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

Phase 2

Completed

Conditions: Childhood Alveolar Soft Part Sarcoma
Childhood Liposarcoma
Childhood Malignant Peripheral Nerve Sheath Tumor
Childhood Synovial Sarcoma
Previously Treated Childhood Rhabdomyosarcoma
Childhood Angiosarcoma
Rhabdomyosarcoma
Childhood Epithelioid Sarcoma
Childhood Fibrosarcoma
Childhood Leiomyosarcoma

Interventions: Biological: Cixutumumab
Other: Laboratory Biomarker Analysis
Drug: Temsirolimus

Registration Number: NCT01614795

Lead Sponsor: National Cancer Institute (NCI)

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 46

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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (cixutumumab, temsirolimus)	Cixutumumab	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.
Treatment (cixutumumab, temsirolimus)	Laboratory Biomarker Analysis	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.
Treatment (cixutumumab, temsirolimus)	Temsirolimus	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.

Primary Outcome Measures

Name	Time	Method
Objective Response Rate (PR or CR) by Response Evaluation Criteria in Solid Tumors (RECIST).	6 cycles (168 days)	Per Response evaluation criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions: Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions. Overall Response (OR)= CR+PR. The combination of sufficient activity is considered if the true response rate is 35% or greater.
Number of Cycles of Toxicity	Duration of protocol therapy - Up to 25 cycles (700 days)	The number of patients-cycles where CTC Version 4 grade 3 or higher increased Alanine aminotransferase was observed

Secondary Outcome Measures

Name	Time	Method
Expression Levels of IGF-1R, Insulin Receptor, ERK, RON, and mTOR	Baseline	Number of patients expressing insulin-like growth factor 1 receptor (IGF-1R), insulin receptor, ERK, RON, and mammalian target of rapamycin (mTOR) at levels 0, 1+, 2+, 3+ by immunohistochemistry.
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	Baseline
Progression-free Interval	10 months after enrollment	Percentage Probability of remaining progression-free 5 years after enrollment estimated by the method of Kaplan and Meier

