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

• Maximum-tolerated dose (MTD) of everolimus in combination with imatinib mesylate determined according to dose-limiting toxicities (DLTs) graded using Common Terminology Criteria for Adverse Events version 3.0 (Phase I) [ Time Frame: 4 weeks ] [ Designated as safety issue: Yes ]
  DLT is defined as the occurrence of any unexpected Grade 3 non-hematologic toxicity including diarrhea (despite use of antidiarrheal prophylaxis or glucocorticoids), or nausea and vomiting (despite use of maximal anti-emetics), and any Grade 4 toxicity.
• Response rate (CR + PR) assessed by RECIST 1.1 (Phase II) [ Time Frame: At 8 weeks ] [ Designated as safety issue: No ]

• Maximum-tolerated dose (MTD) of everolimus in combination with imatinib mesylate (Phase I) [ Designated as safety issue: Yes ]
• Response rate (CR + PR) at the end of 2 courses, as defined by RECIST 1.1, in patients treated with everolimus and imatinib mesylate (Phase II) [ Designated as safety issue: No ]

• Progression-free survival (Phase II) [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
  Estimated using Kaplan-Meier method.
• Overall survival (Phase II) [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
  Estimated using Kaplan-Meier method.

This phase I/II clinical trial is studying the side effects and best dose of everolimus when given with imatinib mesylate and to see how well they work in treating patients with locally advanced, locally recurrent or metastatic soft tissue sarcoma. Everolimus and imatinib mesylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth

PRIMARY OBJECTIVES:

I. To determine the maximum-tolerated dose (MTD) of everolimus in combination with imatinib mesylate in patients with synovial sarcoma. (Phase I) II. To determine the overall response rate (RR = CR + PR). (Phase II)

SECONDARY OBJECTIVES:

I. To determine RR, progression-free survival (PFS), and overall survival (OS). (Phase I) II. To determine predictors of response. (Phase II) III. To obtain tissue biopsy and plasma samples for correlative studies pre- and post-treatment. (Phase II)

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.

• Adult Synovial Sarcoma
• Recurrent Adult Soft Tissue Sarcoma
• Stage III Adult Soft Tissue Sarcoma
• Stage IV Adult Soft Tissue Sarcoma

• Other: diagnostic laboratory biomarker analysis
  Correlative studies
• Drug: everolimus
  Given PO
  Other Names:

  • 42-O-(2-hydroxy)ethyl rapamycin
  • Afinitor
  • RAD001
• Drug: imatinib mesylate
  Given PO
  Other Names:

  • CGP 57148
  • Gleevec
  • Glivec

Inclusion Criteria:

• 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
• 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
• No concurrent combination antiretroviral therapy for HIV-positive patients

• 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