None listed
Conditions
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.
Interventions
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
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.
Sponsors
Consorzio Mario Negri Sud
Study design
Allocation
Non-randomised trial
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to 80 Years
Healthy volunteers
No
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performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.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.
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.
Outcome results
None listed