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

NCT03317158 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: HCRN GU16-243
• Study Type: interventional
• Target: 55
• Locations: 1 country
• Sites: 12

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.

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) 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.

  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 (7)

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

Additional Regimens (to be determined)

Other: To be determined

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)

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 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 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 6

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 had any prior radiation to the prostate or pelvis.
• 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)

Sponsors & Collaborators

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

Study Sites (12)

BCG Oncology

Phoenix, Arizona, 85032, United States

TERMINATED

Stanford University

Stanford, California, 94305, United States

WITHDRAWN

Rush University Medical Cneter

Chicago, Illinois, 60612, United States

WITHDRAWN

Indiana University Melvin and Bren Simon Cancer Center

Indianapolis, Indiana, 46202, United States

RECRUITING

University of Iowa Hospitals and Clinics

Iowa City, Iowa, 52242, United States

RECRUITING

Johns Hopkins University: Sidney Kimmel Comprehensive Cancer Center

Baltimore, Maryland, 21231, United States

RECRUITING

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

WITHDRAWN

Washington University School of Medicine

St Louis, Missouri, 63110, United States

RECRUITING

University of Nebraska Medical Center

Omaha, Nebraska, 68198, United States

RECRUITING

Columbia University Irving Medical Center

New York, New York, 10032, United States

RECRUITING

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, 27599, United States

ACTIVE NOT RECRUITING

Fox Chase Cancer Center

Philadelphia, Pennsylvania, 19111, United States

RECRUITING

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

Central Study Contacts

Noah Hahn, MD

CONTACT

443-287-2886; nhahn4@jhmi.edu

LeaEtta Hyer

CONTACT

317-634-5842; lhyer@hoosiercancer.org

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, 2026
• Study Completion (Estimated): December 31, 2027
• Last Updated: April 15, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (12)