Clinical Trials Register

Summary
EudraCT Number:	2022-001236-28
Sponsor's Protocol Code Number:	R39_21_01
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2022-09-27
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

France - ANSM

A.2

EudraCT number

2022-001236-28

A.3

Full title of the trial

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

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A study of ONCOFID-P-B administered intravesically to patients with Carcinoma in Situ of the bladder who have not responded to the standard treatment

A.4.1

Sponsor's protocol code number

R39_21_01

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT05024773

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Fidia Farmaceutici S.p.A.
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Fidia Farmaceutici S.p.A.
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Fidia Farmaceutici S.p.A.
B.5.2	Functional name of contact point	Nicola Giordan
B.5.3	Address:
B.5.3.1	Street Address	Via Ponte della Fabbrica, 3/A
B.5.3.2	Town/ city	Abano Terme (PD)
B.5.3.3	Post code	35031
B.5.3.4	Country	Italy
B.5.4	Telephone number	00390498232512
B.5.6	E-mail	ngiordan@fidiapharma.it

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	ONCOFID-P-B
D.3.2	Product code	ONCOFID-P-B
D.3.4	Pharmaceutical form	Intravesical solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravesical use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ONCOFID-P20
D.3.9.1	CAS number	850233-83-9
D.3.9.2	Current sponsor code	ONCOFID-P20
D.3.9.3	Other descriptive name	ONCOFID-P20
D.3.9.4	EV Substance Code	SUB266646
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	12
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

BCG-unresponsive Carcinoma in Situ of the bladder with or without Ta-T1 papillary disease

E.1.1.1

Medical condition in easily understood language

Localized bladder cancer with or without papillary disease who has not responded to the standard treatment

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10007400
E.1.2	Term	Carcinoma in situ of the bladder
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the antitumor activity of ONCOFID-P-B using centrally assessed complete response rate (CRR) following 12 weekly intravesical instillations (induction phase).

E.2.2

Secondary objectives of the trial

1. To further evaluate the antitumor activity of ONCOFID-P-B using centrally assessed CRR at 6, 9, 18 and 24 months after treatment start.
2. To evaluate the duration of response (DoR).
3. To evaluate the DoR rates at 6, 9, 12, 15, 18, 21 and 24 after treatment start.
4. To evaluate progression rates at 3, 15 and 24 months after treatment start.
5. To evaluate time to progression.
6. To evaluate the rate of patients undergoing cystectomy at 3, 15 and 24 months after treatment start.
7. To evaluate event-free survival (EFS).
8. To evaluate overall survival (OS).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Willing and able to freely provide written informed consent (in presence of an Independent Witness if applicable) prior to performing study procedures.
2. Age 18 years or older, male or female.
3. Persistent or recurrent CIS of the bladder histologically confirmed, with or without concomitant Ta-T1 and with no evidence of metastases demonstrated by abdominal CT scan.
4. "BCG unresponsive" patients who refuse radical cystectomy or are not clinically suitable for cystectomy. BCG unresponsive disease includes BCG refractory (persistent high-grade disease at 6 months despite adequate BCG treatment) and BCG relapsing (recurrence of high-grade disease after achieving a disease-free state at 6 months after adequate BCG). Patients can be within 6 to 9 months of the last BCG exposure, thereby allowing a 3-month lead time for referral.
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.
5. Complete resection of Ta-T1 papillary lesions before entering the trial in patients with concomitant CIS and papillary tumors (residual CIS acceptable).
a. In patients with T1 papillary lesions undergoing resection of the base of the lesion, the biopsy should contain muscle fibers.
b. In patients with high-risk disease undergoing transurethral resection of their bladder tumors, absence of locally advanced disease confirmed by pelvic examination under anesthesia.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
7. Adequate organ function: absolute neutrophil count ≥ 1,500/mm3, platelets ≥ 100,000/mm3, hemoglobin ≥ 10.0 g/dL, ALT/AST ≤ 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.
8. Women in non-reproductive years (defined as surgically sterile or one year postmenopausal). Women of childbearing potential (WOCBP) must 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 do not need contraception measures.
9. Able and willing to comply with the scheduled visits, therapy plans, and laboratory tests required in this protocol.

E.4

Principal exclusion criteria

1. Current or previous muscle-invasive disease (T2-T4) or metastatic urothelial carcinoma.
2. Suspected hypersensitivity to paclitaxel or to any of the ONCOFID-P-B constituents.
3. 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.
4. Current or prior systemic therapy for bladder cancer.
5. 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, or previous intravesical BCG therapy, which can be given at least 5 weeks before the diagnostic biopsy required for study entry.
6. Symptomatic urinary tract infection or bacterial cystitis. Once successfully treated (negative urine culture), patients may enter the study.
7. Major surgery, other than diagnostic, within 4 weeks prior to treatment.
8. Previous (within the last 5 years) or current malignancies at other sites, except for adequately treated basal cell or squamous cell skin cancer or in situ carcinoma of the cervix uteri.
9. 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).
10. Presence of significant urologic disease interfering with intravesical therapy.
11. Current enrollment or participation in another therapeutic clinical trial within 3 months preceding treatment start.
12. Known substance and/or alcohol abuse.
13. 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.
14. Pregnancy, lactating women or women of childbearing potential unwilling to use adequate birth control measures for the duration of the study and until 3 months after the end of treatment.
15. Subjects who have a mean QTc >480 msec at baseline and who need concomitant medications which may cause QT prolongation.

E.5 End points

E.5.1

Primary end point(s)

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. Local assessments will be used by Investigators to decide on whether to start the maintenance phase, while the statistical analysis of the efficacy endpoints will be performed on central assessments. A CR is defined as at least one of the following:
• Negative cystoscopy and negative (including atypical) urine cytology.
• Positive cystoscopy with biopsy-proven benign or low-grade NMIBC and negative cytology.
• Negative cystoscopy with malignant urine cytology if cancer is found in the upper tract or prostatic urethra and random (mapping) bladder biopsies are negative.

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 12

E.5.2

Secondary end point(s)

1. CRR calculated as the proportion of patients achieving a CR at 6, 9, 18 and 24 months after treatment start
2. 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
3. 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.
4. 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
5. Time to progression defined as time from treatment start to time of documented tumor progression to MIBC or extravesical disease.
6. Proportion of patients undergoing cystectomy for disease progression at 3 months (end of induction phase), 15 and 24 months after treatment start.
7. EFS defined as time from treatment start to the time of documented recurrence after CR, or progression or death due to any cause.
8. OS defined as time from treatment start to death due to any cause.

E.5.2.1

Timepoint(s) of evaluation of this end point

Multiple, please see E.5.2

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised