Safety and Efficacy of Everolimus (Afinitor®) in Chinese Adult Patients With Angiomyolipoma Associated With Tuberous Sclerosis Complex.

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03525834
• Collaborator: (none)
• Enrollment: 40
• Locations: 5
• Arm: 1
• Actual Duration (Months): 22.5
• Patients Per Site: 8
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The purpose of this study was to assess the safety and efficacy of everolimus (Afinitor®) in Chinese patients with renal angiomyolipoma (AML) associated with tuberous sclerosis complex (TSC).

Condition or Disease	Intervention/Treatment	Phase
Renal Angiomyolipoma	Drug: Everolimus	Phase 4

Detailed Description

This was an open label, single arm, multi-center, Phase IV Post-Approval Commitment (PAC) study with once daily oral dose of 10 mg everolimus in participants with renal AML associated with TSC. There were three separate phases in this study: a Screening phase, an Open-label treatment phase where participants received everolimus for 48 weeks or until disease progression, and a Treatment discontinuation follow-up phase for patients who discontinue study drug for reasons other than disease progression. Every participant had an End of Treatment visit within 28 days after last dose and a safety follow-up visit 30 days after last dose.

Study Design

• Study Type: Interventional
• Actual Enrollment: 40 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: Single arm, open labelSingle arm, open label
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase IV, Single Arm Study of Safety and Efficacy of Everolimus in Chinese Adults With Tuberous Sclerosis Complex Who Have Renal Angiomyolipoma Not Requiring Immediate Surgery
• Actual Study Start Date: Nov 9, 2018
• Actual Primary Completion Date: Sep 25, 2020
• Actual Study Completion Date: Sep 25, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Everolimus Participants targeted to receive Everolimus tablets 10 mg orally once daily for 48 weeks.	Drug: Everolimus; Everolimus 2.5 mg and 5 mg tablets with dosage regimen of 10 mg orally once daily.; Other Names: RAD001, Afinitor®

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [From the start of treatment to 30 days after end of treatment, assessed up to maximum duration of 52 weeks]

   Percentage of participants with AEs and SAEs including significant changes from baseline in vital signs, electrocardiograms and laboratory parameters (laboratory assessments included hematology, biochemistry, coagulation and urinalysis) qualifying and reported as AEs. The percentage of participants in each category is reported in the table.

Secondary Outcome Measures

1. Percentage of Participants With Best Overall Response (BOR) Status of Angiomyolipoma (AML) Response During Maximum Treatment Duration of 48 Weeks [Baseline, 48 weeks]

   BOR status is the best status recorded from start of treatment until disease progression. AML response status: reduction in AML volume of at least 50% relative to screening AML. In addition, AML response have to satisfy: no new AML ≥ 1 cm in longest diameter are identified, neither kidney increases in volume by more than 20% from nadir (where nadir is the lowest kidney volume at the screening), the participant does not have any angiomyolipoma-related bleeding of grade equal or over 2 (as defined by NCI CTCAE, version 4.03). Up to five of the largest measurable lesions (≥ 1 cm in longest diameter) in each kidney were measured at screening via Magnetic Resonance Imaging/Computed tomography (MRI/CT) and were defined as screening AML. The sum of the volumes of these individual lesions was defined as AML volume and it was measured at each assessment during the trial. Increases in the AML volume were evidence of worsening AML, decreases were evidence of clinical response.

2. Percentage of Participants With Best Overall Response Status of Angiomyolipoma (AML) Progression During Maximum Treatment Duration of 48 Weeks [Baseline, 48 weeks]

   AML progression status is defined as one or more of the following: an increase from nadir of 25% or more in AML volume to a value greater than screening AML (where nadir is the lowest AML volume obtained for the participant previously in the trial), the appearance of a new AML ≥ 1.0 cm in longest diameter, an increase from nadir of 20% or more in the volume of either kidney to a value greater than screening (where nadir is the lowest kidney volume obtained for the participant previously in the trial), angiomyolipoma-related bleeding grade ≥2 (as defined by NCI CTCAE, version 4.03). Up to five of the largest measurable lesions (≥ 1 cm in longest diameter) in each kidney were measured at screening via Magnetic Resonance Imaging/Computed tomography (MRI/CT) and were defined as screening AML. The sum of the volumes of these individual lesions was defined as AML volume and it was measured at each assessment during the trial. Increases in the AML volume were evidence of worsening AML.

3. Percentage of Participants With Severe Renal Impairment [Baseline, 48 weeks]

   Renal impairment is defined as calculated Creatinine Clearance (CrCl) < 30 mL/min. CrCl was measured at baseline and at four other time points; only the baseline and the worst post-baseline value for every participant were counted (lowest value for CrCl). Creatinine clearance was estimated using the Cockcroft-Gault formula: creatinine clearance (mL/minute) = urine creatinine concentration (mL/dL) x volume of urine (mL/24 hour) / plasma creatinine concentration (mg/dL) x 1440 minute/24 hour

4. Percentage of Participants With NCI CTCA Grade 3/4 Serum Creatinine [Baseline, 48 weeks]

   NCI CTCAE grade 3/4 serum creatinine is defined as > 3.0 x upper limits of normal (ULN). Serum creatinine was measured at baseline and at four other time points; only the worst post-baseline value for every participant was counted (highest value for serum creatinine).

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Eligible for treatment with everolimus as per the locally approved label.

• Presence of at least one AML ≥ 3 cm in its longest diameter using CT or MRI.

Exclusion Criteria:

• AML related bleeding or embolization during the 6 months prior to enrollment.

• History of myocardial infarction, angina or stroke related to atherosclerosis.

• Impaired lung function.

• Significant hematological or hepatic abnormality.

• Any severe and/or uncontrolled medical conditions.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Wuhan	Hubei	China	430030
2	Novartis Investigative Site	Shanghai	Shanghai	China	200032
3	Novartis Investigative Site	Chengdu	Sichuan	China	610041
4	Novartis Investigative Site	Beijing		China	100028
5	Novartis Investigative Site	Beijing		China	100730

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

• Study Protocol - Dec 6, 2019
• Statistical Analysis Plan - Feb 19, 2021

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03525834
• Other Study ID Numbers: CRAD001M2401
• First Posted: May 16, 2018
• Last Update Posted: Sep 9, 2021
• Last Verified: Sep 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: TSC; tuberous sclerosis complex; AML; afinitor; everolimus; RAD001; mTOR; kidney; lymphangioleiomyomatosis; renal angiomyolipoma
• Additional relevant MeSH terms: Tuberous Sclerosis; Angiomyolipoma; Sclerosis; Everolimus

Study Results

Participant Flow

Recruitment Details	All participants were enrolled in 5 different sites in China.
Pre-assignment Detail	Participants underwent a screening period of up to 28 days. All participants started the treatment at 10 mg orally once daily except one that started at 5 mg once daily due to a protocol deviation.

Arm/Group Title	Everolimus
Arm/Group Description	Participants targeted to receive Everolimus tablets 10 mg once daily for 48 weeks.
Period Title: Overall Study
STARTED	40
COMPLETED	39
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Everolimus
Arm/Group Description	Participants targeted to receive Everolimus tablets 10 mg once daily for 48 weeks.
Overall Participants	40
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	33.7 (10.80)
Sex: Female, Male (Count of Participants)
Female	26 65%
Male	14 35%
Race/Ethnicity, Customized (Count of Participants)
Asian, Chinese	40 100%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description	Percentage of participants with AEs and SAEs including significant changes from baseline in vital signs, electrocardiograms and laboratory parameters (laboratory assessments included hematology, biochemistry, coagulation and urinalysis) qualifying and reported as AEs. The percentage of participants in each category is reported in the table.
Time Frame	From the start of treatment to 30 days after end of treatment, assessed up to maximum duration of 52 weeks

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study treatment

Arm/Group Title	Everolimus
Arm/Group Description	Participants targeted to receive Everolimus tablets 10 mg once daily for 48 weeks.
Measure Participants	40
AEs	40 100%
Treatment-related AEs	39 97.5%
SAEs	6 15%
Treatment-related SAEs	2 5%

2. Secondary Outcome

Title	Percentage of Participants With Best Overall Response (BOR) Status of Angiomyolipoma (AML) Response During Maximum Treatment Duration of 48 Weeks
Description	BOR status is the best status recorded from start of treatment until disease progression. AML response status: reduction in AML volume of at least 50% relative to screening AML. In addition, AML response have to satisfy: no new AML ≥ 1 cm in longest diameter are identified, neither kidney increases in volume by more than 20% from nadir (where nadir is the lowest kidney volume at the screening), the participant does not have any angiomyolipoma-related bleeding of grade equal or over 2 (as defined by NCI CTCAE, version 4.03). Up to five of the largest measurable lesions (≥ 1 cm in longest diameter) in each kidney were measured at screening via Magnetic Resonance Imaging/Computed tomography (MRI/CT) and were defined as screening AML. The sum of the volumes of these individual lesions was defined as AML volume and it was measured at each assessment during the trial. Increases in the AML volume were evidence of worsening AML, decreases were evidence of clinical response.
Time Frame	Baseline, 48 weeks

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study treatment

Arm/Group Title	Everolimus
Arm/Group Description	Participants targeted to receive Everolimus tablets 10 mg once daily for 48 weeks.
Measure Participants	40
Count of Participants [Participants]	28 70%

3. Secondary Outcome

Title	Percentage of Participants With Best Overall Response Status of Angiomyolipoma (AML) Progression During Maximum Treatment Duration of 48 Weeks
Description	AML progression status is defined as one or more of the following: an increase from nadir of 25% or more in AML volume to a value greater than screening AML (where nadir is the lowest AML volume obtained for the participant previously in the trial), the appearance of a new AML ≥ 1.0 cm in longest diameter, an increase from nadir of 20% or more in the volume of either kidney to a value greater than screening (where nadir is the lowest kidney volume obtained for the participant previously in the trial), angiomyolipoma-related bleeding grade ≥2 (as defined by NCI CTCAE, version 4.03). Up to five of the largest measurable lesions (≥ 1 cm in longest diameter) in each kidney were measured at screening via Magnetic Resonance Imaging/Computed tomography (MRI/CT) and were defined as screening AML. The sum of the volumes of these individual lesions was defined as AML volume and it was measured at each assessment during the trial. Increases in the AML volume were evidence of worsening AML.
Time Frame	Baseline, 48 weeks

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study treatment

Arm/Group Title	Everolimus
Arm/Group Description	Participants targeted to receive Everolimus tablets 10 mg once daily for 48 weeks.
Measure Participants	40
Count of Participants [Participants]	1 2.5%

4. Secondary Outcome

Title	Percentage of Participants With Severe Renal Impairment
Description	Renal impairment is defined as calculated Creatinine Clearance (CrCl) < 30 mL/min. CrCl was measured at baseline and at four other time points; only the baseline and the worst post-baseline value for every participant were counted (lowest value for CrCl). Creatinine clearance was estimated using the Cockcroft-Gault formula: creatinine clearance (mL/minute) = urine creatinine concentration (mL/dL) x volume of urine (mL/24 hour) / plasma creatinine concentration (mg/dL) x 1440 minute/24 hour
Time Frame	Baseline, 48 weeks

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study treatment

Arm/Group Title	Everolimus
Arm/Group Description	Participants targeted to receive Everolimus tablets 10 mg once daily for 48 weeks.
Measure Participants	40
Baseline	0 0%
Post-baseline, 48 weeks	1 2.5%

