Selumetinib With or Without Temsirolimus in Treating Patients With Metastatic, Recurrent, or Locally Advanced Soft Tissue Sarcoma That Cannot Be Removed By Surgery

Study Overview
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Brief Summary
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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.

Detailed Description
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PRIMARY OBJECTIVES: I. Compare the progression-free survival of the MEK inhibitor, AZD6244 (selumetinib) alone, and the combination of AZD6244 and a mammalian target of rapamycin inhibitor (mTORi), temsirolimus (CCI-779) in patients with recurrent metastatic or recurrent locally unresectable soft-tissue sarcomas. SECONDARY OBJECTIVES: I. Determine the rates of apoptosis, autophagy, and proliferation with AZD6244 alone, and in combination with temsirolimus by immunohistochemistry in tumor and surrogate skin tissue biopsies. (exploratory) II. Assess the activation status of protein kinase B (Akt), 5E-BP1, eukaryotic translation initiation factor 4 gamma, 1 (eIF-4G), and ribosomal protein S6 kinase (S6K) in tumor biopsy samples and surrogate skin tissue biopsy samples.(exploratory) III. Assess inhibition of activated mitogen-activated protein kinase 1/2 (ERK1/2) in stimulated peripheral blood mononuclear cells. (exploratory) IV. Assess response by Choi criteria. V. Compare the response rate and 4-month progression-free survival (PFS) rate in patients treated with these regimens. VI. Compare the response rate, 4-month PFS rate and toxicity of AZD6244 alone and in combination with temsirolimus. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive selumetinib orally (PO) twice daily on days 1-28 and temsirolimus intravenously (IV) over 30-60 minutes on days 1, 8, 15, and 22. ARM II: Patients receive selumetinib as in arm I. Patients who experience disease progression may cross over to arm I. In both arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study therapy, patients are followed up for 30 days.

Official Title
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Randomized, Phase II Trial of AZD6244 Alone and AZD6244 Plus Temsirolimus for Soft-Tissue Sarcomas

Conditions
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Recurrent Adult Soft Tissue Sarcoma, Stage III Adult Soft Tissue Sarcoma, Stage IV Adult Soft Tissue Sarcoma

Intervention / Treatment
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* Other: Laboratory Biomarker Analysis
* Drug: Selumetinib
* Drug: Temsirolimus


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (selumetinib and temsirolimus)<br>Patients receive selumetinib PO twice daily on days 1-28 and temsirolimus IV over 30-60 minutes on days 1, 8, 15, and 22. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Selumetinib<br>* Given PO<br>* Other names: MEK Inhibitor AZD6244;Drug: Temsirolimus<br>* Given IV<br>* Other names: Torisel;|
| Experimental: Arm II (selumetinib)<br>Patients receive selumetinib as in arm I. Patients who experience disease progression may cross over to arm I. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Selumetinib<br>* Given PO<br>* Other names: MEK Inhibitor AZD6244;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Progression-free survival was estimated using the product-limit method of Kaplan and Meier. Progression wasl evaluated in this study using the Response Evaluation Criteria in Solid Tumors (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions, or death. | Until disease progression or death, up to 4.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Objective Response | Response evaluated using the Choi criteria. CR - disappearance of all lesions and no new lesions; PR - a decrease in size (the sum of longest diameters of target lesions as defined in RECIST) of 10% or more or a decrease in tumor density (HU) of 15% or more on CT and no new lesions and no obvious progression of nonmeasurable disease; SD - does not meet the criteria for CR, PR, or PD and no symptomatic deterioration attributed to tumor progression; PD - an increase in tumor size of 10% or more and does not meet criteria of PR by tumor density (HU) on CT or new lesions or new intratumoral nodules or increase in the size of the existing intratumoral nodules. Objective response = CR+PR. | Evaluated for response after every two cycles, up to 4.5 years. | 
| 4 -Month Progression-free Survival Rate. | Progression-free survival rate was calculated using the survival distribution function, and 95% confidence limits were calculated using the log-log transformation. Progression was defined using the Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions, or death. | Four months |