Phase I Dose-Escalation Study Of Azacitidine In Combination With Temozolomide

Sponsor

Columbia University (Other)

Overall Status

Unknown status

CT.gov ID

NCT00629343

Collaborator

Schering-Plough (Industry), Celgene Corporation (Industry)

Enrollment

Location

Arm

Duration (Months)

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Soft Tissue Sarcoma Mesothelioma	Drug: Azacitidine In Combination With Temozolomide	Phase 1

Detailed Description

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:

A single nucleotide polymorphism chip-based method (MSNP) for genome wide epigenetic profiling
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.

Study Design

Study Type:

Interventional

Actual Enrollment :

28 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase I Dose-Escalation Study Of Azacitidine In Combination With Temozolomide In Patients With Unresectable Or Metastatic Soft Tissue Sarcoma or Malignant Mesothelioma

Study Start Date :

Oct 1, 2007

Actual Primary Completion Date :

Oct 1, 2012

Anticipated Study Completion Date :

Aug 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment	Drug: Azacitidine In Combination With Temozolomide mg, oral

Arm

Intervention/Treatment

Experimental: Treatment

Drug: Azacitidine In Combination With Temozolomide

mg, oral

Outcome Measures

Primary Outcome Measures

The primary endpoint is dose limiting toxicity. [Study Completion]

Secondary Outcome Measures

Clinical response, time to progression and overall survival. [Study Completion]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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 therapy.
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.

Exclusion Criteria:

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.