3.0 ENROLLMENT PROCEDURES AND ELIGIBILITY CRITERIA

3.1 Study Enrollment

3.1.1 Patient Registration via Remote Data Entry (RDE)

Prior to enrollment on study, patients must be assigned a COG patient ID number. This number is obtained via the eRDE system once authorization for the release of protected health information (PHI) has been obtained. The COG patient ID number is used to identify the patient in all future interactions with COG. If you have problems with registration, please refer to the online help.

A Biopathology Center (BPC) number will be assigned as part of the registration process. Each patient will be assigned only one BPC number per COG Patient ID. For additional information about the labeling of specimens please refer to the Pathology and/or Biology Guidelines in this protocol.

3.1.2 IRB Approval

Local IRB/REB approval of this study must be obtained by a site prior to enrolling patients. Sites must submit IRB/REB approvals to the NCI’s Cancer Trials Support Unit (CTSU) Regulatory Office and allow 3 business days for processing. The submission must include a fax coversheet (or optional CTSU IRB Transmittal Sheet) and the IRB approval document(s). The CTSU IRB Certification Form may be submitted in lieu of the signed IRB approval letter. All CTSU forms can be located on the CTSU web page (https://www.ctsu.org). Any other regulatory documents needed for access to the study enrollment screens will be listed for the study on the CTSU Member’s Website under the RSS Tab.

IRB/REB approval documents may be faxed (1-215-569-0206), Emailed (CTSURegulatory@ctsu.coccg.org) or mailed to the CTSU Regulatory office.

When a site has a pending patient enrollment within the next 24 hours, this is considered a “Time of Need” registration. For Time of Need registrations, in addition to marking your submissions as ‘URGENT’ and faxing the regulatory documents, call the CTSU Regulatory Helpdesk at: 1-866-651-CTSU. For general (non-regulatory) questions call the CTSU General Helpdesk at: 1-888-823-5923.

3.1.3 Reservation Requirements

Investigators should refer to the COG website to determine if the study is currently open for accrual. If the study is listed as active, investigators should then access the Studies Requiring Reservations page to ensure that a reservation for the study is available. To access the Studies Requiring Reservations page:

1. Log in to https://members.childrensoncologygroup.org.

2. From the menu bar, click eRDES. The eRDES sub-menu appears.

3. Click Reservation. The Studies requiring Reservations page appears.

Prior to obtaining informed consent and enrolling a patient, a reservation must be made with the Statistical and Data Center through the eRDE system.

Reservations may be obtained 24-hours a day through the COG website. Please refer to the Reservation System eRDES User Guide that can be downloaded from:

https://members.childrensoncologygroup.org/_files/Help/eRDES_ReservationSystem_UserGuide.pdf

3.1.4 Study Enrollment

Patients may be enrolled on the study once all eligibility requirements for the study have been met. Study enrollment is accomplished by going to the Enrollment application in the RDE system. If you have problems with enrollment, refer to online help in the Applications area of the COG website.

3.1.5 Timing

Patients must be enrolled before treatment begins. The date protocol therapy is projected to start must be no later than 5 calendar days after the date of study enrollment. Patients who are started on protocol therapy prior to study enrollment will be considered ineligible and will not be able to receive further protocol therapy.

See Section 3.2 for timing requirements for eligibility studies. See Section 3.1.7 for timing requirements for baseline studies to be obtained prior to start of therapy. Note: Repeat laboratory and imaging studies may be required if enrollment and start of therapy do not occur on the same day.

3.1.6 Institutional Pathology Report

At the time of enrollment, the institutional pathology report for the diagnosis under which the patient is being enrolled must be faxed to the Operations Center using the Document Imaging System at (626) 447-2204. Reports must be faxed with the Shuttle Sheet Fax Covers (available with the other study CRFs).

3.1.7 Requirements to Initiate Protocol Therapy

3.1.7.1 Laboratory Studies: If more than 7 calendar days elapse between the date laboratory studies to determine eligibility were obtained (Section 3.2.7) and the start date of treatment, then the following studies must be repeated prior to initiating protocol therapy: CBC with differential, bilirubin, ALT (SGPT) and serum creatinine. If any of these repeat laboratory studies are outside the parameters required for eligibility (labs may again be repeated within 48-72 hours), then the patient is off protocol therapy.

3.1.7.2 Imaging Studies: Imaging studies must be performed within 14 calendar days of initiating protocol therapy. If more than 14 calendar days have elapsed between the date imaging studies to determine eligibility were obtained (Section 3.2.3) and the start date of treatment, then repeat imaging studies must be obtained prior to initiating protocol therapy.

3.2 Eligibility: Inclusion Criteria

Important note: The inclusion criteria listed below are interpreted literally and cannot be waived. All clinical and laboratory data required for determining eligibility of a patient enrolled on this trial must be available in the patient's medical/research record. These source documents must be available for verification at the time of audit.

All clinical and laboratory studies to determine eligibility must be performed within 7 days prior to enrollment. Imaging studies must be performed within 14 days prior to study enrollment.

3.2.1 Age: Patients must be ≥ 12 months and 30 years of age at the time of study entry.

3.2.2 Diagnosis and Tumor Tissue Availability:

3.2.2.1 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:

a) Osteosarcoma

b) Ewing’s sarcoma / peripheral PNET

c) Rhabdomyosarcoma

d) Non-rhabdomyosarcoma soft tissue sarcoma

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

3.2.2.3 All patients are required to submit archival tumor samples for immunohistochemical analysis (either paraffin-embedded tumor blocks, or unstained slides as per Section 7.2.)

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 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 as described in Section 7.2 should be shipped to the BPC within 7 days of study enrollment.

3.2.3 Disease Status: Patients must have radiographically measurable disease

3.2.3.1 Measurable disease is defined as the presence of at least one lesion on MRI or 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).

Note: The following do not qualify as measurable disease:

- malignant fluid collections (eg, ascites, pleural effusions);

- bone marrow infiltration;

- lesions only detected by nuclear medicine studies (eg, bone, gallium or PET scans);

- elevated tumor markers in plasma or CSF;

- previously radiated lesions that have not demonstrated clear progression post radiation;

- leptomeningeal lesions that do not meet the measurements noted above.

3.2.4 Therapeutic Options: 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.

3.2.5 Performance Level: Patients must have a Lansky or Karnofsky performance status score of ≥ 50, corresponding to ECOG categories 0, 1 or 2. Use Karnofsky for patients > 16 years of age and Lansky for patients ≤ 16 years of age.

Note: 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.

(See https://members.childrensoncologygroup.org/prot/reference_materials.asp.)

3.2.6 Prior Therapy

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.

a. Myelosuppressive chemotherapy: Patients must not have received myelosuppressive chemotherapy within 3 weeks of enrollment (6 weeks if prior nitrosourea).

b. Hematopoietic growth factors: 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.

c. Biologic (anti-neoplastic agent): 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.

d. Monoclonal antibodies: At least 3 half-lives must have elapsed since prior therapy that included a monoclonal antibody. (See posting of half-lives for commonly used monoclonal antibodies on the DVL homepage: https://members.childrensoncologygroup.org/Disc/devtherapeutics/default.asp.

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

f. Stem Cell Transplant or Rescue: No evidence of active graft vs. host disease and 2 months must have elapsed since transplant.

3.2.7 Organ Function Requirements

All patients must have:

3.2.7.1 Adequate Bone Marrow Function Defined As:

a. 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 RBC transfusions).

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

- Peripheral absolute neutrophil count (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.

3.2.7.2 Adequate Renal Function Defined As:

- Creatinine clearance or radioisotope GFR 70 mL/min/1.73 m2 or a serum creatinine based on age/gender as follows:

The threshold creatinine values in this Table were derived from the Schwartz formula for estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and stature data published by the CDC.

3.2.7.3 Adequate Liver Function Defined As:

- Total bilirubin 1.5 x upper limit of normal (ULN) for age

- SGPT (ALT) ≤ 2.5 x ULN (for the purpose of this study, the ULN for SGPT is 45 U/L)

- Serum albumin ≥ 2 g/dL.

3.2.7.4 Central Nervous System Function Defined As:

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

3.2.7.5 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.

3.2.7.6 Serum cholesterol levels must be < Grade 2 (< 300 mg/dL), and serum triglyceride levels must be < Grade 2 (< 2.5 x ULN).

3.2.8 CNS Metastases

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.

3.3 Eligibility: Exclusion Criteria

Important note: The exclusion criteria listed below are interpreted literally and cannot be waived. All clinical and laboratory data required for determining eligibility of a patient enrolled on this trial must be available in the patient's medical/research record. These source documents must be available for verification at the time of audit.

3.3.1 Pregnancy or Breast-Feeding

Patients who are pregnant or breast-feeding are not eligible for this study as there is yet no available information regarding human fetal or teratogenic toxicities. 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. IgG may also potentially be secreted in milk and therefore breastfeeding women should be excluded.

3.3.2 Concomitant Medications

(Please see Section 4.3 for the concomitant therapy restrictions for patients during the study.)

3.3.2.1 Growth factor(s): 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®).

3.3.2.2 Corticosteroids: 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.

3.3.2.3 Investigational Drugs: Patients who are currently receiving another investigational drug are not eligible.

3.3.2.4 Anti-cancer Agents: Patients who are currently receiving other anti-cancer agents are not eligible.

3.3.2.5 Hormonal Therapy: Patients receiving insulin or growth hormone therapy are not eligible.

3.3.2.6 Anticonvulsants: Patients who are receiving enzyme-inducing anticonvulsants are not eligible (see Appendix I for a list of enzyme-inducing anticonvulsants).

3.3.2.7 Anticoagulants: 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.

3.3.3 Infection: Patients who have an uncontrolled infection are not eligible.

3.3.4 Diabetes Mellitus: Patients with known type I or type II diabetes mellitus are not eligible.

3.3.5 Patients who have received prior therapy targeting IGF-1R with either monoclonal antibodies or small molecule tyrosine kinase inhibitors are NOT eligible. Similarly, prior treatment with mTOR inhibitors (eg, rapamycin, temsirolimus, everolimus, deferolimus) is NOT allowed.

3.3.6 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.

3.3.7 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.

3.4 Regulatory                    

3.4.1 All patients and/or their parents or legal guardians must sign a written informed consent.

3.4.2 All institutional, FDA, and NCI requirements for human studies must be met.