Methoxyamine and Temozolomide in Treating Patients With Advanced Solid Tumors

OBJECTIVES:

- To determine the maximum tolerated dose of methoxyamine given in conjunction with
temozolomide in patients with and without CNS disease.

- To determine the dose limiting toxicities of the combination of methoxyamine and
temozolomide in patients with and without CNS disease.

- To determine the pharmacokinetics of these two agents when given alone or in
combination, as well as the pharmacokinetic profile of methoxyamine after single
one-hour IV administration.

- To determine relative DNA damage, as single or double strand breaks by comet assay in
blood mononuclear cells which will serve as a surrogate for tumor response to the drug
combination.

OUTLINE: This is a dose escalation study of methoxyamine.

Patients receive oral temozolomide for 5 days every 28 days and methoxyamine IV over 1 hour
every 28 days. Methoxyamine IV administration will follow, within 5 minutes, initial
administration of TMZ on day 1. Courses repeat every 28 days in the absence of disease
progression or unacceptable toxicity.

Blood samples are collected periodically for correlative studies. Samples are analyzed for
methoxyamine and temozolomide pharmacokinetics, apurinic/apyrimidinic sites, and DNA strand
break determination by comet assay.

Inclusion Criteria:

- Patients must have a histologically confirmed solid tumor that is considered incurable
and is not amenable to conventional surgical, radiation therapy or chemotherapy
treatment programs.

- Prior chemotherapy and/or radiation are allowed. At least 3 weeks must have elapsed
since prior large-field radiation therapy; patients must have been off previous
anti-cancer therapy for at least 3 weeks (6 weeks for mitomycin-C and nitrosoureas);
and recovered from all treatment related toxicity to < grade 1 according to NCI CTCAE
version 3.0 (with the exception of alopecia and radiation-induced taste changes).
Prior temozolomide treatment is not restricted.

- ECOG performance status (PS) 0-2 (Karnofsky PS 50-100%)

- Life expectancy ≥ 12 weeks

- Patients must have normal organ and marrow function as defined below:

- Absolute neutrophil count ≥ 1,500/μL

- Platelet count ≥ 100,000/μL

- Hemoglobin ≥ 10.0 g/dL

- Total bilirubin ≤ 1.5 mg/dL

- AST ≤ 2.5 times upper limit of normal

- Creatinine ≤ 1.5 mg/dL and/or creatinine clearance ≥ 60 mL/min

- Patients with known primary or metastatic CNS disease, are eligible for participation
in cohort B, but not in cohort A.

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and for
the duration of study participation. Should a woman become pregnant or suspect she is
pregnant while participating in this study, she should inform her treating physician
immediately.

- Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

- Patients may not be receiving any other investigational agents or have received other
investigational agents for at least 3 weeks.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

- Pregnant and lactating women are excluded from this study because the methoxyamine and
temozolomide combination is likely to be teratogenic.

- NYHA classification III or IV heart disease

- Patients with known primary or metastatic CNS disease (cohort B) are not eligible if
they have a mini mental status exam score < 15 or evidence of leptomeningeal disease.

- Patients with pre-existing neurologic toxicity > grade1 (as per CTCAE, version 3.0)
are not eligible for participation in cohort A.

- Patients screened for participation in cohort B with pre-existing neurologic toxicity
> grade 2 (as per CTCAE, version 3.0) are not eligible, unless pre-existing neurologic
toxicity is documented in detail and patient's participation in the trial has been
approved by the neuro-oncology team at participating institutions.