Boron Phenylalanine With or Without Mannitol in Treating Patients With Glioblastoma Multiforme

Brain and Central Nervous System Tumors Clinical Trial

Official title:

A Cancer Research UK Pharmacokinetic Study of BPA in Patients With High Grade Glioma to Optimize Uptake Parameters for Clinical Trials of BNCT

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01233492
• Other study ID #: CDR0000687653
• Secondary ID: CRUK-PH1/093EUDR
• Status: Terminated
• Phase: Phase 1
• First received: November 2, 2010
• Last updated: October 7, 2013
• Start date: October 2007
• Est. completion date: September 2013

Study information

• Verified date: October 2013
• Source: Cancer Research UK
• Contact: n/a
• Is FDA regulated: No
• Health authority: United Kingdom: Medicines and Healthcare Products Regulatory AgencyUnited Kingdom: Research Ethics Committee
• Study type: Interventional

Clinical Trial Summary

RATIONALE: Giving boron phenylalanine in different ways and measuring it in tissue in patients with glioblastoma multiforme may help in planning better radiation therapy, such as boron neutron capture therapy, for patients in the future.

PURPOSE: This phase I trial is studying the side effects, best dose boron phenylalanine, and best way of giving it with or without mannitol in treating patients with glioblastoma multiforme.

Description:

OBJECTIVES:

Primary

• To determine the optimal way to deliver boron phenylalanine (BPA) with or without mannitol in terms of route (intravenous vs intraarterial), blood-brain barrier disruption, and dose for use in subsequent therapeutic trials of boron neutron capture therapy (BNCT) in patients with high-grade glioma.

• To evaluate the toxicity profile of BPA administered intravenously or intra-arterially.

• To evaluate the pharmacokinetic behavior of BPA using samples of blood, urine, tumor tissue, normal brain tissue, extracellular fluid, and cerebrospinal fluid.

Secondary

• To produce indicative treatment plans using BPA administered either intravenously or intra-arterially with or without mannitol to support the design of combination studies using BPA and thermal neutrons for BNCT.

Tertiary

• To evaluate the micro-distribution of boron resulting from the different routes of administration using secondary ion mass spectroscopy (SIMS).

• To store surplus tissues removed during the trial for possible future studies.

OUTLINE: This is a dose-escalation study.

• Stage 1 (Route and Blood Brain Barrier Disruption [BBBD]): Patients receive one dose of boron phenylalanine intravenously (IV) or intra-arterially (IA) over 2 hours. Some patients may receive mannitol IA over 30 seconds before receiving boron phenylalanine. Patients then undergo planned biopsy of the tumor. Some patients may then undergo immediate surgical debulking of the tumor.

Boron distribution data is analyzed to determine the optimal administration schedule. Patients in stage 2 receives boron phenylalanine via the optimal route established in stage

1. If addition of mannitol is found to be beneficial, then mannitol is used in stage 2

• Stage 2 (Dose-escalation): Patients receive 1 or 2 doses of boron phenylalanine IV or IA (as determined in stage 1) over 2 hours on day 1. Patients may also receive mannitol IA as in stage 1.

Tumor tissue, normal brain tissue, and cerebrospinal fluid are collected during biopsy and/or surgery. Some patients undergo blood, urine, extracellular fluid sample collection periodically for pharmacokinetic studies. Tumor tissue will be stored for future studies.

After completion of study treatment, patients are followed for 7 days and then once a month.

Peer Reviewed and Funded or Endorsed by Cancer Research UK

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 36
• Est. completion date: September 2013
• Est. primary completion date: September 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 45 Years to 75 Years

Eligibility

DISEASE CHARACTERISTICS:

• Radiologically and clinically suspected solitary glioblastoma multiforme

• High-grade disease

• Agreed to undergo stereotactic biopsy as part of routine diagnostic work-up

PATIENT CHARACTERISTICS:

• WHO performance status 0-2 (0-1 for patients = 65 years old)

• Life expectancy > 4 months

• Hemoglobin = 9.0 g/dL

• Neutrophil count = 1.5 x 10^9/L

• Platelet count = 100 x 10^9/L

• Serum bilirubin = 1.5 times upper normal of limit (ULN)

• AST = 1.5 times ULN

• Uncorrected EDTA-Isotope creatinine clearance = 40 mL/min

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use two forms of effective contraception 4 weeks prior to, during, and for 6 months after completion of study therapy

• Able to cooperate with procedures and follow-up

• Not at high risk of complications from blood-brain barrier disruption with mannitol on pre-treatment CT scan (an open quadrigeminal plate cistern, absence of dilatation of the contralateral frontal horn, and absence of uncal herniation)

• No history of uncontrolled seizures

• No phenylketonuria

• No current or previous malignancies at sites other than the brain, except for adequately treated cone-biopsied carcinoma in-situ of the uterine cervix or basal cell or squamous cell carcinoma of the skin

• Not at high medical risk due to nonmalignant systemic disease, including active uncontrolled infection

• No known hepatitis B, hepatitis C, or HIV positivity by serology

• No concurrent congestive heart failure, history of NYHA class III-IV cardiac disease, history of myocardial infarction or active ischemic heart disease within the past year, or history of cardiac arrhythmia or thromboembolic disease

• No other condition that, in the investigator's opinion, would not make the patient a good candidate for the clinical trial

PRIOR CONCURRENT THERAPY:

• At least 12 hours since prior and no concurrent steroids

• At least 48 hours since prior phenylalanine-containing drinks (e.g., colas)

• At least 48 hours since prior excessive consumption of phenylalanine-containing foods, including any of the following:

• Low phenylalanine content (e.g., fruit juice, fruits [except bananas], vegetables, and low-protein breads and pastas

• Medium phenylalanine content (e.g., corn, bread, french fries, potatoes, peas, rice, and regular pasta)

• High phenylalanine content (e.g., refried beans, chicken, nuts, hamburgers, peanuts, cheese, eggs, pork chops, steak, bananas, and milk)

• At least 4 weeks since prior major thoracic and/or abdominal surgery and recovered

• No prior cranial radiotherapy

• No prior endocrine therapy, immunotherapy, or chemotherapy for the brain tumor

• No other concurrent anticancer therapy or investigational drugs

Study Design

Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Brain and Central Nervous System Tumors
• Central Nervous System Neoplasms
• Nervous System Neoplasms

Intervention

Drug:
• boron phenylalanine

• mannitol

Other:
• biologic sample preservation procedure

Radiation:
• radiation therapy treatment planning/simulation

Locations

Country	Name	City	State
United Kingdom	Cancer Research UK Clinical Trials Unit - Birmingham	Birmingham	England
United Kingdom	Queen Elizabeth Hospital at University Hospital of Birmingham NHS Trust	Birmingham	England

Sponsors (1)

Lead Sponsor	Collaborator
Cancer Research UK

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Optimal dose of boron phenylalanine (BPA)			No
Primary	Causality of each adverse event to BPA and grading severity according to NCI CTCAE Version 3.0			Yes
Primary	Pharmacokinetic (PK) parameters used to construct a PK model with the aim of being able to predict boron up-take by tumor and normal brain tissue			No
Secondary	Change in mean dose to the planning target volume of greater than 15%, for a constant maximum and mean dose to normal tissue in any treatment cohort of the study			No
Secondary	Change in the intra-nuclear percentage of 10B atoms in any cohort of the study of greater than 20%			No
Secondary	Establishment of a repository of samples including serum and tumor tissue for future studies using techniques such as proteomics and DNA array			No