Cixutumumab and Temsirolimus in Treating Younger Patients With Recurrent or Refractory Sarcoma

PRIMARY OBJECTIVES:

I. To determine the objective response rate to the combination of cixutumumab and
temsirolimus in patients with relapsed or refractory osteosarcoma, Ewing sarcoma,
rhabdomyosarcoma, or non-rhabdomyosarcoma soft tissue sarcoma.

II. To further describe the toxicities (including dose-limiting toxicities) of cixutumumab
and temsirolimus administered on this schedule.

SECONDARY OBJECTIVES:

I. To assess the progression-free survival for patients treated in each disease stratum with
this drug combination.

II. To assess the incidence of insulin-like growth factor 1 receptor (IGF-1R), insulin
receptor, ERK, RON, and mammalian target of rapamycin (mTOR) pathway activation in archival
tumor material, and correlate with response.

III. To evaluate minimal residual disease and IGF-1R tumor cell expression in the blood and
bone marrow of Ewing sarcoma patients using flow cytometry.

OUTLINE: This is a multicenter study. Patients are stratified according to diagnosis
(osteosarcoma vs Ewing sarcoma/PNET vs rhabdomyosarcoma vs non-rhabdomyosarcoma soft tissue
sarcoma).

Patients receive cixutumumab IV over 1 hour and temsirolimus IV over 30 minutes on days 1, 8,
15, and 22. Treatment repeats every 28 days for up to 25 courses in the absence of disease
progression or unacceptable toxicity.

Archived tumor tissue samples from most recent biopsy are collected and analyzed for IGF-1R,
insulin receptor, AKT, ERK, mTOR, and S6 kinase pathway activation by immunohistochemistry
(IHC) and banked for future correlative studies. Blood and bone marrow samples, from patients
with Ewing sarcoma, may be collected at baseline and periodically during treatment for
minimal residual disease analysis by flow cytometry.

After completion of study treatment, patients are followed up periodically for 5 years.

Inclusion Criteria:

- Patients with any of the following tumors who have experienced relapse following
front-line therapy, or who are refractory to front-line therapy, are eligible:

- Osteosarcoma

- Ewing sarcoma/peripheral primitive neuroectodermal tumor (PNET)

- Rhabdomyosarcoma

- Non-rhabdomyosarcoma soft tissue sarcoma

- Patients must have had histologic verification of malignancy at original diagnosis or
relapse

- All patients are required to submit archival tumor samples for immunohistochemical
analysis (either paraffin-embedded tumor blocks or unstained slides)

- Tissue samples collected at original diagnosis or at relapse or at any subsequent
resections or biopsies should be available and ready for shipment to the
Biopathology Center (BPC) at time of study enrollment; the samples are required
even if tissue samples have previously been sent to the BPC for other purposes or
studies; blocks or slides should be shipped to the BPC within 7 days of study
enrollment

- Patients must have radiographically measurable disease

- Measurable disease is defined as the presence of at least one lesion on magnetic
resonance imaging (MRI) or computed tomography (CT) scan that can be accurately
measured with the longest diameter a minimum of 10 mm in at least one dimension
(CT scan slice thickness no greater than 5 mm)

- The following do not qualify as measurable disease:

- Malignant fluid collections (e.g., ascites, pleural effusions)

- Bone marrow infiltration

- Lesions only detected by nuclear medicine studies (e.g., bone, gallium, or
positron emission tomography [PET] scans)

- Elevated tumor markers in plasma or cerebrospinal fluid(CSF)

- Previously radiated lesions that have not demonstrated clear progression
post radiation

- Leptomeningeal lesions that do not meet the measurements noted above

- Patient?s current disease state must be one for which there is no known curative
therapy or therapy proven to prolong survival with an acceptable quality of life

- Patients with known central nervous system metastases are excluded unless treated
surgically or with radiotherapy and stable with no recurrent lesions for at least 3
months

- Patients must have a Lansky or Karnofsky performance status score of ? 50%,
corresponding to Eastern Cooperative Oncology Group (ECOG) categories 0, 1, or 2; use
Karnofsky for patients > 16 years of age and Lansky for patients ? 16 years of age

- Patients who are unable to walk because of paralysis, but who are up in a
wheelchair, will be considered ambulatory for the purpose of assessing the
performance score

- For patients with solid tumors without bone marrow involvement:

- Peripheral absolute neutrophil count (ANC) ? 1,000/?L

- Platelet count ? 100,000/?L (transfusion independent, defined as not receiving
platelet transfusions within a 7-day period prior to enrollment)

- Hemoglobin ? 8.0 g/dL (may receive red blood cell [RBC] transfusions)

- For patients with solid tumors and known bone marrow metastatic disease:

- ANC ? 750/?L

- Platelet count ? 50,000/?L (may receive platelet transfusions)

- Hemoglobin ? 8.0 g/dL (may receive RBC transfusions)

- For patients with known bone marrow metastatic disease, transfusions are
permitted to meet both platelet and hemoglobin criteria; patients must not
be known to be refractory to red blood cell or platelet transfusions

- Creatinine clearance or radioisotope GFR ? 70 mL/min OR a serum creatinine based on
age/gender as follows:

- 0.6 mg/dL (1 to < 2 years of age)

- 0.8 mg/dL (2 to < 6 years of age)

- 1.0 mg/dL (6 to < 10 years of age)

- 1.2 mg/dL (10 to < 13 years of age)

- 1.5 mg/dL (males) or 1.4 mg/dL (females) (13 to < 16 years of age)

- 1.7 mg/dL (males) or 1.4 mg/dL (females) ( ? 16 years of age)

- Total bilirubin ? 1.5 times upper limit of normal (ULN)

- Serum glutamic pyruvate transaminase(SGPT) (alanine aminotransaminase [ALT]) ? 2.5
times ULN (for the purpose of this study, the ULN for SGPT is 45 U/L)

- Serum albumin ? 2 g/dL

- Patients with seizure disorder may be enrolled if receiving non-enzyme-inducing
anticonvulsants and well controlled

- Patients with known type I or type II diabetes mellitus are not eligible

- Serum glucose values must be within the normal limits for age; if the initial blood
glucose is a random sample that is outside normal limits, then a follow-up fasting
blood glucose should be obtained and must be within the normal limits for age

- Serum cholesterol levels must be < grade 2 (< 300 mg/dL), and serum triglyceride
levels must be < grade 2 (< 2.5 times ULN)

- Patients who are pregnant or breast-feeding are not eligible for this study

- Negative pregnancy tests must be obtained in girls who are post-menarchal

- Males or females of reproductive potential may not participate unless they have agreed
to use an effective contraceptive method for the duration of the study and for 3
months after the last dose of cixutumumab

- Patients who have an uncontrolled infection are not eligible

- Patients who, in the opinion of the investigator, may not be able to comply with the
safety monitoring requirements of the study are not eligible

- See Disease Characteristics

- There is no limit to the number of prior treatment regimens; however, patients must
have fully recovered from the acute toxic effects of all prior chemotherapy,
immunotherapy, or radiotherapy prior to study enrollment

- Patients must not have received myelosuppressive chemotherapy within 3 weeks of
enrollment (6 weeks if prior nitrosourea)

- At least 7 days must have elapsed since the completion of therapy with a growth
factor; at least 14 days must have elapsed after receiving pegfilgrastim

- At least 7 days must have elapsed since the completion of therapy with a biologic
agent; for agents that have known adverse events occurring beyond 7 days after
administration, this period prior to enrollment must be extended beyond the time
during which adverse events are known to occur

- At least 3 half-lives must have elapsed since prior therapy that included a monoclonal
antibody

- ? 2 weeks must have elapsed since local palliative radiotherapy (XRT) (small port); 3
months must have elapsed if 50% radiation of pelvis; 6 weeks must have elapsed if
therapeutic doses of metaiodobenzylguanidine(MIBG) or other substantial bone marrow
irradiation was given

- No evidence of active graft-vs-host disease and 2 months must have elapsed since stem
cell transplant or rescue

- Growth factors that support platelet or white cell number or function must not have
been administered within the 7 days prior to enrollment (14 days if Neulasta?)

- Patients receiving corticosteroids who have not been on a stable or decreasing dose of
corticosteroid for the 7 days prior to enrollment are not eligible

- Patients who are currently receiving another investigational drug are not eligible

- Patients who are currently receiving other anti-cancer agents, including chemotherapy,
radiotherapy, immunotherapy, or biologic therapy, are not eligible

- Patients receiving insulin or growth hormone therapy are not eligible

- Patients who are receiving enzyme-inducing anticonvulsants are not eligible

- Use of warfarin is not allowed while on study; patients already on warfarin should use
alternative anticoagulants while on this study; warfarin must not have been
administered within 7 days of starting protocol therapy

- Patients who have received prior therapy targeting IGF-1R with either monoclonal
antibodies or small molecule tyrosine kinase inhibitors are NOT eligible

- Prior treatment with mTOR inhibitors (e.g., rapamycin, temsirolimus, everolimus,
deforolimus) is NOT allowed

- Patients who have had major surgery within 3 weeks prior to enrollment are not
eligible; procedures such as placement of a central vascular catheter or limited tumor
biopsy are not considered major surgery