Lenalidomide in Treating Young Patients With Recurrent, Progressive, or Refractory CNS Tumors

PRIMARY OBJECTIVES:

I. To estimate the MTD of oral CC-5013 administered to children with recurrent or refractory primary CNS tumors once daily for 21 days of a 28 day course.

II. To describe the toxicity profile and define the dose-limiting toxicity of CC-5013 in children with recurrent or refractory primary CNS tumors.

SECONDARY OBJECTIVES:

I. To characterize the pharmacokinetics of CC-5013 in children and adolescents. II. To characterize the pharmacogenetics of CC-5013 in children and adolescents.

III. To evaluate changes in circulating endothelial cells (CECs) and circulating endothelial cell precursors (CEPs) in patients treated with CC-5013, and to investigate the correlation between changes in CECs and CEPs, plasma, serum and urine levels of proteins associated with angiogenesis including thrombospondin, b-FGF, TNF-α, IL-12, IL-8 and VEGF, and correlate these changes with changes in MR perfusion and clinical outcome.

IV. To evaluate changes in MR perfusion and diffusion during treatment.

OUTLINE: This is a dose-escalation, multicenter study.

Patients receive oral lenalidomide once daily on days 1-21. Treatment repeats every 28 days for 24 courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 2-3 patients receive escalating doses of lenalidomide until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which an estimated 25% of patients experience dose-limiting toxicity.

All patients are followed for at least 30 days after the last dose of lenalidomide. Patients with treatment-related toxicity are followed for up to 3 months.

Inclusion criteria

• Patients with a histological diagnosis of a primary CNS tumor (including histologically benign brain tumors (e.g. low-grade glioma) that is recurrent, progressive, or refractory to standard therapy; patients with intrinsic brain stem or diffuse optic pathway tumors do not require histological confirmation of disease but should have clinical and/or radiographic evidence of progression
• Karnofsky Performance Scale (KPS for >= 16 yrs of age) or Lansky Performance Score (LPS for ≤ 16 years of age) ≥ 60 assessed within two weeks prior to registration
• Patient must be able to swallow capsules
• Patients must have recovered from any significant acute toxicity associated with prior therapy; patients must have no known curative therapy available; patients will be eligible regardless of the number of prior therapies, as long as other eligibility criteria are met
• Chemo: Prior use of thalidomide is acceptable; patients must have:

• Received their last dose of known myelosuppressive anticancer chemotherapy or biological therapy at least three (3) weeks prior to study registration
• Received their last dose of nitrosourea or mitomycin-C at least six (6) weeks prior to study registration
• Received their last dose of other investigational agent or an anticancer drug known to not be myelosuppressive at least seven (7) days prior to study registration
• XRT: Patients must have had their last fraction of craniospinal irradiation ≥ 3 months prior to registration and their last fraction of local irradiation to primary tumor ≥ 4 weeks prior to registration
• Bone Marrow Transplant: ≥ 6 months since allogeneic bone marrow transplant and ≥ 3 months since autologous bone marrow/stem cell prior to registration
• Growth factors: Off all colony forming growth factor(s) > 2 weeks prior to registration (filgrastim, sargramostim, erythropoietin)
• The following laboratory values must be assessed within two (2) weeks prior to registration and again within seven (7) days prior to the start of therapy; laboratory tests should be repeated within 48 hours of beginning therapy if there has been a significant clinical change
• Absolute neutrophil count ≥ 1000/μl (unsupported)
• Platelets ≥ 100,000/μl (unsupported)
• Hemoglobin ≥ 8.0 g/dL (may be supported)
• Serum creatinine within upper limit of institutional normal for age
• Or GFR ≥ 70 ml/min/1.73m^2
• Bilirubin ≤ 1.5 times upper limit of normal for age
• SGPT (ALT) ≤ 2.5x institutional upper limit of normal for age
• Albumin ≥ 2 g/dL
• No overt renal, hepatic, cardiac or pulmonary disease
• Female patients of childbearing potential must have negative serum or urine pregnancy test (sensitivity of at least 50mIU/ml); patients must not be pregnant or breast-feeding
• All sexually active females must begin 2 methods of birth control, including 1 highly effective method, and 1 additional method (at the same time) at least 4 weeks prior to the first dose of CC-5013; this applies to all sexually active females of childbearing potential unless they have not had a menstrual period in 2 years or have undergone a hysterectomy
• Patients of child fathering potential must agree to use latex condoms during intercourse with a woman while taking CC-5013 and for 4 weeks thereafter
• Signed informed consent according to institutional guidelines must be obtained

Exclusion criteria

• Patients with a body surface area (BSA) ≤ 0.4 m^2 are excluded
• Patients with a first-degree relative with a history of venous thrombosis before age 50 yrs or an arterial thrombosis before age 40 yrs are excluded
• Patients who have had a thromboembolic event that is not line-related are excluded
• Patients with any significant medical illnesses that, in the investigator's opinion, cannot be adequately controlled with appropriate therapy or would compromise a patient's ability to tolerate this therapy
• Patients with any disease that would obscure toxicity or dangerously alter drug metabolism
• Patients receiving any other chemotherapeutics or investigational agents
• Patients with uncontrolled infection
• Patients unable to swallow capsules
• Patients with known hypersensitivity to anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate