The purpose of this study is to determine safety and toxicity for the combination of
Temozolomide and Azacitidine in the treatment of Advanced Soft Tissue Sarcoma or Malignant
Mesothelioma. This is a single-center, open-label, single-arm Phase I dose-escalation trial.
Patients will be evaluated with complete history and physical as well as laboratory studies
(complete blood count, metabolic panel, liver function tests), biopsy, and imaging of all
sites of measurable disease. This study will be conducted over the course of 3 years.
The primary objective of the study is to determine the clinical and laboratory toxicities as
well as acceptability/tolerance of this dose schedule of combined drug treatment with
temozolomide and azacitidine.
Secondary objectives include determination of biochemical response to azacitidine as defined
as change in methylation status. We will specifically be looking at changes in genome wide
methylation patterns as determined by two high-throughput platforms:
1. A single nucleotide polymorphism chip-based method (MSNP) for genome wide epigenetic
2. CpG island promoter arrays will be performed to focus on promoter methylation status.
We will also monitor clinical response, time to progression and overall survival.
- Histologically confirmed soft tissue sarcoma or mesothelioma.
- Ineligible for other high priority national or institutional study.
- Non-pregnant, non-lactating.
- Recurrent or progressive disease defined as an increase in size of any existing tumor
mass, or the development of new tumor mass or masses, which is not amenable to
definitive surgical therapy.
- Measurable disease defined as lesions that can be measured in at least one dimension
by physical examination or by means of medical imaging techniques. Ascites and
pleural effusions will not be considered measurable disease.
- Prior chemotherapy is allowed with the exception of prior treatment with Temozolomide
or Azacitidine. Patients must have received prior 1st line therapy. There is no upper
limit to the number of prior therapies received. Prior treatment with an alkylating
agent is acceptable.
- Prior radiation therapy is allowed.
- At least 4 weeks since prior chemotherapy or at least 6 weeks since prior radiation
- Patients may have had another cancer but there must be convincing clinical evidence
that the sarcoma is the disease requiring therapeutic intervention. (i.e. Several
sarcoma patients have had had a prior cancer [Hodgkin's disease or breast cancer]
treated years previously and then developed a clinically active sarcoma.)
- Clinical parameters: Life expectancy > 3 months, Age > 18 years, Performance
Karnofsky performance status of greater than or equal to 60%.
- Required initial laboratory data:
- Absolute neutrophil count > 1,500/mm3
- Hemoglobin > 10.0 g/dl
- Platelet count > 100,000/mm3
- Total Bilirubin < 1.5 times upper limit of normal (ULN) for the laboratory.
- Transaminases: aspartate aminotransferase (AST) or alanine aminotransferase
(ALT) levels must be < 2 x ULN. If there is known hepatic metastasis,
transaminases may be < 5 times upper limit of normal.
- Serum creatinine levels < 1.5 x ULN.
- Women of child-bearing potential must have a negative serum pregnancy test prior
to initiation of treatment.
- Men and women of child-bearing potential must be willing to consent to using
effective contraception while on treatment and for a reasonable period thereafter
(approximately 3 months).
- Capable of providing written, informed consent. Each patient must be completely
aware of the nature of his/her disease process and must willingly give consent after
being informed of the procedure to be followed, the experimental nature of the
therapy, alternatives, potential benefits, side-effects, risks and discomforts.
- No serious medical or psychiatric illness preventing informed consent or intensive
treatment (e.g. serious infection).
- No uncontrolled central nervous system metastases.
- Known or suspected hypersensitivity to azacitidine or mannitol
- Pregnant or breast-feeding
- Histology other than soft-tissue sarcoma or mesothelioma
- Active or uncontrolled infection or other serious systemic disease
- Prior treatment with temozolomide or azacitidine
- Pregnant or lactating women
- Uncontrolled central nervous system metastases
- Liver metastases
- Patients will not be excluded if they do not wish to participate in the second biopsy
for tissue evaluation
- Subjects who have not had prior chemotherapy.