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

Sponsor

Matthew Galsky (Other)

Overall Status

Terminated

CT.gov ID

NCT01215136

Collaborator

Hoosier Cancer Research Network (Other), Novartis Pharmaceuticals (Industry)

Enrollment

Locations

Arms

88.7

Duration (Months)

3.3

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Transitional Cell Carcinoma Bladder Carcinoma Urothelial Carcinoma	Drug: Everolimus Drug: Everolimus Drug: Paclitaxel	Phase 2

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 Design

Study Type:

Interventional

Actual Enrollment :

36 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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 Start Date :

Dec 1, 2010

Actual Primary Completion Date :

Apr 24, 2017

Actual Study Completion Date :

Apr 24, 2018

Arms and Interventions

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.

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

Drug: Paclitaxel

Paclitaxel 80 mg/m2 IV as a 1 hour infusion on days 1, 8, and 15, of a 28-day cycle.

Outcome Measures

Primary Outcome Measures

Response Rate [4 months]
To evaluate clinical benefit rate (complete response, partial response, and stable disease) at 4 months from initiation of treatment.

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

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