Bladder Cancer, Urothelial Carcinoma
Conditions
Keywords
non-muscle invasive bladder cancer, BCG, immunotherapy
Brief summary
Upon successful screening and registration, enrollment to a cohort will begin. If DLT criteria are exceeded in a cohort, that cohort will close and will not proceed to Phase 2 of the study. Provided the safety of a cohort is established, enrollment will continue. Within BCG-containing cohorts, treatment will begin at full-dose BCG. If DLT criteria are exceeded with full-dose BCG, a one level dose reduction of BCG will be implemented. If DLT criteria are exceeded with reduced-dose BCG, the BCG-containing cohort will not proceed to Phase 2 of the study Phase 1 Cohorts: * Durvalumab Monotherapy (cohort 1); ENROLLMENT COMPLETE * Durvalumab plus BCG (cohort 2); ENROLLMENT COMPLETE * Durvalumab plus External Beam Radiotherapy (EBRT) (cohort 3); ENROLLMENT COMPLETE * Durvalumab plus Intravesical Gemcitabine plus Intravesical Docetaxel (cohort 4); ENROLLMENT COMPLETE * Durvalumab plus Tremelimumab plus Intravesical Gemcitabine plus Intravesical Docetaxel (cohort 5); ENROLLMENT DID NOT OCCUR * Intravesical N-803NAI plus Intravesical Gemcitabine (cohort 6) * Intravesical N-803NAI plus Intravesical Gemcitabine plus Intravesical Docetaxel (cohort 7) * Subcutaneous N-803NAI plus Intravesical N-803NAI plus Intravesical Gemcitabine plus Intravesical Docetaxel (cohort 8) If any of the combination regimen cohorts establishes a RP2D in Phase 1 of the study, enrollment to Phase 2 of the study may proceed within the individual phase 2 expansion cohorts defined by patient BCG exposure history. Upon successful screening and registration, Phase 2 subjects will be assigned to one of the treatment arms. Assignment will occur amongst the arms that are open to accrual at the time of subject registration. Phase 2 subjects will be administered treatment at the RP2D's established for each regimen within Phase 1 of the study. However, within BCG-containing cohorts, the BCG dose will be reduced to Dose level -1 (1/3rd-dose BCG) even if the RP2D established in the Phase 1 of the study was full-dose BCG. The rationale for this stems from ongoing global BCG supply shortages that have arisen since the launch of the trial and multiple prior clinical trials demonstrating similar efficacy with decreased toxicity when reduced-dose BCG regimens are utilized compared to full-dose BCG therapy. This modification was deemed necessary to facilitate continued enrollment to the study while not sacrificing clinical efficacy or safety. This modification also aligns with recent AUA consensus guidelines on BCG dosing during BCG shortages. It is anticipated that individual treatment cohorts will be closed and added during the conduct of the study as cohorts complete accrual, individual cohort safety data is analyzed, and new cohorts are added. Enrollment to Phase 2 cohorts will not begin until at least one cohort has successfully established a RP2D in the Phase 1 portion of the study and deemed safe to proceed to the Phase 2 portion of the trial.
Interventions
DRUGDurvalumab (Cohort 1-3)
Durvalumab 1120 mg intravenously Day 1 every 21 days x 8 cycles.
RADIATIONExternal Beam Radiotherapy (EBRT)
EBRT 6 Gy x 3; Cycle 1 Day 1, 3, and 5
BIOLOGICALBacillus Calmette-Guérin (BCG)
Dose level 0 (starting dose) = Full-dose Dose level-1 = 1/3rd-dose BCG. Dose level -1 is expected to be utilized during the phase II portion of the study due to the ongoing and persistent shortage of BCG in the US.
DRUGGemcitabine
Gemcitabine 1000 mg intravesical weekly (+/- 2 days) x 6 doses
DRUGDocetaxel
Docetaxel 37.5 mg intravesical weekly (+/- 2 days) x 6 doses.
BIOLOGICALTremelimumab
Tremelimumab 75 mg intravenously Day 1 (+/- 2 days) every 28 days x 4 cycles.
DRUGDurvalumab (Cohort 4/5)
Durvalumab 1500 mg intravenously Day 1 (+/- 2 days) every 28 days x 6 cycles.
OTHERTo be determined
Other regimens to be determined
DRUGIntravesical NAI (Cohorts 6-7)
For all cohorts containing intravesical NAI treatment, starting in Week 1, induction intravesical NAI 400 ug will be administered weekly x 6 doses via a foley catheter into an empty bladder and maintained in the bladder for 60 minutes.
DRUGSubcutaneous NAI (Cohort 8)
For all cohorts containing subcutaneous NAI treatment, starting in Week 1, NAI 10 ug/kg will be administered biweekly for 3 doses via subcutaneous injection.
Sponsors
Noah Hahn, M.D.
AstraZeneca
Hoosier Cancer Research Network
ImmunityBio, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Masking description
Open-Label
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
(All Patients): Subject must meet all of the following applicable criteria to participate in this study: • Histologically confirmed non-muscle invasive urothelial carcinoma of the bladder (Ta, T1, or Tis stage) on TURBT obtained within 60 days of registration. NOTE: Mixed histologies are permitted, provided a component of urothelial carcinoma is present. Patients with histologically confirmed non- muscle invasive urothelial carcinoma of the bladder (Ta, T1, or Tis stage) on prior TURBT who undergo re-resection of the tumor base to confirm the diagnosis and/or exclude the presence of muscle-invasive disease (T2 or greater) who do not have appreciable tumor in the re-resection TURBT are eligible to enroll provided their re-resection was obtained within 60 days of registration and they meet all other eligibility criteria. * ECOG (WHO) performance status 0 or 1 * Age ≥ 18 years old at time of consent * Adequate hematologic, hepatic, and renal function as defined by the following laboratory parameters: * White blood cell count (WBC) \> 3.0 K/mm3 * Absolute neutrophil count (ANC) ≥ 1.5 K/mm3 * Platelets ≥ 100 K/mm3 * Hemoglobin (Hgb) ≥ 9 g/dL * Serum total bilirubin: ≤ 1.5 x ULN * ALT and AST ≤ 2.5 x ULN * Serum creatinine clearance (CrCl) ≥ 30 mL/min using the modified Cockcroft- Gault equation * Subjects who give a written informed consent obtained according to local guidelines Inclusion Criteria (Phase 1 Only): In addition to the inclusion criteria required of all patients above, the following inclusion criteria are also required of patients enrolling to Phase 1 of the study. • BCG-unresponsive disease defined by any of the following: * Persistent or recurrent CIS with or without the presence of concurrent Ta or T1 tumors within 12 months of completion of adequate BCG therapy * Recurrent high-grade Ta or T1 tumors within 6 months of completion of adequate BCG therapy. NOTE: In recognition of the fact that procedure scheduling factors beyond the control of the patient or treating physician may cause unintended delays in disease evaluations, patients with pure papillary tumors (Ta or T1) with no components of CIS with recurrence documented within 9 months of completion of adequate BCG therapy who meet all other eligibility criteria may be considered for enrollment after consultation with the study chair. * Persistent T1 high-grade tumors at the first disease evaluation (e.g. 3- month post-treatment evaluation) following an adequate BCG induction course * Prostatic urethra involvement of NMIBC * Adequate BCG therapy is defined as at least one of the following: * At least 5 of 6 doses of an initial induction BCG course plus at least 2 of 3 doses of maintenance therapy * At least 5 of 6 doses of an initial induction BCG course plus at least 2 of 6 doses of a second induction course. NOTE: In cohorts that administer intravenous systemic therapy as part of the treatment regimen (cohorts 1-5), patients with concurrent non-muscle high-grade invasive tumors (CIS, Ta, T1) in the prostatic urethra and/or concurrent non-invasive high-grade tumors (CIS, Ta) in the upper urinary tracts (ureter, renal pelvis) are permitted to enroll in Phase 1 of the study. Patients with concurrent high-grade T1 tumors in the upper urinary tracts (ureter, renal pelvis) are not eligible to enroll in Phase 1 of the study. In cohorts that do not administer intravenous systemic therapy as part of the treatment regimen (cohorts 6-8), patients with concurrent non-muscle invasive high-grade tumors (CIS, Ta, T1) in the prostatic urethra and/or concurrent non-muscle invasive high-grade tumors (CIS, Ta, T1) in the upper urinary tracts (ureter, renal pelvis) are not eligible to enroll in Phase 1 of the study. Patients who have met the BCG-unresponsive criteria