ADSTILADRIN (=INSTILADRIN) in Patients With High Grade, Bacillus Calmette-Guerin (BCG) Unresponsive Non-Muscle Invasive Bladder Cancer (NMIBC)

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ClinicalTrials.gov Identifier: NCT02773849

Recruitment Status : Completed

First Posted : May 16, 2016

Results First Posted : July 13, 2022

Last Update Posted : December 22, 2023

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Sponsor:

Collaborators:

FKD Therapies Oy

Society of Urologic Oncology Clinical Trials Consortium

Information provided by (Responsible Party):

Ferring Pharmaceuticals

Study Type	Interventional
Study Design	Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition	Superficial Bladder Cancer
Intervention	Biological: ADSTILADRIN
Enrollment	157

Participant Flow

Recruitment Details	Patients enrolled in the study who had at entry, confirmed by a pathology report: CIS only or Ta/T1 high- grade disease with concomitant CIS, or Ta/T1 high-grade disease without concomitant CIS and were "BCG unresponsive" which referred to patients with high-grade NMIBC who were unlikely to benefit from and who did not receive further intravesical BCG.
Pre-assignment Details


Arm/Group Title	ADSTILADRIN
Arm/Group Description	Intravesical administration of ADST...
Arm/Group Description	Intravesical administration of ADSTILADRIN into the bladder
Period Title: Overall Study
Started	157
Completed	63
Not Completed	94
Reason Not Completed
Adverse Event	3
Lack of Efficacy	89
Withdrawal by Subject	1
Withdrawal of Consent	1

Baseline Characteristics

Arm/Group Title		Carcinoma in Situ	Papillary Disease	Total
Arm/Group Description		Patients with Carcinoma in situ (CI...	Patients with high-grade Ta or T1 p...	Total of all reporting groups
Arm/Group Description		Patients with Carcinoma in situ (CIS) with or without concomitant high-grade Ta or T1 papillary disease	Patients with high-grade Ta or T1 papillary disease (without concomitant CIS)	Total of all reporting groups
Overall Number of Baseline Participants		107	50	157
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Categorical Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	107 participants	50 participants	157 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	25 23.4%	13 26.0%	38 24.2%
	>=65 years	82 76.6%	37 74.0%	119 75.8%
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	107 participants	50 participants	157 participants
	Female	12 11.2%	16 32.0%	28 17.8%
	Male	95 88.8%	34 68.0%	129 82.2%
Ethnicity (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	107 participants	50 participants	157 participants
	Hispanic or Latino	3 2.8%	1 2.0%	4 2.5%
	Not Hispanic or Latino	99 92.5%	49 98.0%	148 94.3%
	Unknown or Not Reported	5 4.7%	0 0.0%	5 3.2%
Race (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	107 participants	50 participants	157 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	2 1.9%	1 2.0%	3 1.9%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	6 5.6%	2 4.0%	8 5.1%
	White	99 92.5%	47 94.0%	146 93.0%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Region of Enrollment Measure Type: Number Unit of measure: Participants
United States	Number Analyzed	107 participants	50 participants	157 participants
United States		107	50	157
Height Mean (Standard Deviation) Unit of measure: Cm
	Number Analyzed	107 participants	50 participants	157 participants
		174.7 (9.8)	170.9 (10.3)	173.5 (10.1)
Weight Mean (Standard Deviation) Unit of measure: Kg
	Number Analyzed	107 participants	50 participants	157 participants
		90.14 (20.9)	85.88 (18.6)	88.78 (20.2)
Body Mass Index Mean (Standard Deviation) Unit of measure: Kg/m^2
	Number Analyzed	107 participants	50 participants	157 participants
		29.38 (5.7)	29.28 (5.1)	29.34 (5.5)
ECOG Status ^[1] Measure Type: Count of Participants Unit of measure: Participants	Number Analyzed	107 participants	50 participants	157 participants
Total ECOG of 0		97 90.7%	43 86.0%	140 89.2%
Total ECOG of 1		7 6.5%	6 12.0%	13 8.3%
Total ECOG of 2		3 2.8%	1 2.0%	4 2.5%
		[1] Measure Description: The ECOG performance status was assessed according to a scale from 0 to 5, where 0 is fully active, able to carry on all pre-disease performance without restriction and where 4 is completely disabled, cannot carry on any self-care, totally confined to bed or chair and 5 is dead.

Outcome Measures

1.Primary Outcome


Title	Number of Patients With a Complete Response Rate in Patients With Carcinoma in Situ (CIS), With or Without Concomitant High-grade Ta or T1 Papillary Disease.
Description	A patient in the CIS cohort was judged to have achieved CR where urine...
Description	A patient in the CIS cohort was judged to have achieved CR where urine cytology was reported as normal, atypical, degenerative, reactive, inflammatory, or nonspecific AND cystoscopy was reported as normal or with findings that did not include evidence of low-grade or high-grade recurrence. Bladder biopsy, if performed (not mandatory), demonstrated an absence of low-grade or high-grade recurrence.
Time Frame	12 Months

Outcome Measure Data

Analysis Population Description

Subjects analyzed for this endpoint represent subjects who were evaluable for this outcome measure.


Arm/Group Title	Carcinoma in Situ
Arm/Group Description:	CIS participants had at entry, conf...
Arm/Group Description:	CIS participants had at entry, confirmed by a pathology report: Carcinoma in situ (CIS) only or Ta/T1 highgrade disease with concomitant CIS AND were "BCG unresponsive" which referred to patients with highgrade NMIBC who were unlikely to benefit from and who did not receive further intravesical BCG. The term "BCG unresponsive" included patients who did not respond to BCG treatment and had a persistent high-grade recurrence within 12 months after BCG was initiated, and those who, despite an initial CR to BCG, relapsed with CIS within 12 months of their last intravesical treatment with BCG or relapsed with high-grade Ta/T1 NMIBC within 6 months of their last intravesical treatment with BCG.
Overall Number of Participants Analyzed	103
Measure Type: Count of Participants Unit of Measure: Participants
	55 53.4%

2.Secondary Outcome


Title	Durability of Complete Response in Patients With CIS (With or Without Concomitant Ta or T1 Papillary Disease) Who Achieve a Complete Response.
Description	Durability will be measured by determining the number of patients with...
Description	Durability will be measured by determining the number of patients without recurrence of high-grade disease using results from urine cytology, cystoscopy, and biopsy of the bladder.
Time Frame	Up to 60 months

Outcome Measure Data Not Reported

3.Secondary Outcome


Title	Rate of Event-free Survival, Where Event-free Survival is Defined as High-grade Recurrence Free Survival in Patients With High-grade Ta or T1 Disease (Without Concomitant CIS)
Description	Complete response rate will be measured by determining the number of p...
Description	Complete response rate will be measured by determining the number of patients without recurrence of high-grade disease using results from urine cytology, cystoscopy, and biopsy of the bladder.
Time Frame	up to 60 months

Outcome Measure Data Not Reported

4.Secondary Outcome


Title	Durability of Event-free Survival in Patients With High-grade Ta or T1 Papillary Disease (Without Concomitant CIS), Who Have no Recurrence of High-grade Ta or T1 Papillary Disease.
Description	Durability will be measured by determining the number of patients with...
Description	Durability will be measured by determining the number of patients without recurrence of high-grade disease using results from urine cytology, cystoscopy, and biopsy of the bladder if clinically indicated.
Time Frame	Up to 60 months

Outcome Measure Data Not Reported

5.Secondary Outcome


Title	Incidence of Cystectomy in the Study
Description	The incidence of and time to cystectomy will be measured in the study
Description	The incidence of and time to cystectomy will be measured in the study
Time Frame	60 Months

Outcome Measure Data Not Reported

6.Secondary Outcome


Title	Overall Survival in All Patients
Description	The incidence of and time to survival will be measured in the study
Description	The incidence of and time to survival will be measured in the study
Time Frame	60 Months

Outcome Measure Data Not Reported

7.Secondary Outcome


Title	Anti-adenoviral Antibody Levels for Correlation to Response Rate
Description	Measurement of anti-adenoviral antibody levels at each dosing period, ...
Description	Measurement of anti-adenoviral antibody levels at each dosing period, withdrawal, and at 12 months were done. A patient was considered to have a positive immunogenic response in anti-adenoviral antibodies if a post-baseline titration demonstrated a greater than 2-fold increase from baseline. The table represent data at any time during the 12 months period, which means that the patient will be included in the Yes group if they at any measurement during the trial has a 2-fold increase from baseline.
Time Frame	12 Months

Outcome Measure Data

Analysis Population Description

Patients with Positive Immunogenic Response in Anti-Adenoviral Antibodies at Post-Baseline based on patients who have achieved High-Grade Recurrence Free Survival at 12 months


Arm/Group Title	Carcinoma in Situ	Papillary Disease
Arm/Group Description:	Patients with Carcinoma in situ (CI...	Patients with high-grade Ta or T1 p...
Arm/Group Description:	Patients with Carcinoma in situ (CIS) with or without concomitant high-grade Ta or T1 papillary disease	Patients with high-grade Ta or T1 papillary disease (without concomitant CIS)
Overall Number of Participants Analyzed	89	45
Measure Type: Count of Participants Unit of Measure: Participants
Yes	63 70.8%	34 75.6%
No	26 29.2%	11 24.4%

8.Secondary Outcome


Title	Safety of ADSTILADRIN
Description	The type, incidence, relatedness and severity of treatment emergent ad...
Description	The type, incidence, relatedness and severity of treatment emergent adverse events of ADSTILADRIN as assessed by NCI-CTCAE V4.03 will be monitored.
Time Frame	60 Months

Outcome Measure Data Not Reported

9.Secondary Outcome


Title	Durability of Response During the Long Term Follow up Period.
Description	Durability will be measured by determining the number of patients with...
Description	Durability will be measured by determining the number of patients without recurrence of high-grade disease using results from urine cytology, cystoscopy, and biopsy of the bladder if clinically indicated.
Time Frame	60 Months

Outcome Measure Data Not Reported

Adverse Events

Time Frame	12 months
Adverse Event Reporting Description	The Month 12 final dataset was used for all Adverse Event Reporting data.

Arm/Group Title	Carcinoma in Situ		Ta/T1 High-grade Disease Without Concomitant CIS		TEAE Total Study
Arm/Group Description	Patients had at entry, confirmed by...		Patients had at entry, confirmed by...		Total Treatment-Emergent Adverse Ev...
Arm/Group Description	Patients had at entry, confirmed by a pathology report: Carcinoma in situ (CIS) only or Ta/T1 high-grade disease with concomitant CIS and were "BCG unresponsive" which referred to patients with high-grade NMIBC who were unlikely to benefit from and who did not receive further intravesical BCG. The term "BCG unresponsive" included patients who did not respond to BCG treatment and had a persistent high-grade recurrence within 12 months after BCG was initiated, and those who, despite an initial CR to BCG, relapsed with CIS within 12 months of their last intravesical treatment with BCG or relapsed with high-grade Ta/T1 NMIBC within 6 months of their last intravesical treatment with BCG.		Patients had at entry, confirmed by a pathology report Ta/T1 high-grade disease without concomitant CIS and were "BCG unresponsive" which referred to patients with high-grade NMIBC who were unlikely to benefit from and who did not receive further intravesical BCG. The term "BCG unresponsive" included patients who did not respond to BCG treatment and had a persistent high-grade recurrence within 12 months after BCG was initiated, and those who, despite an initial CR to BCG, relapsed with high-grade Ta/T1 high-grade disease without concomitant CIS within 12 months of their last intravesical treatment with BCG or relapsed with high- grade Ta/T1 NMIBC within 6 months of their last intravesical treatment with BCG.		Total Treatment-Emergent Adverse Events in the Study.
All-Cause Mortality
	Carcinoma in Situ		Ta/T1 High-grade Disease Without Concomitant CIS		TEAE Total Study
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	4/107 (3.74%)		2/50 (4.00%)		6/157 (3.82%)
Serious Adverse Events Serious Adverse Events
	Carcinoma in Situ		Ta/T1 High-grade Disease Without Concomitant CIS		TEAE Total Study
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/107 (6.54%)		7/50 (14.00%)		14/157 (8.92%)
Cardiac disorders
Acute coronary syndrome ^† 1	1/107 (0.93%)	1	0/50 (0.00%)	0	1/157 (0.64%)	1
Arrhythmia ^† 1	1/107 (0.93%)	1	0/50 (0.00%)	0	1/157 (0.64%)	1
Atrial fibrillation ^† 1	1/107 (0.93%)	1	0/50 (0.00%)	0	1/157 (0.64%)	1
Cardiac failure ^† 1	0/107 (0.00%)	0	1/50 (2.00%)	1	1/157 (0.64%)	1
Coronary Artery Disease ^† 1	1/107 (0.93%)	1	1/50 (2.00%)	1	2/157 (1.27%)	2
Myocardial infarction ^† 1	0/107 (0.00%)	0	1/50 (2.00%)	1	1/157 (0.64%)	1
Pericarditis ^† 1	0/107 (0.00%)	0	1/50 (2.00%)	1	1/157 (0.64%)	1
Hepatobiliary disorders
Bile duct stone ^† 1	0/107 (0.00%)	0	1/50 (2.00%)	1	1/157 (0.64%)	1
Immune system disorders
Anaphylactic reaction ^† 1	0/107 (0.00%)	0	1/50 (2.00%)	1	1/157 (0.64%)	1
Infections and infestations
Pneumonia ^† 1	0/107 (0.00%)	0	1/50 (2.00%)	1	1/157 (0.64%)	1
Sepsis ^† 1	1/107 (0.93%)	1	0/50 (0.00%)	0	1/157 (0.64%)	1
Injury, poisoning and procedural complications
Corneal abrasion ^† 1	0/107 (0.00%)	0	1/50 (2.00%)	1	1/157 (0.64%)	1
Metabolism and nutrition disorders
Dehydration ^† 1	1/107 (0.93%)	1	0/50 (0.00%)	0	1/157 (0.64%)	1
Hypoglycaemia ^† 1	0/107 (0.00%)	0	1/50 (2.00%)	1	1/157 (0.64%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung cancer metastatic ^† 1	0/107 (0.00%)	0	1/50 (2.00%)	1	1/157 (0.64%)	1
Lung neoplasm malignant ^† 1	0/107 (0.00%)	0	1/50 (2.00%)	1	1/157 (0.64%)	1
Pancreatic carcinoma ^† 1	0/107 (0.00%)	0	1/50 (2.00%)	1	1/157 (0.64%)	1
Transitional cell cancer of the renal pelvis and ureter ^† 1	0/107 (0.00%)	0	1/50 (2.00%)	1	1/157 (0.64%)	1
Nervous system disorders
Brain oedema ^† 1	1/107 (0.93%)	1	0/50 (0.00%)	0	1/157 (0.64%)	1
Syncope ^† 1	0/107 (0.00%)	0	1/50 (2.00%)	1	1/157 (0.64%)	1
Transient global amnesia ^† 1	0/107 (0.00%)	0	1/50 (2.00%)	1	1/157 (0.64%)	1
Renal and urinary disorders
Haematuria ^† 1	1/107 (0.93%)	1	0/50 (0.00%)	0	1/157 (0.64%)	1
Skin and subcutaneous tissue disorders
Subcutaneous emphysema ^† 1	0/107 (0.00%)	0	1/50 (2.00%)	1	1/157 (0.64%)	1
1 Term from vocabulary, MedDRA (21.0) † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Carcinoma in Situ		Ta/T1 High-grade Disease Without Concomitant CIS		TEAE Total Study
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	101/107 (94.39%)		45/50 (90.00%)		146/157 (92.99%)
Gastrointestinal disorders
Abdominal pain ^† 1	2/107 (1.87%)	2	5/50 (10.00%)	5	7/157 (4.46%)	7
Constipation ^† 1	0/107 (0.00%)	0	3/50 (6.00%)	3	3/157 (1.91%)	3
Diarrhoea ^† 1	10/107 (9.35%)	10	7/50 (14.00%)	7	17/157 (10.83%)	17
Nausea ^† 1	8/107 (7.48%)	8	4/50 (8.00%)	4	12/157 (7.64%)	12
Vomiting ^† 1	3/107 (2.80%)	3	3/50 (6.00%)	3	6/157 (3.82%)	6
General disorders
Chills ^† 1	18/107 (16.82%)	18	6/50 (12.00%)	6	24/157 (15.29%)	24
Fatigue ^† 1	29/107 (27.10%)	29	8/50 (16.00%)	8	37/157 (23.57%)	37
Influenza like illness ^† 1	4/107 (3.74%)	4	4/50 (8.00%)	4	8/157 (5.10%)	8
Instillation site discharge ^† 1	37/107 (34.58%)	37	15/50 (30.00%)	15	52/157 (33.12%)	52
Malaise ^† 1	2/107 (1.87%)	2	4/50 (8.00%)	4	6/157 (3.82%)	6
Pain ^† 1	9/107 (8.41%)	9	2/50 (4.00%)	2	11/157 (7.01%)	11
Pyrexia ^† 1	18/107 (16.82%)	18	6/50 (12.00%)	6	24/157 (15.29%)	24
Infections and infestations
Bronchitis ^† 1	1/107 (0.93%)	1	4/50 (8.00%)	4	5/157 (3.18%)	5
Nasopharyngitis ^† 1	8/107 (7.48%)	8	2/50 (4.00%)	2	10/157 (6.37%)	10
Sinusitus ^† 1	3/107 (2.80%)	3	3/50 (6.00%)	3	6/157 (3.82%)	6
Urinary tract infection ^† 1	10/107 (9.35%)	10	9/50 (18.00%)	9	19/157 (12.10%)	19
Metabolism and nutrition disorders
Decreased appetite ^† 1	2/107 (1.87%)	2	3/50 (6.00%)	3	5/157 (3.18%)	5
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	6/107 (5.61%)	6	3/50 (6.00%)	3	9/157 (5.73%)	9
Back pain ^† 1	4/107 (3.74%)	4	4/50 (8.00%)	4	8/157 (5.10%)	8
Myalgia ^† 1	7/107 (6.54%)	7	5/50 (10.00%)	5	12/157 (7.64%)	12
Nervous system disorders
Dizziness ^† 1	8/107 (7.48%)	8	6/50 (12.00%)	6	14/157 (8.92%)	14
Headache ^† 1	16/107 (14.95%)	16	8/50 (16.00%)	8	24/157 (15.29%)	24
Hypoaesthesia ^† 1	1/107 (0.93%)	1	3/50 (6.00%)	3	4/157 (2.55%)	4
Renal and urinary disorders
Bladder pain ^† 1	9/107 (8.41%)	9	3/50 (6.00%)	3	12/157 (7.64%)	12
Bladder spasm ^† 1	22/107 (20.56%)	22	9/50 (18.00%)	9	31/157 (19.75%)	31
Dysuria ^† 1	15/107 (14.02%)	15	7/50 (14.00%)	7	22/157 (14.01%)	22
Haematuria ^† 1	19/107 (17.76%)	19	7/50 (14.00%)	7	26/157 (16.56%)	26
Micturition urgency ^† 1	19/107 (17.76%)	19	9/50 (18.00%)	9	28/157 (17.83%)	28
Pollakiuria ^† 1	8/107 (7.48%)	8	5/50 (10.00%)	5	13/157 (8.28%)	13
Urinary incontinence ^† 1	6/107 (5.61%)	6	1/50 (2.00%)	1	7/157 (4.46%)	7
Respiratory, thoracic and mediastinal disorders
Cough ^† 1	1/107 (0.93%)	1	3/50 (6.00%)	3	4/157 (2.55%)	4
Skin and subcutaneous tissue disorders
Night sweats ^† 1	0/107 (0.00%)	0	4/50 (8.00%)	4	4/157 (2.55%)	4
Vascular disorders
Hypertension ^† 1	8/107 (7.48%)	8	3/50 (6.00%)	3	11/157 (7.01%)	11
1 Term from vocabulary, MedDRA (21.0) † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Global Clinical Compliance
Organization:	Ferring Pharmaceuticals
EMail:	DK0-Disclosure@ferring.com

Publications of Results:

Boorjian SA, Alemozaffar M, Konety BR, Shore ND, Gomella LG, Kamat AM, Bivalacqua TJ, Montgomery JS, Lerner SP, Busby JE, Poch M, Crispen PL, Steinberg GD, Schuckman AK, Downs TM, Svatek RS, Mashni J Jr, Lane BR, Guzzo TJ, Bratslavsky G, Karsh LI, Woods ME, Brown G, Canter D, Luchey A, Lotan Y, Krupski T, Inman BA, Williams MB, Cookson MS, Keegan KA, Andriole GL Jr, Sankin AI, Boyd A, O'Donnell MA, Sawutz D, Philipson R, Coll R, Narayan VM, Treasure FP, Yla-Herttuala S, Parker NR, Dinney CPN. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial. Lancet Oncol. 2021 Jan;22(1):107-117. doi: 10.1016/S1470-2045(20)30540-4. Epub 2020 Nov 27.

Layout table for additonal information

Responsible Party:	Ferring Pharmaceuticals
ClinicalTrials.gov Identifier:	NCT02773849
Other Study ID Numbers:	rAd-IFN-CS-003
First Submitted:	April 19, 2016
First Posted:	May 16, 2016
Results First Submitted:	May 11, 2022
Results First Posted:	July 13, 2022
Last Update Posted:	December 22, 2023

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