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Trial registered on ANZCTR


Registration number
ACTRN12608000614392
Ethics application status
Approved
Date submitted
21/10/2008
Date registered
5/12/2008
Date last updated
9/05/2011
Type of registration
Retrospectively registered

Titles & IDs
Public title
An Open-Label, Phase 1/2 Study of RAD001 in Subjects with Myelofibrosis
Scientific title
An Open-Label, Phase 1/2 Study on safety and effectiveness of RAD001 in Subjects with Myelofibrosis sponsored by Associazione italiana del Farmaco (AIFA).
Secondary ID [1] 262129 0
EudraCT 2008-000522-39
Universal Trial Number (UTN)
Trial acronym
RAD001
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Myelofibrosis 3853 0
Condition category
Condition code
Blood 4049 4049 0 0
Haematological diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The objectives of study Portion 1 are to determine the maximum tolerated dose (MTD) based on dose-limiting toxicity (DLT) of RAD001. Subjects will be assigned to cohorts of increasing doses until MTD is reached, starting from daily oral dose of 5 mg for three months (cohort 1), to a daily oral dose of 7.5 mg for three months (cohort 2) to daily oral dose of 10 mg for three months (cohort 3).When the MTD is defined, an expansion of the cohort will be made for efficacy assessment, with the aim to determine the rate of complete or major clinical-hematological response from treatment with RAD001 in this subject population as measured by the EUMNET (European Myelofibrosis Network) response criteria (Barosi G, Blood 2005; 106:2849).Patients in this portion will be treated using the MTD for a total period time of four months.
Intervention code [1] 3580 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 4948 0
From Phase 1: To determine the maximum tolerated dose (MTD) based on dose-limiting toxicity (DLT) of single-agent therapy with RAD001 in subject with Myelofibrosis (MF) who require therapy.
In case a AE occurs, treatment with RAD001 will be immediately stopped, and the patient managed at best of cure depending on the type, characteristic and severity of Adverse Event (AE)
Timepoint [1] 4948 0
13 months
For the Phase 1: MTD will be calculated based on DLT at the end of each month of treatment
Secondary outcome [1] 8344 0
To examine the effect of treatment with RAD001 on biological and molecular markers of the disease, and on markers of drug activity on target genes, including the following:
-histologically assessed bone marrow fibrosis and bone marrow cellularity as standardized by the European Working Group
-bone marrow angiogenesis (as measured by microvessel density by immunostaining with anti-CD34 antibody)
- Janus Kinake 2 (JAK2 V617F) and MPL receptor for thrombopoietin (MPL W515) mutational status in peripheral blood granulocytes by quantitative Real Time PCR (RT-PCR)
-CD34+ cell count in peripheral blood measured by FACS analysis
-WT1 expression on granulocyte Ribonucleic Acid (RNA) , by RT-PCR
-Quantification of glut1 and cyclinD1 messenger Ribonucleic Acid (mRNA) level changes, by RT-PCR.
Timepoint [1] 8344 0
13 months
Secondary outcome [2] 8516 0
From Phase 2: To determine the rate of complete or major clinical-hematological response from treatment with RAD001 in Myelofibrosis (MF) patients as measured by the European Myelofibrosis network (EUMNET) response criteria (Blood 2005; 106:2849) evaluated with ad hoc case report form (CRF)
Timepoint [2] 8516 0
13 months
For the Phase 2: patients in this portion will be treated using the MTD for a total period time of 4 months

Eligibility
Key inclusion criteria
-Age >=18 years at the time of voluntarily signing an Institutional review Board (IRB)-approved informed consent form.
-Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.
-Female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control (ie, a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study. Male subject agrees to use an acceptable method for contraception for the duration of the study.
-Patients must be diagnosed with myelofibrosis requiring therapy. Patients previously treated must have failed at least 1 previous treatment and in the opinion of the investigator require further treatment. If a subject has had a transplant, he/she must be at least 6 months post-transplant. Any subject who has not received previous therapy and in the opinion of the investigator requires treatment will also be considered for enrollment. A general rule for need of treatment is falling into intermediate or high risk class according to Lille scoring system (adverse prognostic factors are: Haemoglobin (Hb)<10g/dL, White Blood Cell (WBC) <4 or > 30 x 109/L; risk group:0=low;1= intermediate; 2=high). Low-risk scoring system but with progressive splenomegaly is an additional reason for treatment.
-Patients must have discontinued conventional chemotherapy (hydroxyurea, anagrelide, other myelosuppressive agents, or any other experimental therapy) as well as growth factors or systemic use of corticosteroids for at least 7 days prior to starting study drug. In case of interferon alpha or thalidomide, a time interval of drug wash-out for 28 days is required. Supportive transfusional therapy is ad libitum, but must be registered.
-Ability to communicate meaningfully with the investigational staff, competence to give written informed consent, and ability to comply with the entire study procedures.
Minimum age
18 Years
Maximum age
80 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
-Patient has a platelet count of <100x 109/L within 14 days before enrollment.
-Patient has an hemoglobin value <9 g/L within 14 days before enrollment.
-Patient has an absolute neutrophil count of <1.5 x 109/L. within 14 days before enrollment.
-Patient has a percentage of blast cell in peripheral blood greater than 5% within 14 days before enrollment
-Patient has a calculated or measured creatinine clearance of <40 mL/min within 14 days before enrollment.
-Alanine Aminotransferase (ALT) orAspartate Aminotransferase (AST) > 2.5 x ULN
-Total serum bilirubin = 1.5 x Upper Limit of Normal (ULN)
-INR > 1.3 x Upper Limit of Normal ( or >3 ULN on anticoagulants)
-Serum creatinine = 1.5 x Upper Limit of Normal (ULN)
-Patient has hypersensitivity to RAD001 (Everolimus) or other rapamycins ( sirolimus, temsirolimus) or any of the eccipients.
-Female subject is pregnant or breast-feeding. Confirmation that the subject is not pregnant must be established by a negative serum beta-human chorionic gonadotropin (beta-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women.
-Serious medical or psychiatric illness likely to interfere with participation in this clinical study.
-Patients receiving chronic treatment with steroids or another immunosuppressive agent
-Patients who are using other investigational agents or who had received investigational drugs = 4 weeks prior to study treatment start
-Patients with uncontrolled or symptomatic Central Nervous System (CNS) disease
-Patients with a known history of Human Immunoddeficiency Virus (HIV) seropositivity (HIV testing is not mandatory)
-Patients with an active, bleeding diathesis or on oral anti-vitamin K medication (except low dose coumadin)
-Patients treated with drugs known to be strong inhibitors or inducers of isoenzyme CYP3A
-Persistent =Grade 2 neuropathy or history of grade 3/4 neuropathy of any etiology
-Patients who have any severe and/or uncontrolled medical conditions such as:
-unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction, = 6 months prior to enrollment, serious uncontrolled cardiac arrhythmia
-uncontrolled diabetes as defined by fasting serum glucose >1.5X Upper Limit of Normal (ULN)
-= grade 3 hypercholesterolemia / hypertriglyceridemia or = grade 2; hypercholesterolemia/hypertriglyceridemia with history of coronary artery disease (despite lipid-lowering treatment if given)
-acute and chronic, active infectious disorders and nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the complications of this study therapy
-impairment of gastrointestinal function or who have gastrointestinal disease that may significantly alter the absorption of RAD001 (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome).
-active skin, mucosa, ocular or gastro Intestinal (GI) disorders of grade >2
-significant deterioration of lung function, defined as any of the following: 30% decrease in predicted lung volumes, and/or 30% decrease in Carbon monoxyde diffusing capacity (DLCO), and/or = 88% Oxygen (O2) saturation at rest on room air
-Patients who have liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 1286 0
Italy
State/province [1] 1286 0

Funding & Sponsors
Funding source category [1] 4032 0
Government body
Name [1] 4032 0
Agenzia Italiana del Farmaco
Address [1] 4032 0
Via della Sierra Nevada, 60
00144 - ROMA
Country [1] 4032 0
Italy
Primary sponsor type
Other
Name
Consorzio Mario Negri Sud
Address
Via nazionale 8/A
66030- Santa Maria Imbaro (Chieti)
Country
Italy
Secondary sponsor category [1] 3625 0
None
Name [1] 3625 0
Address [1] 3625 0
Country [1] 3625 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 6116 0
Comitato Etico Azienda Ospedaliero-Universitaria Careggi
Ethics committee address [1] 6116 0
Viale Pieraccini, 28
50139- Firenze
Ethics committee country [1] 6116 0
Italy
Date submitted for ethics approval [1] 6116 0
Approval date [1] 6116 0
22/07/2008
Ethics approval number [1] 6116 0

Summary
Brief summary
The purpose of this study is 1. to determine the maximum tolerated dose based on dose-limiting toxicity of single-agent therapy with RAD001 in subject with Myelofibrosis who require therapy; and 2. to determine the rate of complete or major clinical-hematological response from treatment with RAD001 in myelofibrotic patients.
Trial website
http://heart.negrisud.it/RAD001
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 29059 0
Address 29059 0
Country 29059 0
Phone 29059 0
Fax 29059 0
Email 29059 0
Contact person for public queries
Name 12216 0
Arianna Masciulli
Address 12216 0
Via nazionale 8/A
66030, Santa Maria Imbaro (Chieti)
Country 12216 0
Italy
Phone 12216 0
0039-0872/570286
Fax 12216 0
0039-0872/570206
Email 12216 0
masciulli@negrisud.it
Contact person for scientific queries
Name 3144 0
Arianna Masciulli
Address 3144 0
Via nazionale 8/A
66030, Santa Maria Imbaro (Chieti)
Country 3144 0
Italy
Phone 3144 0
0039-0872/570286
Fax 3144 0
0039-0872/570206
Email 3144 0
masciulli@negrisud.it, addeo@negrisud.it

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary