An open-label, single-arm phase II study of RAD001 in patients with mantle cell lymphoma who are refractory or intolerant to Velcade (bortezomib) therapy
The goal of this clinical research study is to learn if Everolimus (RAD001) can help to control MCL. The safety of this drug will also be studied. You are being asked to allow extra blood to be drawn for biomarker testing. Biomarkers are chemical "markers" in the blood/tissue that may be related to your response to the study drug.
Disease Group: Lymphoma
Treatment Agent: RAD001
Treatment Location: Both at MD Anderson & outside MD Anderson at one or more Collaborating Sites or Institutions
Estimatated Length of Stay in Houston: N/A
Return Visit: RAD001 will be taken daily fm Visit 2, Day 1until disease progression or unacceptable toxicity or discontinuation from the study for any other reason. On days when PK sample collection is performed, study drug administration will occur at the clinic.
Home Care: Patients will be instructed to take RAD001 at the same time each day, 10 mg;orally once daily (qd), two 5 mg tablets at once (one tablet after another) ;with a glass of water.
Primary objectives 1) Assess the overall response rate (ORR) to treatment with oral RAD001 (10 mg qd) monotherapy in patients with mantle cell lymphoma who are refractory or intolerant to Velcade (bortezomib) Secondary objectives 1) Assess the duration of response, 2) Assess the progression-free survival (PFS), 3) Assess the overall survival (OS), 4) Determine the safety and tolerability of 10 mg qd RAD001 monotherapy Exploratory objectives 1) Assess tumor cell phenotype, mTOR pathway activation and response to RAD001 treatment in patients with peripheral disease using flow cytometry (FC). 2) Measure molecular markers in pretreatment archival tumor biopsy samples, where available, and correlate these markers with response to RAD001. Given adequate tissue, markers to be tested include Cyclin D1, p53 mutations and deletions, protein levels of pS6, pAKT, and PTEN, and RNA expression profiles 3) Correlate pharmacodynamic changes in peripheral tumor cells as measured by FC with RAD001 PK blood levels 4) To capture the RAD001 exposure near the Cmax in this patient population at daily dose of 10 mg/day
IRB Review and Approval Date: 12/29/2008
Recruitment Status: Not Accepting
Projected Accrual: 57
1) Age >/=18 years old
2) Patients with histopathologically proven Mantle cell lymphoma (MCL), including staining for overexpression of cyclin D1 or evidence of t(11;14) (q13;q32) translocation (cytogenetics or FISH), confirmed by Central Pathology review
3) Available archival diagnostic tumor specimen for Central Pathology review and confirmation of diagnosis, preferably prior to study treatment. Otherwise, there must be evidence in the patient source documents that the specimen has been shipped to the designated Central Pathology lab prior to initiation of study treatment
4) At least one prior bone marrow biopsy for staging. Patients with no prior bone marrow tumor involvement should have a core bone marrow biopsy performed at screening and reviewed by both local and Central Pathology
5) Patients with mantle cell lymphoma who have documented refractory disease to bortezomib (Velcade®) or who have documented intolerance to Velcade® treatment for a documented safety reason. As patients must be off Velcade® for a minimum of 4 weeks prior to their first treament with RAD001, their screening tumor assessment may also confirm some level of disease progression (i.e., increased tumor size at any value when compared to their prior CT of MRI evaluation).
6) Continued from Inclusion # 5: Patients are considered refractory to Velcade® if they have documented radiological progression on or within 12 months of the last dose of Velcade® when given alone or, on or within 12 months of the last dose of the last component of a combination therapy which included Velcade®. Patients are considered refractory to Velcade®, if Velcade®, is part of a combination treatment for the disease.
7) Patients must have received at least one prior antineoplastic agent other than Velcade®, either separately or in combination with bortezomib (Velcade®). Prior autologous stem cell transplantation (ASCT) and the associated conditioning chemotherapy will be considered as a single prior therapy
8) At least one site of measurable nodal disease at baseline > 2.0 cm in the longest transverse diameter and clearly measurable in at least two perpendicular dimensions, as determined by CT scan (MRI is allowed only if CT scan can not be performed)
9) Eastern Cooperative Oncology Group (ECOG) Performance Status 0, 1 or 2
10) Life expectancy >/= 3 months
11) Adequate bone marrow function as shown by: ANC >/=1.5 x 109/L; Platelets >/=75 x 109/L (untransfused platelets); Hb >/=9 g/dL (may be transfused)
12) Adequate liver function: Serum bilirubin: </=1.5 x ULN; ALT and AST </=2.5 x ULN; Patients with known liver involvement: AST and ALT </=5 x ULN
13) Adequate renal function: Serum creatinine </= 1.5 x ULN
14) Women of childbearing potential must have had a negative serum pregnancy test within 7 days prior to the administration of the first treatment with RAD001
15) Patients who give a written informed consent obtained according to local guidelines
1) Patients with Grade 3 and Grade 4 unresolved toxicity from prior
2) Patients currently receiving anticancer therapies or who have received anticancer therapies within 4 weeks of the start of study drug (including chemotherapy, radiation therapy, antibody based therapy, targeted therapy, etc.)
3) Patients with prior allogeneic stem cell transplant
4) Patients who have previously received mTOR inhibitors (e.g. everolimus, sirolimus, temsirolimus etc.)
5) Patients who are taking other investigational agents or who had received investigational drugs within 4 weeks of the start of study drug
6) Patients with presence or history of central nervous system (CNS) lymphoma - Head MRI (or CT scan if MRI is not available), is required prior to study entry
7) Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent, except corticosteroids with a daily dosage equivalent to prednisone </= 20 mg for adrenal insufficiency. However, patients receiving corticosteroids must have been on a stable dosage regimen for a minimum of 4 weeks prior to the first treatment with RAD001. Topical or inhaled corticosteroids are allowed.
8) Patients with a known history of HIV seropositivity (testing is not required for study entry; however review of previous medical history is required)
9) Patients with uncontrolled hyperlipidemia (>/=Grade 3 hyperlipidemia despite optimal supportive medical therapy)
10) Patients with an active, bleeding diathesis
11) Patients, who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia) or patients that may require major surgery during the course of the study
12) Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as: Symptomatic congestive heart failure of New York heart Association Class III or IV; unstable angina pectoris, myocardial infarction within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease;severely impaired lung function (spirometry and DLCO that is 50% or less of the normal predicted value and/or Oxygen saturation that is 88% or less at rest, in room air);
13) Continuation #12: uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN; active (acute or chronic) or uncontrolled severe infections; liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis
14) Patients who have a history of another primary malignancy </=3 years before study entry, with the exception of non-melanoma skin cancer, and carcinoma in situ of uterine cervix
15) Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods. If barrier contraceptives are being used, these must be continued throughout the trial by both sexes. Hormonal contraceptives are not acceptable as a sole method of contraception.
16) Patients unwilling to or unable to comply with the protocol
Information and next steps
For general questions about clinical trials: