Clinical trial NCT02138734: A Study of Intravesical BCG in Combination With ALT-803 in Patients With Non-Muscle Invasive Bladder Cancer
Official title: A Study of Intravesical Bacillus Calmette-Guerin (BCG) in Combination With ALT-803 (N-803) in Patients With Non-Muscle Invasive Bladder Cancer
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Non-muscle Invasive Bladder Cancer
Keywords: antitumor
BCG
bladder cancer
cancer
immunotherapy
instillation
interleukin-15
intravesical
naive
non-muscle invasive
transitional cell carcinoma
ALT-803
N-803
Lead sponsor: ImmunityBio, Inc.
Sponsor class: INDUSTRY
First posted: 2014-05-15
Enrollment: 596
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Single arm phase Ib.

Two-arm phase IIb, two-cohort: each randomized 1:1 via randomization scheme stratified by disease and ECOG status.

Cohort A: patients with CIS disease (with or without Ta/T1); planned enrollment = 366 Cohort B: patients with high-grade papillary disease (Ta/T1 only); planned enrollment = 230
Primary purpose: TREATMENT

Brief summary: This is a Phase Ib/IIb, randomized, two-cohort, open-label, multicenter study of intravesical N-803 plus BCG versus BCG alone, in BCG naïve patients with high-grade NMIBC.

Detailed description: The study includes a dose escalation phase (phase Ib) and an expansion phase (phase IIb).

In the phase Ib, patients will be treated with intravesical N-803 in combination with BCG. The purpose of the phase Ib portion of the study is to evaluate the safety, identify the Maximum Tolerated Dose (MTD) of N-803 and determine the Recommended Dose (RD) level of N-803 in combination with BCG for the phase IIb expansion.

In the phase IIb expansion, patients will be randomized to receive either intravesical N-803 in combination with BCG or BCG alone. Patients will be enrolled into one of two study cohorts (Cohort A and Cohort B). These will be two independent study cohorts, evaluated separately for treatment efficacy.

Eligibility criteria: Inclusion Criteria

1. Histologic confirmation of non-muscle invasive bladder cancer of the transitional cell carcinoma high-grade subtype (mixed histology tumors allowed if transitional cell histology is predominant histology).

   1. Cohort A: Histologically confirmed CIS (with or without Ta/T1 disease); Cohort B: Histologically confirmed high-grade papillary disease (Ta/T1 only).
   2. Patients are eligible if the diagnostic biopsy was done within 3 months of treatment start and a cystoscopy demonstrating no resectable disease was done within 6 calendar weeks (inclusive of 48 days) of treatment start (residual CIS is acceptable; patients with T1 disease must undergo repeat resection if muscularis propria is not present in each biopsy sample). Patients with high-grade Ta and/or T1 disease should have complete resection before study treatment.
   3. Upper tract imaging within 6 months prior to study entry must not be suspicious for upper tract malignancy.
2. Currently eligible for intravesical BCG therapy.
3. Age ≥ 18 years.
4. Performance status: ECOG performance status of 0, 1, or 2.
5. BCG-naive disease as defined as either of the following:

   1. Have not received prior intravesical BCG; or
   2. Previously received BCG, but stopped receiving more than 3 years before date of randomization.
6. Laboratory tests performed within 21 days of treatment start:

   1. Absolute lymphocyte count ≥ Institutional lower limit of normal
   2. Absolute neutrophil count (AGC/ANC) ≥ 1,000/μL
   3. Platelets ≥ 100,000/µL \[Patients may be transfused to meet this requirement\]
   4. Hemoglobin ≥ 8 g/dL \[Patients may be transfused to meet this requirement\]
   5. Calculated glomerular filtration rate (GFR\*) \>40 mL/min or Serum creatinine ≤ 1.5 x ULN
   6. Total bilirubin ≤ 2.0 X ULN
   7. AST, ALT, ALP ≤ 3.0 X ULN
7. Adequate pulmonary function without any clinical sign of severe pulmonary dysfunction. PFT \> 50% FEV1 if clinically indicated by the investigator.
8. Negative serum pregnancy test if female and of childbearing potential (non-childbearing is defined as greater than one year postmenopausal or surgically sterilized).
9. Female participants of childbearing potential must adhere to using a medically accepted method of birth control prior to screening and agree to continue its use during the study or be surgically sterilized (e.g., hysterectomy or tubal ligation) and males must agree to use barrier methods of birth control while on study.
10. Provide signed informed consent and HIPPA authorization and agree to comply with all protocol-specified procedures and follow-up evaluations.

