Modern Immunotherapy in BCG-Unresponsive, BCG-Relapsing and High Risk BCG-Naive Non-Muscle Invasive Urothelial Carcinoma of the Bladder

Conditions

• Bladder Cancer
• Urothelial Carcinoma

Eligibility Criteria

Sex

ALL

Age

18 Years - N/A

Healthy Volunteers

Not accepted

Interventions

• Durvalumab (Cohort 1-3) — DRUG
  Durvalumab 1120 mg intravenously Day 1 every 21 days x 8 cycles.
• External Beam Radiotherapy (EBRT) — RADIATION
  EBRT 6 Gy x 3; Cycle 1 Day 1, 3, and 5
• Bacillus Calmette-Guérin (BCG) — BIOLOGICAL
  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.
• Gemcitabine — DRUG
  Gemcitabine 1000 mg intravesical weekly (+/- 2 days) x 6 doses
• Docetaxel — DRUG
  Docetaxel 37.5 mg intravesical weekly (+/- 2 days) x 6 doses.
• Tremelimumab — BIOLOGICAL
  Tremelimumab 75 mg intravenously Day 1 (+/- 2 days) every 28 days x 4 cycles.
• Durvalumab (Cohort 4/5) — DRUG
  Durvalumab 1500 mg intravenously Day 1 (+/- 2 days) every 28 days x 6 cycles.
• To be determined — OTHER
  Other regimens to be determined
• Intravesical NAI (Cohorts 6-7) — DRUG
  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.
• Subcutaneous NAI (Cohort 8) — DRUG
  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.

Study Details

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.

Key Dates

First listed

Oct 23, 2017

Start date

Nov 21, 2017

Status verified

Jul 2026

Primary completion

Dec 31, 2028

Completion

Dec 31, 2029

Study Design

Enrollment

186 participants (estimated)

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

TREATMENT

Arms

• Experimental: Phase 1: Cohort 1
  Durvalumab monotherapy
• Experimental: Phase 1: Cohort 2
  Durvalumab plus BCG
• Experimental: Phase 1: Cohort 3
  Durvalumab plus External Beam Radiotherapy (EBRT) (BCG re-treatment) - Cross-over to Durvalumab Monotherapy
• Experimental: Phase 1: Cohort 4
  Durvalumab + Gemcitabine/Intravesical Docetaxel (Gem/Doc) The sequence of administration is flexible to allow for scheduling of both the infusion and intravesical treatments.
• Experimental: Phase 1: Cohort 5
  NOTE: Cohort 5 was abandoned prior to any patients enrolled. Durvalumab + Tremelimumab + Gem/Doc The sequence of administration is flexible to allow for scheduling of both the infusion and intravesical treatments. For the intravenous medications, durvalumab should be administered first followed by tremelimumab.
• Experimental: Phase 1: Cohort 6
  Intravesical NAI plus Gemcitabine
• Experimental: Phase 2: Cohort 4 Expansion
  Durvalumab + Gemcitabine/Intravesical Docetaxel (Gem/Doc) The sequence of administration is flexible to allow for scheduling of both the infusion and intravesical treatments.
• Experimental: Phase 1: Cohort 7
  Intravesical NAI plus Gemcitabine and Docetaxel
• Experimental: Phase 1: Cohort 8
  Subcutaneous NAI plus Intravesical NAI plus Gemcitabine and Docetaxel
• Experimental: Phase 1: Cohort 9
  Additional Regimens TBD

Primary Outcome Measure

Phase 1: Determine the recommended phase 2 dose (RP2D) from BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) [ Time Frame: 6 months ]

Locations (9)

Find similar trials in Phoenix, AZ

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