Bladder Cancer, Cancer of the Bladder, Malignant Tumor of the Urinary Bladder, Urinary Bladder Cancer, Urinary Bladder Neoplasm, Urogenital Neoplasms, Urologic Cancer, Urologic Neoplasms, Urothelial Carcinoma
Conditions
Keywords
non-muscle invasive bladder cancer, muscle invasive bladder cancer, high-risk bladder cancer, BCG-unresponsive bladder cancer, BCG failure, BCG-refractory bladder cancer, BCG-resistant bladder cancer, NMIBC, MIBC
Brief summary
This is a clinical trial studying the administration of NanoDoce as a direct injection to the bladder wall immediately after tumor resection and as an intravesical instillation. All participants will receive NanoDoce, and will be evaluated for safety and tolerability, as well as the potential effects of NanoDoce on urothelial carcinoma.
Detailed description
In this clinical trial, subjects with high-risk non-muscle invasive bladder cancer (NMIBC) or muscle invasive bladder cancer (MIBC), will receive NanoDoce. Subjects will be stratified into two treatment groups, Group 1 (NMIBC) and Group 2 (MIBC). All subjects will receive NanoDoce injected into the index tumor resection site on the bladder wall, immediately following transurethral resection of the bladder tumor (TURBT), followed by an initial NanoDoce intravesical instillation. Once the TURBT resection site is healed (approximately 1 month), Group 1 (NMIBC) subjects will proceed to a 3-month Induction period (6 weekly NanoDoce intravesical instillations, followed by 6 weeks of rest). After the Induction period, following confirmation of non-recurrence, Group 1 subjects will proceed to a 3-month Maintenance period (3 weekly NanoDoce intravesical instillations, followed by 9 weeks of rest). After NanoDoce direct injection and the initial intravesical instillation, Group 2 subjects will proceed to institutional standard of care and will not receive Induction or Maintenance intravesical instillations.
Interventions
DRUGNanoDoce (direct injection)
Subjects will receive NanoDoce injected into the index tumor resection site on the bladder wall, immediately following transurethral resection of the bladder tumor (TURBT)
DRUGNanoDoce (intravesical instillation) - Visit 2 Instillation
All subjects will receive an initial intravesical instillation within 2 hours of direct injection.
Group 2 (MIBC) will receive institutional standard of care treatments after the Visit 2 intravesical instillation.
DRUGNanoDoce (intravesical instillation) - Induction and Maintenance Instillations
Group 1 (NMIBC) will receive intravesical instillations in an Induction Period and a Maintenance Period.
Sponsors
US Biotest, Inc.
NanOlogy, LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Open-label, dose rising trial consisting of a dose escalation phase and a dose confirmation phase for direct injection doses. In the dose escalation phase, subjects will be enrolled in sequential cohorts of three subjects starting at the lowest concentration. The dose determined to be most suitable for further evaluation will enroll additional subjects to total up to 12 subjects at that dose level. The study will also dose escalate Groups 1 and 2 for the intravesical instillation of NanoDoce concentrations (2.0 and 3.0 mg/mL).
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Signed informed consent; * Age ≥18 years; * Patients with either: * High-risk Non-Muscle Invasive Bladder Cancer (NMIBC); * Muscle Invasive Bladder Cancer (MIBC); * Urothelial carcinoma confirmed by biopsy, urine cytology, computed tomography scan (CT) or other institution-approved diagnostic methodology; * All visible tumors removed during bladder resection (TURBT); * Performance Status (ECOG) 0-2 at study entry; * Life expectancy of at least 6 months; * Adequate marrow, liver, and renal function; * ANC ≥ 1.5 x 10\^9/L; * Hemoglobin ≥ 9.5 grams/dL; * Platelets ≥ 75 x 10\^9/L; * Total bilirubin ≤ 1.5x institutional ULN; * AST/ ALT ≤ 2.5x institutional ULN; * Creatinine ≤ 1.5x institutional ULN; * Adequate method of birth control.
Exclusion criteria
* Metastatic disease; * Previous (within 12 months) or concurrent history of non-bladder malignancy, except for non-melanoma skin cancer; * Intravesical therapy within 6 weeks prior to consent (chemotherapy or immunotherapy including BCG administered directly into the bladder); * Resection surface area greater than 8 cm2; * Upper tract and urethral disease within 18 months; * Known hypersensitivity to any of the study drug components or reconstitution components; * Pregnant or breastfeeding; * Participation in the treatment phase of another clinical trial within 3 months prior to consent; * Investigator's opinion of subject's probable noncompliance or inability to understand the trial and/or give adequate informed consent; * Ongoing drug or alcohol abuse.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Treatment Emergent Adverse Events (Safety and Tolerability) | Up to End of Treatment (Month 6 for Group 1 and Group 2 Subset, and Day 45 for Group 2) | Treatment Emergent Adverse Events included laboratory assessments, physical examination findings, and vital signs. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Recurrence Free Survival (RFS) | At Months 6, 9, and 12 | No evidence of tumor recurrence or disease progression |
| Disease Progression | Day 45 | Disease progression at Day 45 derived from cytology and biopsy assessments |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Non-Muscle Invasive Bladder Cancer (Group 1) 0.75 mg/mL NanoDoce (direct injection): Subjects received NanoDoce 0.75 mg/mL (up to 4 mL) injected into the index tumor resection site on the bladder wall, immediately following transurethral resection of the bladder tumor (TURBT).
NanoDoce (intravesical instillation) - Subjects received an initial intravesical instillation of NanoDoce at 2.0 mg/mL within 2 hours of direct injection.
NanoDoce (intravesical instillation) - Induction and Maintenance Instillations: Subjects received intravesical instillations of NanoDoce in an Induction Period (6 weekly NanoDoce intravesical instillations at 2.0 mg/mL or 3.0 mg/mL, followed by 6 weeks of rest) and a Maintenance Period (3 weekly NanoDoce intravesical instillations at 3.0 mg/mL, followed by 9 weeks of rest). Total dose administered for intravesical instillations could not exceed 50 mg in 25 mL of saline for a final concentration of 2.0 mg/mL or 75 mg in 25 mL of saline for a final concentration of 3.0 mg/mL. | 4 |
| Non-Muscle Invasive Bladder Cancer (Group 1) 1.5 mg/mL NanoDoce (direct injection): Subjects received NanoDoce 1.5 mg/mL (up to 4 mL) injected into the index tumor resection site on the bladder wall, immediately following transurethral resection of the bladder tumor (TURBT).
NanoDoce (intravesical instillation) - Subjects received an initial intravesical instillation of NanoDoce at 2.0 mg/mL within 2 hours of direct injection.
NanoDoce (intravesical instillation) - Induction and Maintenance Instillations: Subjects received intravesical instillations of NanoDoce in an Induction Period (6 weekly NanoDoce intravesical instillations at 2.0 mg/mL or 3.0 mg/mL, followed by 6 weeks of rest) and a Maintenance Period (3 weekly NanoDoce intravesical instillations at 3.0 mg/mL, followed by 9 weeks of rest). Total dose administered for intravesical instillations could not exceed 50 mg in 25 mL of saline for a final concentration of 2.0 mg/mL or 75 mg in 25 mL of saline for a final concentration of 3.0 mg/mL. | 3 |
| Non-Muscle Invasive Bladder Cancer (Group 1) 2.5 mg/mL NanoDoce (direct injection): Subjects received NanoDoce 2.5 mg/mL (up to 4 mL) injected into the index tumor resection site on the bladder wall, immediately following transurethral resection of the bladder tumor (TURBT).
NanoDoce (intravesical instillation) - Subjects received an initial intravesical instillation of NanoDoce at 2.0 mg/mL within 2 hours of direct injection.
NanoDoce (intravesical instillation) - Induction and Maintenance Instillations: Subjects received intravesical instillations of NanoDoce in an Induction Period (6 weekly NanoDoce intravesical instillations at 2.0 mg/mL or 3.0 mg/mL, followed by 6 weeks of rest) and a Maintenance Period (3 weekly NanoDoce intravesical instillations at 3.0 mg/mL, followed by 9 weeks of rest). Total dose administered for intravesical instillations could not exceed 50 mg in 25 mL of saline for a final concentration of 2.0 mg/mL or 75 mg in 25 mL of saline for a final concentration of 3.0 mg/mL. | 3 |
| Non-Muscle Invasive Bladder Cancer (Group 1) 3.75 mg/mL NanoDoce (direct injection): Subjects received NanoDoce 3.75 mg/mL (up to 4 mL) injected into the index tumor resection site on the bladder wall, immediately following transurethral resection of the bladder tumor (TURBT).
NanoDoce (intravesical instillation) - Subjects received an initial intravesical instillation of NanoDoce at 2.0 or 3.0 mg/mL within 2 hours of direct injection.
NanoDoce (intravesical instillation) - Induction and Maintenance Instillations: Subjects received intravesical instillations of NanoDoce in an Induction Period (6 weekly NanoDoce intravesical instillations at 2.0 or 3.0 mg/mL, followed by 6 weeks of rest) and a Maintenance Period (3 weekly NanoDoce intravesical instillations at 3.0 mg/mL, followed by 9 weeks of rest). Total dose administered for intravesical instillations could not exceed 50 mg in 25 mL of saline for a final concentration of 2.0 mg/mL or 75 mg in 25 mL of saline for a final concentration of 3.0 mg/mL. | 9 |
| Muscle Invasive Bladder Cancer (Group 2) Subset 3.75 mg/mL NanoDoce (direct injection): Subject received NanoDoce 3.75 mg/mL (up to 4 mL) injected into the index tumor resection site on the bladder wall, immediately following transurethral resection of the bladder tumor (TURBT).
NanoDoce (intravesical instillation) - Subject received an initial intravesical instillation of NanoDoce at 3.0 mg/mL within 2 hours of direct injection.
NanoDoce (intravesical instillation) - Induction and Maintenance Instillations: Subject received intravesical instillations of NanoDoce at 3.0 mg/mL in an Induction Period (6 weekly NanoDoce intravesical instillations, followed by 6 weeks of rest) and a Maintenance Period (3 weekly NanoDoce intravesical instillations, followed by 9 weeks of rest). Total dose administered for intravesical instillations could not exceed 75 mg in 25 mL of saline for a final concentration of 3.0 mg/mL. | 1 |
| Muscle Invasive Bladder Cancer (Group 2) 0.75 mg/mL NanoDoce (direct injection): Subjects received NanoDoce 0.75 mg/mL (up to 4 mL) injected into the index tumor resection site on the bladder wall, immediately following transurethral resection of the bladder tumor (TURBT).
NanoDoce (intravesical instillation) - Subjects received an intravesical instillation of NanoDoce 2.0 mg/mL within 2 hours of direct injection. Total dose administered for intravesical instillation could not exceed 50 mg in 25 mL of saline for a final concentration of 2.0 mg/mL. | 5 |
| Muscle Invasive Bladder Cancer (Group 2) 1.5 mg/mL NanoDoce (direct injection): Subjects received NanoDoce 1.5 mg/mL (up to 4 mL) injected into the index tumor resection site on the bladder wall, immediately following transurethral resection of the bladder tumor (TURBT).
NanoDoce (intravesical instillation) - Subjects received an intravesical instillation of NanoDoce 2.0 mg/mL within 2 hours of direct injection. Total dose administered for intravesical instillation could not exceed 50 mg in 25 mL of saline for a final concentration of 2.0 mg/mL. | 2 |
| Muscle Invasive Bladder Cancer (Group 2) 2.5 mg/mL NanoDoce (direct injection): Subjects received NanoDoce 2.5 mg/mL (up to 4 mL) injected into the index tumor resection site on the bladder wall, immediately following transurethral resection of the bladder tumor (TURBT).
NanoDoce (intravesical instillation) - Subjects received an intravesical instillation of NanoDoce 2.0 mg/mL within 2 hours of direct injection. Total dose administered for intravesical instillation could not exceed 50 mg in 25 mL of saline for a final concentration of 2.0 mg/mL. | 2 |
| Muscle Invasive Bladder Cancer (Group 2) 3.75 mg/mL NanoDoce (direct injection): Subjects received NanoDoce 3.75 mg/mL (up to 4 mL) injected into the index tumor resection site on the bladder wall, immediately following transurethral resection of the bladder tumor (TURBT).
NanoDoce (intravesical instillation) - Subjects received an intravesical instillation of NanoDoce 3.0 mg/mL within 2 hours of direct injection. Total dose administered for intravesical instillation could not exceed 75 mg in 25 mL of saline for a final concentration of 3.0 mg/mL. | 7 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 3 | 0 | 2 | 1 | 0 | 4 | 2 | 0 | 4 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Non-Muscle Invasive Bladder Cancer (Group 1) 1.5 mg/mL | Non-Muscle Invasive Bladder Cancer (Group 1) 2.5 mg/mL | Non-Muscle Invasive Bladder Cancer (Group 1) 0.75 mg/mL | Non-Muscle Invasive Bladder Cancer (Group 1) 3.75 mg/mL | Muscle Invasive Bladder Cancer (Group 2) Subset 3.75 mg/mL | Muscle Invasive Bladder Cancer (Group 2) 0.75 mg/mL | Muscle Invasive Bladder Cancer (Group 2) 1.5 mg/mL | Muscle Invasive Bladder Cancer (Group 2) 2.5 mg/mL | Muscle Invasive Bladder Cancer (Group 2) 3.75 mg/mL |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 32 Participants | 2 Participants | 3 Participants | 4 Participants | 7 Participants | 1 Participants | 5 Participants | 2 Participants | 2 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 29 Participants | 3 Participants | 2 Participants | 4 Participants | 8 Participants | 1 Participants | 5 Participants | 2 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 33 Participants | 3 Participants | 3 Participants | 4 Participants | 8 Participants | 1 Participants | 4 Participants | 2 Participants | 2 Participants | 6 Participants |
| Sex: Female, Male Female | 8 Participants | 1 Participants | 1 Participants | 0 Participants | 3 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Sex: Female, Male Male | 28 Participants | 2 Participants | 2 Participants | 4 Participants | 6 Participants | 0 Participants | 5 Participants | 2 Participants | 2 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 3 | 0 / 3 | 0 / 9 | 0 / 1 | 0 / 5 | 0 / 2 | 0 / 2 | 0 / 7 |
| other Total, other adverse events | 3 / 4 | 3 / 3 | 3 / 3 | 9 / 9 | 1 / 1 | 4 / 5 | 2 / 2 | 2 / 2 | 7 / 7 |
| serious Total, serious adverse events | 0 / 4 | 0 / 3 | 0 / 3 | 1 / 9 | 0 / 1 | 1 / 5 | 0 / 2 | 0 / 2 | 1 / 7 |
Outcome results
Primary
Incidence of Treatment Emergent Adverse Events (Safety and Tolerability)
Treatment Emergent Adverse Events included laboratory assessments, physical examination findings, and vital signs.
