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

NCT03317158 | Active Not Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: HCRN GU16-243
• Study Type: interventional
• Target: 186
• Locations: 1 country
• Sites: 9

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.

Conditions

Urothelial Carcinoma; Bladder Cancer

Keywords

non-muscle invasive bladder cancer; BCG; immunotherapy

Outcome Measures

Primary Outcomes (2)

• Phase 1: Determine the recommended phase 2 dose (RP2D) from BCG-unresponsive non-muscle invasive bladder cancer (NMIBC)

  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.

  6 months

• 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

  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.

  6 months

Secondary Outcomes (6)

• Phase 1: Assess Adverse Events

  6 months

• Phase 1: Characterize the complete response rate of BCG-unresponsive NMIBC subjects treated with each study regimen

  2 years (24 months)

• Phase 1: Characterize the 12-month recurrence free survival (RFS) rate of BCG-unresponsive NMIBC subjects treated with each study regimen

  12 month

• 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

• 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

Study Arms (10)

Phase 1: Cohort 1

EXPERIMENTAL

Durvalumab monotherapy

Drug: Durvalumab (Cohort 1-3)

Phase 1: Cohort 2

EXPERIMENTAL

Durvalumab plus BCG

Drug: Durvalumab (Cohort 1-3); Biological: Bacillus Calmette-Guérin (BCG)

Phase 1: Cohort 3

EXPERIMENTAL

Durvalumab plus External Beam Radiotherapy (EBRT) (BCG re-treatment) - Cross-over to Durvalumab Monotherapy

Drug: Durvalumab (Cohort 1-3); Radiation: External Beam Radiotherapy (EBRT)

Phase 1: Cohort 4

EXPERIMENTAL

Durvalumab + Gemcitabine/Intravesical Docetaxel (Gem/Doc) The sequence of administration is flexible to allow for scheduling of both the infusion and intravesical treatments.

Drug: Gemcitabine; Drug: Docetaxel; Drug: Durvalumab (Cohort 4/5)

Phase 1: Cohort 5

EXPERIMENTAL

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.

Drug: Gemcitabine; Drug: Docetaxel; Biological: Tremelimumab; Drug: Durvalumab (Cohort 4/5)

Phase 1: Cohort 6

EXPERIMENTAL

Intravesical NAI plus Gemcitabine

Drug: Gemcitabine; Drug: Intravesical NAI (Cohorts 6-7)

Phase 2: Cohort 4 Expansion

EXPERIMENTAL

Durvalumab + Gemcitabine/Intravesical Docetaxel (Gem/Doc) The sequence of administration is flexible to allow for scheduling of both the infusion and intravesical treatments.

Drug: Gemcitabine; Drug: Docetaxel; Drug: Durvalumab (Cohort 4/5)

Phase 1: Cohort 7

EXPERIMENTAL

Intravesical NAI plus Gemcitabine and Docetaxel

Drug: Gemcitabine; Drug: Docetaxel; Drug: Intravesical NAI (Cohorts 6-7)

Phase 1: Cohort 8

EXPERIMENTAL

Subcutaneous NAI plus Intravesical NAI plus Gemcitabine and Docetaxel

Drug: Gemcitabine; Drug: Docetaxel; Drug: Intravesical NAI (Cohorts 6-7); Drug: Subcutaneous NAI (Cohort 8)

Phase 1: Cohort 9

EXPERIMENTAL

Additional Regimens TBD

Other: To be determined

Interventions

Durvalumab (Cohort 1-3) DRUG

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

Also known as: Imfinzi

Phase 1: Cohort 1; Phase 1: Cohort 2; Phase 1: Cohort 3

Gemcitabine DRUG

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

Also known as: Gemzar

Phase 1: Cohort 4; Phase 1: Cohort 5; Phase 1: Cohort 6; Phase 1: Cohort 7; Phase 1: Cohort 8; Phase 2: Cohort 4 Expansion

External Beam Radiotherapy (EBRT) RADIATION

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

Phase 1: Cohort 3

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.

Phase 1: Cohort 2

Docetaxel DRUG

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

Also known as: Taxotere

Phase 1: Cohort 4; Phase 1: Cohort 5; Phase 1: Cohort 7; Phase 1: Cohort 8; Phase 2: Cohort 4 Expansion

Tremelimumab BIOLOGICAL

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

Phase 1: Cohort 5

Durvalumab (Cohort 4/5) DRUG

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

Also known as: Imfinzi

Phase 1: Cohort 4; Phase 1: Cohort 5; Phase 2: Cohort 4 Expansion

To be determined OTHER

Other regimens to be determined

Phase 1: Cohort 9

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.

Phase 1: Cohort 6; Phase 1: Cohort 7; Phase 1: Cohort 8

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.

Phase 1: Cohort 8

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• BCG-unresponsive disease defined by any of the following:

You may not qualify if:

• Subjects with muscle-invasive (i.e. T2, T3, T4) locally advanced unresectable, or metastatic urothelial carcinoma as assessed on baseline radiographic imaging obtained within 60 days prior to study registration. The required radiographic imaging includes:
• Abdomen/Pelvis - CT scan
• Chest - chest x-ray or CT scan
• Subjects with another active second malignancy other than non-melanoma skin cancers and biochemical relapsed prostate cancer. Subjects that have completed all necessary therapy and are considered to be at less than 30% risk of relapse are not considered to have an active second malignancy and are eligible for enrollment.
• Subjects who have received the last administration of an anti-cancer therapy including chemotherapy, immunotherapy, and monoclonal antibodies ≤ 4 weeks prior to starting study drug, or who have not recovered from the side effects of such therapy.
• Patients with Grade ≥ 2 neuropathy will be evaluated on a case-by- case basis after consultation with the sponsor-investigator.
• Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the sponsor-investigator.
• Subjects who have received prior therapy with PD-1, PD-L1, or CTLA-4 directed agents.
• Subjects who have undergone major surgery (e.g. intra-thoracic, intra- abdominal or intra-pelvic), open biopsy or significant traumatic injury ≤ 4 weeks prior to starting study drug, or subjects who have had minor procedures (i.e. TURBT), percutaneous biopsies or placement of vascular access device ≤ 1 week prior to starting study drug, or who have not recovered from side effects of such procedure or injury
• Subjects with any of the following concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study:
• Clinically significant cardiac diseases, including any of the following:
• \--- History or presence of serious uncontrolled ventricular arrhythmias
• \--- Clinically significant resting bradycardia
• Any of the following within 3 months prior to starting study drug: myocardial infarction (MI), severe/unstable angina, Coronary Artery Bypass Graft (CABG), Congestive Heart Failure (CHF), Cerebrovascular Accident (CVA), Transient Ischemic Attack (TIA), Pulmonary Embolism (PE)
• Uncontrolled hypertension defined by a SBP ≥ 160 mm Hg and/or DBP ≥ 100 mm Hg, with or without anti-hypertensive medication(s)

Sponsors & Collaborators

• Noah Hahn, M.D.: lead
• AstraZeneca: collaborator
• Hoosier Cancer Research Network: collaborator
• ImmunityBio, Inc.: collaborator

Study Sites (9)

BCG Oncology

Phoenix, Arizona, 85032, United States

Location

Indiana University Melvin and Bren Simon Cancer Center

Indianapolis, Indiana, 46202, United States

Location

University of Iowa Hospitals and Clinics

Iowa City, Iowa, 52242, United States

Location

Johns Hopkins University: Sidney Kimmel Comprehensive Cancer Center

Baltimore, Maryland, 21231, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

University of Nebraska Medical Center

Omaha, Nebraska, 68198, United States

Location

Columbia University Irving Medical Center

New York, New York, 10032, United States

Location

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, 27599, United States

Location

Fox Chase Cancer Center

Philadelphia, Pennsylvania, 19111, United States

Location

Related Links

• Hoosier Cancer Research Network Website

MeSH Terms

Conditions

Carcinoma, Transitional Cell; Urinary Bladder Neoplasms; Non-Muscle Invasive Bladder Neoplasms

Interventions

durvalumab; Gemcitabine; Docetaxel; tremelimumab

Condition Hierarchy (Ancestors)

Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Urinary Bladder Diseases; Urologic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes

Study Officials

• Noah M. Hahn, MD

  Hoosier Cancer Research Network

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: Open-Label
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Sponsor-Investigator

Study Record Dates

• First Submitted: October 12, 2017
• First Posted: October 23, 2017
• Study Start: November 21, 2017
• Primary Completion (Estimated): December 31, 2028
• Study Completion (Estimated): December 31, 2029
• Last Updated: July 15, 2026

Record last verified: 2026-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (9)