SAGE: Sporadic Angiomyolipomas (AMLs) Growth Kinetics While on Everolimus

• Sponsor: Fox Chase Cancer Center (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02539459
• Collaborator: Novartis Pharmaceuticals (Industry)
• Enrollment: 20
• Locations: 8
• Arm: 1
• Actual Duration (Months): 34.9
• Patients Per Site: 2.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this research study is to see if oral everolimus is tolerable and effective in the treatment of sporadic Angiomyolipomas (AMLs). AMLs are the most common non-cancerous tumor of the kidney. They are composed of blood vessels, muscle cells and fat cells.Everolimus is already an approved drug for several other diseases like kidney cancer, but is being studied now specifically to see if it is helpful for people with AML.

Condition or Disease	Intervention/Treatment	Phase
Sporadic Angiomyolipomas (AMLs)	Drug: Everolimus	Phase 2

Detailed Description

Primary Objective

1. To evaluate the efficacy and tolerability of everolimus in reducing tumor volume in sporadic AMLs as measured by dynamic contrast enhanced magnetic resonance imaging (DCE MRI), in patients who might otherwise be considered for active surgical or percutaneous intervention.

Secondary Objectives

1. To evaluate health-related quality of life (HRQoL) in subjects treated with everolimus for sporadic AMLs.

2. To assess the growth kinetics of sporadic AMLs in patients who have been treated with everolimus as part of the study and demonstrate an objective response as well as those who have been treated with everolimus during the study with a suboptimal or no response.

3. To measure the rate of surgical or percutaneous (embolization) intervention at 1 year from day 1 of study.

4. To assess the safety and tolerability of everolimus in patients with sporadic AML.

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Sporadic Angiomyolipomas (AMLs) Growth Kinetics While on Everolimus Therapy
• Actual Study Start Date: Sep 23, 2015
• Actual Primary Completion Date: Aug 20, 2018
• Actual Study Completion Date: Aug 20, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (everolimus) Patients will take 10 mg (1 tablet) of everolimus each day for 4 months	Drug: Everolimus; 10 mg tablets

Outcome Measures

Primary Outcome Measures

1. Number of Patients With Tumor Volume Reduction Greater Than 25% [12 months]

   Measuring the efficacy and tolerability of everolimus by measuring the number of patients with tumor volume reduction greater than 25% in sporadic AMLs as measured by DCE MRI

Secondary Outcome Measures

1. Safety and Tolerability of Everolimus in Patients With Sporadic AML [12 months]

   Number of participants with treatment-related adverse events requiring dose reduction or study withdrawal as assessed by Common Toxicity Criteria for Adverse Effects (CTCAE v4.0)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Must have a diagnosis of renal AML > 3 cm confirmed on pre-enrollment Dynamic Contrast Enhanced MRI (DCE-MRI)

• Must not have received any prior treatment for AML

• Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1

• Absolute neutrophil count >= 1,500/ microliter (mcL)

• Hemoglobin >=10 g/dL

• Platelets >= 100,000/ mcL

• international normalized ratio (INR) <= 1.2 X Upper limit Normal (ULN)

• activated partial thromboplastin time (aPTT) <= 1.2 X ULN

• aspartate aminotransferase (AST) / alanine transaminase (ALT) <= 2.5 X ULN

• Total bilirubin <= 2.0mg/dL

• Renal Function epidermal growth factor receptor (eGFR) >= 30 mL/min via calculated creatinine clearance

• Fasting serum cholesterol <= 300 mg/dL OR <= 7.75 mmol/L AND fasting triglycerides <= 2.5x ULN.

Exclusion Criteria:

• History of tuberous sclerosis, LAM or any active malignancy

• Treatment with any other investigational agents for any other disease

• Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding or affect absorption of investigational product

• Active diarrhea of any grade.

• History of human immunodeficiency virus (HIV) infection, hepatitis B or C (screening for all three is mandatory prior to study); prior hepatitis C infection

• Presence of any active or ongoing infection.

• Any known uncontrolled underlying pulmonary disease by history, physical exam or if applicable pulmonary function test (PFTs)

• History of certain cardiovascular conditions within the past 6 months

• History of Class III or IV congestive heart failure, as defined by the New York Heart Association Classification of Congestive Heart Failure.

• History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months.

• Corrected QT interval (QTc) > 480 milliseconds

• Poorly controlled hypertension, defined as systolic blood pressure (SBP) of >= 140 millimeters of mercury(mmHg) or diastolic blood pressure (DBP) of >= 90 mmHg.

• Evidence of active bleeding or bleeding diathesis

• Uncontrolled diabetes mellitus (defined by a Hgb A1c >8) obtained within 14 days prior to registration. Optimal glucose control (Hgb A1c <= 8) must be achieved before registration and monitored during protocol treatment

• Any serious and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with subject's safety, provision of informed consent, or compliance to study procedures.

• Unable or unwilling to discontinue use of prohibited medications

• Concurrent therapy given to treat cancer including treatment with an investigational agent or concurrent participation in another clinical trial involving anti-cancer investigational drug.

• Administration of any investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of study treatment.

• Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to everolimus

• Prior or current use of systemic anti-vascular endothelial growth factor (VEGF) inhibitors, cytokines or mechanistic target of rapamycin (mTOR) inhibitors (e.g. interferon, interleukin 2).

• Pregnant or nursing (lactating) women

• Women of child-bearing potential (WOCBP) must use highly effective methods of contraception during the study and 8 weeks after.

• Unable to obtain a contrast (gadolinium) based DCE MRI, including include patients with pacemakers, automatic implantable cardioverter/defibrillator (AICDs), non MRI compatible metallic implants or eGFR <30.

• Must not have received immunization with an attenuated live vaccine within seven days prior to registration nor have plans to receive such vaccination while on protocol treatment

• Must not be taking, nor plan to take while on protocol treatment, strong cytochrome P450 3A4 (CYP3A4) inhibitors, (e.g. ketoconazole, itraconazole, voriconazole, posaconazole, fluvoxamine, nefazodone, nelfinavir, ritonavir) and/or strong CYP3A4 inducers (e.g. phenytoin, rifampin, rifabutin) within 14 days prior to randomization.

• History of another primary malignancy, with the exceptions of: non-melanoma skin cancer, and carcinoma in situ of the cervix, uteri, or breast from which the patient has been disease free for >= 3 years

• Childs-Pugh A-C liver disease (Appendix II)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Yale School of Medicine	New Haven	Connecticut	United States
2	Dana Farber Cancer Institute	Boston	Massachusetts	United States
3	Mayo Clinic	Rochester	Minnesota	United States
4	Memorial Sloan Kettering	New York	New York	United States
5	Duke University Health System	Durham	North Carolina	United States
6	Fox Chase Cancer Center	Philadelphia	Pennsylvania	United States	19111
7	University of Pennsylvania	Philadelphia	Pennsylvania	United States
8	M D Anderson Cancer Center	Houston	Texas	United States

Sponsors and Collaborators

• Fox Chase Cancer Center
• Novartis Pharmaceuticals

Investigators

• Principal Investigator: Robert G Uzzo, MD, PI

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 28, 2017

More Information

Publications

None provided.

• Responsible Party: Fox Chase Cancer Center
• ClinicalTrials.gov Identifier: NCT02539459
• Other Study ID Numbers: GU-070
• First Posted: Sep 3, 2015
• Last Update Posted: Mar 9, 2021
• Last Verified: Feb 1, 2021

• Additional relevant MeSH terms: Angiomyolipoma; Everolimus

Study Results

Participant Flow

Arm/Group Title	Treatment (Everolimus)
Arm/Group Description	Patients will take 10 mg (1 tablet) of everolimus each day for 4 months Everolimus: 10 mg tablets
Period Title: Overall Study
STARTED	20
COMPLETED	18
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Treatment (Everolimus)
Arm/Group Description	Patients will take 10 mg (1 tablet) of everolimus each day for 4 months Everolimus: 10 mg tablets
Overall Participants	20
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	68
Sex: Female, Male (Count of Participants)
Female	15 75%
Male	5 25%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 10%
Not Hispanic or Latino	18 90%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 5%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	19 95%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	20 100%
BMI (kg/m^2) [Median (Full Range) ]
Median (Full Range) [kg/m^2]	29.4
AML volume (cc) [Median (Full Range) ]
Median (Full Range) [cc]	47.3

Outcome Measures

1. Primary Outcome

Title	Number of Patients With Tumor Volume Reduction Greater Than 25%
Description	Measuring the efficacy and tolerability of everolimus by measuring the number of patients with tumor volume reduction greater than 25% in sporadic AMLs as measured by DCE MRI
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

Some participants experienced adverse events and were withdrawn from the study, and therefore tumor volume reduction was not measured in these patients.

