Everolimus in Combination With Imatinib Mesylate in Treating Patients With Locally Advanced, Locally Recurrent, or Metastatic Soft Tissue Sarcoma

OBJECTIVES:

Primary

- To determine the maximum-tolerated dose (MTD) of everolimus in combination with
imatinib mesylate in patients with synovial sarcoma. (Phase I)

- To determine the overall response rate (RR = CR + PR). (Phase II)

Secondary

- To determine RR, progression-free survival (PFS), and overall survival (OS).

- To determine predictors of response. (Phase II)

- To obtain tissue biopsy and plasma samples for correlative studies pre- and
post-treatment. (Phase II) (Exploratory)

OUTLINE: This is a phase I, dose-escalation study of everolimus followed by a phase II
study.

Patients receive everolimus orally (PO) once daily and imatinib mesylate PO once daily on
days 1-28. Course repeat every 28 days in the absence of disease progression or unacceptable
toxicity.

Patients undergo blood and tumor tissue sample collection at baseline and periodically
during study for correlative biomarker and protein expression studies.

After completion of study therapy, patients are followed up for 30 days.

DISEASE CHARACTERISTICS:

- Histologically or cytologically confirmed synovial sarcoma that is platelet-derived
growth factor receptor, alpha polypeptide positive (PDGFRA+)

- Metastatic and/or locally advanced or locally recurrent disease

- Patients must consent to tumor biopsies before therapy and after the second week of
therapy

- Patients who do not have accessible tumor for biopsy may be enrolled at the
discretion of the principal investigator

- Patients must have measurable disease, by RECIST 1.1, defined as at least one lesion
that can be accurately measured in at least one dimension (longest diameter to be
recorded) as ≥ 20 mm by conventional techniques or as ≥ 10 mm by spiral CT scan

- Tumor lesions that are situated in a previously irradiated area may be
considered measurable for the purposes of this study only if there is evidence
of growth of the area following a course of irradiation that cannot be
attributed to necrosis or bleeding into the tumor

- Patients with brain metastasis that has been treated with definitive surgery or
radiotherapy, and who have been clinically stable for 3 months following the
procedure with no neurological signs or symptoms and no requirement for systemic
glucocorticoids, are eligible for study

PATIENT CHARACTERISTICS:

- ECOG performance status 0-1

- Life expectancy greater than 3 months

- ANC ≥ 1,500/mm³

- Platelet count ≥ 75,000/mm³

- Total bilirubin ≤ 1.5 times upper limit of normal (ULN) (except for patients with
known Gilbert syndrome)

- AST/ALT ≤ 3 times ULN

- Serum creatinine ≤ 1.5 times ULN

- Serum glucose ≤ 120 mg/dL

- Total cholesterol < 300 mg/dL

- Triglycerides < 2.5 times ULN

- Not pregnant or nursing

- Negative pregnancy test

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal, barrier method of birth control, or abstinence) during therapy and for at
least 8 weeks after completion of therapy

- Patients must not have current evidence of another malignancy

- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition to everolimus, imatinib mesylate, or other agents used in the
study

- No uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, including HIV, active hepatitis B or C, symptomatic congestive heart
failure, unstable angina pectoris, cardiac arrhythmia, poorly controlled diabetes, or
psychiatric illness/social situations that would limit compliance with study
requirements

- No patients with significant compromised respiratory problems or an active and
unexplained pneumonitis

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- At least 4 weeks since any number of prior chemotherapy regimens (6 weeks for
carmustine or mitomycin C) for recurrent/metastatic disease

- No prior tyrosine kinase inhibitors

- Recovered to ≤ grade 1 NCI CTCAE version 4 adverse events related to prior
tumor-specific therapy

- No patients who have had major surgery within the past 4 weeks, or who have not
recovered from adverse events to ≤ grade 1 NCI CTCAE adverse events associated with
surgery

- Surgical changes not expected to improve ( e.g., removal of muscle tissue)
allowed

- No prior mTOR inhibitors, such as sirolimus, everolimus, ridaforolimus, or
temsirolimus

- No other concurrent investigational agents

- No concurrent combination antiretroviral therapy for HIV-positive patients