An exploratory, open label, non-randomized, within-patient multiple dose-escalation safety, tolerability, PK and efficacy trial of RAD001 (everolimus) in patients with Lymphangioleiomyomatosis

• Register: EUCTR
• Last refreshed on: 10 July 2015
• Main ID: EUCTR2010-019825-32-FR
• Date of registration: 28/05/2010
• Prospective Registration: Yes
• Primary sponsor: Novartis Pharma Service AG
• Public title: An exploratory, open label, non-randomized, within-patient multiple dose-escalation safety, tolerability, PK and efficacy trial of RAD001 (everolimus) in patients with Lymphangioleiomyomatosis
• Scientific title: An exploratory, open label, non-randomized, within-patient multiple dose-escalation safety, tolerability, PK and efficacy trial of RAD001 (everolimus) in patients with Lymphangioleiomyomatosis
• Date of first enrolment: 29/06/2010
• Target sample size: 24
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2010-019825-32
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: Open: Single blind: Double blind: Parallel group: Cross over: Other: If controlled, specify comparator, Other Medicinial Product: Placebo: Other:

Countries of recruitment

France, Italy

Key inclusion & exclusion criteria

Inclusion criteria:
1. Female aged 18 years or older with a diagnosis of LAM as determined by either of the
following:
a. Lung biopsy and chest HRCT scan with findings compatible with LAM or
b. Typical clinical syndrome and chest HRCT scan findings compatible with LAM
in plus
c. one or more of the following:
?????? CT or histological evidence of renal angiomyolipoma or
?????? Chylous pleural or abdominal collection or
?????? Abdominal / pelvic lymphangioleiomyoma or
?????? Characteristic HRCT scan and clinical syndrome compatible with an
established genetic diagnosis of tuberous sclerosis complex (using revised
diagnostic criteria).
2. Pulmonary function abnormalities as follows:
a. Forced expiratory volume in one second (FEV1) of = 80% of the predicted value
following administration of a standard dose of a short acting ß2-agonist (*200 µg
Salbutamol, measured between 10 and 15 minutes of inhalation)
OR
b. FEV1 < 90% of the predicted value of bronchodilator following administration of a
standard dose of a short acting ß2-agonist (*200 µg Salbutamol, measured between
10 and 15 minutes of inhalation) and Dlco (uncorrected) <80% predicted.
3. Female patients including those of childbearing potential will be included in this
study. Given this, the following measures to reduce the risk of pregnancy must apply:
a. Postmenopausal females must have had no regular menstrual bleeding for at least
one year prior to initial dosing. Menopause will be confirmed by a plasma FSH
level of >40 IU/L at screening, or
b. Female patients who report surgical sterilization must have had the procedure at
least six (6) months prior to initial dosing. Surgical sterilization procedures should
be supported with clinical documentation made available to the sponsor and noted
in the Relevant Medical History / Current Medical Conditions section of the CRF,
or
c. Two forms of barrier contraception (e.g., condom and occlusive cap plus
spermicide), or
d. If female subject has a male partner who has undergone vasectomy, the vasectomy
must have occurred more than six (6) months prior to first dosing, or
e. The subject must abstain from vaginal intercourse for the entire duration of the
study”
f. The male partners of female patients must refrain from fathering a child for at least
8 weeks following the last study drug administration.
4. All female patients must have negative pregnancy test results at screening and at
baseline
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
1. WHO class IV functional status.
2. FEV1<50% of predicted post-bronchodilator.
3. Change in FVC (ml) > ± 15% of screening value at baseline visit (not less than 14d
after screening visit).
4. Listed for organ transplantation and on active status.
5. Use of Sirolimus (Rapamycin™) in the 4 months prior to the screening visit and for
the duration of the study
6. Use of doxycycline or other tetracycline derivatives within 30 days prior to the
screening visit and for the duration of the study
7. Use of an investigational drug within the last 30 days prior to the screening visit
8. Use of any medicine containing estrogen in the 4 months prior to the screening visit
and for the duration of the study
9. Use of alternative or complimentary medications within 30 days prior to the screening
visit and for the duration of the study
10. Use of antibiotics or a clinical history consistent with bacterial infection in the 30 days
prior to study entry
11. Pregnant or breast feeding
12. Significant hematologic (Hemoglobin <10mg/dl, White Blood Cell count <3000/ml or
Absolute Neutrophil Count<1000/ml), renal (creatinine >2 mg/dl) , hepatic laboratory
abnormality (transaminase levels > three times the upper limit of normal range) or
amylase > 1.5x the upper limit of the normal range at the screening or baseline visits
13. Fasting blood glucose > 126mg/dl or random blood glucose >200mg/dl at screening
and/or baseline
14. Recent surgery (involving entry into a body cavity or requiring sutures) within 2
months of the screening visit or any evidence of unhealed surgical wound.
15. Uncontrolled hyperlipidemia or a history of clinical atherosclerotic disease
16. Any type of pleural disease severe enough to affect pulmonary function as determined
by the site investigator.
17. History of acute pneumothorax or chylothorax within 2 months of the screening visit
18. Previous organ transplantation
19. Inability to attend scheduled clinic visits
20. Inability to give informed consent
21. Inability to perform pulmonary function or 6 minute walk tests and imaging
assessments
22. History of malignancy in the two years prior to the screening visit, other than
squamous or basal cell skin cancer, angiomyolipoma or menigioma.
23. Any other reason that the investigator feels that the subject would not be able to
adequately perform the procedures necessary for study participation or that may put
patient at risk from participating in the trial.
24. Contraindications to MRI:
a. Brain Aneurysm Clip
b. Implanted neural stimulator
c. Implanted cardiac pacemaker, pacemaker wires or defibrillator
d. Prosthetic heart valves
e. Cochlear implant
f. Ocular foreign body
g. Other implanted medical devices
h. Implanted insulin pump
i. Metal shrapnel or bullet
25. BMI > 40 kg/m2 since patients will be difficult to position comfortably inside the MRI
26. History of immunodeficiency diseases, including a positive HIV test result.
27. A positive Hepatitis B surface antigen (HBsAg) or Hepatitis C virus (HCV) test result.
28. Subjects with a platelet count of <75,000/mm3 will be excluded from the study


Age minimum:
Age maximum:
Gender:
Female: yes
Male: no

Health Condition(s) or Problem(s) studied

Lymphangioleiomyomatosis
MedDRA version: 12.1 Level: LLT Classification code 10049459 Term: Lymphangioleiomyomatosis

Intervention(s)

Product Code: RAD001
Pharmaceutical Form: Tablet
INN or Proposed INN: everolimus
Current Sponsor code: RAD001
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 2.5-

Trade Name: Afinitor
Product Code: RAD001
Pharmaceutical Form: Tablet
INN or Proposed INN: everolimus
Current Sponsor code: RAD001
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-

Trade Name: Afinitor
Product Code: RAD001
Pharmaceutical Form: Tablet
INN or Proposed INN: everolimus
Current Sponsor code: RAD001
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 10-

Primary Outcome(s)

Primary end point(s): Safety and tolerability evaluation (Vital signs and safety measurements)

Main Objective: The primary objective is to assess the safety, pharmacokinetics (PK) and pharmacodynamics (PD, assessed by serum VEGF-D) of everolimus in patients with lymphangioleiomyomatosis (LAM).

Secondary Objective: The key secondary objectives are:
- to assess the clinical efficacy of everolimus as measured by improvement in pulmonary function (FVC).
- to assess the efficacy of everolimus as measured by improvement in other measures of pulmonary function (FEV-1, lung volumes (TLC, TGV, RV), DLCO).
- to assess the efficacy of everolimus as measured by improvement in exercise capacity (6-minute walk test), and change in O2 saturation (with supplemental oxygen unchanged).

For exploratory objectives, please refer to the protocol

Secondary ID(s)

CRAD001X2201

2010-019825-32-IT