Selumetinib With or Without Temsirolimus in Treating Patients With Metastatic, Recurrent, or Locally Advanced Soft Tissue Sarcoma That Cannot Be Removed By Surgery
Condition: Recurrent Adult Soft Tissue Sarcoma; Stage III Adult Soft Tissue Sarcoma; Stage IV Adult Soft Tissue Sarcoma
MeSH terms: Sarcoma
Intervention: Laboratory Biomarker Analysis; Selumetinib; Temsirolimus
Intervention description: Correlative studies; Given PO; Given IV
Intervention MeSH terms: Sirolimus; Temsirolimus; MTOR Inhibitors
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 70.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This randomized phase II trial is studying how well giving selumetinib together with or
      without temsirolimus works in treating patients with metastatic, recurrent, or locally
      advanced soft tissue sarcoma that cannot be removed by surgery. Selumetinib and temsirolimus
      may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It
      is not yet known whether giving selumetinib together with temsirolimus is more effective than
      giving selumetinib alone.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients must have had histologic verification of soft-tissue sarcoma at original
             diagnosis (GIST subtype is eligible)

          -  Patients must have metastatic (de novo or recurrent) or locally advanced, unresectable
             disease; patients must have measurable disease, defined as at least one lesion that
             can be accurately measured in at least one dimension (longest diameter to be recorded)
             as >= 20 mm with conventional techniques or as >= 10 mm with spiral CT scan

          -  ECOG 0-2 (Karnofsky >= 50%)

          -  Patients may have received 0-2 prior cytotoxic chemotherapeutic regimens for
             metastatic or recurrent disease (single-agent or combination chemotherapies)

          -  Estimated life expectancy > 12 weeks

          -  Peripheral absolute neutrophil count (ANC) >= 1000/uL

          -  Platelet count >= 100,000/uL (transfusion independent)

          -  Hemoglobin >= 8.0 gm/dL (may receive RBC transfusions)

          -  Creatinine =< 1.5 x upper institutional limits of normal, or calculated creatinine
             clearance >= 45mL/min, based on the Cockcroft-Gault formula

          -  Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for
             age

          -  SGPT (ALT) =< 5 x upper limit of normal (ULN) for age

          -  No evidence of dyspnea at rest, no exercise intolerance

          -  Pulse oximetry > 94% if there is clinical indication for determination

          -  For women: must be surgically sterile, postmenopausal, or compliant with a medically
             approved contraceptive regimen (for example, intrauterine device [IUD], birth control
             pills, or barrier device) during and until 4 weeks after the last dose of study
             treatment; must have a negative serum or urine pregnancy test within 7 days before
             study enrollment, and must not be breast-feeding; should a woman become pregnant or
             suspect she is pregnant while she or her partner participating in this study, the
             patient should inform her treating physician immediately; for men: must be surgically
             sterile or compliant with a contraceptive regimen during and for 16 weeks after the
             treatment period; please note that the AZD6244 manufacturer recommends that adequate
             contraception for male patients should be used for 16 weeks post-last dose due to
             sperm life cycle

          -  All patients must sign a written informed consent

        Exclusion Criteria:

          -  Patients with pediatric-type sarcomas (Ewing's or primitive neuroectodermal tumor,
             rhabdomyosarcoma, and desmoplastic small round cell tumor)

          -  Concomitant Medications

               -  Growth factor(s): growth factors that support platelet or white cell number or
                  function must not have been administered within the past 7 days

               -  Steroids: patients with CNS tumors who have not been on a stable or decreasing
                  dose of dexamethasone for the past 7 days

               -  Investigational Drugs: patients who are currently receiving another
                  investigational drug

               -  Anti-cancer Agents: patients who are currently receiving other anti-cancer
                  agents; at least 3 weeks must have elapsed since prior chemotherapy or radiation
                  (6 weeks for mitomycin-C and nitrosureas)

          -  Patients with known brain metastases should be excluded from this clinical trial
             because of their poor prognosis and because they often develop progressive neurologic
             dysfunction that would confound the evaluation of neurologic and other adverse events

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to AZD6244

          -  Previous MEK inhibitor use

          -  Patients with QTc interval > 450 msecs or other factors that increase the risk of QT
             prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of
             long QT interval syndrome); this may be determined by either Bazett's correction (QTc
             =QT/RR0.5) or Friderica's correction (QTc = QT/RR0.33); QTc exclusion > 450 msec
             requires calculation according to both formulas

          -  Patients unable to swallow the AZD6244 capsules are ineligible

          -  Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g., inflammatory
             bowel disease), or significant bowel resection that would preclude adequate absorption

          -  Uncontrolled intercurrent illness including, but not limited to, uncontrolled, ongoing
             or active infection or psychiatric illness/social situations that would limit
             compliance with study requirements

          -  Pregnant women are excluded from this study because the effects of AZD6244 on the
             developing human fetus at the recommended therapeutic dose are unknown; because there
             is an unknown but potential risk for adverse events in nursing infants secondary to
             treatment of the mother, breastfeeding should be discontinued if the mother is treated
             with AZD6244

          -  HIV-positive patients on combination antiretroviral therapy are ineligible because of
             the potential for pharmacokinetic interactions with AZD6244; appropriate studies will
             be undertaken in patients receiving combination antiretroviral therapy when indicated

          -  Patients who in the opinion of the investigator may not be able to comply with the
             safety monitoring requirements of the study

          -  Prior cardiac history of uncontrolled hypertension, New York Heart Association (NYHA)
             Classification >= class II, current or prior cardiomyopathy, baseline LVEF < 50%,
             ongoing atrial fibrillation, recent myocardial infarction or unstable ischemic heart
             disease

          -  Concomitant Strong CYP1A2 or CYP3A4 inducers and/or inhibitors; prior treatment with
             an mTOR inhibitor for recurrent soft-tissue sarcoma