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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-2016-01147,2016-0033,P30CA016672
  • NCT ID: NCT02812420
  • NCT Alias:
  • Sponsor: M.D. Anderson Cancer Center - Other
  • Source: M.D. Anderson Cancer Center

Brief Summary

This pilot phase I trial studies the side effects of durvalumab and tremelimumab in treating patients with muscle-invasive, high-risk urothelial cancer that cannot be treated with cisplatin-based therapy before surgery. Immunotherapy with monoclonal antibodies, such as durvalumab and tremelimumab, may induce changes in the body's immune system and may interfere with the ability of tumor cells to grow and spread.

Detailed Description


PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability of durvalumab and tremelimumab in patients with
muscle-invasive, high-risk bladder cancer who are ineligible for neoadjuvant
cisplatin-containing chemotherapies.

SECONDARY OBJECTIVES:

I. To assess immunologic/molecular responses (e.g. peripheral blood cluster of
differentiation [CD] 4+inducible T-cell co-stimulator [ICOS]+ T cells) to durvalumab and
tremelimumab in patients with muscle-invasive, high-risk bladder cancer who are ineligible
for neoadjuvant cisplatin-containing chemotherapies.

II. To evaluate pathologic T0 rate after neoadjuvant treatment with durvalumab and
tremelimumab in patients with muscle-invasive, high-risk bladder cancer comparing to
historical data (about 10% in patients with high-risk disease).

III. To evaluate relapse-free survival (RFS) and overall survival (OS).

OUTLINE:

Patients receive tremelimumab intravenously (IV) over 1 hour and durvalumab IV over 1 hour on
day 1 of weeks 1 and 4. Beginning 4-6 weeks after the last infusion, patients undergo
cystectomy with pelvic lymph node dissection surgery.

After completion of study treatment, patients are followed up at 90 days, and then every 3
months for up 1 year.

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

Primary Outcomes:

Primary Outcome 1 - Measure: Incidence of adverse events determined by extreme toxicity

Primary Outcome 1 - Time Frame: Up to 90 days after last dose of treatment

Condition:

  • Hydronephrosis
  • Infiltrating Bladder Urothelial Carcinoma Sarcomatoid Variant
  • Infiltrating Bladder Urothelial Carcinoma, Micropapillary Variant
  • Infiltrating Bladder Urothelial Carcinoma, Plasmacytoid Variant
  • Infiltrating Renal Pelvis Urothelial Carcinoma, Sarcomatoid Variant
  • Renal Pelvis Urothelial Carcinoma
  • Stage II Bladder Urothelial Carcinoma AJCC v6 and v7
  • Stage II Renal Pelvis Cancer AJCC v7
  • Stage II Ureter Cancer AJCC v7
  • Stage II Urethral Cancer AJCC v7
  • Stage III Bladder Urothelial Carcinoma AJCC v6 and v7
  • Stage III Renal Pelvis Cancer AJCC v7
  • Stage III Ureter Cancer AJCC v7
  • Stage III Urethral Cancer AJCC v7
  • Stage IV Renal Pelvis Cancer AJCC v7
  • Stage IV Ureter Cancer AJCC v7
  • Stage IV Urethral Cancer AJCC v7
  • Ureter Urothelial Carcinoma
  • Urethral Urothelial Carcinoma

Eligibility

Criteria:
Inclusion Criteria:

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

- 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

- 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-dimensional (3-D) mass on exam under anesthesia (EUA);
lymphovascular 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 computed tomography (CT) or magnetic resonance
imaging (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 investigator

- 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

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

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

- Adequate organ and marrow function (subjects must not have received transfusions or
growth factor support within 28 days prior to first dose)

- Hemoglobin >= 9 g/dL

- Absolute neutrophil count >= 1,000/mm^3

- Platelet count >= 100,000/mm^3

- Total bilirubin =< 1.5 x upper limit of normal (ULN) except subjects with documented
Gilbert's syndrome (> 3 x ULN), who must have a baseline total bilirubin =< 3.0 mg/dL

- Subjects must be considered cisplatin ineligible as per treating physician due to
renal dysfunction, or hearing impairment, or co-morbidities; cisplatin ineligibility
defined as: glomerular filtration rate (GFR) less than 60 or; congestive heart failure
(CHF) New York Heart Association (NYHA) class III or higher or; peripheral neuropathy
grade 2 or higher or; Eastern Cooperative Oncology Group (ECOG) performance status
(PS) 2 or higher or; impaired hearing; patient's refusal of traditional chemotherapy

- 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

- 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

- 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
participate

Exclusion Criteria:

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

- 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

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

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

- Unresolved toxicities from prior anticancer therapy, defined as having not resolved to
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)
version (v) 4.03 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

- 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; patients with a history of Hashimoto's thyroiditis only
requiring hormone replacement, type I diabetes, or psoriasis not requiring systemic
treatment, or conditions not expected to recur in the absence of an external trigger
are allowed to participate; 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

- History of primary immunodeficiency

- Patients who have organ allografts

- True active infections of hepatitis B, or C during screening

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

- 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)

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

- 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

- 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

- Any evidence of metastatic urothelial carcinoma

- Known allergy or hypersensitivity to study drug formulations

- 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

Role: Principal Investigator

Affiliation: M.D. Anderson Cancer Center

Overall Contact

Name: Jianjun Gao

Phone: 713-792-2830

Email: jgao1@mdanderson.org

Link: MD Anderson Cancer Center Website

Location

Facility Status Contact
M D Anderson Cancer Center
Houston, Texas 77030
United States
Recruiting Jianjun Gao
713-792-2830