This study will investigate the combined use of temozolomide (TMZ) and
O6-benzylguanine (O6BG) for treating cancer. TMZ is an anti-cancer drug approved
to treat certain brain tumors in adults. TMZ loses its effectiveness over
time because a protein called AGT makes the tumor resistant to the drug.
O6BG inactivates AGT and, therefore, may prolong TMZ's effectiveness.

Children and young adults under age 21 with various types of cancer (brain,
liver, bone and others) for whom standard treatment was not successful may
be eligible for this study. Participants will receive TMZ capsules by mouth
and an intravenous (through a vein) infusion of O6BG 5 days in a row every
month for up to 12 months. Blood will be drawn on days 3 and 5 of the first
course of treatment to measure AGT levels. Also on day 5 of the first treatment
course, 16 blood samples (1 teaspoon each) will be taken over a 48-hour period
to study how the two drugs work in the body. If possible, a heparin lock
will be placed in the vein to avoid having multiple needle sticks. A tissue
biopsy (removal of a small piece of tumor) may be taken if the tumor is close
to the skin and not near a vital organ. The sample will be used to evaluate
the effect of O6BG on AGT levels.

A doctor will see the patients weekly. Routine blood tests will be done
twice a week. MRI or CT scans will be done before treatment begins and every
1 to 2 months during treatment to measure the size of the tumor. Patients
with a brain tumor will also have a magnetic resonance spectroscopic test
(similar to MRI) every 1 to 2 months to measure chemicals in the tumor. Patients
will complete a Quality of Life Assessment questionnaire about the effect
of the illness on the patient's behavior and everyday activities.

Potential benefits to patients in this study are tumor shrinkage and symptom
improvement, such as pain relief. Because this is an experimental
therapy, however, the likelihood of tumor shrinkage cannot be predicted.

Condition	Treatment or Intervention	Phase
Brain Neoplasm Embryonal Neoplasm Ewing's Sarcoma Germ Cell Neoplasm Liver Neoplasm Nephroblastoma Osteosarcoma Rhabdomyosarcoma Sarcoma	Drug: O(6) Benzylguanine	Phase I

Further Study Details: 

Temozolomide is a prodrug that spontaneously degrades to the active metabolite,
MTIC, under physiologic conditions. MTIC is an alkylating agent that preferentially
methylates the O(6)-position on guanine. The DNA repair protein, O(6)-alkylguanine-DNA
alkyltransferase (AGT) removes the methyl group from the O(6)-position of
guanine, repairing the lesion produced by MTIC. AGT is expressed in many
tumors and has been associated with tumor resistance and poor clinical response
to methylating agents, such as the nitrosoureas and temozolomide. O(6)-Benzylguanine
(O(6)BG) is an AGT substrate that permanently inactivates AGT. O(6)BG depletes
tumor AGT, blocks repair of the lesion produced by temozolomide and thereby
enhances its cytotoxicity.

A pediatric phase I trial using the combination of temozolomide and O(6)BG
on a daily times 5 days schedule every 4 weeks will be conducted in children
with refractory solid tumors and brain tumors to determine the maximum tolerated
dose (MTD) of temozolomide when given in combination with a biologically
active dose of O(6)BG. Pharmacokinetic studies of O(6)BG and temozolomide
will also be performed.

Genders Eligible for Study:  Both

Criteria

INCLUSION CRITERIA:
1. Age: Patients must be less than or equal to 21 years of age.
2. Histological diagnosis: Patients must have a histologically confirmed solid
tumor, which may include, but is not limited to, rhabdomyosarcoma and other
soft tissue sarcomas, Ewing's family tumors, osteosarcoma, neuroblastoma,
Wilms' tumor, hepatic tumors, germ cell tumors or primary brain tumor. For
patients with brainstem gliomas or optic gliomas, the requirement for histological
confirmation may be waived.
3. Prior therapy:
3.1 The patient's tumor must be refractory to standard treatment. Patients
must have no known potentially curative therapy available to them. Curative
therapy may include surgery, radiation therapy, chemotherapy, or any combination
of these modalities.
3.2 Patients must have had their last dose of limited-field radiation therapy
at least four weeks prior to study entry. Patients who have received extensive
prior radiation therapy (craniospinal radiation, total body radiation, or
radiation to more than half of the pelvis) must be at least 4 months post-completion
of radiation therapy. Patients must have received their last dose of chemotherapy
at least three weeks prior to study entry (four weeks for nitrosoureas),
and their last investigational therapy at least four weeks prior to study
entry.
3.3 Patients must have recovered from the toxic effects of all prior therapy
prior to entry onto this trial.
3.4 Patients with brain tumors who are receiving corticosteroids for the
control of tumor-associated edema must be on a stable or decreasing
dose for at least 1 week prior to study enrollment.
3.5 Patients who have previously received temozolomide are eligible if they
have not received the drug in the past 3 months and they did not experience
severe toxicities during their previous course of therapy with temozolomide.
Severe toxicity is defined as any grade 4 non-hematologic toxicity
or failure to recover (to grade less than or equal to 1 level) from any
non-hematologic or hematologic toxicity within six weeks of receiving
temozolomide. Patients who received temozolomide in combination with
other agents that were designed to inactivate AGT are not eligible for this
trial.
3.6 Patients should be off colony stimulating factors such as G-CSF, GM-CSF,
and Epo for at least one week prior to study entry.
4. Measurable/Evaluable disease: Patients must have measurable or evaluable
disease. There must be evidence of progressive disease on prior chemotherapy
or radiation therapy or persistent disease after surgery.
5. Performance status: Patients should have an ECOG performance status of
0, 1, or 2 and a life expectancy of at least eight (8) weeks. Patients who
are unable to walk because of paralysis, but who are up in a wheel chair
will be considered ambulatory for the purpose of calculating the performance
score.
6. Hematological function: Patients must have adequate bone marrow function
defined as a peripheral absolute granulocyte count of greater than
1500/mm(3), hemoglobin greater than 8 gm/dL, and platelet count greater than
100,000/mm(3).
7. Hepatic function: Patients must have adequate liver function, defined
as bilirubin within normal limits and SGPT less than 2 times the upper
limit of normal.
8. Renal function: Patients must have an age-adjusted normal serum creatinine
or a creatinine clearance greater than or equal to 60 mL/min/1.73 m(2).
9. Patients must be able to swallow capsules.
10. Informed consent: All patients or their legal guardians (if the patient
is less than 18 years old) must sign a document of informed consent
indicating their understanding of the investigational nature and their risks
of this study before any protocol related studies are performed. When
appropriate, pediatric patients will be included in all discussions in order
to obtain verbal assent.
11. Durable Power of Attorney (DPA): Assignment of a DPA to a family member
or guardian should be offered to all patients 18 to 21 years of age
who have a brain tumor.
EXCLUSION CRITERIA:
1. Patients currently receiving other investigational chemotherapeutic agents.
2. Patients with a history of myeloablative therapy requiring bone marrow
or stem cell transplantation within the previous 4 months.
3. Pregnant or breast-feeding females are excluded.
4. Clinically significant unrelated systemic illness (serious infections
or significant cardiac, pulmonary, hepatic or other organ dysfunction)
which in the judgment of the Principal or Associate Investigator would compromise
the patient's ability to tolerate this therapy or are likely to interfere
with the study procedures or results.
5. Patients with a history of hypersensitivity to dacarbazine, temozolomide,
or polyethylene glycol (PEG).

Maryland
      National Cancer Institute (NCI), 9000 Rockville Pike,  Bethesda, 
Maryland,  20892,  United States; Recruiting

Study ID Numbers  000105;  00-C-0105
Study Start Date April 4, 2000
Record last reviewed  March 1, 2004
Last Updated  March 1, 2004
ClinicalTrials.gov Identifier  NCT00005019
ClinicalTrials.gov processed
this record on 2004-08-31