Study of ONCOFID-P-B (PACLITAXEL-HYALURONIC ACID)

Study Overview
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Brief Summary
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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 who achieve a CR by Investigator assessment at the end of the induction phase will enter the maintenance phase and receive monthly treatment for an additional 12 months or until recurrence of CIS/Ta-T1 or progression to MIBC or extravesical disease.

Official Title
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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)

Conditions
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Bladder Carcinoma in Situ (CIS)

Intervention / Treatment
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* Drug: ONCOFID P-B (PACLITAXEL-HYALURONIC ACID)


Participation Criteria
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Eligibility Criteria
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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. 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 ≥ 10.0 g/dL, ALT/AST ≤1. 5 x upper limit of normal (ULN), alkaline phosphatase ≤ 5 x ULN, total serum bilirubin ≤ 1.5 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. Exclusion Criteria: Current or previous muscle-invasive disease (T2-T4) or metastatic urothelial carcinoma. 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. Previous (within the last 5 years) or current malignancies at other sites, except for 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 cT1. 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). Presence of significant urologic disease interfering with intravesical therapy. Current enrollment or participation in another therapeutic clinical trial within 6 months preceding treatment start. Patients previously included in a BCG-only study arm might be enrolled following discussion with the medical monitor and/or sponsor if the definition of adequate BCG therapy is met. Known substance and/or alcohol abuse. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for entry in this study or could compromise protocol objectives. Pregnancy, lactating women or women of childbearing potential (WOCBP) unwilling to use adequate birth control measures for the duration of the study and until 3 months after the end of treatment. Male patients with WOCBP partners unwilling to use contraceptive methods for the duration of the study and until 6 months after the end of treatment. Subjects who have a mean QTc >480 msec at baseline and who need concomitant medications which may cause QT prolongation. Applies to France Only: Persons deprived of liberty by judical or administrative decision, adults subjects to a legal protection measure (under guardianship/curators), persons under protective measures and persons not affiliated with social security will be excluded from the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ONCOFID P-B (PACLITAXEL-HYALURONIC ACID)<br> | Drug: ONCOFID P-B (PACLITAXEL-HYALURONIC ACID)<br>* Schedule: once a week for 12 consecutive weeks (induction phase). Patients who achieve a complete response at the end of the induction phase will enter the maintenance phase, during which ONCOFID-P-B is administered once a month for 12 months until recurrence or progression of the disease.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Centrally assessed Complete Response Rate (CRR) - end of induction phase | CRR calculated as the proportion of patients achieving a CR after 12 weekly intravesical instillations (end of induction phase). CRR will be based on central assessment of response | CRR will be evaluated at the end of the induction phase, at 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Centrally assessed CRR | CRR calculated as the proportion of patients achieving a CR at 6, 9, 18 and 24 months after treatment start | CRR will be evaluated at 6, 9, 18 and 24 months after treatment start | 
| Duration of Response (DoR) | DoR defined as the time from first documented evidence of CR to time of documented recurrence (CIS or Ta-T1), progression to higher grade (MIBC), to extravesical disease or death | DoR will be evaluated at any time during the study up to 24 months after treatment start | 
| Duration of Response (DoR) rate | DoR rate calculated as the proportion of patients who maintained a CR after 6, 9, 12, 15, 18, 21 and 24 months after treatment start. | DoR rates will be evaluated at 6, 9, 12, 15, 18, 21 and 24 after treatment start | 
| Progression rate | Progression rate calculated as the proportion of patients with muscle invasion or extravesical expansion of the disease at 3, 15 and 24 months after treatment start | Progression rate will be evaluated at 3, 15 and 24 months after treatment start | 
| Time to progression | Time to progression defined as time from treatment start to time of documented tumor progression to MIBC or extravesical disease. | Time to progression will be evaluated at any time during the study up to 24 months after treatment start | 
| Rate of patients undergoing cystectomy | Proportion of patients undergoing cystectomy for disease progression at 3 months (end of induction phase), 15 and 24 months after treatment start. | Rate of patients undergoing cystectomy will be evaluated at 3 months (end of induction phase), 15 and 24 months after treatment start. | 
| event-free survival (EFS) | EFS defined as time from treatment start to the time of documented recurrence after CR, or progression or death due to any cause. | event-free survival (EFS) will be evaluated at any time during the study up to 24 months after treatment start | 
| Overall survival (OS) | OS defined as time from treatment start to death due to any cause. | overall survival (OS) will be evaluated at any time during the study up to 24 months after treatment start | 
| Incidence of Treatment-Emergent Adverse Events (Overall Safety) | Overall safety and tolerability evaluated throughout the study on the basis of the incidence, nature, severity and causality of TEAEs, coded to preferred term and system organ class (SOC) using the Medical Dictionary for Regulatory Activities (MedDRA) and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5 and the incidence of serious adverse events (SAEs) | Safety data will be evaluated up to 16 months | 
| Treatment time of retention (tolerability) | The tolerability of ONCOFID-P-B expressed as the ability to retain intravesical instillation for the desired dwell time (up to 120 minutes) and measured as time of retention. | Tolerability will be evaluated up to 16 months |