INCLUSION CRITERIA:
1. AGE: greater than or equal to 2 to less than 18 years of age.
2. DIAGNOSES: Histologically confirmed solid tumors, which may include but are not limited to rhabdomyosarcoma and other soft tissue sarcomas, Ewing sarcoma family of tumors, osteosarcoma, neuroblastoma, Wilms tumor, hepatic tumors, germ cell tumors, and primary brain tumors. In patients with brain stem or optic gliomas the requirement for histological confirmation can be waived if a biopsy was not performed.
3. TUMOR STATUS: Measurable or evaluable tumors. Patients with neuroblastoma that is only detectable by MIBG are eligible and considered to have measurable disease using the Curie scale. Patients with neuroblastoma that is only detected by bone marrow aspirate/biopsy are eligible and considered to have evaluable disease.
4. PRIOR THERAPY: The patient's cancer must have relapsed after or failed to respond to frontline curative therapy or there must not be other potentially curative treatment options available. Curative therapy may include surgery, radiation therapy, chemotherapy, or any combination of these modalities. Patients must have fully recovered to grade less than or equal to 1 from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.
-Myelosuppressive chemotherapy: The last dose of all myelosuppressive anticancer drugs must be at least 3 weeks prior to study entry.
-Biologic (anti-cancer agent): The last dose of all biologic agents for the treatment of the patient's cancer (such as retinoids) must be at least 7 days prior to study entry. The last dose of other monoclonal antibodies must be at least 30 days prior to study entry.
-Investigational anti-cancer agent: The last dose of all investigational agents must be at least 30 days prior to study entry.
-Radiation therapy: The last dose of radiation (including therapeutic 131IMIBG) to more than 25 percent of marrow containing bones (pelvis, spine, skull) must be at least 4 weeks prior to study entry. The last dose of all other local palliative (limited port) radiation must be at least 2 weeks prior to study entry.
-Stem Cell Transplantation. Patients must be at least 2 months post-autologous transplant and must have recovered from toxicities. Patients must be at least 6 months post-allogeneic transplant, must have recovered from toxicities, and must have no evidence of active graft-versus-host disease. Patients must also have been off of immunosuppressive treatment at least 30 days.
-Number of prior treatment regimens: No limitation on the number of prior chemotherapy regimens that the patient may have received prior to study entry.
-Colony stimulating factors: The last dose of colony stimulating factors, such as filgrastim, sargramostim, and epoetin, must be at least 48 hours prior to study entry, and the last dose of long-acting colony stimulating factors, such as pegfilgrastim, must be at least 10 days prior to study entry.
5. PERFORMANCE SCORE: 60-100 (Karnofsky scale, for patients greater than or equal to 10 years of age) or 60-100 (Lansky scale, for children younger than 10 years of age).
6. HEMATOLOGICAL FUNCTION:
a. Absolute neutrophil count (ANC) greater than or equal to 1.5 times 10(9)/L.
b. Platelet count greater than or equal to 100 times 10(9)/L.
c. Patients with an ANC less than 1.5 times 10(9)/L or platelet count less than 100 times 10(9)/L due to bone marrow involvement by tumor or the effects of prior therapy are eligible only for the expanded cohort at the optimal dose/MTD on the qW schedule, but will not be evaluable for hematological toxicity. These patients should have an ANC greater than 0.5 times 10(9)/L and a platelet count greater than 50 times 10(9)/L.
7. RENAL FUNCTION: Age-adjusted normal serum creatinine (see Table below) OR a creatinine clearance greater than or equal to60 mL/min/1.73 m(2) based on a 24 h urine collection.
Table 3 Normal Serum Creatinine in Children:
Age 2 to less than 6 years - Maximum Serum Creatinine (mg/dl) - Males 0.8 and Females 0.8.
Age 6 to less than 10 years - Maximum Serum Creatinine (mg/dl) - Males 1 and Females 1.
Age 10 to less than 13 years - Maximum Serum Creatinine (mg/dl) - Males 1.2 and Females 1.2.
Age 13 years to less than 16 years- Maximum Serum Creatinine (mg/dl) Males 1.5 and Females 1.4.
Greater than 16 years - Maximum Serum Creatinine (mg/dl) Males 1.7 and Females 1.4.
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.
8. HEPATIC FUNCTION:
a. Serum total bilirubin less than 1.5 times ULN.
b. ALT/AST less than or equal to 2.5 times the ULN (less than or equal to 5 times the ULN for patients with known hepatic metastases).
9. CARDIAC FUNCTION: Left Ventricle Shortening fraction greater than or equal to 28 percent (or equivalent left ventricular ejection fraction greater than 45 percent) by echocardiogram.
10. Patients with CNS metastases are eligible for enrollment if they have received prior surgical resection of or radiotherapy to site(s) of CNS disease and have been off corticosteroids for at least 2 weeks. Neurological deficits in these patients must have been stable for at least 4 weeks.
11. Patients must being willing to participate in the pharmacokinetic studies that are performed on cycle 1, because this represents the primary endpoint of the trial.
12. Patients and their legal representatives must be able to read, understand and provide written informed consent to participate in the trial.
13. Females of childbearing potential as well as fertile males and their partners must agree to use an effective form of contraception during the study and for 120 days following the last dose of study medication (effective forms of contraception include abstinence, a contraceptive or a double barrier method).
EXCLISION CRITERIA:
1. Active infection or fever greater than or equal to 38.5 degrees Celsius within 3 days of the first scheduled day of dosing unless the fever is felt to be tumor-related.
2. Treatment with pharmacologic doses of corticosteroids within the past 2 weeks; current or past use of anti-IGF-1R antibodies; current treatment with immunosuppressive agents.
3. Known hypersensitivity to any of the components of R1507 or who have had prior hypersensitivity reactions to monoclonal antibodies.
4. Patients who are receiving concurrent investigational therapy (agents that have no FDA approved indication) or who have received investigational therapy within a period of 30 days prior to the first scheduled day of dosing. Investigational therapy is defined as treatment for which there is currently no FDA approved indication.
5. Patients with diabetes mellitus defined as:
a. Casual serum glucose concentration of greater than or equal to 200 mg/dL.
b. Fasting serum glucose of greater than or equal to 125 mg/dL.
c. Need for use of an oral hypoglycemic agent or insulin in order to keep the serum glucose below the above levels.
6. Severe uncontrolled systemic disease.
7. Patients who are pregnant or breast feeding.
8. Patients with reproductive potential not willing to use an effective method of contraception, which includes abstinence.
9. Any other medical condition, including mental illness or substance abuse, deemed by the Investigator to be likely to interfere with a patient's ability to sign informed consent, cooperate and participate in the study, or interfere with the interpretation of the results.
10. Known HIV or Hepatitis B or C (active, previously treated or both).
National Institutes of Health Clinical Center
Bethesda, Maryland 20892. Last update: 01/13/2009