Simvastatin With Topotecan and Cyclophosphamide in Relapsed and/or Refractory Pediatric Solid and CNS Tumors (AflacST1402)
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|ClinicalTrials.gov Identifier: NCT02390843|
Recruitment Status : Recruiting
First Posted : March 18, 2015
Last Update Posted : August 7, 2017
|Condition or disease||Intervention/treatment||Phase|
|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 Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||36 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase 1 Study Using Simvastatin in Combination With Topotecan and Cyclophosphamide in Relapsed and/or Refractory Pediatric Solid and CNS Tumors|
|Study Start Date :||February 2015|
|Estimated Primary Completion Date :||February 2019|
|Estimated Study Completion Date :||February 2021|
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
- 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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02390843
|Contact: Amy Autry-Bushfirstname.lastname@example.org|
|United States, Georgia|
|Children's Healthcare of Atlanta/Emory University||Recruiting|
|Atlanta, Georgia, United States, 30322|
|Contact: Amy Autry-Bush 404-785-6011 email@example.com|
|Principal Investigator: Kelly Goldsmith, MD|
|Sub-Investigator: William T Cash, MD|
|Principal Investigator:||Kelly Goldsmith, MD||Emory University/Children's Healthcare of Atlanta|