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BRIEF TITLE: Pre-Surgical Study Evaluating Anti-PD-L1 Antibody (Durvalumab) Plus Anti-CTLA-4 (Tremelimumab) in Patients With Muscle-Invasive, High-Risk Urothelial Carcinoma Who Are Ineligible for Cisplatin-Based Neoadjuvant Chemotherapy

A Pilot Pre-Surgical Study Evaluating Anti-PD-L1 Antibody (Durvalumab) Plus Anti-CTLA-4 (Tremelimumab) in Patients With Muscle-Invasive, High-Risk Urothelial Carcinoma Who Are Ineligible for Cisplatin-Based Neoadjuvant Chemotherapy

  • Org Study ID: 2016-0033
  • Secondary ID: NCI-2016-01147
  • NCT ID: NCT02812420
  • NCT Alias:
  • Sponsor: M.D. Anderson Cancer Center - Other
  • Source: M.D. Anderson Cancer Center

Brief Summary

The goal of this clinical research study is to learn if the combination of durvalumab and tremelimumab is safe and tolerable when given to patients with bladder cancer before surgery to remove the bladder. This is an investigational study. Tremelimumab and durvalumab are not FDA or commercially available for the treatment of bladder cancer. The use of these drugs are considered investigational. Up to 35 participants will be enrolled in this study. All will take part at MD Anderson.

Detailed Description

Study Drug Administration:

If you are found to be eligible to take part in this study, you will receive durvalumab and
tremelimumab by vein on Day 1 of Weeks 1 and 4. Each study drug infusion will last 1 hour.
You will receive tremelimumab first and then you will receive durvalumab about 1 hour later.
You will be monitored for side effects after you receive the study drugs. You will be in the
clinic for up to 6 hours.

Study Visits:

During Day 1 of Weeks 1 and 4:

- You will have a physical exam.

- Your vital signs will be measured within 30 minutes before, every 15 minutes while you
are receiving the study drugs, and 3 times over 1 hour after the end of your dose of

- Blood (about 2-3 teaspoons) and urine will be collected for routine tests. This blood or
urine collection will also include a pregnancy test if you can become pregnant.

- Blood (about 3-4 tablespoons) will be drawn for immune system testing and thyroid
function testing.

- If the doctor thinks it is needed, you will have a cystoscopy to check the status of the
disease. If the doctor thinks it is needed, you may need to have a surgery to remove the
tumors. If you need this surgery because the disease got worse very quickly, you may be
taken off study.

During Week 9 to 11:

- You will have a physical exam, including measurement of your vital signs.

- You will have an EKG.

- Blood (about 3-4 tablespoons) will be drawn for immune system testing.

- Urine will be collected to check the status of the disease.

During Week 9 to 11, you will have surgery to remove part or all of your bladder. You will
sign a separate consent explaining the surgery and its risks. If during screening you were
told that you were not eligible to have surgery at Week 9 to 11, you will have a biopsy after
your last dose of study drugs.

Length of Study:

You will be off study after the Week 17 visit. You will no longer be able to take the study
drugs if the disease gets worse, if intolerable side effects occur, or if you are unable to
follow study directions.

Your participation on the study will be over after the follow-up visits.

Follow-up Visits:

- About 90 days after last dose of study drug, you will asked about any side effects and
how you are doing.

- Every 3 months for a total of 1 year from the start on the study, you will be called and
asked how you are doing. This phone call should last about 15 minutes.

Overal Status Start Date Phase Study Type
Recruiting March 7, 2017 Early Phase 1 Interventional

Primary Outcomes:

Primary Outcome 1 - Measure: Toxicity of Durvalumab Plus Tremelimumab

Primary Outcome 1 - Time Frame: 4 months


  • Malignant Neoplasms of Urinary Tract


Inclusion Criteria:

1. Age >/= 18 years at the time of screening. In general, urothelial cancer occurs in the
6th to 8th decade of life, so it is unlikely that pediatric patients will be included.

2. Patients must have tissue resected by transurethral resection of bladder tissue
(TURBT) at the MD Anderson Cancer Center.

3. Patients must have histologic proof of urothelial cancer. This includes bladder
cancer, in addition to other tumors of the urothelial lining including renal pelvis,
ureteral, and urethral cancer. Upper tract urothelial carcinoma will also be included.
This group may include any patient requiring cystectomy (or applicable surgery to
resect tumors), including muscle invasive disease (cT2-3aN0M0), whose tumor could not
be completely removed at transurethral resection.

4. continued 3) Patients with the following high-risk features who are not candidates for
traditional neoadjuvant chemotherapy will be included for this trial: micropapillary,
sarcomatoid and plasmacytoid features; 3-D mass on exam under anesthesia (EUA);
lymphovascular continued from 3)invasion; hydronephrosis (unless in the opinion of the
treating physician, this is not due to tumor); high grade (grade 3) tumors of the
ureter, renal pelvis, or tumors in these areas with radiographic abnormality large
enough to recognize as an abnormal mass by CT or MRI imaging; direct invasion of the
prostatic stroma or the vaginal wall (i.e. cT4a disease). Patients who are candidates
for but refusing conventional chemotherapy may be considered eligible. For patients in
whom eligibility is unclear, final arbitration will be determined by the Principal

5. Subjects must have no prior exposure to immunotherapy, such as, but not limited to
other anti-CTLA-4, anti-PD-1, or anti-PD-L1 antibodies excluding vaccines

6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

7. Able and willing to give valid written consent for available archival tumor samples or
fresh tumor biopsies/resections.

8. Adequate organ and marrow function (subjects must not have received transfusions or
growth factor support within 28 days prior to first dose), as defined below: a.
Hemoglobin >/= 9 g/dL b. Absolute neutrophil count >/= 1,000/mm^3 c. Platelet count
>/= 100,000/mm^3 d. Total bilirubin Gilbert's syndrome (> 3 × ULN), who must have a baseline total bilirubin e.Subjects must be considered cisplatin ineligible as per treating physician due to
renal dysfunction, or hearing impairment, or co-morbidities. Cisplatin ineligibility
defined as: GFR less than 60 or; CHF NYHA class III or higher or; Peripheral
neuropathy grade 2 or higher or; ECOG PS 2 or higher or; impaired hearing. Patient's
refusal of traditional chemotherapy.

9. Females of childbearing potential who are sexually active with a nonsterilized male
partner must use a highly effective method of contraception from the time of
screening, and must agree to continue using such precautions for 180 days after the
final dose of investigational product. Cessation of contraception after this point
should be discussed with a responsible physician. Periodic abstinence, the rhythm
method, and the withdrawal method are not acceptable methods of contraception. They
must also refrain from egg cell donation for 180 days after the final dose of
investigational product.

10. Nonsterilized males who are sexually active with a female partner of childbearing
potential must agree to use a highly effective method of contraception from Day 1
through 90 days after receipt of the final dose of investigational product. In
addition, they must refrain from sperm donation for 90 days after the final dose of
investigational product.

11. Mild autoimmune conditions (such as localized psoriasis) requiring minimal treatment
or systemic autoimmune conditions well controlled by target agents such as an
anti-IL-17 that do not affect overall immune system. Patients with a history of
Hashimoto's thyroiditis only requiring hormone replacement, Type I diabetes, or
conditions not expected to recur in the absence of an external trigger are allowed to

Exclusion Criteria:

1. Concurrent enrollment in another clinical trial, unless in a follow-up period or it is
an observational study.

2. Any concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer
treatment. Concurrent use of hormones for non-cancer-related conditions (e.g. insulin
for diabetes and hormone replacement therapy) is acceptable.

3. Any investigational anticancer therapy received within 28 days prior to the first dose
of durvalumab and tremelimumab.

4. Major surgical procedure (as defined by the PI or co-PIs within 28 days prior to the
first dose of durvalumab and tremelimumab or still recovering from prior surgery.

5. Unresolved toxicities from prior anticancer therapy, defined as having not resolved to
NCI CTCAE v4.03 Grade 0 or 1 with the exception of alopecia and laboratory values
listed per the inclusion criteria. Subjects with irreversible toxicity that is not
reasonably expected to be exacerbated by durvalumab and tremelimumab may be included
(e.g. hearing loss) after consultation with the Principal Investigator.

6. Known or suspected autoimmune disease. Patients with a history of inflammatory bowel
disease (including Crohn's disease and ulcerative colitis) and autoimmune disorders
such as rheumatoid arthritis, systemic progressive sclerosis [scleroderma], Systemic
Lupus Erythematosus or autoimmune vasculitis [e.g., Wegener's Granulomatosis] are
excluded from this study. Any condition requiring systemic treatment with
corticosteroids (>10mg daily prednisone equivalents) or other immunosuppressive
medications within 14 days prior to first dose of study drug. Inhaled steroids and
adrenal replacement steroids doses >10mg daily prednisone equivalents are permitted in
the absence of active autoimmune disease.

7. History of primary immunodeficiency.

8. Patients who have organ allografts.

9. True positive test results for hepatitis A, B, or C during screening.

10. Known history of testing positive for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome (AIDS).

11. Receipt of live, attenuated vaccine within 28 days prior to the first dose of
durvalumab and tremelimumab (NOTE: Subjects, if enrolled, should not receive live
vaccine during the study and for 180 days after the last dose of both drugs).

12. Females who are pregnant, lactating, or intend to become pregnant during their
participation in the study.

13. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, current pneumonitis, symptomatic congestive heart failure, unstable angina
pectoris, cardiac arrhythmia, interstitial lung disease, or psychiatric illness/social
situations that would limit compliance with study requirements or compromise the
ability of the subject to give written informed consent.

14. Other invasive malignancies within 2 years except for noninvasive malignancies such as
cervical carcinoma in situ, non-melanomatous carcinoma of the skin, or ductal
carcinoma in situ of the breast, etc. that has/have been surgically cured.

15. Any evidence of metastatic urothelial carcinoma.

16. Known allergy or hypersensitivity to study drug formulations.

17. Patient currently on dialysis
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Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

Official Information

Name: Jianjun Gao, MD, PHD

Role: Principal Investigator

Affiliation: M.D. Anderson Cancer Center

Overall Contact

Name: Jianjun Gao, MD, PHD

Phone: 713-792-2830


Link: University of Texas MD Anderson Cancer Center Website


Facility Status Contact
University of Texas MD Anderson Cancer Center
Houston, Texas 77030
United States
Recruiting Clinical Research Operations