NCT01670175

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

• Status: Completed
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 21 (actual)
• Sponsor: University of California, San Francisco · Academic / Other
• Sex: All
• Age: 25 Years
• Healthy volunteers: Not accepted

Summary

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.

Detailed description

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.

Conditions

• Malignant Solid Tumor
• Childhood Solid Tumor

Interventions

Type	Name	Description
DRUG	Sirolimus, Cyclophosphamide, Topotecan	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.

Timeline

• Start date: 2012-08-01
• Primary completion: 2016-09-01
• Completion: 2016-09-01
• First posted: 2012-08-22
• Last updated: 2017-06-21

Locations

1 site across 1 country: United States