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A Phase II Study of Cixutumumab (IMC-A12; IND# 100947) in Combination With Temsirolimus (IND# 61010) in Pediatric Patients With Recurrent or Refractory Solid Tumors

Phase 2
1 Year
30 Years
Not Enrolling
Childhood Alveolar Soft-part Sarcoma, Childhood Angiosarcoma, Childhood Epithelioid Sarcoma, Childhood Fibrosarcoma, Childhood Gliosarcoma, Childhood Leiomyosarcoma, Childhood Liposarcoma, Childhood Neurofibrosarcoma, Childhood Synovial Sarcoma, Previously Treated Childhood Rhabdomyosarcoma, Recurrent Childhood Rhabdomyosarcoma, Recurrent Childhood Soft Tissue Sarcoma, Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor, Recurrent Osteosarcoma

Thank you

Trial Information

A Phase II Study of Cixutumumab (IMC-A12; IND# 100947) in Combination With Temsirolimus (IND# 61010) in Pediatric Patients With Recurrent or Refractory Solid Tumors


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.


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

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

- 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

- 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/μL

- Platelet count ≥ 100,000/μL (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/μL

- Platelet count ≥ 50,000/μL (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,
deferolimus) 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

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Objective response rate (PR or CR) by Response Evaluation Criteria in Solid Tumors (RECIST)

Outcome Description:

We will consider the combination of sufficient activity if the true response rate is 35% or greater.

Outcome Time Frame:

Up to 5 years

Safety Issue:


Principal Investigator

Lars Wagner

Investigator Role:

Principal Investigator

Investigator Affiliation:

Children's Oncology Group


United States: Food and Drug Administration

Study ID:




Start Date:

June 2012

Completion Date:

Related Keywords:

  • Childhood Alveolar Soft-part Sarcoma
  • Childhood Angiosarcoma
  • Childhood Epithelioid Sarcoma
  • Childhood Fibrosarcoma
  • Childhood Gliosarcoma
  • Childhood Leiomyosarcoma
  • Childhood Liposarcoma
  • Childhood Neurofibrosarcoma
  • Childhood Synovial Sarcoma
  • Previously Treated Childhood Rhabdomyosarcoma
  • Recurrent Childhood Rhabdomyosarcoma
  • Recurrent Childhood Soft Tissue Sarcoma
  • Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor
  • Recurrent Osteosarcoma
  • Fibrosarcoma
  • Hemangiosarcoma
  • Leiomyosarcoma
  • Liposarcoma
  • Osteosarcoma
  • Rhabdomyosarcoma
  • Sarcoma, Synovial
  • Sarcoma
  • Neuroectodermal Tumors
  • Neuroectodermal Tumors, Primitive
  • Sarcoma, Alveolar Soft Part
  • Gliosarcoma
  • Neurofibrosarcoma
  • Neurilemmoma
  • Rhabdomyosarcoma, Embryonal
  • Sarcoma, Ewing's
  • Neuroectodermal Tumors, Primitive, Peripheral



