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Sirolimus, Cyclophosphamide, Topotecan Patients accrued to dose levels in cohorts of 3 (3+3 design). Patients will receive daily oral sirolimus and cyclophosphamide days 1-21 in 28-day cycle, combined with oral topotecan given on days 1-14. Sirolimus will be dosed based on steady-state plasma trough concentrations.

Dosing of cyclophosphamide and topotecan will be 25 mg/m2/dose and 0.8 mg/ m2 /dose respectively for dose levels 1 and 2. Level 3 dosing will escalate cyclophosphamide to 50 mg/ m2/dose. If level 1 dosing not tolerated, patients will be enrolled in level -1 cohort with cyclophosphamide and sirolimus administered only on days 1-14. If level -1 not tolerated, patients will be enrolled in level -2 with topotecan administration limited to days 1-7.

Sirolimus, Cyclophosphamide, Topotecan

Steven Dubois, MD

Katherine Matthay, MD

This is a Phase I study of the combination of three drugs: sirolimus, cyclophosphamide, and topotecan. This is the first study to evaluate the safety and clinical activity of the combination of oral sirolimus, oral cyclophosphamide and oral topotecan in pediatric and young adult patients with relapsed and refractory solid tumors.

In this phase I study, the mTOR inhibitor sirolimus will be administered in combination with oral cyclophosphamide and oral topotecan to children with relapsed or refractory solid tumors. The primary aim of this study is to recommend a phase II dose schedule and describe the toxicity of this combination. Myelosuppression will be a targeted toxicity.

The combination of cyclophosphamide and topotecan is well-tolerated and provides an oral therapy option for heavily pre-treated patients. The toxicity profile and activity level suggest that this combination will provide a useful platform onto which novel compounds may be added. Sirolimus has been shown to demonstrate single-agent activity in preclinical models of rhabdomyosarcoma, Ewing sarcoma, medulloblastoma, glioblastoma, neuroblastoma, and osteosarcoma. Sirolimus has also been shown to have additive effects in pre-clinical models of solid tumors when combined with cyclophosphamide. This trial therefore will evaluate the combination of sirolimus with cyclophosphamide and topotecan. Pharmacokinetic studies of sirolimus as well as pharmacodynamic studies to assess antiangiogensis and inhibition of the mTOR pathway will be done.

Patients will be accrued to dose levels in cohorts of 3 using a 3 + 3 design. Patients will initially be enrolled on dose level 1. Patients will receive daily oral sirolimus and cyclophosphamide on days 1 - 21 in a 28 day cycle. This will be combined with oral topotecan given on days 1 - 14. Sirolimus will be dosed based on steady-state plasma trough concentrations with a goal level in dose level 1 of 3-7.9 ng/ML and goal levels in subsequent dose levels of 8-12.0 ng/ML. Dosing of cyclophosphamide and topotecan will be 25 mg/m2/dose and 0.8 mg/ m2 /dose respectively for dose levels 1 and 2. Level 3 dosing will escalate cyclophosphamide to 50 mg/ m2/dose. If level 1 dosing is not tolerated, patients will then be enrolled in a level -1 cohort with cyclophosphamide and sirolimus administered only on days 1 - 14. If level -1 is not tolerated, patients will be enrolled in level -2 with topotecan administration limited to days 1 - 7.

Sirolimus With Cyclophosphamide and Topotecan for Pediatric/Adolescent Relapsed and Refractory Solid Tumors

A Phase I Study of Sirolimus in Combination With Oral Cyclophosphamide and Oral Topotecan in Children and Young Adults With Relapsed and Refractory Solid Tumors

Correlative biology studies including pharmacodynamic measures of sirolimus and measures of anti-angiogenesis will be determined using standard methods and reported quantitatively at baseline and after one cycle of treatment.

Blood tests to assess PBMC phospho-S6, phospho-AKT, plasma VEGF, VEGFR2, endoglin and phospho-4eBP1 quantitative changes after one cycle of therapy as will be done.

Define the dose limiting toxicities to recommend a Phase 2 trough concentration of sirolimus when administered on a protracted schedule in combination with oral topotecan and oral cyclophosphamide.

Evaluations done during first Cycle to assess/define DLT:

Physical exams, vitals, blood tests: CBC, CMB, coagulation-PT, LDH, D-dimer, peripheral smear, urine glucose, performance evaluations.

All toxicities observed will be summarized in terms of type (organ affected or laboratory determination), severity (by NCI CTCAE v 4.0), and attribution. The MTD is the highest dose level tested at which 0/6 or 1/6 patients experience DLT that is possibly, probably, or definitely related to the study drug(s) with at least 2/3 or 2/6 patients encountering DLT at the next higher dose. If 0/6 or 1/6 patients experience DLT at the highest dose level (dose level 3), then that dose level will be called the MTD.

Disease evaluation will take place after completion of the first cycle (CT, MRI, PET and/or MIBG). If the patient has a Partial Response (PR), Complete Response (CR) or Stable Disease (SD) the patient may continue on study.

Collect preliminary data on the biologic effects of sirolimus on proteins involved in the mTOR signaling pathway.

Pharmacokinetic and pharmacodynamic studies (blood tests) of sirolimus to assess inhibition of the mTOR pathway will be done twice during the first 28-day Cycle.

Collect preliminary data regarding the antiangiogenic properties of the combination of sirolimus, topotecan and cyclophosphamide when administered on this schedule.

Pharmacokinetic and pharmacodynamic studies (blood tests) of sirolimus to assess antiangiogensis will be done twice during the first 28-day Cycle.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Sirolimus With Cyclophosphamide and Topotecan for Pediatric/Adolescent Relapsed and Refractory Solid Tumors	NCT01670175	Malignant Solid... Childhood Solid...	Sirolimus, Cycl...	- 25 Years	University of California, San Francisco
Sirolimus With Cyclophosphamide and Topotecan for Pediatric/Adolescent Relapsed and Refractory Solid Tumors	NCT01670175	Malignant Solid... Childhood Solid...	Sirolimus, Cycl...	- 25 Years	University of California, San Francisco

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