Trial Locations

Locations (76): Stony Brook University Medical Center
🇺🇸
Stony Brook, New York, United States
Children's Hospital Medical Center of Akron
🇺🇸
Akron, Ohio, United States
Sinai Hospital of Baltimore
🇺🇸
Baltimore, Maryland, United States
Nationwide Children's Hospital
🇺🇸
Columbus, Ohio, United States
Children's Hospital of Philadelphia
🇺🇸
Philadelphia, Pennsylvania, United States
Yale University
🇺🇸
New Haven, Connecticut, United States
University of Chicago Comprehensive Cancer Center
🇺🇸
Chicago, Illinois, United States
Seattle Children's Hospital
🇺🇸
Seattle, Washington, United States
Dana-Farber Cancer Institute
🇺🇸
Boston, Massachusetts, United States
Saint Vincent Hospital and Health Care Center
🇺🇸
Indianapolis, Indiana, United States
Riley Hospital for Children
🇺🇸
Indianapolis, Indiana, United States
UCSF Medical Center-Parnassus
🇺🇸
San Francisco, California, United States
Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center
🇺🇸
Denver, Colorado, United States
Wayne State University/Karmanos Cancer Institute
🇺🇸
Detroit, Michigan, United States
Children's Hospital of Alabama
🇺🇸
Birmingham, Alabama, United States
University of Alabama at Birmingham Cancer Center
🇺🇸
Birmingham, Alabama, United States
Legacy Emanuel Children's Hospital
🇺🇸
Portland, Oregon, United States
Oregon Health and Science University
🇺🇸
Portland, Oregon, United States
Vanderbilt University/Ingram Cancer Center
🇺🇸
Nashville, Tennessee, United States
Mayo Clinic
🇺🇸
Rochester, Minnesota, United States
Children's Hospital of Wisconsin
🇺🇸
Milwaukee, Wisconsin, United States
Loma Linda University Medical Center
🇺🇸
Loma Linda, California, United States
University of Arkansas for Medical Sciences
🇺🇸
Little Rock, Arkansas, United States
Children's Hospital and Research Center at Oakland
🇺🇸
Oakland, California, United States
Miller Children's and Women's Hospital Long Beach
🇺🇸
Long Beach, California, United States
Nicklaus Children's Hospital
🇺🇸
Miami, Florida, United States
Nemours Children's Clinic - Orlando
🇺🇸
Orlando, Florida, United States
University of Minnesota/Masonic Cancer Center
🇺🇸
Minneapolis, Minnesota, United States
The Childrens Mercy Hospital
🇺🇸
Kansas City, Missouri, United States
University of New Mexico Cancer Center
🇺🇸
Albuquerque, New Mexico, United States
Mercy Children's Hospital
🇺🇸
Toledo, Ohio, United States
UT Southwestern/Simmons Cancer Center-Dallas
🇺🇸
Dallas, Texas, United States
Cook Children's Medical Center
🇺🇸
Fort Worth, Texas, United States
Centre Hospitalier Universitaire de Quebec
🇨🇦
Quebec, Canada
Mary Bridge Children's Hospital and Health Center
🇺🇸
Tacoma, Washington, United States
Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
🇺🇸
Houston, Texas, United States
M D Anderson Cancer Center
🇺🇸
Houston, Texas, United States
Virginia Commonwealth University/Massey Cancer Center
🇺🇸
Richmond, Virginia, United States
Memorial Sloan-Kettering Cancer Center
🇺🇸
New York, New York, United States
UNC Lineberger Comprehensive Cancer Center
🇺🇸
Chapel Hill, North Carolina, United States
Children's Hospital of Orange County
🇺🇸
Orange, California, United States
Lee Memorial Health System
🇺🇸
Fort Myers, Florida, United States
Florida Hospital Orlando
🇺🇸
Orlando, Florida, United States
Memorial University Medical Center
🇺🇸
Savannah, Georgia, United States
Children's Healthcare of Atlanta - Egleston
🇺🇸
Atlanta, Georgia, United States
Nemours Children's Clinic - Pensacola
🇺🇸
Pensacola, Florida, United States
Johns Hopkins All Children's Hospital
🇺🇸
Saint Petersburg, Florida, United States
University of Hawaii Cancer Center
🇺🇸
Honolulu, Hawaii, United States
University of Kentucky/Markey Cancer Center
🇺🇸
Lexington, Kentucky, United States
Massachusetts General Hospital Cancer Center
🇺🇸
Boston, Massachusetts, United States
Washington University School of Medicine
🇺🇸
Saint Louis, Missouri, United States
Mercy Hospital Saint Louis
🇺🇸
Saint Louis, Missouri, United States
Morristown Medical Center
🇺🇸
Morristown, New Jersey, United States
Children's Hospital and Medical Center of Omaha
🇺🇸
Omaha, Nebraska, United States
Hackensack University Medical Center
🇺🇸
Hackensack, New Jersey, United States
Columbia University/Herbert Irving Cancer Center
🇺🇸
New York, New York, United States
Overlook Hospital
🇺🇸
Summit, New Jersey, United States
Carolinas Medical Center/Levine Cancer Institute
🇺🇸
Charlotte, North Carolina, United States
Novant Health Presbyterian Medical Center
🇺🇸
Charlotte, North Carolina, United States
Cincinnati Children's Hospital Medical Center
🇺🇸
Cincinnati, Ohio, United States
Palmetto Health Richland
🇺🇸
Columbia, South Carolina, United States
BI-LO Charities Children's Cancer Center
🇺🇸
Greenville, South Carolina, United States
East Tennessee Childrens Hospital
🇺🇸
Knoxville, Tennessee, United States
Scott and White Memorial Hospital
🇺🇸
Temple, Texas, United States
Marshfield Clinic
🇺🇸
Marshfield, Wisconsin, United States
Providence Sacred Heart Medical Center and Children's Hospital
🇺🇸
Spokane, Washington, United States
Centre Hospitalier Universitaire Sainte-Justine
🇨🇦
Montreal, Quebec, Canada
Alfred I duPont Hospital for Children
🇺🇸
Wilmington, Delaware, United States
Children's Hospital Los Angeles
🇺🇸
Los Angeles, California, United States
Nemours Children's Clinic-Jacksonville
🇺🇸
Jacksonville, Florida, United States
Lucile Packard Children's Hospital Stanford University
🇺🇸
Palo Alto, California, United States
Connecticut Children's Medical Center
🇺🇸
Hartford, Connecticut, United States
Ochsner Medical Center Jefferson
🇺🇸
New Orleans, Louisiana, United States
University of Mississippi Medical Center
🇺🇸
Jackson, Mississippi, United States
University of Oklahoma Health Sciences Center
🇺🇸
Oklahoma City, Oklahoma, United States
Children's National Medical Center
🇺🇸
Washington, District of Columbia, United States