ADVL0918, A Phase 1 Study of Temsirolimus in Combination with Irinotecan and Temozolomide in Children, Adolescents, and Young Adults with Relapsed or Refractory Solid Tumors
Temozolomide will be administered orally on a daily x 5 every 3 weeks schedule. The maximum temozolomide dose to be administered is 250 mg for patients enrolled at 125 mg/m2/dose and 300 mg for patients enrolled at 150 mg/m2/dose. Dosing nomograms are included in Appendices II, IIA and IIB. If emesis occurs within 20 minutes of taking a dose of temozolomide, then the dose may be repeated once. If emesis occurs after 20 minutes, the dose should not be repeated. Instructions for administration of oral temozolomide to young children are included in Appendix III of the protocol.
Irinotecan will be administered orally (50 mg/m2/dose) on a daily x 5 every 3 weeks schedule. Irinotecan should be administered one hour after the administration of temozolomide. If emesis occurs within 20 minutes of taking a dose of irinotecan, then the dose may be repeated once. If emesis occurs after 20 minutes, the dose should not be repeated. Instructions for administration of oral irinotecan are included in Appendix IV of the protocol. Aprepitant is an inducer, a moderate inhibitor, and substrate of CYP3A4 and should not be used as an anti-emetic.
Temsirolimus will be administered intravenously over 30 minutes on days 1 and 8 (beginning at 15 mg/m2/dose). For patients on dose level 4C, 5C, or 7B, temsirolimus will be administered on days 1, 8, and 15. Temsirolimus should be given within 8 hours following administration of temozolomide and irinotecan. Patients should receive premedication with diphenhydramine (1 mg/kg, max 50 mg) prior to the temsirolimus dose. Note: Patients enrolled on dose level -1 do NOT receive the day 8 temsirolimus dose. A cycle of therapy is considered to be 21 days. Patients with stable disease or better may be treated for up to 17 cycles (approximately 12 months).
1. Patients must be > than 12 months and <= 21 years of age at the time of study enrollment.
2. Patients must have had histologic verification of malignancy at original diagnosis or relapse except in patients with intrinsic brain stem tumors, patients with optic pathway gliomas, and patients with pineal tumors and elevations of serum or CSF alpha-fetoprotein or beta-HCG.
3. Patients must have either measurable or evaluable disease
4. Patient[Single Quote]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.
5. Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients < 16 years of age.
6. Patients must have fully recovered from the acute toxic effects of all prior anticancer
7. Patient must have adequate bone marrow, renal, liver, pulmonary and neurologic function (as described in the protocol).
8. PT and INR < 1.2 x ULN
9. Serum triglyceride level <=300 mg/dL (<=3.42 mmol/L) and serum cholesterol level <=300 mg/dL (7.75 mmol/L)
10. Random or fasting blood glucose within the upper normal limits for age. If the initial blood glucose is a random sample that is outside of thenormal limits, then a follow-up fasting blood glucose can be obtainedand must be within the upper normal limits for age.
11. All patients and/or their parents or legal guardians must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines.