Urothelial Carcinoma, Bladder Cancer
Conditions
Keywords
non-muscle invasive bladder cancer, BCG, immunotherapy
Brief summary
Upon successful screening and registration, enrollment to durvalumab monotherapy (cohort 1) will begin. If DLT criteria outlined in the protocol are exceeded with durvalumab monotherapy (cohort 1), the study will close. Provided the safety of durvalumab monotherapy is established, enrollment to combination regimen cohorts will proceed. Cohorts will simultaneously enroll in parallel to each other with patients assigned to cohorts based on patient slot availability and study site choice of radiation arm participation. Patient assignment to future phase 1 arms would proceed similarly. Within BCG-containing cohorts, treatment will begin at full-dose BCG. If DLT criteria outlined in Section 5.1.4 are exceeded with full-dose BCG, a one level dose reduction of BCG will be implemented. If DLT criteria outlined in Section 5.1.4 are exceeded with reduced-dose BCG, the BCG-containing cohort will not proceed to Phase 2 of the study. Similarly, if DLT criteria outlined in Section 5.1.4 are exceeded within non-BCG containing cohorts, the non-BCG containing cohort will not proceed to phase 2 of the study. Due to the prolonged half-life of antibody therapies, no dose adjustments are planned for durvalumab in any of the cohorts.
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
Sponsors
AstraZeneca
Hoosier Cancer Research Network
Noah Hahn, M.D.
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: Patients with concurrent non-muscle invasive tumors (CIS, Ta, T1) in the prostatic urethra and/or concurrent non-invasive tumors (CIS, Ta) in the upper urinary tracts (ureter, renal pelvis) are permitted to enroll in Phase 1 of the study. Patients with concurrent T1 tumors 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: Patients with concurrent non-muscle invasive tumors (CIS, Ta, T1) in the prostatic urethra are permitted to enroll in Phase 2 of the study. 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. o 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 * 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) 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. Additional details provided in the protocol. |
| 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: 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 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 4-6. |
| 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 4-6. |
| 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 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. |
Countries
United States
Contacts
Primary ContactNoah Hahn, MD
Backup ContactGabrielle Tiggs
Outcome results
None listed