Vicinium Treatment for Subjects With Non-muscle Invasive Bladder Cancer Previously Treated With BCG

Sponsor

Viventia Bio (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT02449239

Collaborator

(none)

134

Enrollment

Locations

Arm

Duration (Months)

1.9

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Because of the high risk for development of muscle invasive disease, cystectomy is recommended for CIS, high-grade Ta and T1 patients who experience disease recurrence following intravesical therapy. Vicinium is an experimental agent that may provide an alternative to cystectomy

Condition or Disease	Intervention/Treatment	Phase
Bladder Cancer	Biological: Vicinium	Phase 3

Detailed Description

Bladder cancer is the 6th most common cancer in the United States, affecting more men than women. The usual first treatment for NMIBC (Ta, T1, and CIS) is transurethral resection of the bladder tumors followed by intravesical immunotherapy, most commonly with bacillus Calmette-Guérin (BCG).

Because of the high risk for development of muscle invasive disease, cystectomy is recommended for CIS and high-grade Ta and T1 patients who experience disease recurrence following intravesical therapy. For patients unable or unwilling to undergo cystectomy, treatment options are limited.

Vicinium contains the active pharmaceutical ingredient VB4-845, which is a recombinant fusion protein produced in Escherichia coli (E. coli) that expresses a humanized single-chain antibody fragment specific for the epithelial cell adhesion molecule (EpCAM) antigen linked to ETA(252-608). Once bound to the EpCAM antigen on the surface of carcinoma cells, Vicinium is internalized through an endocytic pathway. The ETA(252-608) is cleaved off and induces cell death by irreversibly blocking protein synthesis.

In vitro and in vivo pharmacology demonstrated that Vicinium exhibits potent activity [inhibitory concentration 50% (IC50) = 0.001 - 10 pM] against numerous cell lines and effectively inhibits tumor growth in several human xenograft animal models. A Phase 2 study evaluated once-weekly instillations of Vicinium 30 mg over 6 or 12 weeks, followed by up to 3 maintenance cycles (3 once-weekly instillations followed by a 9-week drug-free period) in 45 subjects with histologically-confirmed TCC of the bladder and residual CIS with or without concurrent Ta or T1 who were refractory or intolerant to BCG. A complete response (defined as no histological evidence of disease and negative urine cytology at the 3-monthly evaluations) was achieved by 44% of subjects, and 16% of subjects remained disease-free at 1-year. A post-study assessment found that these subjects were still disease-free at 18-25 months. The median time to recurrence was 134 days longer in subjects who received 12 weeks of induction therapy compared to 6 weeks.

This is an open-label, non-randomized, multicenter study in adults with NMIBC, specifically CIS (with or without papillary disease), high-grade Ta or any grade T1 papillary disease, who have previously failed BCG treatment (i.e., not those who are intolerant) with or without interferon. The study consists of a Screening period, a 12-week Induction Phase, and a Maintenance Phase of up to 21 monthly cycles for a total treatment period of up to 104 weeks. This is an outpatient study, but all treatments are administered in the study clinic.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

134 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Open-Label, Multicenter, Ph 3 Study to Evaluate the Efficacy and Tolerability of Intravesical Vicinium™ in Subjects With Non Muscle-Invasive Carcinoma in Situ and/or High-Grade Papillary Disease of the Bladder Treated With BCG

Study Start Date :

Aug 1, 2015

Actual Primary Completion Date :

May 1, 2020

Anticipated Study Completion Date :

May 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Vicinium Induction - 30 mg of Vicinium in 50 mL of saline administered twice weekly (BIW) for 6 weeks followed by once weekly for 6 weeks, for a total of 12 weeks. Maintenance - 30 mg of Vicinium in 50 mL of saline administered once weekly every other week for up to 104 weeks.	Biological: Vicinium Intravesical administration Other Names: VB4-845

Arm

Intervention/Treatment

Experimental: Vicinium

Induction - 30 mg of Vicinium in 50 mL of saline administered twice weekly (BIW) for 6 weeks followed by once weekly for 6 weeks, for a total of 12 weeks. Maintenance - 30 mg of Vicinium in 50 mL of saline administered once weekly every other week for up to 104 weeks.

Biological: Vicinium

Intravesical administration

Other Names:

VB4-845

Outcome Measures

Primary Outcome Measures

Complete response rate [Up to 24 months]
Complete response rate in patients with CIS with or without resected papillary disease following initiation of Vicinium therapy

Secondary Outcome Measures

Recurrence Rate [Patients will be followed for up to 104 weeks]
Number of subjects with recurrence of high-grade disease, tumor progression to muscle invasive bladder cancer, cystectomy for any reason, or death, whichever occurs first.
Event-free survival [Time to event endpoint; patients will be followed for up to 104 weeks]
Interval from the date of first dose of study treatment to persistent high-grade disease or low grade T1 if that was the baseline disease, high-grade disease tumor recurrence, tumor progression to muscle invasive bladder cancer, cystectomy for any reason, or death
Number of patients with adverse events as a measure of tolerability [Every 4 weeks up to 104 weeks]
Frequency and severity of adverse events
Changes in ECG [Every 4 weeks up to 104 weeks]
Changes in ECG from baseline
Changes in vital signs [Every 4 weeks up to 104 weeks]
Changes in vital signs from baseline
Changes in laboratory or physical examination [Every 4 weeks up to 104 weeks]
Changes in laboratory or physical examination from baseline
Complete response rate [Months 3, 6, 9, 12, 15,18, 21 and 24]
Complete response rate in subjects after 3, 6, 9, 12, 15, 18, 21, and 24 months of Vicinium therapy.
Time to cystectomy [Time to event endpoint; patients will be followed for up to 104 weeks]
Number of weeks from the date of first dose of study treatment to physical removal of the bladder
Time to disease recurrence [Time to event endpoint; patients will be followed for up to 104 weeks]
Number of weeks from the date of the first documented no histological evidence of high-grade disease at the end of the Induction Phase to the date of first high grade disease recurrence
Time to progression [Time to event endpoint; patients will be followed for up to 104 weeks]
Number of weeks from date of first dose of study treatment to the date of invasive disease being determined and documented
Progression-free survival [Time to event endpoint; patients will be followed for up to 104 weeks]
Number of weeks from the date of first dose of study treatment to the date of invasive disease being determined and documented or death due to any cause
Overall survival [Time to event endpoint; patients will be followed for up to 104 weeks]
Number of weeks from the date of first dose of study treatment to death due to any cause

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically-confirmed non muscle-invasive urothelial carcinoma (transitional cell carcinoma) of the bladder as follows:
CIS (with or without papillary disease) OR
Any grade T1 papillary disease OR
High-grade Ta papillary disease based on a biopsy within 8 weeks of the initial dose of study treatment. If multiple bladder biopsies are required to confirm eligibility, the last bladder biopsy to the initial dose of study treatment must be within 8 weeks. This diagnosis must be confirmed by the independent central pathology reviewer prior to subject enrollment. A subject with persistent T1 disease on the second (i.e., restaging) TURBT may be enrolled in this study only if the investigator documents the subject declines cystectomy.
Subjects must have received adequate BCG treatment defined as at least 2 courses of BCG, i.e., at least one induction and one maintenance course or at least 2 induction courses. The initial induction course must be at least 5 treatments within a 7-week period. The second course (induction or maintenance) must be at least 2 treatments within a 6-week period. The "5+2" doses of BCG must be given within approximately 1 year (i.e., the start of one course to start of the second course within 12 months ±1 month) and for the same disease episode for which the subject is enrolling. Treatment must be considered "full-dose" BCG (see Section 10). If additional doses or courses of BCG above the minimum "5+2" are given, these do not have to be within the same approximate 12 month timeframe.

Subjects who were unable to receive at least 5 doses of BCG in a first course and at least 2 doses of BCG in a second course due to intolerance are not eligible.

Subjects who began their initial course of BCG with "full-dose" BCG and required dose-reductions due to adverse events but are still able to tolerate at least "5+2" doses of BCG are considered to meet the requirement for "adequate BCG." Subjects who received less than "full dose" BCG (e.g., 1/3rd dosing) as a standard regimen and not due to dose reductions because of AEs are not eligible.

The BCG may have been given in combination with interferon. When BCG is given simultaneously in combination with interferon, 1/3rd dosing of BCG is acceptable.

The subject's disease is refractory or has relapsed following adequate BCG treatment. Refractory disease is defined as disease which persists at the first evaluation following adequate BCG. Relapsed disease is defined as having a complete response to adequate BCG but recurs at a subsequent evaluation.

Subjects will enroll into one of three cohorts based on their type of disease and the time to refractory/relapsed disease following their last dose of BCG as follows:

Cohort 1: Subjects with CIS with or without associated papillary disease whose disease is determined to be refractory or relapsed within 6 months of the last dose of adequate BCG treatment.
Cohort 2: Subjects with CIS with or without associated papillary disease whose disease is determined to be refractory or relapsed more than 6 months but within 11 months of the last dose of adequate BCG treatment.
Cohort 3: Subjects with high-grade Ta or any grade T1 papillary disease (without CIS) whose disease is determined to be refractory or relapsed within 6 months of the last dose of adequate BCG treatment.

For eligibility and cohort assignment, 6 months is defined as 30 weeks i.e., 26 weeks (6 months) plus an additional 4 weeks to accommodate scheduling variations and for diagnostic work-up and 11 months is defined as 50 weeks i.e., 48 weeks (11 months) plus an additional 2 weeks to accommodate scheduling variations and for diagnostic work-up.

For subjects enrolling in Cohort 2: The investigator documents he/she would not treat the subject with additional BCG at the time of study entry.

Male or non-pregnant, non-breastfeeding female, age 18 years or older at date of consent.
All women of childbearing potential (WOCBP) must have a negative pregnancy test within 7 days of the first dose of study therapy. A woman is not of childbearing potential if she has undergone surgical sterilization (bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy) or if she is ≥55 years of age and has had no menstrual bleeding of any kind including menstrual period, irregular bleeding, spotting, etc., for at least 12 months and there is no other cause of amenorrhea (e.g., hormonal therapy, prior chemotherapy).
All sexually active subjects agree to use barrier contraception (i.e., condoms) while receiving study treatment and for 120 days following their last dose of study treatment. WOCBP and males whose sexual partners are WOCBP agree to use barrier contraception and a second form of contraception while receiving study treatment and for 120 days following their last dose of study treatment.
Karnofsky performance status ≥ 60 (Appendix 1).
Adequate organ function, as defined by the following criteria:

Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x upper limit of normal (ULN);
Total serum bilirubin ≤ 1.5 x ULN (CTCAE Grade ≤ 1);
Serum creatinine ≤ 1.5 x ULN; or a creatinine clearance ≥40 mL/min;
Hemoglobin ≥8.0 g/dL;
Absolute neutrophil count ≥1500/mm3;
Platelets ≥75,000/mm3

Ability to understand and sign an Independent Ethics Committee- or Institutional Review Board-approved informed consent document indicating that the subject (or legally acceptable representative) has been informed of all aspects of the trial and is willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. The informed consent document must be signed prior to the subject undergoing tests or procedures solely for determining study eligibility and prior to receiving any protocol treatment.

Exclusion Criteria:

The subject is pregnant or breastfeeding.
Evidence of urethral or upper tract transitional cell carcinoma (TCC) within the past 2 years. Subjects with T1 disease must have no evidence of upper or lower tract disease or a more advanced stage of disease by CT urogram or MRI urogram of the abdomen and pelvis performed within 8 weeks of the first dose of study treatment. If intravenous contrast is contraindicated, retrograde ureteropyelography, or CT or MRI without intravenous contrast may be performed.
Subjects with hydronephrosis, except for those subjects where hydronephrosis has been longstanding (i.e., predates the diagnosis of the CIS, Ta or T1 by more than 2 years) and diagnostic evaluation at Screening shows no evidence of tumor. Subjects with hydronephrosis that is unequivocally unrelated to upper tract malignancy may be considered eligible with Sponsor approval.
Any intravesicular or other chemotherapy treatment within 2 weeks or any investigational agent within 4 weeks prior to the initial dose of study drug.
History of recurrent severe urinary tract infections (UTIs) per investigator judgment. Subjects with a current UTI requiring antibiotic treatment may defer the initiation of Vicinium treatment on Day 1 until resolution of the UTI (even if this extends the screening period requirements to start of Vicinium treatment).
Active, uncontrolled impairment of the urogenital, renal, hepatobiliary, cardiovascular, gastrointestinal, neurologic or hematopoietic systems which, in the opinion of the Investigator, would predispose the subject to the development of complications from the administration of intravesical therapy and/or general anesthesia.
The subject has a diagnosis of another malignancy within 2 years before the first dose of study treatment, except for superficial skin cancer or localized solid tumors deemed cured by surgery and not treated with systemic anticancer therapy and not expected to require anticancer therapy in the next 2 years i.e., while the subject may be taking study treatment. However, subjects with low-risk prostate cancer, e.g.:

Clinically localized disease (≤T2a) and
Gleason score 6 (3+3) and
Serum PSA <10 ng/mL undergoing active surveillance may be enrolled with agreement of the sponsor.

