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

Phase 2
18 Years
Open (Enrolling)
Recurrent Adult Soft Tissue Sarcoma, Stage III Adult Soft Tissue Sarcoma, Stage IV Adult Soft Tissue Sarcoma

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Trial Information

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


I. Compare the progression-free survival of the MEK inhibitor, AZD6244 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.


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 oral MEK inhibitor AZD6244 twice daily on days 1-28 and temsirolimus
IV over 30-60 minutes on days 1, 8, 15, and 22.

ARM II: Patients receive MEK inhibitor AZD6244 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.

Inclusion Criteria:

- Histologically confirmed soft-tissue sarcoma at original diagnosis meeting 1 of the
following criteria:

- Metastatic (de novo or recurrent) disease

- Locally advanced unresectable disease

- Gastrointestinal stromal tumor (GIST) subtype allowed

- No pediatric-type sarcomas (e.g., Ewing's or primitive neuroectodermal tumor,
rhabdomyosarcoma, and desmoplastic small round cell tumor)

- Measurable disease, defined as ≥ 1 lesion that can be accurately measured in ≥ 1
dimension (longest diameter to be recorded) as ≥ 20 mm by conventional techniques or
as ≥ 10 mm by spiral computed tomography (CT) scan

- Patients with CNS tumors must have been on a stable or decreasing dose of
dexamethasone for more than 7 days

- No known brain metastases

- ECOG performance status (PS) 0-2 (Karnofsky PS 60-100%)

- Life expectancy > 12 weeks

- ANC ≥ 1,000/μL

- Platelet count ≥ 100,000/μL (transfusion independent)

- Hemoglobin ≥ 8.0 mg/dL (may receive red blood cell transfusions)

- Creatinine ≤ 1.5 times upper limit of normal (ULN) OR creatinine clearance ≥ 45

- Bilirubin (sum of conjugated plus unconjugated) ≤ 1.5 times ULN

- ALT ≤ 5 times ULN

- Serum albumin ≥ 2 g/dL

- Fertile patients must use effective contraception during and for 4 weeks (women) or
for 16 weeks (men) after completion of last dose of treatment

- Negative pregnancy test

- Not pregnant or nursing

- No evidence of dyspnea at rest and/or exercise intolerance

- Pulse oximetry > 94% if there is clinical indication for determination

- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition toMEK inhibitor AZD6244

- No QTc interval > 450 msecs, other factors that increase the risk of QT prolongation,
or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT
interval syndrome)

- Able to swallow capsules

- No refractory nausea and vomiting, chronic gastrointestinal diseases (e.g.,
inflammatory bowel disease),or significant bowel resection that would preclude
adequate absorption

- No uncontrolled intercurrent illness including, but not limited to, any of the

- Ongoing or active infection

- Psychiatric illness and/or social situations that would limit compliance with
study requirements

- No patients who, in the opinion of the investigator, may not be able to comply with
the safety monitoring requirements of the study

- None of the following:

- Cardiac history of uncontrolled hypertension

- NYHA class II-IV cardiac disease

- Prior or current cardiomyopathy

- Baseline LVEF < 50%

- Ongoing atrial fibrillation

- Recent myocardial infarction

- Unstable ischemic heart disease

- No concurrent strong CYP1A2 or CYP3A4 inducers and/or inhibitors

- Up to 2 prior cytotoxic chemotherapeutic regimens (single-agent or combination of
chemotherapies) for metastatic or recurrent disease allowed

- At least 1 week since prior growth factors that support platelet or white cell number
or function

- At least 3 weeks since prior chemotherapy or radiotherapy (6 weeks for mitomycin C
and nitrosoureas)

- No prior MEK inhibitor(s)

- No prior mTOR inhibitor for recurrent soft-tissue sarcoma

- No concurrent growth factor(s) that support platelet or white cell count or function
within the past 7 days

- No other concurrent investigational drug

- No other concurrent anticancer agents including chemotherapy, radiotherapy,
immunotherapy, or biologic therapy

- No concurrent combination antiretroviral therapy for HIV-positive patients

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:


Outcome Time Frame:

Up to 30 days

Safety Issue:


Principal Investigator

Warren Chow

Investigator Role:

Principal Investigator

Investigator Affiliation:

City of Hope Medical Center


United States: Food and Drug Administration

Study ID:




Start Date:

October 2010

Completion Date:

Related Keywords:

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



University of Pittsburgh Cancer InstitutePittsburgh, Pennsylvania  15213
City of Hope Medical CenterDuarte, California  91010
Tower Cancer Research FoundationBeverly Hills, California  90211
University of Southern CaliforniaLos Angeles, California  90033
Penn State Milton S Hershey Medical CenterHershey, Pennsylvania  17033
University of California Davis Phase 2 ConsortiumSacramento, California  95817