Modern Immunotherapy in BCG-Unresponsive, BCG-Relapsing and High Risk BCG-Naive Non-Muscle Invasive Urothelial Carcinoma of the Bladder
- Conditions
- Urothelial CarcinomaBladder Cancer
- Interventions
- Other: To be determinedBiological: Bacillus Calmette-Guérin (BCG)Radiation: External Beam Radiotherapy (EBRT)
- Registration Number
- NCT03317158
- Lead Sponsor
- Noah Hahn, M.D.
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 55
Not provided
Exclusion Criteria (All Patients):
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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
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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.
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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.
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Any unresolved toxicity NCI CTCAE v4.03 for Cohorts 1-3 and v5.0 for cohorts 4-6 Grade ≥ 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
- 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.
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Subjects who have received prior therapy with PD-1, PD-L1, or CTLA-4 directed agents.
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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.
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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
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Subjects with any of the following concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study:
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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)
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Cirrhosis
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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)
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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
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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
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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.
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Pregnant or breast-feeding women. Women of child-bearing potential must have a negative serum test ≤ 14 days prior to starting study drug.
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Women of child-bearing potential, who are biologically able to conceive, and not employing contraception as described in the protocol.
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Fertile males not willing to use contraception, as stated in the protocol.
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Subjects unwilling or unable to comply with the protocol
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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.
3.2.2 Exclusion Criteria (Cohorts 4 and 5 Only)
• 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.
Exclusion Criteria (Phase 1 Only) In Phase 1 of the study, there are no additional exclusion criteria beyond those described of all patients above.
Exclusion Criteria (Phase 2 Only) In addition to the exclusion criteria described of all patients above, the following exclusion criteria apply to patients enrolling to Phase 2 of the study.
• 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description Phase 2: Cohort 4 Expansion Durvalumab (Cohort 4/5) Durvalumab + Gemcitabine/Intravesical Docetaxel (Gem/Doc) The sequence of administration is flexible to allow for scheduling of both the infusion and intravesical treatments. Phase 1: Cohort 3 Durvalumab (Cohort 1-3) Durvalumab plus External Beam Radiotherapy (EBRT) (BCG re-treatment) - Cross-over to Durvalumab Monotherapy Phase 2: Cohort 4 Expansion Docetaxel Durvalumab + Gemcitabine/Intravesical Docetaxel (Gem/Doc) The sequence of administration is flexible to allow for scheduling of both the infusion and intravesical treatments. Phase 1: Cohort 2 Durvalumab (Cohort 1-3) Durvalumab plus BCG Phase 1: Cohort 4 Durvalumab (Cohort 4/5) Durvalumab + Gemcitabine/Intravesical Docetaxel (Gem/Doc) The sequence of administration is flexible to allow for scheduling of both the infusion and intravesical treatments. Phase 1: Cohort 6 To be determined Additional Regimens (to be determined) Phase 1: Cohort 2 Bacillus Calmette-Guérin (BCG) Durvalumab plus BCG Phase 1: Cohort 3 External Beam Radiotherapy (EBRT) Durvalumab plus External Beam Radiotherapy (EBRT) (BCG re-treatment) - Cross-over to Durvalumab Monotherapy Phase 1: Cohort 5 Durvalumab (Cohort 4/5) 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. Phase 1: Cohort 1 Durvalumab (Cohort 1-3) Durvalumab monotherapy Phase 1: Cohort 4 Gemcitabine Durvalumab + Gemcitabine/Intravesical Docetaxel (Gem/Doc) The sequence of administration is flexible to allow for scheduling of both the infusion and intravesical treatments. Phase 1: Cohort 5 Gemcitabine 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. Phase 1: Cohort 5 Docetaxel 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. Phase 1: Cohort 4 Docetaxel Durvalumab + Gemcitabine/Intravesical Docetaxel (Gem/Doc) The sequence of administration is flexible to allow for scheduling of both the infusion and intravesical treatments. Phase 1: Cohort 5 Tremelimumab 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. Phase 2: Cohort 4 Expansion Gemcitabine Durvalumab + Gemcitabine/Intravesical Docetaxel (Gem/Doc) The sequence of administration is flexible to allow for scheduling of both the infusion and intravesical treatments.
- Primary Outcome Measures
Name Time Method Phase 1: Determine the recommended phase 2 dose (RP2D) from BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) 6 months 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.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 6 months 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.
- Secondary Outcome Measures
Name Time Method 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 The 12-month RFS rate of BCG-unresponsive, BCG-relapsing/persistent, and high-risk BCG-naive NMIBC subjects treated within each arm is defined as the proportion of patients within each arm with no evidence of recurrent high grade urothelial carcinoma of the bladder of any stage at the 12-month post-treatment assessment.
Phase 1: Assess Adverse Events 6 months The safety profile of BCG-unresponsive NMIBC subjects treated within each study regimen will be assessed by NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 for Cohorts 1-3 and v5.0 for Cohorts 4-6.
Phase 1: Characterize the 12-month recurrence free survival (RFS) rate of BCG-unresponsive NMIBC subjects treated with each study regimen 12 month The 12-month RFS rate of BCG-unresponsive NMIBC subjects treated within each study regimen is defined as the proportion of patients within each arm with no evidence of recurrent high grade urothelial carcinoma of the bladder of any stage at the 12-month post-treatment disease assessment.
Phase 2: Assess Adverse Events 6 months The safety profile within individual phase 2 expansion cohorts of BCG-unresponsive, BCG-relapsing/persistent, and high-risk BCG-naive NMIBC subjects treated within each study arm will be assessed by NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 for Cohorts 1-3 and v5.0 for Cohorts 4-6.
Phase 1: Characterize the complete response rate of BCG-unresponsive NMIBC subjects treated with each study regimen 2 years (24 months) 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.
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 Associations between complete response rate and 12-month RFS rates will be assessed by baseline tumor immunohistochemistry staining patterns of PD-L1 (assessed by the SP263 PD-L1 antibody) and other relevant mechanism of action targets for each drug.
Trial Locations
- Locations (12)
Fox Chase Cancer Center
🇺🇸Philadelphia, Pennsylvania, United States
Stanford University
🇺🇸Stanford, California, United States
Rush University Medical Cneter
🇺🇸Chicago, Illinois, United States
University of Iowa Hospitals and Clinics
🇺🇸Iowa City, Iowa, United States
Johns Hopkins University: Sidney Kimmel Comprehensive Cancer Center
🇺🇸Baltimore, Maryland, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
Columbia University Irving Medical Center
🇺🇸New York, New York, United States
University of North Carolina at Chapel Hill
🇺🇸Chapel Hill, North Carolina, United States
BCG Oncology
🇺🇸Phoenix, Arizona, United States
Indiana University Melvin and Bren Simon Cancer Center
🇺🇸Indianapolis, Indiana, United States
University of Nebraska Medical Center
🇺🇸Omaha, Nebraska, United States
Dana-Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States