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

Phase 1
18 Years
Open (Enrolling)
Brain and Central Nervous System Tumors, Lymphoma, Metastatic Cancer

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Trial Information

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


- 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.

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


- 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

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose (MTD)of Melphalan as measured by NCI CTC v2 toxicities

Outcome Description:

MTD = dose of Melphalan that produces grade 3 neurotoxicity in 33% of subjects

Outcome Time Frame:

5 years

Safety Issue:


Principal Investigator

Edward A. Neuwelt, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

OHSU Knight Cancer Institute


United States: Institutional Review Board

Study ID:




Start Date:

May 1998

Completion Date:

December 2013

Related Keywords:

  • Brain and Central Nervous System Tumors
  • Lymphoma
  • Metastatic Cancer
  • 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
  • Lymphoma
  • Neoplasm Metastasis
  • Neoplasms
  • Neoplasms, Second Primary
  • Nervous System Neoplasms
  • Central Nervous System Neoplasms



Knight Cancer Institute at Oregon Health and Science University Portland, Oregon  97239-3098