be evaluated at any time during the study up to 48 months after treatment start)
- Incidence of Treatment-Emergent Adverse Events (Overall Safety)(Safety data will be evaluated up to study month 16)