Radiation Therapy and Durvalumab, With or Without Tremelimumab, in Patients With Bladder Cancer

NCT03150836 | Withdrawn Phase 2 DMC FDA Drug

• 1 other identifier: 16529
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

This is a multi-site, randomized, prospective, open-label phase II study. Patients in this study will have localized (cT3-cT4), or metastatic bladder cancer with a symptomatic, intact primary bladder tumor. In this study, patients will undergo stereotactic body radiation therapy (SBRT) to the bladder tumor and will receive durvalumab with or without tremelimumab.

Conditions

Bladder Cancer

Keywords

bladder cancer; urothelial

Outcome Measures

Primary Outcomes (2)

• Toxicity according to NCI CTCAE v. 4.03 criteria

  Safety profile

  Over the duration of the study, which is estimated to be approximately 50 months.

• Progression-free survival (PFS)

  PFS will be determined from first day of treatment to date of progression. Progression will be defined based on RECIST 1.1

  Over the duration of the study, which is estimated to be approximately 50 months.

Secondary Outcomes (7)

• Local control at the primary irradiated site

  Over the duration of the study, which is estimated to be approximately 50 months.

• Pathologic Complete Response (CR) rate of primary irradiated tumor

  Over the duration of the study, which is estimated to be approximately 50 months.

• Overall response rate (ORR)

  Over the duration of the study, which is estimated to be approximately 50 months.

• Abscopal response (in patients with metastatic disease)

  Over the duration of the study, which is estimated to be approximately 50 months.

• Duration of response

  Over the duration of the study, which is estimated to be approximately 50 months.

Study Arms (6)

Safety Lead-In, Regimen A1 Durvalumab + RT

EXPERIMENTAL

Durvalumab 1500 mg will be delivered via IV infusion q4wk. Radiation Therapy (RT) will be delivered beginning on day 8 ± 3 of durvalumab. RT (33Gy delivered as 6.6Gy x 5 fractions) should be completed within 14 days from the start of RT ideally over 5 consecutive days. Durvalumab 1500 mg q4wk will be continued to complete either 13 total cycles OR until disease progression, unacceptable toxicity, or patient withdrawal from study, whichever comes first.

Drug: Durvalumab; Radiation: Radiation Therapy

Safety Lead-In, Regimen A2 Durvalumab + RT

EXPERIMENTAL

In cohort A2 the dose of radiation will be decreased to a total dose of 30 Gy administered in 5 fractions of 6 Gy. Durvalumab 1500 mg will be delivered via IV infusion q4wk. Radiation Therapy (RT) will be delivered beginning on day 8 ± 3 of durvalumab. RT (30 Gy delivered as 6.0Gy x 5 fractions) should be completed within 14 days from the start of RT ideally over 5 consecutive days. Durvalumab 1500 mg q4wk will be continued to complete either 13 total cycles OR until disease progression, unacceptable toxicity, or patient withdrawal from study, whichever comes first.

Drug: Durvalumab; Radiation: Radiation Therapy

Safety Lead-In, Regimen B1 Durvalumab + Tremelimumab + RT

EXPERIMENTAL

Tremelimumab 75 mg will be administered via IV infusion q4wk for 2 cycles with durvalumab 1500 mg via IV infusion. Radiation Therapy (RT), at the optimal dose determined in the safety lead-in from Regimen A, will be delivered beginning on day 8 ± 3 of durvalumab. After two doses of tremelimumab and durvalumab, durvalumab 1500 mg q4wk will be continued to complete either 13 total cycles of durvalumab OR until disease progression, unacceptable toxicity, or patient withdrawal from study, whichever comes first.

