Clinical trial NCT01215136: First-line Everolimus +/- Paclitaxel for Cisplatin-ineligible Patients With Advanced Urothelial Carcinoma
Official title: Phase II Trial of Everolimus or Everolimus Plus Paclitaxel as First-line Therapy in Cisplatin-ineligible Patients With Advanced Urothelial Carcinoma: Hoosier Cancer Research Network GU10-147
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Transitional Cell Carcinoma
Bladder Carcinoma
Urothelial Carcinoma
Lead sponsor: Hoosier Cancer Research Network
Sponsor class: OTHER
Collaborators: name: Hoosier Cancer Research Network
name: Novartis Pharmaceuticals
First posted: 2010-10-06
Enrollment: 36
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this trial is to explore the activity and safety of everolimus +/- paclitaxel as first-line therapy for cisplatin-ineligible patients with advanced urothelial carcinoma.

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

Patients will be enrolled into one of two parallel cohorts:

* Cohort 1: impaired renal function AND poor performance status (cycle length = 28 days). Everolimus 10 mg orally daily
* Cohort 2: impaired renal function OR poor performance status (cycle length = 28 days). Everolimus 10 mg orally daily + IV Paclitaxel 80 mg/m2 on D1, 8, 15

Restaging evaluations will be performed after every 2 cycles.

Treatment will continue until disease progression or unacceptable toxicity.

Karnofsky performance status 60-70%

Life Expectancy: Not specified

Hematopoietic:

* Absolute neutrophil count (ANC) ≥ 1.5 K/mm3
* Hemoglobin (Hgb) ≥ 9 g/dL
* Platelets ≥ 100 K/mm3
* INR ≤ 1.5 (Anticoagulants are allowed if target INR ≤ 1.5 on a stable dose of warfarin or on a stable dose of Low molecular weight (LMW) heparin for at least 2 weeks prior to registration for protocol therapy).
* Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L
* Fasting triglycerides ≤ 2.5 x ULN.
* Fasting serum glucose \< 1.5 x ULN

Hepatic:

* Bilirubin ≤ 1.5 x ULN
* Aminotransferases (AST and ALT) ≤ 2.5 x ULN (unless liver metastases, then ≤ 5 x ULN)

Renal:

* Calculated creatinine clearance of \< 60 using the Cockcroft-Gault formula

Cardiovascular:

* No symptomatic congestive heart failure of New York heart Association Class III or IV.
* No unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease.

Eligibility criteria: Inclusion Criteria:

* Histological or cytological proof of transitional cell carcinoma (TCC) of the bladder, urethra, ureter, or renal pelvis (urothelial carcinoma). Histology may be mixed, but still requires a component of TCC.
* Measurable disease according to RECIST and obtained by imaging within 30 days prior to registration for protocol therapy.
* Must be ineligible for cisplatin, based on the following, within 30 days prior to registration for protocol therapy.
* Prior radiation therapy is allowed to \< 25% of the bone marrow.
* Written informed consent and HIPAA authorization for release of personal health information.
* Age \> 18 years at the time of consent.
* Females of childbearing potential and males must be willing to use an effective method of contraception (hormonal or barrier method of birth control; abstinence) from the time consent is signed until 8 weeks after treatment discontinuation.
* Females of childbearing potential must have a negative pregnancy test within 7 days prior to prior to registration for protocol therapy.
* Females must not be breastfeeding.

Exclusion Criteria:

* No prior chemotherapy for metastatic disease. Prior chemotherapy in the neoadjuvant/adjuvant setting is allowed if completed at least 12 months prior to registration for protocol therapy.
* No active CNS metastases or leptomeningeal metastases. Patients with neurological symptoms must undergo a head CT scan or brain MRI to exclude brain metastasis.
* No prior malignancy is allowed except for adequately treated basal cell or adequately treated squamous cell skin cancer, in situ cervical cancer, Gleason ≤ grade 7 prostate cancers (treated definitively with no evidence of PSA progression), or other cancer for which the patient has been disease-free for at least 5 years.
* No treatment with any anticancer therapy or investigational agent within 30 days prior to registration for protocol therapy.
* No known hypersensitivity to any protocol treatment.
* No prior treatment with mTOR inhibitor (sirolimus, temsirolimus, everolimus).
* No history of immunization with attenuated live vaccines within one week prior to registration for protocol therapy or during study period.
* No severely impaired lung function as defined as spirometry and DLCO that is 50% of the normal predicted value and/or 02 saturation that is 88% or less at rest on room air.
* No uncontrolled diabetes as defined by fasting serum glucose \>1.5 x ULN.
* No active (acute or chronic) or uncontrolled severe infections.
* No liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis.
* No known history of HIV seropositivity.
* No impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of everolimus (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection).
* No active, bleeding diathesis.
* No history of major surgery (defined as requiring general anesthesia) or significant traumatic injury within 30 days prior to registration for protocol therapy.

Primary outcomes:
measure: Response Rate of Single-Agent Everolimus and Everolimus + Paclitaxel
timeFrame: 4 months
Secondary outcomes:
measure: Number of Adverse Events as a Measure of Safety and Tolerability
timeFrame: 5 months
measure: Progression Free Survival
timeFrame: 4 months
measure: Overall Survival
timeFrame: 12 months
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama Hematology Oncology Clinic at Medical West
state: Alabama
city: Chicago
country: United States
facility: Northwestern University, Robert H. Lurie Comprehensive Cancer Center
state: Illinois
city: Bloomington
country: United States
facility: Cancer Care Center of Southern Indiana
state: Indiana
city: Indianapolis
country: United States
facility: Indiana University Melvin and Bren Simon Cancer Center
state: Indiana
city: Indianapolis
country: United States
facility: IU Health Central Indiana Cancer Centers
state: Indiana
city: Wyoming
country: United States
facility: Metro Health Cancer Care
state: Michigan
city: Omaha
country: United States
facility: Nebraska Cancer Specialists
state: Nebraska
city: New York
country: United States
facility: Icahn School of Medicine: Tisch Cancer Institute at Mount Sinai Medical Center
state: New York
city: Charleston
country: United States
facility: MUSC Hollings Cancer Center
state: South Carolina
city: Galveston
country: United States
facility: University of Texas Medical Branch
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: Jun T, Hahn NM, Sonpavde G, Albany C, MacVicar GR, Hauke R, Fleming M, Gourdin T, Jana B, Oh WK, Taik P, Wang H, Varadarajan AR, Uzilov A, Galsky MD. Phase II Clinical and Translational Study of Everolimus +/- Paclitaxel as First-Line Therapy in Cisplatin-Ineligible Advanced Urothelial Carcinoma. Oncologist. 2022 Jun 8;27(6):432-e452. doi: 10.1093/oncolo/oyab075.