Arm/Group Title	Treatment (Everolimus)
Arm/Group Description	Patients will take 10 mg (1 tablet) of everolimus each day for 4 months Everolimus: 10 mg tablets
Measure Participants	10
Count of Participants [Participants]	5 25%

2. Secondary Outcome

Title	Safety and Tolerability of Everolimus in Patients With Sporadic AML
Description	Number of participants with treatment-related adverse events requiring dose reduction or study withdrawal as assessed by Common Toxicity Criteria for Adverse Effects (CTCAE v4.0)
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Everolimus)
Arm/Group Description	Patients will take 10 mg (1 tablet) of everolimus each day for 4 months Everolimus: 10 mg tablets
Measure Participants	20
Count of Participants [Participants]	10 50%

Adverse Events

Time Frame	12 months
Arm/Group Title	Treatment (Everolimus)
Arm/Group Description	Patients will take 10 mg (1 tablet) of everolimus each day for 4 months Everolimus: 10 mg tablets
All Cause Mortality
	Treatment (Everolimus)
	Affected / at Risk (%)	# Events
Total	0/20 (0%)
Serious Adverse Events
	Treatment (Everolimus)
	Affected / at Risk (%)	# Events
Total	3/20 (15%)
Cardiac disorders
chest pain	1/20 (5%)
heart palpitations	1/20 (5%)
Gastrointestinal disorders
flank pain	1/20 (5%)
Infections and infestations
pneumonitis	1/20 (5%)
Renal and urinary disorders
dysuria	1/20 (5%)
Other (Not Including Serious) Adverse Events
	Treatment (Everolimus)
	Affected / at Risk (%)	# Events
Total	20/20 (100%)
Blood and lymphatic system disorders
anemia	9/20 (45%)
Hypercholesterolemia	7/20 (35%)
Leukocyte decrease	5/20 (25%)
Hypertriglyceridemia	4/20 (20%)
Lymphocyte decrease	3/20 (15%)
limb edema	2/20 (10%)
Neutrophil decrease	2/20 (10%)
Gastrointestinal disorders
diarrhea	5/20 (25%)
constipation	3/20 (15%)
General disorders
fatigue	7/20 (35%)
Xerostomia	3/20 (15%)
Dysgeusia	3/20 (15%)
Chills	2/20 (10%)
fever	2/20 (10%)
headache	2/20 (10%)
Infections and infestations
oral mucositis	14/20 (70%)	20
UTI	2/20 (10%)
pneumonitis	2/20 (10%)
Metabolism and nutrition disorders
Hyperglycemia	3/20 (15%)
Metabolism + nutrional disorders - other	3/20 (15%)
Nervous system disorders
Nervous system disorders - other	2/20 (10%)
involuntary movements	1/20 (5%)
Renal and urinary disorders
Alanine aminotransferase increase	10/20 (50%)
Aspartate aminotransferase increase	9/20 (45%)
Elevated creatinine	2/20 (10%)
Respiratory, thoracic and mediastinal disorders
cough	3/20 (15%)
Skin and subcutaneous tissue disorders
Maculopapular rash	7/20 (35%)
Pruritis	4/20 (20%)
Skin + subcutaneous tissue disorders - other	3/20 (15%)
rash	2/20 (10%)
acneiform rash	2/20 (10%)
Vascular disorders
Epistaxis	3/20 (15%)

Limitations/Caveats

Lack of tissue to correlate response to molecular markers of aberrant mTOR pathways. Lack for serum everolimus levels. Clinical significance of 25% volume reduction unknown. Patient withdrawals and incomplete protocol imaging.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.