Drug: Durvalumab; Drug: Tremelimumab; Radiation: Radiation Therapy

Safety Lead-In, Regimen B2 Durvalumab + Tremelimumab + RT

EXPERIMENTAL

Tremelimumab 75 mg will be administered via IV infusion q4wk for 1 cycle with durvalumab 1500 mg via IV infusion. Radiation Therapy (RT), at the optimal dose determined in the safety lead-in from Regimen A, will be delivered beginning on day 8 ± 3 of durvalumab. After one dose of tremelimumab and durvalumab, durvalumab 1500 mg q4wk will be continued to complete either 13 total cycles of durvalumab OR until disease progression, unacceptable toxicity, or patient withdrawal from study, whichever comes first.

Drug: Durvalumab; Drug: Tremelimumab; Radiation: Radiation Therapy

Expansion Cohort, Regimen A: Durvalumab + RT

EXPERIMENTAL

Durvalumab 1500 mg will be delivered via IV infusion q4wk. Radiation Therapy (RT) will be delivered beginning on day 8 ± 3 of durvalumab. RT (either 33Gy delivered as 6.6Gy x 5 fractions or 30 Gy delivered as 6.0 Gy x 5 fractions, as determined during the safety lead-in for Regimen B) should be completed within 14 days from the start of RT ideally over 5 consecutive days. Durvalumab 1500 mg q4wk will be continued to complete either 13 total cycles OR until disease progression, unacceptable toxicity, or patient withdrawal from study, whichever comes first.

Drug: Durvalumab; Radiation: Radiation Therapy

Expansion Cohort Regimen B: Durvalumab + Tremelimumab + RT

EXPERIMENTAL

Tremelimumab 75 mg will be administered via IV infusion q4wk for 1 or 2 cycles (as determined during the safety lead-in for Regimen B) with durvalumab 1500 mg via IV infusion. Radiation Therapy (RT), at the optimal dose determined in the safety lead-in from Regimen A, will be delivered beginning on day 8 ± 3 of durvalumab. After 1 or 2 doses of tremelimumab and durvalumab, durvalumab 1500 mg q4wk will be continued to complete either 13 total cycles of durvalumab OR until disease progression, unacceptable toxicity, or patient withdrawal from study, whichever comes first.

Drug: Durvalumab; Drug: Tremelimumab; Radiation: Radiation Therapy

Interventions

Durvalumab DRUG

All participants will receive durvalumab 1500 mg via IV infusion every 4 weeks for up to 13 doses.

Also known as: Imfinzi

Expansion Cohort Regimen B: Durvalumab + Tremelimumab + RT; Expansion Cohort, Regimen A: Durvalumab + RT; Safety Lead-In, Regimen A1 Durvalumab + RT; Safety Lead-In, Regimen A2 Durvalumab + RT; Safety Lead-In, Regimen B1 Durvalumab + Tremelimumab + RT; Safety Lead-In, Regimen B2 Durvalumab + Tremelimumab + RT

Tremelimumab DRUG

Participants receiving Regimen B (safety lead-in or expansion cohort) will be administered tremelimumab 75 mg via IV infusion every 4 weeks for 1 cycle or 2 cycles.

Expansion Cohort Regimen B: Durvalumab + Tremelimumab + RT; Safety Lead-In, Regimen B1 Durvalumab + Tremelimumab + RT; Safety Lead-In, Regimen B2 Durvalumab + Tremelimumab + RT

Radiation Therapy RADIATION

In all arms of the study, participants will receive 5 fractions of radiation. The radiation dose will either be 6.6 Gy for a total dose of 33 Gy, or 6.0 Gy for a total dose of 30 Gy.

