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

NCT ID: NCT01206140

Last Updated: 2015-10-05

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 70 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-10-31
• Study Completion Date: 2015-04-30

Brief 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.

Detailed Description

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.

Conditions

Recurrent Adult Soft Tissue Sarcoma; Stage III Adult Soft Tissue Sarcoma; Stage IV Adult Soft Tissue Sarcoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm I (selumetinib and temsirolimus)

Patients receive selumetinib PO twice daily on days 1-28 and temsirolimus IV over 30-60 minutes on days 1, 8, 15, and 22.

Group Type: EXPERIMENTAL

Laboratory Biomarker Analysis

Intervention Type: OTHER

Correlative studies

Selumetinib

Intervention Type: DRUG

Given PO

Temsirolimus

Intervention Type: DRUG

Given IV

Arm II (selumetinib)

Patients receive selumetinib as in arm I. Patients who experience disease progression may cross over to arm I.

Group Type: EXPERIMENTAL

Laboratory Biomarker Analysis

Intervention Type: OTHER

Correlative studies

Selumetinib

Intervention Type: DRUG

Given PO

Interventions

Laboratory Biomarker Analysis

Correlative studies

Intervention Type: OTHER

Selumetinib

Given PO

Intervention Type: DRUG

Temsirolimus

Given IV

Intervention Type: DRUG

Other Intervention Names

ARRY-142886; AZD6244; MEK Inhibitor AZD6244; CCI-779; CCI-779 Rapamycin Analog; Cell Cycle Inhibitor 779; Rapamycin Analog; Rapamycin Analog CCI-779; Torisel

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Comprehensive Cancer Network

NETWORK

Sponsor Role: collaborator

National Cancer Institute (NCI)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Warren Chow

Role: PRINCIPAL_INVESTIGATOR

City of Hope Comprehensive Cancer Center

Locations

Tower Cancer Research Foundation

Beverly Hills, California, United States

City of Hope Comprehensive Cancer Center

Duarte, California, United States

USC / Norris Comprehensive Cancer Center

Los Angeles, California, United States

University of California Davis Comprehensive Cancer Center

Sacramento, California, United States

University of California Davis Phase 2 Consortium

Sacramento, California, United States

Penn State Milton S Hershey Medical Center

Hershey, Pennsylvania, United States

University of Pittsburgh Cancer Institute

Pittsburgh, Pennsylvania, United States

University of Pittsburgh

Pittsburgh, Pennsylvania, United States

Countries

United States

Other Identifiers

NCI-2011-02532

Identifier Type: REGISTRY

Identifier Source: secondary_id

CDR0000685408

Identifier Type: -

Identifier Source: secondary_id

CHNMC-PHII-95

Identifier Type: -

Identifier Source: secondary_id

NCCN-T06

Identifier Type: -

Identifier Source: secondary_id

PHII-95

Identifier Type: OTHER

Identifier Source: secondary_id

8412

Identifier Type: OTHER

Identifier Source: secondary_id

N01CM00038

Identifier Type: NIH

Identifier Source: secondary_id

View Link

P30CA033572

Identifier Type: NIH

Identifier Source: secondary_id

View Link

NCI-2011-02532

Identifier Type: -

Identifier Source: org_study_id