at any time point in their treatment history are permitted to enroll in Phase 1 of the study regardless of the time frame between their most recent BCG treatment administration and study registration dates. Inclusion Criteria (Phase 2 Only): In addition to the inclusion criteria required of all patients above, the following inclusion criteria are also required of patients enrolling to Phase 2 of the study. • High-risk NMIBC defined according to modified EORTC risk criteria summarized as follows: NOTE: Intermediate- and Low-risk tumors as defined below are not eligible. NOTE: At least half of the subjects enrolled to each cohort must have a component of CIS present. * Low-risk Tumors: Initial or recurrent tumor \> 12 months after resection with all of the following: * Solitary tumor * Low-grade * \< 3 cm * No CIS * Intermediate-Risk Tumors \--- All tumors not defined in the two adjacent categories (between the category of low and high risk) * High-risk Tumors. Any of the following: \--- T1 tumor * High-grade * CIS * Multiple and recurrent and large (\> 3 cm) Ta low-grade tumors (all conditions must be met for this point on Ta low-grade tumors) • BCG-unresponsive, BCG-relapsing, BCG-persistent, or high-risk BCG-naïve NMIBC defined as follows: NOTE: Patients enrolling to phase 2 will enroll separately into a maximum of three expanded cohorts defined by the BCG exposure population eligibility criteria defined below (BCG-unresponsive, BCG-relapsing, BCG-persistent, and high-risk BCG-naïve). The three possible cohorts for each regimen expanded to phase 2 enrollment will be: BCG-unresponsive, BCG-relapsing and/or BCG-persistent (combined within a single cohort), and high-risk BCG-naïve. It is not anticipated that all three possible phase 2 expansion cohort populations will be pursued for every regimen entering phase 2 expansion. Questions regarding phase 2 expansion cohort populations and patient eligibility should be directed to the study chair. The individual eligibility for phase 2 expanded cohorts according to BCG exposure history are summarized below. * BCG-unresponsive NMIBC phase 2 expanded cohort. BCG-unresponsive NMIBC is defined by any of the following: * Persistent or recurrent CIS with or without the presence of concurrent Ta or T1 tumors within 12 months of completion of adequate BCG therapy * Recurrent high-grade Ta or T1 tumors within 6 months of completion of adequate BCG therapy. NOTE: In recognition of the fact that procedure scheduling factors beyond the control of the patient or treating physician may cause unintended delays in disease evaluations, patients with pure high-grade papillary tumors (Ta or T1) with no components of CIS with recurrence documented within 9 months of completion of adequate BCG therapy who meet all other eligibility criteria may be considered for enrollment after consultation with the study chair. * Persistent T1 high-grade tumors at the first disease evaluation (e.g. 3-month post-treatment evaluation) following an adequate BCG induction course * Prostatic urethra involvement of NMIBC o Adequate BCG therapy is defined as at least one of the following: * At least 5 of 6 doses of an initial induction BCG course plus at least 2 of 3 doses of maintenance therapy * At least 5 of 6 doses of an initial induction BCG course plus at least 2 of 6 doses of a second induction course NOTE: Patients who satisfy the above definition of BCG-unresponsive NMIBC continue to be considered BCG-unresponsive regardless of the receipt of any intervening or additional non-BCG based intravesical therapies (e.g. chemotherapy, non-BCG investigational agents) * BCG-relapsing and/or BCG-persistent NMIBC phase 2 expanded Cohort. BCG-relapsing and/or BCG-persistent NMIBC is defined by either of the following: • BCG-relapsing NMIBC is defined as recurrent high-risk NMIBC after achievement of a complete response to BCG induction therapy which does not meet any of the BCG-unresponsive criteria outlined in the protocol. * BCG-persistent NMIBC is defined as persistent high-risk NMIBC at the first disease evaluation after initial BCG induction therapy (with no intervening achievement of complete response) for which a second course of BCG induction therapy is considered a standard of care (e.g. CIS or high grade Ta tumors) which does not meet any of the BCG-unresponsive criteria outlined in the protocol. * High-risk BCG-naive NMIBC cohort. High-risk BCG-naive NMIBC is defined as high-risk NMIBC in a patient that has never received intravesical BCG therapy. NOTE: Patients who satisfy the above definition of BCG-unresponsive NMIBC continue to be considered BCG-unresponsive regardless of the receipt of any intervening or additional non-BCG based intravesical therapies (e.g. chemotherapy, non-BCG investigational agents) Primary
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Determine the recommended phase 2 dose (RP2D) from BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) | 6 months | Determine the recommended phase 2 dose (RP2D) from BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) patients treated with each of the following immunotherapy study regimens: Durvalumab (cohort 1) Durvalumab + intravesical BCG (cohort 2) Durvalumab + radiation (cohort 3) Durvalumab + intravesical Gemcitabine + intravesical Docetaxel (cohort 4) Durvalumab + Tremelimumab + intravesical Gemcitabine + intravesical Docetaxel (cohort 5) Intravesical NAI + intravesical Gemcitabine (cohort 6) Intravesical NAI + intravesical Gemcitabine + intravesical Docetaxel (cohort 7) Subcutaneous NAI + intravesical NAI + intravesical Gemcitabine + intravesical Docetaxel (cohort 8) The RP2D of each immunotherapy study arm is defined as the dose level at which \< 2 out of 6, \< 4 out of 9, or \< 5 out of 12 patients enrolled within an individual study arm experience dose-limiting toxicity. |
| Phase 2: Determine the complete response rate within individual phase 2 expansion cohorts of BCG-unresponsive, BCG-relapsing/persistent, and high-risk BCG-naïve NMIBC subjects treated with each study regimen | 6 months | The complete response rate within each study arm is defined as the proportion of patients within each arm that demonstrate no evidence of recurrent or persistent high grade urothelial carcinoma of the bladder of any stage at any post-treatment disease assessment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Assess Adverse Events | 6 months | The safety profile of BCG-unresponsive NMIBC subjects treated within each study regimen will be assessed by NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 for Cohorts 1-3 and v5.0 for Cohorts 4-8. |
| Phase 1: Characterize the complete response rate of BCG-unresponsive NMIBC subjects treated with each study regimen | 2 years (24 months) | The complete response rate within each study arm is defined as the proportion of patients within each arm that demonstrate no evidence of recurrent or persistent high grade urothelial carcinoma of the bladder of any stage at any post-treatment disease assessment. |
| Phase 1: Characterize the 12-month recurrence free survival (RFS) rate of BCG-unresponsive NMIBC subjects treated with each study regimen | 12 month | The 12-month RFS rate of BCG-unresponsive NMIBC subjects treated within each study regimen is defined as the proportion of patients within each arm with no evidence of recurrent high grade urothelial carcinoma of the bladder of any stage at the 12-month post-treatment disease assessment. |
| Phase 2: Determine the 12-month RFS rate within individual phase 2 expansion cohorts of BCG-unresponsive, BCG-relapsing/persistent, and high-risk BCG-naive NMIBC subjects treated with each study regimen | 12 months | The 12-month RFS rate of BCG-unresponsive, BCG-relapsing/persistent, and high-risk BCG-naive NMIBC subjects treated within each arm is defined as the proportion of patients within each arm with no evidence of recurrent high grade urothelial carcinoma of the bladder of any stage at the 12-month post-treatment assessment. |
| Phase 2: Identify significant associations between complete response rates and 12-month RFS rates and baseline tumor immunohistochemistry staining patterns of PD-L1 and other relevant mechanism of action targets for each study regimen | 12 months | Associations between complete response rate and 12-month RFS rates will be assessed by baseline tumor immunohistochemistry staining patterns of PD-L1 (assessed by the SP263 PD-L1 antibody) and other relevant mechanism of action targets for each drug. |
| Phase 2: Assess Adverse Events | 6 months | The safety profile within individual phase 2 expansion cohorts of BCG-unresponsive, BCG-relapsing/persistent, and high-risk BCG-naive NMIBC subjects treated within each study arm will be assessed by NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 for Cohorts 1-3 and v5.0 for Cohorts 4-8. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORNoah M. Hahn, MD
Hoosier Cancer Research Network
Outcome results
None listed