Expansion Cohort Regimen B: Durvalumab + Tremelimumab + RT; Expansion Cohort, Regimen A: Durvalumab + RT; Safety Lead-In, Regimen A1 Durvalumab + RT; Safety Lead-In, Regimen A2 Durvalumab + RT; Safety Lead-In, Regimen B1 Durvalumab + Tremelimumab + RT; Safety Lead-In, Regimen B2 Durvalumab + Tremelimumab + RT

Eligibility Criteria

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

You may qualify if:

• Written informed consent obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations
• Locally advanced (cT3 or cT4) or metastatic (N+ or M+) urothelial bladder cancer. Mixed histologies with predominant urothelial pattern are allowed
• If metastatic disease present patients must have an intact, symptomatic bladder tumor, appropriate for palliative RT to the bladder.
• Measurable metastatic disease according to RECIST v1.1 criteria. Thus, patients with metastatic disease must have at least 1 lesion, not previously irradiated, that can be accurately measured at baseline as at least 10 mm in the longest diameter (except lymph nodes which must have a short axis greater than or equal to 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) and that is suitable for accurate repeated measurement as per RECIST v1.1 guidelines.
• Age greater than or equal to 18 years at time of study entry
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
• Life expectancy of at least 12 weeks
• Patients with non-metastatic bladder cancer must be ineligible for cystectomy in the opinion of the treating investigator.
• Patients must be ineligible for cisplatin-based chemotherapy. The reason for cisplatin ineligibility must be documented. Cisplatin ineligibility is defined as meeting 1 of the following criteria:
• Creatinine clearance (calculated or measured) less than 60 mL/min
• Common Terminology Criteria for Adverse Events (CTCAE) Grade greater than or equal to 2 audiometric hearing loss
• CTCAE Grade 2 or higher peripheral neuropathy
• New York Heart Association Class III heart failure
• Any other criteria deemed by the investigator to make the patient unsuitable for cisplatin-based chemotherapy.
• Subjects must consent to provide an archived tumor specimen from within 12 months prior to study entry (ie, from subject signing consent to participate in the study) for immunologic characterization. If not available, subjects should have at least 1 lesion amenable to biopsy and consent to provide a pre-treatment fresh biopsy. Tumor lesions used for biopsy should not be lesions used as target lesions. Additional archival tissue from beyond 12 months prior to study entry is also requested, if available, to support exploratory analyses.

You may not qualify if:

• ECOG PS 2 or higher
• Upper tract-only or urethral-only urothelial cancer
• Prior cystectomy or definitive RT to the bladder.
• Prior systemic chemotherapy for bladder cancer
• History of autoimmune disease, including, but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegner's granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome, multiple sclerosis, vasculitis, or glomerulonephritis
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[eg, colitis or Crohn's disease\], diverticulitis \[with the exception of diverticulosis\], celiac disease, 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:
• Subjects with childhood atopy or asthma, vitiligo, alopecia, Hashimoto syndrome, Grave's disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded.
• Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone are not excluded.
• Patients with controlled type 1 diabetes mellitus on a stable dose of insulin regimen are not excluded.
• Any chronic skin condition that does not require systemic therapy are not exluded
• Patients without active autoimmune disease in the last 5 years may be included after consultation with the study physician.
• Patients with HIV, active hepatitis B (HBV) or active hepatitis C (HCV)
• Patients with past HBV infection or resolved HBV infection, defined as the presence of hepatitis B core antibody (HBc Ab) and absence of hepatitis B surface antigen (HBsAg) are eligible. HBV DNA must be obtained in these patients prior to day 1 of therapy, but detection of HBV DNA in these patients will not exclude study participation.
• Patients positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan.

Sponsors & Collaborators

• Terence Friedlander, MD: lead
• MedImmune LLC: collaborator

Study Sites (1)

UCSF Helen Diller Family Comprehensive Cancer Center

San Francisco, California, 94115, United States

Location

MeSH Terms

Conditions

Urinary Bladder Neoplasms

Interventions

durvalumab; tremelimumab; Radiotherapy

Condition Hierarchy (Ancestors)

Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Urinary Bladder Diseases; Urologic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Therapeutics

Study Officials

• Terence Friedlander, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Clinical Professor

Study Record Dates

• First Submitted: May 10, 2017
• First Posted: May 12, 2017
• Study Start: October 1, 2017
• Primary Completion: September 1, 2021
• Study Completion: September 1, 2024
• Last Updated: October 19, 2017

Record last verified: 2017-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)