A QTc interval of >470 msec by the Fridericia formula (QTcF), at the Screening ECG. If the subject's QTcF is >470 msec on the initial ECG, a total of 3 ECGs should be obtained at least 3 minutes apart and all within 30 minutes. The average of the 3 QTcF's will be used to determine eligibility. Known or suspected causes of prolonged QTc can be treated (e.g., hypocalcemia, hypokalemia, hypomagnesimia) and the ECGs may be repeated. If the subject initiates treatment with a drug known to prolong the QTc during the Screening period after the initial Screening ECGs were obtained, the Screening ECGs must be repeated once the new drug has reached steady state to ensure the average QTcF remains ≤470 msec. For subject's whose heart rate is <60 bpm, the Bazett correction formula (QTcB) may be used.
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).
Local or severe allergy to any components of the drug regimen.

Contacts and Locations

Locations

	City	State	Country	Postal Code
1	Birmingham	Alabama	United States	35294
2	Phoenix	Arizona	United States	85032
3	Tucson	Arizona	United States	85741
4	Little Rock	Arkansas	United States	72211
5	Los Angeles	California	United States	90017
6	Los Angeles	California	United States	90048
7	Los Angeles	California	United States	90089
8	Los Angeles	California	United States	90095
9	Redwood City	California	United States	94062
10	San Bernardino	California	United States	92404
11	Sherman Oaks	California	United States	91411
12	Torrance	California	United States	90505
13	Englewood	Colorado	United States	80113
14	Washington	District of Columbia	United States	20010
15	Bradenton	Florida	United States	34205
16	Daytona Beach	Florida	United States	32114
17	Orlando	Florida	United States	32803
18	Saint Petersburg	Florida	United States	33710
19	Tampa	Florida	United States	33612
20	Wellington	Florida	United States	33449
21	Atlanta	Georgia	United States	30322
22	Honolulu	Hawaii	United States	96813
23	Coeur d'Alene	Idaho	United States	83814
24	Meridian	Idaho	United States	83642
25	Lake Barrington	Illinois	United States	60010
26	Jeffersonville	Indiana	United States	47130
27	Fairway	Kansas	United States	66205
28	Lenexa	Kansas	United States	66214
29	Wichita	Kansas	United States	67208
30	New Orleans	Louisiana	United States	70112
31	Glen Burnie	Maryland	United States	21061
32	Boston	Massachusetts	United States	02111
33	Burlington	Massachusetts	United States	01805
34	Worcester	Massachusetts	United States	01655
35	Ann Arbor	Michigan	United States	48109
36	Lebanon	New Hampshire	United States	03756
37	Brick	New Jersey	United States	08724
38	Lawrenceville	New Jersey	United States	08648
39	Morristown	New Jersey	United States	07960
40	Albuquerque	New Mexico	United States	87109
41	Albany	New York	United States	12208
42	Bronx	New York	United States	10461
43	New York	New York	United States	10032
44	Poughkeepsie	New York	United States	12601
45	Syracuse	New York	United States	13210
46	Concord	North Carolina	United States	28025
47	Middleburg Heights	Ohio	United States	44130
48	Oklahoma City	Oklahoma	United States	73014
49	Portland	Oregon	United States	97239
50	Bala-Cynwyd	Pennsylvania	United States	19004
51	Bryn Mawr	Pennsylvania	United States	19010
52	Pittsburgh	Pennsylvania	United States	15232
53	Charleston	South Carolina	United States	29401
54	Charleston	South Carolina	United States	29425
55	Dallas	Texas	United States	75231
56	El Paso	Texas	United States	79920
57	Houston	Texas	United States	68130
58	Houston	Texas	United States	77030
59	Temple	Texas	United States	76508
60	Charlottesville	Virginia	United States	22908
61	Richmond	Virginia	United States	23235
62	Halifax	Nova Scotia	Canada	B3H 2Y9
63	Barrie	Ontario	Canada	L4M 7G1
64	Oakville	Ontario	Canada	L6H 3P1
65	Toronto	Ontario	Canada	M4N 3M5
66	Toronto	Ontario	Canada	M5G 2C4
67	Montreal	Quebec	Canada	H2X 0A4
68	Montreal	Quebec	Canada	H4A 3J1
69	Pointe-Claire	Quebec	Canada	H9R 4S3
70	Sherbrooke	Quebec	Canada	J1E 3Z6