Clinical trial NCT01614795: Cixutumumab and Temsirolimus in Treating Younger Patients With Recurrent or Refractory Sarcoma
Official title: A Phase II Study of Cixutumumab (IMC-A12) in Combination With Temsirolimus in Pediatric Patients With Recurrent or Refractory Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Childhood Alveolar Soft Part Sarcoma
Childhood Angiosarcoma
Childhood Epithelioid Sarcoma
Childhood Fibrosarcoma
Childhood Gliosarcoma
Childhood Leiomyosarcoma
Childhood Liposarcoma
Childhood Malignant Peripheral Nerve Sheath Tumor
Childhood Synovial Sarcoma
Previously Treated Childhood Rhabdomyosarcoma
Recurrent Childhood Rhabdomyosarcoma
Recurrent Childhood Soft Tissue Sarcoma
Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor
Recurrent Osteosarcoma
Rhabdomyosarcoma
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2012-06-08
Enrollment: 46
Sex: ALL
Minimum age (years): 1
Maximum age (years): 30
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This phase II trial studies how well cixutumumab and temsirolimus work in treating patients with recurrent or refractory sarcoma. Monoclonal antibodies, such as cixutumumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving cixutumumab and temsirolimus together may kill more tumor cells.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Objective Response Rate (PR or CR) by Response Evaluation Criteria in Solid Tumors (RECIST).
timeFrame: 6 cycles (168 days)
measure: Number of Cycles of Toxicity
timeFrame: Duration of protocol therapy - Up to 25 cycles (700 days)
Secondary outcomes:
measure: Progression-free Interval
timeFrame: 10 months after enrollment
measure: Expression Levels of IGF-1R, Insulin Receptor, ERK, RON, and mTOR
timeFrame: Baseline
measure: Number of Patients With Detectable Bone Marrow Micrometastatic Disease Estimated as the Proportion of Eligible Patients Entered Into the Ewing Sarcoma Stratum Who Have Detectable Tumor Cells in the Marrow at Enrollment
timeFrame: Baseline
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Children's Hospital of Alabama
state: Alabama
city: Birmingham
country: United States
facility: University of Alabama at Birmingham Cancer Center
state: Alabama
city: Little Rock
country: United States
facility: University of Arkansas for Medical Sciences
state: Arkansas
city: Loma Linda
country: United States
facility: Loma Linda University Medical Center
state: California
city: Long Beach
country: United States
facility: Miller Children's and Women's Hospital Long Beach
state: California
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Oakland
country: United States
facility: Children's Hospital and Research Center at Oakland
state: California
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: Palo Alto
country: United States
facility: Lucile Packard Children's Hospital Stanford University
state: California
city: San Francisco
country: United States
facility: UCSF Medical Center-Parnassus
state: California
city: Denver
country: United States
facility: Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center
state: Colorado
city: Hartford
country: United States
facility: Connecticut Children's Medical Center
state: Connecticut
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Wilmington
country: United States
facility: Alfred I duPont Hospital for Children
state: Delaware
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Fort Myers
country: United States
facility: Lee Memorial Health System
state: Florida
city: Jacksonville
country: United States
facility: Nemours Children's Clinic-Jacksonville
state: Florida
city: Miami
country: United States
facility: Nicklaus Children's Hospital
state: Florida
city: Orlando
country: United States
facility: Florida Hospital Orlando
state: Florida
city: Orlando
country: United States
facility: Nemours Children's Clinic - Orlando
state: Florida
city: Pensacola
country: United States
facility: Nemours Children's Clinic - Pensacola
state: Florida
city: Saint Petersburg
country: United States
facility: Johns Hopkins All Children's Hospital
state: Florida
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta - Egleston
state: Georgia
city: Savannah
country: United States
facility: Memorial University Medical Center
state: Georgia
city: Honolulu
country: United States
facility: University of Hawaii Cancer Center
state: Hawaii
city: Chicago
country: United States
facility: University of Chicago Comprehensive Cancer Center
state: Illinois
city: Indianapolis
country: United States
facility: Riley Hospital for Children
state: Indiana
city: Indianapolis
country: United States
facility: Saint Vincent Hospital and Health Care Center
state: Indiana
city: Lexington
country: United States
facility: University of Kentucky/Markey Cancer Center
state: Kentucky
city: New Orleans
country: United States
facility: Ochsner Medical Center Jefferson
state: Louisiana
city: Baltimore
country: United States
facility: Sinai Hospital of Baltimore
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital Cancer Center
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Wayne State University/Karmanos Cancer Institute
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota/Masonic Cancer Center
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Kansas City
country: United States
facility: The Childrens Mercy Hospital
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Saint Louis
country: United States
facility: Mercy Hospital Saint Louis
state: Missouri
city: Omaha
country: United States
facility: Children's Hospital and Medical Center of Omaha
state: Nebraska
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Morristown
country: United States
facility: Morristown Medical Center
state: New Jersey
city: Summit
country: United States
facility: Overlook Hospital
state: New Jersey
city: Albuquerque
country: United States
facility: University of New Mexico Cancer Center
state: New Mexico
city: New York
country: United States
facility: Columbia University/Herbert Irving Cancer Center
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Stony Brook
country: United States
facility: Stony Brook University Medical Center
state: New York
city: Chapel Hill
country: United States
facility: UNC Lineberger Comprehensive Cancer Center
state: North Carolina
city: Charlotte
country: United States
facility: Carolinas Medical Center/Levine Cancer Institute
state: North Carolina
city: Charlotte
country: United States
facility: Novant Health Presbyterian Medical Center
state: North Carolina
city: Akron
country: United States
facility: Children's Hospital Medical Center of Akron
state: Ohio
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Toledo
country: United States
facility: Mercy Children's Hospital
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Portland
country: United States
facility: Legacy Emanuel Children's Hospital
state: Oregon
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Columbia
country: United States
facility: Palmetto Health Richland
state: South Carolina
city: Greenville
country: United States
facility: BI-LO Charities Children's Cancer Center
state: South Carolina
city: Knoxville
country: United States
facility: East Tennessee Childrens Hospital
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University/Ingram Cancer Center
state: Tennessee
city: Dallas
country: United States
facility: UT Southwestern/Simmons Cancer Center-Dallas
state: Texas
city: Fort Worth
country: United States
facility: Cook Children's Medical Center
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
state: Texas
city: Houston
country: United States
facility: M D Anderson Cancer Center
state: Texas
city: Temple
country: United States
facility: Scott and White Memorial Hospital
state: Texas
city: Richmond
country: United States
facility: Virginia Commonwealth University/Massey Cancer Center
state: Virginia
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Spokane
country: United States
facility: Providence Sacred Heart Medical Center and Children's Hospital
state: Washington
city: Tacoma
country: United States
facility: Mary Bridge Children's Hospital and Health Center
state: Washington
city: Marshfield
country: United States
facility: Marshfield Clinic
state: Wisconsin
city: Milwaukee
country: United States
facility: Children's Hospital of Wisconsin
state: Wisconsin
city: Montreal
country: Canada
facility: Centre Hospitalier Universitaire Sainte-Justine
state: Quebec
city: Quebec
country: Canada
facility: Centre Hospitalier Universitaire de Quebec
Study officials:
affiliation: Children's Oncology Group
name: Lars Wagner
role: PRINCIPAL_INVESTIGATOR
References: