Clinical trial NCT01524991: First-Line Gemcitabine, Cisplatin + Ipilimumab for Metastatic Urothelial Carcinoma
Official title: Phase II Trial of Gemcitabine, Cisplatin, Plus Ipilimumab as First-line Treatment for Patients With Metastatic Urothelial Carcinoma: Hoosier Cancer Research Network GU10-148
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Urothelial Carcinoma
Lead sponsor: Hoosier Cancer Research Network
Sponsor class: OTHER
Collaborators: name: Bristol-Myers Squibb
First posted: 2012-02-02
Enrollment: 36
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Gemcitabine plus cisplatin is standard treatment for advanced urothelial cancer. Ipilimumab has shown intriguing activity as neoadjuvant therapy in patients with clinically localized bladder cancer undergoing radical cystectomy. The combination of gemcitabine, cisplatin, plus ipilimumab may build on the chemosensitivity of urothelial carcinoma to produce more durable responses and improved outcomes.

Detailed description: OUTLINE: This is a multi-center study

Gemcitabine 1000 mg/m2 Days 1 \& 8 Cisplatin 70 mg/m2 Day 1 Ipilimumab 10 mg/kg Day 1 (start cycle 3)

Treatment during the induction phase will be administered in six 21-day cycles. During cycles 1 and 2, gemcitabine plus cisplatin will be administered WITHOUT ipilimumab. During cycles 3-6, combination therapy with gemcitabine, cisplatin, plus ipilimumab will be administered. Patients without evidence of disease progression (by irRC) after completion cycle 6 will continue single-agent ipilimumab maintenance every 3 months.

Karnofsky performance status (KPS) ≥ 80% within 14 days prior to registration for protocol therapy.

Life Expectancy: Not Specified

Hematopoietic:

* White blood cell count (WBC) ≥ 3.5K/mm3
* Hemoglobin (Hgb) ≥ 9 g/dL
* Platelets ≥ 100K/mm3
* Absolute neutrophil count (ANC) ≥ 1.5k/mm3

Hepatic:

* Bilirubin ≤ 1.5 times x Upper Limit of Normal (ULN) (except patients with Gilbert's Syndrome, who must have a total bilirubin less than 3.0 mg/dL)
* Aspartate aminotransferase (AST, SGOT) ≤ 2.5 x ULN. NOTE: If the patient has liver metastases present, then ≤ 5 x ULN

Renal:

* Calculated creatinine clearance of ≥ 55 cc/min using the Cockcroft-Gault formula

Cardiovascular: Not Specified

Eligibility criteria: Inclusion Criteria:

* Histological or cytological proof of urothelial carcinoma of the urethra, bladder, ureters, or renal pelvis.
* Advanced (clinical stage T4b, unresectable) or metastatic disease.
* Prior radiation therapy is allowed to \< 25% of the bone marrow.
* Age \> 18 years at the time of consent.
* Written informed consent and HIPAA authorization for release of personal health information.
* Females must not be pregnant or breastfeeding.
* WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours before the start of ipilimumab.
* Men of fathering potential must be using an adequate method of contraception to avoid conception throughout the study \[and for up to 26 weeks after the last dose of investigational product\] in such a manner that the risk of pregnancy is minimized.
* Prior Autoimmune disease: Patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn's Disease, are excluded from this study, as are patients with a history of symptomatic disease (eg, rheumatoid arthritis, systemic progressive sclerosis \[scleroderma\], systemic lupus erythematosus, autoimmune vasculitis \[eg, Wegener's Granulomatosis\]); motor neuropathy considered of autoimmune origin (e.g. Guillain-Barre Syndrome and Myasthenia Gravis). Patients with other immune disorders should not be enrolled without discussion with the principal investigator.

Exclusion Criteria:

* No active CNS metastases. Subjects with neurological symptoms must undergo a head CT scan or brain MRI to exclude brain metastasis.
* No prior malignancy is allowed except for cancers that have been definitively treated with a risk of recurrence of \< 30% based on the treating oncologists assessment.
* Patients may not have received prior systemic chemotherapy for metastatic/advanced urothelial carcinoma. Prior neoadjuvant/adjuvant therapy is permitted if completed ≥ 12 months prior to registration for protocol therapy. Prior intravesical therapy is permitted.
* No treatment with any investigational agent within 30 days prior to registration for protocol therapy.
* No underlying medical or psychiatric condition, which in the opinion of the investigator will make the administration of ipilimumab hazardous or obscure the interpretation of AEs, such as a condition associated with frequent diarrhea.
* No non-oncology vaccine therapy used for prevention of infectious diseases (for up to 1 month before or after any dose of ipilimumab).
* No history of prior treatment with ipilimumab or prior CD137 agonist or CTLA 4 inhibitor or agonist.
* No known active or chronic infection with HIV, Hepatitis B, or Hepatitis C.
* No clinically significant infections as judged by the treating investigator.
* No chronic systemic corticosteroids (defined as the equivalent of prednisone ≥ 20 mg PO daily for \> 6 months during the past year)

Primary outcomes:
measure: Median Overall Survival
timeFrame: 48 months
Secondary outcomes:
measure: Progression-Free Survival
timeFrame: 12 months
measure: Best Overall Response Rate
timeFrame: 12 months
measure: Number of Adverse Events Experienced by Patients
timeFrame: 12 months
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope: Duarte
state: California
city: Goshen
country: United States
facility: IU Health Goshen Hospital
state: Indiana
city: Indianapolis
country: United States
facility: Indiana University Melvin & Bren Simon Cancer Center
state: Indiana
city: Indianapolis
country: United States
facility: IU Health Central Indiana Cancer Centers
state: Indiana
city: Omaha
country: United States
facility: Nebraska Cancer Specialists
state: Nebraska
city: New York
country: United States
facility: Tisch Cancer Institute at Mount Sinai Medical Center
state: New York
city: Dallas
country: United States
facility: Texas Oncology, PA
state: Texas
city: Norfolk
country: United States
facility: Virginia Oncology Associates
state: Virginia
Study officials:
affiliation: Hoosier Cancer Research Network
name: Matthew Galsky, M.D.
role: STUDY_CHAIR
References:
citation: Galsky MD, Hahn NM, Albany C, Fleming MT, Starodub A, Twardowski P, Hauke RJ, Sonpavde G, Merad M, Gnjatic S, Bhardwaj N, Chippada-Venkata U, Oh WK, Kim-Schulze S. Impact of gemcitabine + cisplatin + ipilimumab on circulating immune cells in patients (pts) with metastatic urothelial cancer (mUC). J Clin Oncol 33:5s, 2015 (suppl; abstr 4586)
citation: Galsky MD, Wang H, Hahn NM, Twardowski P, Pal SK, Albany C, Fleming MT, Starodub A, Hauke RJ, Yu M, Zhao Q, Sonpavde G, Donovan MJ, Patel VG, Sfakianos JP, Domingo-Domenech J, Oh WK, Akers N, Losic B, Gnjatic S, Schadt EE, Chen R, Kim-Schulze S, Bhardwaj N, Uzilov AV. Phase 2 Trial of Gemcitabine, Cisplatin, plus Ipilimumab in Patients with Metastatic Urothelial Cancer and Impact of DNA Damage Response Gene Mutations on Outcomes. Eur Urol. 2018 May;73(5):751-759. doi: 10.1016/j.eururo.2017.12.001. Epub 2017 Dec 13.