Phase II Trial of Peginterferon Alpha-2b and Thalidomide in Adults With Recurrent Gliomas
Phase II Trial of Peginterferon Alpha-2b and Thalidomide in Adults With Recurrent Gliomas
This study will examine the safety and effectiveness of peginterferon alpha-2b (PEG-Intron)
 alone and together with thalidomide in patients with gliomas (a type of brain tumor). Gliomas
 are nourished by blood delivered through blood vessels whose formation is stimulated by
 substances produced by the tumor itself. Stopping the growth of new vessels can slow or
 prevent tumor growth. The Food and Drug Administration has approved various interferons for
 treating several diseases, including melanoma and some leukemias. These drugs block new
 vessel growth in patients with recurrent tumors, but in high doses they produce serious side
 effects. Therefore, this study will use a low dose of PEG-Intron given weekly instead of high
 doses given several times a week. Thalidomide, currently approved to treat leprosy, also
 blocks development of new blood vessel formation. In a recent study of thalidomide given to
 36 patients with gliomas, 4 patients had tumor shrinkage, 12 had stable disease for at least
 2 months, and at least 3 had responses to treatment lasting 6 to 14 months.

 Patients 18 years of age and older with a primary glioma whose tumor has recurred or is
 growing following standard treatment and does not respond to radiation therapy may be
 eligible for this study. Candidates will be screened with a physical examination, blood and
 urine tests (including a pregnancy test for women of childbearing potential), and magnetic
 resonance imaging (MRI) or computed tomography (CT) of the head.

 Patients will continue treatment cycles as long as the drug is tolerated without serious side
 effects and the tumor is not growing. While on the study, patients will undergo various tests
 and procedures as follows:

 Physical and neurologic examinations every 6 weeks MRI or CT brain scan every 6 weeks to
 assess tumor status. MRI is a diagnostic test that uses a strong magnetic field and radio
 waves to show structural and chemical changes in tissues. During the scan, the patient lies
 on a table in a narrow cylinder containing a magnetic field. He or she can speak with a staff
 member through an intercom system at all times during the procedure.
Background:

 There is a growing belief that angiogenesis inhibition represents a potentially promising,
 novel therapeutic approach to highly vascular solid tumors like malignant gliomas.
 Thalidomide and Peg-Intron (IFN - Interferon) are attractive drugs to use in combination to
 test the hypothesis of combination anti-angiogenesis therapy inhibition given their proven
 activity as single agents in patients with malignant gliomas and their spectrum of largely
 non-overlapping toxicities.

 Given recent preclinical data describing more potent antiangiogenic and anti-tumor effects of
 low dose, continuous IFN administration, we are interested in evaluating the use of pegylated
 IFN in combination with thalidomide. Thus, we are proposing a phase II trial of pegylated IFN
 with thalidomide in patients with recurrent gliomas.

 Objectives:

 To obtain preliminary evidence of anti-tumor efficacy of PEG-Intron in combination with
 thalidomide in patients with recurrent high grade gliomas as assessed by prolongation of
 progression-free survival compared to historical controls.

 A secondary endpoint in this trial is to determine the response rate associated with the
 combination therapy in each of the two strata and to evaluate and document all toxicities
 from PEG-Intron in combination with thalidomide at the doses prescribed in this protocol in
 this patient population.

 Eligibility:

 Patients with histologically proven supratentorial malignant primary gliomas will be eligible
 for this protocol. These include glioblastoma multiforme (GBM), anaplastic astrocytoma (AA),
 anaplastic oligodendroglioma (AO), anaplastic mixed oligoastrocytoma (AMO), or malignant
 astrocytoma NOS (not otherwise specified).

 Patients must not have received prior therapy with Peg-Intron or Thalidomide.

 Design:

 Patients will be treated with weekly PEG-Intron plus daily oral thalidomide. All patients
 will be treated for 6 weeks following which patients will have a repeat MRI scan to assess
 disease response.
Inclusion Criteria:

 -  Patients with histologically proven supratentorial malignant primary gliomas will be
 eligible for this protocol. These include glioblastoma multiforme (GBM), anaplastic
 astrocytoma (AA), anaplastic oligodendroglioma (AO), anaplastic mixed oligoastrocytoma
 (AMO), or malignant astrocytoma NOS (not otherwise specified).

 -  Patients must have evaluable or measurable disease and have shown unequivocal evidence
 for tumor recurrence or progression by MRI or CT scan. This scan should be performed
 within 14 days prior to registration and on a steroid dosage that has been stable for
 at least 5 days. If the steroid dose is increased between the date of imaging and the
 initiation of treatment, a new 20 baseline MR/CT scan is required. The same type of
 scan, i.e., MRI or CT must be used throughout the period of treatment for tumor
 measurement.

 -  Patients having undergone recent resection of recurrent or progressive tumor will be
 eligible as long as the following conditions apply:

 -  They have recovered from the effects of surgery

 -  Measurable disease following resection of recurrent tumor is not mandated for
 eligibility into the study. Patients must have evaluable disease.

 -  To best assess the extent of residual disease post-operatively, a CT/MRI should be
 done no later than 96 hours in the immediate post-operative period or 4-6 weeks
 post-operatively. If the 96 hour scan is more than 2 weeks from registration, the scan
 needs to be repeated.

 -  The baseline on-study MR/CT is performed within 14 days of registration and on a
 steroid dosage that has been stable. If the steroid dose is increased between the date
 of imaging and the initiation of Peg-Intron with or without Thalidomide, a new
 baseline MR/CT is required on stable steroids for 5 days.

 -  Patient must have failed prior radiation therapy and must have an interval of greater
 than or equal to 4 weeks from the completion of radiation therapy to study entry.

 -  Patients with prior therapy that included interstitial brachytherapy or stereotactic
 radiosurgery must have confirmation of true progressive disease rather than radiation
 necrosis based upon either PET or Thallium scanning, MR spectroscopy or surgical
 documentation of disease.

 -  Prior therapy. There are no limitations to number of prior therapies.

 -  All patients must sign an informed consent indicating that they are aware of the
 investigational nature of this study.

 -  Patients must be > 18 years old, and with a life expectancy > 8 weeks.

 -  Patients must have a Karnofsky performance status of > 60.

 -  Patients must have recovered from the toxic effects of prior therapy (including
 resolution of effects on laboratory values): 2 weeks from any investigational agent, 4
 weeks from prior cytotoxic therapy, 2 weeks from vincristine, 6 weeks from
 nitrosoureas, 3 weeks from procarbazine administration, and 1 week for non-cytotoxic
 agents e.g. tamoxifen, cis- retinoic acid, etc. (radiosensitizer does not count). Any
 questions related to the definition of non-cytotoxic agents should be directed to the
 PI.

 -  Patients must have adequate bone marrow function (WBC > 3,000/l, ANC > 1,500 mm3,
 platelet count of > 100,000/mm3, and hemoglobin > 10 gm%), adequate liver function
 (SGOT and bilirubin < 2 times the upper limit of normal), and adequate renal function
 (creatinine < 1.5 mg/dL or creatinine clearance > 60 cc/min) before starting therapy.
 These tests must be performed within 14 days prior to registration. Eligibility level
 for hemoglobin may be reached by transfusion.

 -  Patients with a history of any other cancer (except non-melanoma skin cancer or
 carcinoma in-situ of the cervix), unless in complete remission and off of all therapy
 for that disease for a minimum of 3 years are ineligible.

 -  This study was designed to include women and minorities, but was not designed to
 measure differences of intervention effects. Males and females will be recruited with
 no preference to gender. No exclusion to this study will be based on race. Minorities
 will actively be recruited to participate.

 -  Patients must not be pregnant or nursing, and all patients (both men and women) must
 be willing to practice birth control for 1 month prior, during and for 4 months after
 treatment with thalidomide. It has been proposed that thalidomide may interfere with
 hormonal-based contraception, therefore, barrier methods of contraception (i.e.
 diaphragm, condom) MUST be used rather than, or in addition to birth control pills.

 -  No peripheral neuropathy > grade 1.

 -  No concurrent use of other investigational agents.

 Exclusion Criteria:

 -  Patients must not have:

 -  Serious active infection

 -  Disease that will obscure toxicity or dangerously alter drug metabolism

 -  Serious intercurrent medical illness.

 -  Significant illness that in the investigator's opinion cannot be adequately controlled
 with appropriate therapy or would compromise the patients ability to tolerate this
 therapy.

 -  Patients must not have received prior therapy with Peg-Intron or Thalidomide.

 -  Concurrent chemotherapy, immunotherapy, or radiotherapy is not permitted.