First-line Everolimus +/- Paclitaxel for Cisplatin-ineligible Patients With Advanced Urothelial Carcinoma

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

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.

Study Overview

• Status: Terminated
• Conditions: Transitional Cell Carcinoma; Urothelial Carcinoma; Bladder Carcinoma
• Intervention / Treatment: Drug: Everolimus; Drug: Paclitaxel

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.

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama Hematology Oncology Clinic at Medical West
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University, Robert H. Lurie Comprehensive Cancer Center
  • Indiana
    • Bloomington, Indiana, United States, 47403
      • Cancer Care Center of Southern Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Melvin and Bren Simon Cancer Center
    • Indianapolis, Indiana, United States, 46219
      • IU Health Central Indiana Cancer Centers
  • Michigan
    • Wyoming, Michigan, United States, 49519
      • Metro Health Cancer Care
  • Nebraska
    • Omaha, Nebraska, United States, 68114
      • Nebraska Cancer Specialists
  • New York
    • New York, New York, United States, 10029
      • Icahn School of Medicine: Tisch Cancer Institute at Mount Sinai Medical Center
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • MUSC Hollings Cancer Center
  • Texas
    • Galveston, Texas, United States, 77555
      • University of Texas Medical Branch
  • Virginia
    • Norfolk, Virginia, United States, 23502
      • Virginia Oncology Associates

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Cohort 1; Single-agent everolimus (enrollment limited to patients with patients with creatinine clearance < 60 ml/min AND Karnofsky performance status of 60-70%)	Drug: Everolimus; 10 mg PO daily (continuously, without scheduled treatment interruptions). The cycle length will last 28 days. Everolimus will be dispensed on Day 1 of each cycle by the study center personnel on an outpatient basis.
Active Comparator: Cohort 2; Everolimus plus paclitaxel (enrollment limited to patients with creatinine clearance < 60 ml/min OR Karnofsky performance status of 60-70%)	Drug: Everolimus; 10 mg PO daily (continuously, without scheduled treatment interruptions). The cycle length will last 28 days. Everolimus will be dispensed on Day 1 of each cycle by the study center personnel on an outpatient basis.; Drug: Paclitaxel; Paclitaxel 80 mg/m2 IV as a 1 hour infusion on days 1, 8, and 15, of a 28-day cycle.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response Rate	To evaluate clinical benefit rate (complete response, partial response, and stable disease) at 4 months from initiation of treatment.	4 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants with Adverse Events as a Measure of Safety and Tolerability	To determine the safety of everolimus and everolimus plus paclitaxel in this patient population.	4 months
Progression Free Survival	To determine progression free survival	4 months
Survival - 1 year	To determine survival at 1-year from the initiation of treatment.	12 months

Collaborators and Investigators

• Sponsor: Matthew Galsky
• Collaborators: Novartis Pharmaceuticals; Hoosier Cancer Research Network

Publications and helpful links

General Publications

• 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.

Helpful Links

• Hoosier Oncology Group Homepage

Study record dates

Study Major Dates

• Study Start: December 1, 2010
• Primary Completion (Actual): April 24, 2017
• Study Completion (Actual): April 24, 2018

Study Registration Dates

• First Submitted: October 4, 2010
• First Submitted That Met QC Criteria: October 4, 2010
• First Posted (Estimate): October 6, 2010

Study Record Updates

• Last Update Posted (Actual): October 16, 2019
• Last Update Submitted That Met QC Criteria: October 14, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Urologic Diseases; Neoplasms, Glandular and Epithelial; Urinary Bladder Diseases; Carcinoma; Urinary Bladder Neoplasms; Carcinoma, Transitional Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Paclitaxel; Everolimus
• Other Study ID Numbers: HCRN GU10-147