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

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.

Conditions

• Urothelial Carcinoma
• Bladder Cancer

Interventions

DRUG

Durvalumab (Cohort 1-3)

Durvalumab 1120 mg intravenously Day 1 every 21 days x 8 cycles.

RADIATION

External Beam Radiotherapy (EBRT)

EBRT 6 Gy x 3; Cycle 1 Day 1, 3, and 5

BIOLOGICAL

Bacillus 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.

DRUG

Gemcitabine

Gemcitabine 1000 mg intravesical weekly (+/- 2 days) x 6 doses

DRUG

Docetaxel

Docetaxel 37.5 mg intravesical weekly (+/- 2 days) x 6 doses.

BIOLOGICAL

Tremelimumab

Tremelimumab 75 mg intravenously Day 1 (+/- 2 days) every 28 days x 4 cycles.

DRUG

Durvalumab (Cohort 4/5)

Durvalumab 1500 mg intravenously Day 1 (+/- 2 days) every 28 days x 6 cycles.

OTHER

To be determined

Other regimens to be determined

DRUG

Intravesical 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.

DRUG

Subcutaneous 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 & Collaborators

• AstraZeneca

  collaborator INDUSTRY

• Hoosier Cancer Research Network

  collaborator OTHER

• ImmunityBio, Inc.

  collaborator INDUSTRY

• Noah Hahn, M.D.

  lead OTHER

Principal Investigators

• Noah M. Hahn, MD · Hoosier Cancer Research Network

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

CROSSOVER

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2017-11-21

Primary Completion

2028-12-31

Completion

2029-12-31

FDA Drug

Yes

Countries

• United States

Study Locations