    * using the following Cockcroft-Gault equation to calculate the eGFR for this study: eGFR in mL/min = {(140-age in years) x (weight in kg) x F}/(serum creatinine in mg/dL x 72) Where F =1 if male; and 0.85 if female

Exclusion Criteria

1. Prior BCG treatment or known hypersensitivity to BCG. Patients who have received more than a single-dose post-operative treatment of mitomycin-C or gemcitabine following the most recent screening TURBT/biopsy are excluded.
2. Concurrent use of other investigational agents (not including FDA-authorized drugs for the prevention and treatment of COVID-19).
3. History of or evidence of muscle-invasive, locally advanced, metastatic and/or extravesical bladder cancer or any other cancer within the past 5 years, except: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage 1 or 2 cancer from which the patient is currently in complete remission, or stable prostate cancer (under active surveillance or hormone control).
4. Symptomatic congestive heart failure (CHF), NYHA (New York Heart Association) Class III or IV or other clinical signs of severe cardiac dysfunction.
5. Severe/unstable angina pectoris, or myocardial infarction within 6 months prior to study entry.
6. History or evidence of uncontrollable CNS disease.
7. Known HIV-positive.
8. Active systemic infection requiring parenteral antibiotic therapy. All prior infections must have resolved following optimal therapy.
9. Concurrent febrile illness, active urinary tract infection, active tuberculosis, a history of hypotension or anaphylactic reactions.
10. Ongoing chronic systemic steroid therapy required (\>10 mg oral prednisone daily or equivalent).
11. Women who are pregnant or nursing. Female patients of childbearing potential must have a negative pregnancy test and must adhere to using a medically acceptable method of birth control prior to screening and agree to continue its use during the study and for 30 days after the last dose of study drug, or be surgically sterilized (e.g., hysterectomy or tubal ligation). Women of childbearing potential are defined as any female who has experienced menarche and who is NOT permanently sterile or postmenopausal. Postmenopausal is defined as 12 consecutive months with no menses without an alternative medical cause. Males must agree to use barrier methods of birth control while on study and for 90 days post last dose of study drug.
12. Psychiatric illness/social situations that would limit compliance with study requirements.
13. Other illness that in the opinion of the investigator would exclude the patient from participating in this study.

Primary outcomes:
measure: Complete Response (CR) Rate
timeFrame: 6 Months
measure: Disease Free Survival (DFS)
timeFrame: 13 Years and 3 Months
Secondary outcomes:
measure: Progression-free survival (PFS)
timeFrame: 13 Years and 3 Months
measure: Overall survival
timeFrame: 13 Years and 3 months
measure: Disease specific survival
timeFrame: 13 Years and 3 months
measure: Time to disease worsening
timeFrame: 13 Years and 3 Months
measure: Cystectomy Free Rate
timeFrame: 13 years and 3 months
measure: Safety Profile: Number and severity of treatment emergent AEs [Time Frame: 39 Months]
timeFrame: 39 Months
measure: Duration of Complete Response
timeFrame: 13 Years and 3 months
measure: Complete Response Rate( All Recurrent Bladder Cancer Including Low Grade Ta Disease)
timeFrame: 13 Years and 3 months
measure: Long Term Complete Response Rate
timeFrame: 13 years and 3 Months
measure: Duration of Complete Response ( All Recurrent Bladder Cancer Including Low Grade Ta Disease)
timeFrame: 13 Years and 3 months
measure: Cohort B: Disease Free Survival Rate
timeFrame: 36 Months
measure: Cohort B: Disease Free Survival
timeFrame: 13 Years and 3 Months
measure: Vital signs and clinical laboratory assessment
timeFrame: 36 Months
measure: Long Term Follow Up(LTFU) data from subjects who were treated
timeFrame: 10 Years after treatment period visits
Other outcomes:
measure: Exploratory Endpoints- Immunogenicity: Serum level of anti-N-803 in patient samples
timeFrame: 36 Months
measure: Quality of Life Endpoint
timeFrame: 39 Months
measure: Exploratory Endpoints- Whole Slide Images (Baseline and any on-study biopsy)
timeFrame: 39 Months
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Anchorage
country: United States
facility: Alaska Clinical Research Center
state: Alaska
city: Little Rock
country: United States
facility: Arkansas Urology
state: Arkansas
city: Irvine
country: United States
facility: Hoag Cancer Center
state: California
city: Los Angeles
country: United States
facility: UCLA Department of Urology
state: California
city: Sacramento
country: United States
facility: University of California, Davis
state: California
city: Sherman Oaks
country: United States
facility: Skyline Sherman Oaks
state: California
city: Torrance
country: United States
facility: Skyline Urology
state: California
city: Norwich
country: United States
facility: Eastern Connecticut Hematology & Oncology Associates
state: Connecticut
city: Pompano Beach
country: United States
facility: Clinical Research Center of Florida
state: Florida
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Honolulu
country: United States
facility: University of Hawaii Cancer Center
state: Hawaii
city: Westwood
country: United States
facility: Kansas University Medical Center
state: Kansas
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
city: Omaha
country: United States
facility: Adult & Pediatric Urology
state: Nebraska
city: Lebanon
country: United States
facility: Dartmouth-Hitchcock Medical Center
state: New Hampshire
city: Albuquerque
country: United States
facility: Urology Group of New Mexico (AccumetRx Clinical Research)
state: New Mexico
city: Mineola
country: United States
facility: Winthrop University Hospital
state: New York
city: New York
country: United States
facility: Manhattan Medical Research
state: New York
city: New York
country: United States
facility: NYU Langone
state: New York
city: Poughkeepsie
country: United States
facility: Premier Medical Group of the Hudson Valley
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina Chapel Hill
state: North Carolina
city: Raleigh
country: United States
facility: Associated Urologists of North Carolina
state: North Carolina
city: Richmond
country: United States
facility: Virginia Urology
state: Virginia
city: Seattle
country: United States
facility: University of Washington School of Medicine
state: Washington
Study officials:
affiliation: ImmunityBio, Inc.
name: Bobby Reddy, MD
role: STUDY_DIRECTOR
References: