Simvastatin With Topotecan and Cyclophosphamide in Relapsed and/or Refractory Pediatric Solid and CNS Tumors (AflacST1402)
|Retinoblastoma Clear Cell Sarcoma Renal Cell Carcinoma Rhabdoid Tumor Wilms Tumor Hepatoblastoma Neuroblastoma Germ Cell Tumors Ewings Sarcoma Non-rhabdomyosarcoma Soft Tissue Sarcoma Osteosarcoma Rhabdomyosarcoma||Drug: Simvastatin Drug: Cyclophosphamide Drug: Topotecan Drug: Myeloid growth factor||Phase 1|
|Study Design:||Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase 1 Study Using Simvastatin in Combination With Topotecan and Cyclophosphamide in Relapsed and/or Refractory Pediatric Solid and CNS Tumors|
- Maximum Tolerated Dose (MTD) of Simvastatin [ Time Frame: First treatment to toxicity (up to 24 months) ]MTD will be the maximum dose at which fewer than one-third of subjects experience dose-limiting toxicities (DLTs) during Cycle 1 of therapy.
- Number of Dose-Limiting Toxicities (DLTs) [ Time Frame: Up to 24 months ]
DLT will be defined as any of the following events that are possibly, probably, or definitely attributable to study drug:
Non-hematological dose-limiting toxicity: Any Grade 3 or 4 non-hematological toxicity (excluding nausea, alanine transaminase (ALT) or aspartate aminotransferase (AST) that returns to baseline or ≤ grade 1 within 7 days of study drug interruption, fever, infection, hypophosphatemia, hypokalemia, hypocalcemia, hypomagnesemia, or creatinine phosphokinase (CPK) elevation that returns to baseline or ≤ grade 1 within 7 days of study drug interruption), Any Grade 2 non-hematological toxicity that persists for ≥ 7 days and is considered sufficiently medically significant or sufficiently intolerable by subjects that it requires treatment interruption, or hematological dose-limiting toxicity, defined as neutropenia or thrombocytopenia that precludes initiation of the next cycle of therapy within 14 days of the scheduled start date.
- Percentage of Participants With Overall Tumor Response (Response Rate) [ Time Frame: 24 months ]
Response is defined as CR (Complete Response) or PR (Partial Response) per Response Evaluation Criteria in Solid Tumor (RECIST criteria). Possible evaluations include: CR: Disappearance of all target lesions. PR: At least a 30% decrease in the size of target lesions.
Response rate (%) = (number of patients with CR+PR/number of patients)*100
- Change in Total Cholesterol Level [ Time Frame: Baseline, 24 months ]Change in serum total cholesterol level after treatment with simvastatin. A decrease from baseline to the end of treatment, a negative value, indicates an improvement.
- Change in serum interleukin-6 (IL-6) level [ Time Frame: Baseline, 24 months ]Change in serum interleukin-6 (IL-6) level after treatment with simvastatin. Serum levels of the IL-6 will be assayed using by enzyme-linked immunosorbent assay (ELISA). Higher levels are typically interpreted as worsening of condition.
- Change in soluble interleukin 6 receptor (sIL-6R) [ Time Frame: Baseline, 24 months ]Change in serum interleukin-6 (IL-6) level after treatment with simvastatin. Serum levels of the sIL-6r will be assayed using by enzyme-linked immunosorbent assay (ELISA). Higher levels are typically interpreted as worsening of condition.
- Change in signal transducer and activator of transcription 3 (STAT-3) expression [ Time Frame: Baseline, 24 months ]Change in STAT-3 expression after treatment with simvastatin. STAT-3 will be measured using phospho-specific flow cytometry, or phospho-flow.
- Change in phospho-STAT3 expression [ Time Frame: Baseline, 24 months ]Change in phospho-STAT3 expression after treatment with simvastatin. Phospho-STAT3 expression will be measured using phospho-specific flow cytometry, or phospho-flow.
|Study Start Date:||February 2015|
|Estimated Study Completion Date:||February 2021|
|Estimated Primary Completion Date:||February 2019 (Final data collection date for primary outcome measure)|
Experimental: simvastatin + topotecan/cyclophosphamide
During dose escalation (phase I), standard 3+3 design will be followed.
The starting dose of simvastatin will be 140 mg/m^2/dose BID for 21 days for the first group. Dose escalation for subsequent groups will be 180 mg/m^2/dose BID, 225 mg/m^2/dose BID, and 290 mg/m^2/dose BID. If the maximum tolerated dose (MTD) has been exceeded at the first dose level, then the subsequent cohort of subjects will be treated at a dose of 100 mg/m2/dose BID (dose level 0). Simvastatin will be administered orally twice daily, approximately 12 hours apart. Feeding tube (nasogastric tube or gastrostomy tube, NOT a jejunum localized tube) administration is allowed. If a subject vomits a dose of simvastatin, it will not be repeated.
Other Name: zocorDrug: Cyclophosphamide
The dose of cyclophosphamide will be fixed at 250 mg/m^2/dose. Cyclophosphamide will be administered intravenously over 30 minutes once daily for 5 days every 21 days.
Other Names:Drug: Topotecan
The dose of topotecan will be fixed at 0.75 mg/m^2/dose. Topotecan will be administered, after cyclophosphamide, intravenously over 30 minutes once daily for 5 days every 21 days.
Other Name: HycamtinDrug: Myeloid growth factor
Myeloid growth factor (G-CSF or pegylated G-CSF) will be initiated 24-48 hours after the completion of topotecan and cyclophosphamide for all subjects, which would be day 6 or 7. Myeloid growth factor should continue until the absolute neutrophil count is greater than 2,000/mm^3
Please refer to this study by its ClinicalTrials.gov identifier: NCT02390843
|Contact: Jaclyn Smith, MBAemail@example.com|
|United States, Georgia|
|Children's Healthcare of Atlanta/Emory University||Recruiting|
|Atlanta, Georgia, United States, 30322|
|Contact: Jaclyn Smith, MBA 404-785-0692 firstname.lastname@example.org|
|Principal Investigator: Kelly Goldsmith, MD|
|Sub-Investigator: William T Cash, MD|
|Principal Investigator:||Kelly Goldsmith, MD||Emory University/Children's Healthcare of Atlanta|