Melphalan With BBBD in Treating Patients With Brain Malignancies

Official Title: “Intra-Arterial Melphalan (L-Phenylalanine Mustard) Administered in Conjunction With Osmotic Blood-Brain Barrier Disruption in Patients With Brain Malignancies: A Phase I Study”

RATIONALE: Drugs used in chemotherapy, such as melphalan, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving drugs directly into the arteries around the tumor may kill more tumor cells. Mannitol may open the blood vessels around the brain [Blood-Brain Barrier Disruption (BBBD)]and allow melphalan to be carried directly to the brain tumor. Giving melphalan together with BBBD may be an effective treatment for central nervous system cancer.

PURPOSE: This phase I trial is studying side effects and best dose of melphalan when given together with mannitol in treating patients with central nervous system cancer.

OBJECTIVES: - Determine the maximum tolerated dose of intra-arterial melphalan when given in combination with BBBD in patients with primary or metastatic CNS malignancy. - Determine the toxic effects of melphalan given with BBBD in these patients. - Determine, preliminarily, the efficacy of this regimen in these patients.

OUTLINE: This is a dose-escalation study of melphalan.

Patients receive intra-arterial mannitol with BBBD followed by intra-arterial melphalan over 10 minutes on days 1 and 2*. Treatment repeats every 4 weeks for up to 12 monthly courses in the absence of disease progression or unacceptable toxicity .

NOTE: *Patients with gliomas localized to the posterior circulation (i.e., brain stem gliomas) receive melphalan on day 1 only.

Cohorts of 3-6 patients receive escalating doses of melphalan until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

After completion of study therapy, patients are followed every 3 months for 1 year; every 6 months for the next 2 years; then annually.

PROJECTED ACCRUAL: A total of 20 patients will be accrued for this study.

Intervention(s) in this Clinical Trial

• Drug: Melphalan
  • All levels: Every 4 weeks for up to one year Dose Escalation Plan: Level 1: 4mg/m2/day x 2 days Level 2: 6mg/m2/day x 2 days Level 3: 8mg/m2/day x 2 days Level 4: 10mg/m2/day x 2 days Level 5: 12mg/m2/day x 2 days

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: All subjects

Primary Measures

• Maximum tolerated dose (MTD)of Melphalan as measured by NCI CTC v2 toxicities
  • Time Frame: 5 years
    Safety Issue?: Yes

Secondary Measures

• Efficacy of chemotherapy regimen as measured by clinical and radiographic response from first day of treatment
  • Time Frame: 5 years
    Safety Issue?: No

INCLUSION CRITERIA:

• Signed written informed consent form in accordance with institutional guidelines
• Histologically confirmed primary or metastatic CNS malignancy (Patients with metastatic disease must have histological confirmation of the primary cancer AND confirmation by surgical specimen, cerebrospinal fluid cytology, elevated tumor markers, or clinical evidence of CNS involvement)
• Single or multiple cerebellar or cerebral cortex lesions allowed
• Life expectancy at least 60 days
• Radiographically evaluable disease by MRI or CT scan
• Age 18 years or older
• At least 28 days since prior radiotherapy (systemic, cranial, and/or spinal)
• At least 28 days since prior chemotherapy (42 days for nitrosoureas)
• Adequate cardiac and pulmonary function to tolerate general anesthesia
• Performance status of ECOG 0-2
• Other tumor masses in the spinal cord allowed provided there is no radiographic or clinical evidence of spinal cord block
• Available for follow-up for at least one year following completion of treatment
• Fertile patients must use effective contraception for 2 months prior to, during, and for 3 months after study participation
• Pre-treatment lab tests within 14 days prior to initiation of treatment:
• WBC > 2,500/mm^3
• Absolute granulocyte count > 1,200/mm^3
• Platelet count > 100,000/mm^3
• Hematocrit > 30% (transfusion allowed)
• Bilirubin ≤ 2 times upper limit of normal (ULN)
• SGOT ≤ 3 times ULN
• Creatinine ≤ 2 times ULN
• Subjects with history of smoking or emphysema require DLCO ≥ 80% of predicted value for age
• Histological sections submitted for pathology review

EXCLUSION CRITERIA:

• Radiographic evidence of excessive intra-cranial mass effect and/or spinal block
• Known hypersensitivity or intolerance to melphalan
• NCI CTC Grade 3 or greater baseline neurologic symptoms
• Immunologically compromised (Concurrent corticosteroids for tumor edema allowed)
• Unable to tolerate general anesthesia
• Pregnant, positive HCG test, or lactating
• HIV positive
• Receiving concurrent radiotherapy or immunotherapy
• Serious illness that would preclude study participation

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Investigator: OHSU Knight Cancer Institute Other

Overall Clinical Trial Officials and Contacts

Edward A. Neuwelt, MD Principal Investigator OHSU Knight Cancer Institute  

Overall Contact: Edward A Neuwelt, MD 503-494-5626 neuwelte@ohsu.edu

Information obtained from ClinicalTrials.gov on February 12, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00253721

Study ID Number: OHSU-1299

ClinicalTrials.gov Identifier: NCT00253721

Health Authority: United States: Institutional Review Board

Clinical trial summary from the National Cancer Institute's PDQ® database