Time frame: Up to End of Treatment (Month 6 for Group 1 and Group 2 Subset, and Day 45 for Group 2)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Non-Muscle Invasive Bladder Cancer (Group 1) 0.75 mg/mL | Incidence of Treatment Emergent Adverse Events (Safety and Tolerability) | 3 Participants |
| Non-Muscle Invasive Bladder Cancer (Group 1) 1.5 mg/mL | Incidence of Treatment Emergent Adverse Events (Safety and Tolerability) | 3 Participants |
| Non-Muscle Invasive Bladder Cancer (Group 1) 2.5 mg/mL | Incidence of Treatment Emergent Adverse Events (Safety and Tolerability) | 3 Participants |
| Non-Muscle Invasive Bladder Cancer (Group 1) 3.75 mg/mL | Incidence of Treatment Emergent Adverse Events (Safety and Tolerability) | 9 Participants |
| Muscle Invasive Bladder Cancer (Group 2) Subset 3.75 mg/mL | Incidence of Treatment Emergent Adverse Events (Safety and Tolerability) | 1 Participants |
| Muscle Invasive Bladder Cancer (Group 2) 0.75 mg/mL | Incidence of Treatment Emergent Adverse Events (Safety and Tolerability) | 5 Participants |
| Muscle Invasive Bladder Cancer (Group 2) 1.5 mg/mL | Incidence of Treatment Emergent Adverse Events (Safety and Tolerability) | 2 Participants |
| Muscle Invasive Bladder Cancer (Group 2) 2.5 mg/mL | Incidence of Treatment Emergent Adverse Events (Safety and Tolerability) | 1 Participants |
| Muscle Invasive Bladder Cancer (Group 2) 3.75 mg/mL | Incidence of Treatment Emergent Adverse Events (Safety and Tolerability) | 6 Participants |
Secondary
Disease Progression
Disease progression at Day 45 derived from cytology and biopsy assessments
Time frame: Day 45
Population: The muscle invasive bladder cancer (MIBC) (Group 2) and MIBC Group 2 Subset were assessed for disease progression at Day 45. There were two subjects in the 3.75 mg/mL NanoDoce cohort for whom disease status at Day 45 was unknown, and there were two subjects withdrawn from the study prior to analysis of disease progression at Day 45.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Non-Muscle Invasive Bladder Cancer (Group 1) 0.75 mg/mL | Disease Progression | 2 Participants |
| Non-Muscle Invasive Bladder Cancer (Group 1) 1.5 mg/mL | Disease Progression | 1 Participants |
| Non-Muscle Invasive Bladder Cancer (Group 1) 2.5 mg/mL | Disease Progression | 0 Participants |
| Non-Muscle Invasive Bladder Cancer (Group 1) 3.75 mg/mL | Disease Progression | 1 Participants |
| Muscle Invasive Bladder Cancer (Group 2) Subset 3.75 mg/mL | Disease Progression | 0 Participants |
Secondary
Recurrence Free Survival (RFS)
No evidence of tumor recurrence or disease progression
Time frame: At Months 6, 9, and 12
Population: All subjects from the NMIBC Group 1 were evaluated for RFS. No subjects in the MIBC Group 2 or MIBC Group 2 Subset were evaluated for RFS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Non-Muscle Invasive Bladder Cancer (Group 1) 0.75 mg/mL | Recurrence Free Survival (RFS) | 5.1 Months | Standard Deviation 1.79 |
| Non-Muscle Invasive Bladder Cancer (Group 1) 1.5 mg/mL | Recurrence Free Survival (RFS) | 6.7 Months | Standard Deviation 3.1 |
| Non-Muscle Invasive Bladder Cancer (Group 1) 2.5 mg/mL | Recurrence Free Survival (RFS) | 4.7 Months | Standard Deviation 1.1 |
| Non-Muscle Invasive Bladder Cancer (Group 1) 3.75 mg/mL | Recurrence Free Survival (RFS) | 9.6 Months | Standard Deviation 3.31 |