Baylor College of MedicineHouston, Texas  77030
Memorial Sloan Kettering Cancer CenterNew York, New York  10021
Mayo ClinicRochester, Minnesota  55905
Children's Hospital of PhiladelphiaPhiladelphia, Pennsylvania  19104
University of Mississippi Medical CenterJackson, Mississippi  39216-4505
Washington University School of MedicineSaint Louis, Missouri  63110
Midwest Children's Cancer CenterMilwaukee, Wisconsin  53226
Sinai Hospital of BaltimoreBaltimore, Maryland  21225
Massachusetts General Hospital Cancer CenterBoston, Massachusetts  02114
Morristown Memorial HospitalMorristown, New Jersey  07962-1956
Marshfield ClinicMarshfield, Wisconsin  54449
Loma Linda University Medical CenterLoma Linda, California  92354
Dana-Farber Cancer InstituteBoston, Massachusetts  02115
University of Arkansas for Medical SciencesLittle Rock, Arkansas  72205
Hackensack University Medical CenterHackensack, New Jersey  07601
Children's Hospital Los AngelesLos Angeles, California  90027-0700
Children's National Medical CenterWashington, District of Columbia  20010-2970
Miami Children's HospitalMiami, Florida  33155-4069
All Children's HospitalSt. Petersburg, Florida  33701
Ochsner Clinic FoundationNew Orleans, Louisiana  70121
Carolinas Medical CenterCharlotte, North Carolina  28232-2861
University of Oklahoma Health Sciences CenterOklahoma City, Oklahoma  73104
Scott and White Memorial HospitalTemple, Texas  76508
Children's Hospital Medical Center of AkronAkron, Ohio  44308
Cincinnati Children's Hospital Medical CenterCincinnati, Ohio  45229-3039
University of New Mexico Cancer CenterAlbuquerque, New Mexico  87131-5636
Nationwide Children's HospitalColumbus, Ohio  43205-2696
Children's Hospital and Research Center at OaklandOakland, California  94609-1809
Mary Bridge Children's Hospital and Health CenterTacoma, Washington  98415-0299
Presbyterian HospitalCharlotte, North Carolina  28233-3549
Lee Memorial Health SystemFort Myers, Florida  33902
Children's Hospital of AlabamaBirmingham, Alabama  35233
Connecticut Children's Medical CenterHartford, Connecticut  06106
Vanderbilt UniversityNashville, Tennessee  37232-6305
University of North CarolinaChapel Hill, North Carolina  27599
Nemours Children's Clinic - PensacolaPensacola, Florida  32504
Yale UniversityNew Haven, Connecticut  06520
Wayne State UniversityDetroit, Michigan  48202
Mercy Children's HospitalToledo, Ohio  43608
Legacy Emanuel Children's HospitalPortland, Oregon  97227
BI-LO Charities Children's Cancer CenterGreenville, South Carolina  29605
University of Texas Southwestern Medical CenterDallas, Texas  
University of KentuckyLexington, Kentucky  40536-0098
Oregon Health and Science UniversityPortland, Oregon  97201
Virginia Commonwealth UniversityRichmond, Virginia  
Florida HospitalOrlando, Florida  32803
Memorial Health University Medical CenterSavannah, Georgia  31404
University of Chicago Comprehensive Cancer CenterChicago, Illinois  60637-1470
M D Anderson Cancer CenterHouston, Texas  77030
Seattle Children's HospitalSeattle, Washington  98105
University of HawaiiHonolulu, Hawaii  96813
Saint Vincent Hospital and Health ServicesIndianapolis, Indiana  46260
Saint John's Mercy Medical CenterSaint Louis, Missouri  63141
Columbia University Medical CenterNew York, New York  10032
Stony Brook University Medical CenterStony Brook, New York  11794
Cook Children's Medical CenterFort Worth, Texas  76104
University of Minnesota Medical Center-FairviewMinneapolis, Minnesota  55455
University of California San Francisco Medical CenterSan Francisco, California  94143
Riley Hospital for ChildrenIndianapolis, Indiana  46202
Miller Children's HospitalLong Beach, California  90806
Childrens Hospital of Orange CountyOrange, California  92868-3874
Alfred I duPont Hospital for ChildrenWilmington, Delaware  19803
Nemours Children's Clinic - JacksonvilleJacksonville, Florida  32207-8426
Nemours Childrens Clinic - OrlandoOrlando, Florida  32806
Children's Healthcare of Atlanta - EglestonAtlanta, Georgia  30322
The Childrens Mercy HospitalKansas City, Missouri  64108
Palmetto Health RichlandColumbia, South Carolina  29203
East Tennessee Childrens HospitalKnoxville, Tennessee  37916
Children's Hospital and Medical Center of OmahaOmaha, Nebraska  68114
Lucile Packard Children's Hospital Stanford UniversityPalo Alto, California  94304
Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical CenterDenver, Colorado  80218
Providence Sacred Heart Medical Center and Children's HospitalSpokane, Washington  99204