5. Secondary Outcome

Title	Percentage of Participants With NCI CTCA Grade 3/4 Serum Creatinine
Description	NCI CTCAE grade 3/4 serum creatinine is defined as > 3.0 x upper limits of normal (ULN). Serum creatinine was measured at baseline and at four other time points; only the worst post-baseline value for every participant was counted (highest value for serum creatinine).
Time Frame	Baseline, 48 weeks

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study treatment

Arm/Group Title	Everolimus
Arm/Group Description	Participants targeted to receive Everolimus tablets 10 mg once daily for 48 weeks.
Measure Participants	40
Baseline	0 0%
Post-baseline, 48 weeks	0 0%

Adverse Events

Time Frame	Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of 52 weeks.
Arm/Group Title	Everolimus
Arm/Group Description	Participants targeted to receive Everolimus tablets 10 mg once daily for 48 weeks.
All Cause Mortality
	Everolimus
	Affected / at Risk (%)	# Events
Total	0/40 (0%)
Serious Adverse Events
	Everolimus
	Affected / at Risk (%)	# Events
Total	6/40 (15%)
Gastrointestinal disorders
Haemorrhoids	1/40 (2.5%)
Stomatitis	1/40 (2.5%)
Infections and infestations
Gastroenteritis	1/40 (2.5%)
Pneumonia	1/40 (2.5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Uterine leiomyoma	1/40 (2.5%)
Psychiatric disorders
Transient psychosis	1/40 (2.5%)
Other (Not Including Serious) Adverse Events
	Everolimus
	Affected / at Risk (%)	# Events
Total	39/40 (97.5%)
Blood and lymphatic system disorders
Anaemia	8/40 (20%)
Gastrointestinal disorders
Angular cheilitis	3/40 (7.5%)
Diarrhoea	4/40 (10%)
Mouth ulceration	15/40 (37.5%)
Stomatitis	18/40 (45%)
Toothache	2/40 (5%)
General disorders
Asthenia	2/40 (5%)
Pyrexia	6/40 (15%)
Infections and infestations
Folliculitis	5/40 (12.5%)
Nasopharyngitis	4/40 (10%)
Pneumonia	3/40 (7.5%)
Upper respiratory tract infection	4/40 (10%)
Urinary tract infection	4/40 (10%)
Investigations
Alanine aminotransferase increased	7/40 (17.5%)
Aspartate aminotransferase increased	5/40 (12.5%)
Blood alkaline phosphatase increased	2/40 (5%)
Blood cholesterol increased	10/40 (25%)
Blood creatinine increased	6/40 (15%)
Blood lactate dehydrogenase increased	8/40 (20%)
Blood triglycerides increased	11/40 (27.5%)
Creatinine renal clearance decreased	2/40 (5%)
Haemoglobin decreased	2/40 (5%)
Lymphocyte count decreased	2/40 (5%)
Neutrophil count decreased	4/40 (10%)
Platelet count decreased	2/40 (5%)
Protein urine present	8/40 (20%)
Weight decreased	6/40 (15%)
White blood cell count decreased	6/40 (15%)
Metabolism and nutrition disorders
Hypercholesterolaemia	10/40 (25%)
Hypertriglyceridaemia	10/40 (25%)
Nervous system disorders
Epilepsy	2/40 (5%)
Headache	3/40 (7.5%)
Renal and urinary disorders
Proteinuria	4/40 (10%)
Reproductive system and breast disorders
Menstrual disorder	5/40 (12.5%)
Menstruation delayed	6/40 (15%)
Menstruation irregular	3/40 (7.5%)
Respiratory, thoracic and mediastinal disorders
Cough	2/40 (5%)
Epistaxis	3/40 (7.5%)
Oropharyngeal pain	2/40 (5%)
Skin and subcutaneous tissue disorders
Dermatitis acneiform	5/40 (12.5%)
Erythema	2/40 (5%)
Rash	3/40 (7.5%)
Skin disorder	3/40 (7.5%)
Vascular disorders
Hypertension	3/40 (7.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial.