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

NCT ID: NCT03317158

Last Updated: 2025-01-30

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 55 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-11-21
• Study Completion Date: 2026-12-31

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Phase 1: Cohort 1

Durvalumab monotherapy

Group Type: EXPERIMENTAL

Durvalumab (Cohort 1-3)

Intervention Type: DRUG

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

Phase 1: Cohort 2

Durvalumab plus BCG

Group Type: EXPERIMENTAL

Durvalumab (Cohort 1-3)

Intervention Type: DRUG

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

Bacillus Calmette-Guérin (BCG)

Intervention Type: 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 3

Durvalumab plus External Beam Radiotherapy (EBRT)

(BCG re-treatment) - Cross-over to Durvalumab Monotherapy

Group Type: EXPERIMENTAL

Durvalumab (Cohort 1-3)

Intervention Type: DRUG

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

External Beam Radiotherapy (EBRT)

Intervention Type: RADIATION

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

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.

Group Type: EXPERIMENTAL

Gemcitabine

Intervention Type: DRUG

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

Docetaxel

Intervention Type: DRUG

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

Durvalumab (Cohort 4/5)

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

Gemcitabine

Intervention Type: DRUG

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

Docetaxel

Intervention Type: DRUG

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

Tremelimumab

Intervention Type: BIOLOGICAL

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

Durvalumab (Cohort 4/5)

Intervention Type: DRUG

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

Phase 1: Cohort 6

Additional Regimens (to be determined)

Group Type: EXPERIMENTAL

To be determined

Intervention Type: OTHER

Other regimens to be determined

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.

Group Type: EXPERIMENTAL

Gemcitabine

Intervention Type: DRUG

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

Docetaxel

Intervention Type: DRUG

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

Durvalumab (Cohort 4/5)

Intervention Type: DRUG

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

Interventions

Durvalumab (Cohort 1-3)

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

Intervention Type: DRUG

External Beam Radiotherapy (EBRT)

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

Intervention Type: RADIATION

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.

Intervention Type: BIOLOGICAL

Gemcitabine

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

Intervention Type: DRUG

Docetaxel

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

Intervention Type: DRUG

Tremelimumab

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

Intervention Type: BIOLOGICAL

Durvalumab (Cohort 4/5)

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

Intervention Type: DRUG

To be determined

Other regimens to be determined

Intervention Type: OTHER

Other Intervention Names

Imfinzi; Gemzar; Taxotere; Imfinzi

Eligibility Criteria

Inclusion Criteria

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:

• 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.

• 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)

• 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.

NOTE: The exclusion of patients who have had any prior radiation to the prostate or pelvis applies to both phase 1 and 2 of the trial only within radiation containing study regimens. Patients with a prior history of prostate or pelvic radiation who meet all other eligibility criteria may be considered for phase 1 and phase 2 enrollment to non-radiation containing study regimens after consultation with the study chair.

• 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)
• Cirrhosis
• Active Infection (includes chronic active and chronic persistent) --- Tuberculosis --- Hepatitis B (known positive HBV surface antigen (HbsAg). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HbsAg) are eligible

--- Hepatitis C. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.

--- Known diagnosis of human immunodeficiency virus (HIV/positive HIV 1/2 antibodies) infection (HIV testing is not mandatory)

• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this criterion:

--- Patients with vitiligo or alopecia

--- Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement

--- Any chronic skin condition that does not require systemic therapy

--- Patients without active disease in the last 5 years may be included but only after consultation with the study physician

--- Patients with celiac disease controlled by diet alone

• Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g. active or uncontrolled infection, uncontrolled diabetes) that could cause unacceptable safety risks or compromise compliance with the protocol
• Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion:

• Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
• Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
• Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
• Usage of non-steroidal anti-inflammatory medications (NSAIDS) for the treatment of osteoarthritis and uric acid synthesis inhibitors for the treatment of gout are permitted. For questions, please consult the sponsor-investigator.
• Pregnant or breast-feeding women. Women of child-bearing potential must have a negative serum test ≤ 14 days prior to starting study drug.
• Women of child-bearing potential, who are biologically able to conceive, and not employing contraception as described in the protocol.
• Fertile males not willing to use contraception, as stated in the protocol.
• Subjects unwilling or unable to comply with the protocol
• Receipt of live attenuated vaccine within 30 days prior to the first dose of IP.

NOTE: Patients, if enrolled, should not receive live vaccine whilst receiving study drugs and up to 30 days after the last dose of study drug.

• Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.

Exclusion Criteria

• 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.

• Subjects who have received prior intravesical therapy with BOTH gemcitabine and docetaxel

NOTE: Patients who have received either intravesical gemcitabine or intravesical docetaxel (or other taxanes) but not both remain eligible. For example, patients receiving post-TURBT single dose intravesical gemcitabine administration are eligible. Similarly, patients treated with intravesical gemcitabine induction and/or maintenance are eligible. While we typically do not see patients treated with intravesical docetaxel (or other taxanes) monotherapy, if such a patient were identified and screened, they would be eligible. Patients who have received treatment with separate courses of intravesical gemcitabine monotherapy and intravesical docetaxel (or other taxanes) monotherapy are not eligible, unless such therapies occurred more than 24 months ago.

• Subjects with concurrent upper urinary tract (i.e. ureter, renal pelvis) high-grade urothelial carcinoma. NOTE: Subjects with concurrent low-grade non-invasive (Ta) upper urinary tract urothelial carcinoma are eligible. Similarly, patients with a history of high-grade upper tract urothelial carcinoma that has been definitively treated with at least one post-treatment disease assessment (i.e. cytology, biopsy, imaging) that demonstrates no evidence of residual disease are eligible.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

AstraZeneca

INDUSTRY

Sponsor Role: collaborator

Hoosier Cancer Research Network

OTHER

Sponsor Role: collaborator

Noah Hahn, M.D.

OTHER

Sponsor Role: lead

Responsible Party

Noah Hahn, M.D.

Sponsor-Investigator

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Noah M. Hahn, MD

Role: PRINCIPAL_INVESTIGATOR

Hoosier Cancer Research Network

Locations

BCG Oncology

Phoenix, Arizona, United States

Site Status: TERMINATED

Stanford University

Stanford, California, United States

Site Status: WITHDRAWN

Rush University Medical Cneter

Chicago, Illinois, United States

Site Status: WITHDRAWN

Indiana University Melvin and Bren Simon Cancer Center

Indianapolis, Indiana, United States

Site Status: RECRUITING

University of Iowa Hospitals and Clinics

Iowa City, Iowa, United States

Site Status: RECRUITING

Johns Hopkins University: Sidney Kimmel Comprehensive Cancer Center

Baltimore, Maryland, United States

Site Status: RECRUITING

Dana-Farber Cancer Institute

Boston, Massachusetts, United States

Site Status: WITHDRAWN

Washington University School of Medicine

St Louis, Missouri, United States

Site Status: RECRUITING

University of Nebraska Medical Center

Omaha, Nebraska, United States

Site Status: RECRUITING

Columbia University Irving Medical Center

New York, New York, United States

Site Status: RECRUITING

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, United States

Site Status: ACTIVE_NOT_RECRUITING

Fox Chase Cancer Center

Philadelphia, Pennsylvania, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Noah Hahn, MD

Role: CONTACT

nhahn4@jhmi.edu

443-287-2886

Gabrielle Tiggs

Role: CONTACT

gtiggs@hoosiercancer.org

317-634-5842 ext. 62

Facility Contacts

Nabil Adra, MD

Role: primary

nadra@iu.edu

317-948-6942

Yvonne Lafary

Role: backup

ylafary@iu.edu

317-278-5613

Tiffany Kriegel

Role: primary

tiffany-kriegel@uiowa.edu

319-353-4582

Noah Hahn, M.D.

Role: primary

nhahn4@jhmi.edu

443-287-2886

Linnea Smith-Walters

Role: backup

lsmithw1@jhmi.edu

410.502.0017

Kirsten Cady

Role: primary

cadyk@wustl.edu

314-362-7773

Kathleen Stibbs

Role: primary

kstibbs@unmc.edu

402-552-3178

Susie Flores

Role: primary

sf2780@cumc.columbia.edu

212-304-6343

Tracy Kradzinski

Role: primary

Tracy.Kradzinski@fccc.edu

215-728-1133

Related Links

http://hoosiercancer.org

Hoosier Cancer Research Network Website

Other Identifiers

HCRN GU16-243

Identifier Type: -

Identifier Source: org_study_id