Melphalan With BBBD in Treating Patients With Brain Malignancies

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00253721
Recruitment Status : Terminated (Other competing clinical trials affecting enrollment)
First Posted : November 15, 2005
Last Update Posted : April 21, 2017
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Edward Neuwelt, OHSU Knight Cancer Institute

Brief Summary:

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.

Condition or disease Intervention/treatment Phase
Brain and Central Nervous System Tumors Lymphoma Metastatic Cancer Drug: Melphalan Phase 1

Detailed Description:


  • Determine the maximum tolerated dose of intra-arterial melphalan when given in combination with BBBD in patients with primary or metastatic central nervous system (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.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 21 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Study Start Date : May 1998
Actual Primary Completion Date : December 2015
Actual Study Completion Date : December 2016

Arm Intervention/treatment
Experimental: All subjects 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

Primary Outcome Measures :
  1. Maximum tolerated dose (MTD)of Melphalan as measured by NCI common toxicity criteria (CTC) v2 toxicities [ Time Frame: 5 years ]
    MTD = dose of Melphalan that produces grade 3 neurotoxicity in 33% of subjects

Secondary Outcome Measures :
  1. Efficacy of chemotherapy regimen as measured by clinical and radiographic response from first day of treatment [ Time Frame: 5 years ]

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Ages Eligible for Study:   18 Years to 120 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No


  • 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 Eastern Cooperative Oncology Group (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:

    • White blood cell count (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)
    • Serum glutamic oxaloacetic transaminase (SGOT) ≤ 3 times ULN
    • Creatinine ≤ 2 times ULN
  • Subjects with history of smoking or emphysema require diffusing capacity of lung for carbon monoxide (DLCO) ≥ 80% of predicted value for age
  • Histological sections submitted for pathology review


  • 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 human chorionic gonadotropin (HCG) test, or lactating
  • HIV positive
  • Receiving concurrent radiotherapy or immunotherapy
  • Serious illness that would preclude study participation

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00253721

United States, Oregon
Knight Cancer Institute at Oregon Health and Science University
Portland, Oregon, United States, 97239-3098
Sponsors and Collaborators
OHSU Knight Cancer Institute
National Cancer Institute (NCI)
Principal Investigator: Edward A. Neuwelt, MD OHSU Knight Cancer Institute

Responsible Party: Edward Neuwelt, Professor, OHSU Knight Cancer Institute Identifier: NCT00253721     History of Changes
Other Study ID Numbers: IRB00001299
P30CA069533 ( U.S. NIH Grant/Contract )
1299 ( Other Identifier: OHSU eIRB )
ONC-98018-L ( Other Identifier: OHSU Knight Cancer Institute )
4834 ( Other Identifier: OHSU IRB (discontinued number) )
First Posted: November 15, 2005    Key Record Dates
Last Update Posted: April 21, 2017
Last Verified: April 2017

Keywords provided by Edward Neuwelt, OHSU Knight Cancer Institute:
adult anaplastic astrocytoma
adult brain stem glioma
adult diffuse astrocytoma
adult central nervous system germ cell tumor
adult medulloblastoma
adult supratentorial primitive neuroectodermal tumor (PNET)
adult anaplastic oligodendroglioma
adult oligodendroglioma
adult pineoblastoma
tumors metastatic to brain
adult mixed glioma
recurrent adult brain tumor
primary central nervous system non-Hodgkin lymphoma

Additional relevant MeSH terms:
Neoplasm Metastasis
Nervous System Neoplasms
Central Nervous System Neoplasms
Neoplastic Processes
Pathologic Processes
Neoplasms by Site
Nervous System Diseases
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs