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Simvastatin, Topotecan Hydrochloride, and Cyclophosphamide in Treating Younger Patients with Relapsed and / or Refractory Solid and CNS Tumors

Trial Status: Active

This phase I trial studies the side effects and best dose of simvastatin when given together with topotecan hydrochloride and cyclophosphamide in treating younger patients with solid and central nervous system (CNS) tumors that have returned (relapsed) and / or that do not respond to treatment (refractory). Simvastatin may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as topotecan hydrochloride and cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving simvastatin together with topotecan hydrochloride and cyclophosphamide may be a better treatment for solid and CNS tumors.

Inclusion Criteria

  • Subjects must have had histologic verification of malignancy at original diagnosis or relapse; all subjects with relapsed or refractory solid tumors are eligible including primary or metastatic CNS tumors; in the case of diffuse intrinsic pontine glioma (DIPG), or optic pathway glioma, imaging findings consistent with these tumors will suffice without the need for biopsy for histologic verification
  • Subjects must have either measurable or evaluable disease
  • Subject’s current disease state must be one for which there is no known curative therapy
  • Karnofsky >= 60% for subjects > 16 years of age and Lansky >= 50 for subjects =< 16 years of age; note: subjects who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
  • Prior therapy: * Subjects must have fully recovered from the acute toxic effects of all prior anti-cancer chemotherapy ** Myelosuppressive chemotherapy: at least 21 days after the last dose of myelosuppressive chemotherapy (42 days if prior nitrosourea) ** Hematopoietic growth factors: at least 14 days after the last dose of a long-acting growth factor (e.g. pegfilgrastim) or 7 days for short acting growth factor; for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur; the duration of this interval must be discussed with the study chair ** Biologic (anti-neoplastic agent): at least 7 days after the last dose of a biologic agent; for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur; the duration of this interval must be discussed with the study chair ** Immunotherapy: at least 42 days after the completion of any type of immunotherapy, e.g. tumor vaccines ** Antibodies: > 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade < 1 ** External beam radiation therapy (XRT): at least 14 days after local palliative XRT (small port); 6 weeks must have elapsed since treatment with therapeutic doses of iodine 131-metaiodobenzylguanidine (I131-MIBG); at least 150 days must have elapsed if prior total body irradiation (TBI), craniospinal XRT, or if >= 50% radiation of pelvis; at least 42 days must have elapsed if other substantial bone marrow (BM) radiation ** Stem cell infusion without TBI: no evidence of active graft vs. host disease and at least 84 days must have elapsed after transplant and 42 days for autologous stem cell infusion after I131-MIBG therapy ** Subjects must not have received any prior therapy with simvastatin
  • For subjects with solid tumors without known bone marrow involvement: peripheral absolute neutrophil count (ANC) >= 750/mm^3
  • For subjects with solid tumors without known bone marrow involvement: platelet count >= 75,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
  • Subjects with known bone marrow metastatic disease will be eligible for study provided they meet the specified blood counts (may receive transfusions provided they are not known to be refractory to red cell or platelet transfusions); these subjects will not be evaluable for hematologic toxicity; if dose-limiting hematologic toxicity is observed, all subsequent subjects enrolled must be evaluable for hematologic toxicity
  • Creatinine clearance or radioisotope glomerular filtration rate (GFR) 70 ml/min/1.73 m^2 or a serum creatinine based on age/gender as follows: * Age 1 to < 2 years: 0.6 mg/dL for males, 0.6 mg/dL for females * Age 2 to < 6 years: 0.8 mg/dL for males, 0.8 mg/dL for females * Age 6 to < 10 years: 1.0 mg/dL for males, 1.0 mg/dL for females * Age 10 to < 13 years: 1.2 mg/dL for males, 1.2 mg/dL for females * Age 13 to < 16 years: 1.5 mg/dL for males, 1.4 mg/dL for females * Age >= 16 years: 1.7 mg/dL for males, 1.4 mg/dL for females
  • Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age
  • Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L; for the purpose of this study, the ULN for SGPT is 45 U/L
  • Corrected QT interval (QTc) =< 480 msec
  • Normal creatinine phosphokinase (CPK) defined as not exceeding maximum value listed below : * Age: 0 to < 4 years; 305 units/L for males and 305 units/L for females * Age: 4 to < 7 years; 230 units/L for males and 230 units/L for females * Age: 7 to < 10 years; 365 units/L for males and 365 units/L for females * Age: 10 to < 12 years; 215 units/L for males and 230 units/L for females * Age: 12 to < 14 years; 330 units/L for males and 295 units/L for females * Age: 14 to < 16 years; 335 units/L for males and 240 units/L for females * Age: 16 to < 19 years; 370 units/L for males and 230 units/L for females * Age: >= 19 years; 170 units/L for males and 145 units/L for females
  • All subjects and/or their parents or legally authorized representatives must sign a written informed consent; assent, when appropriate, will be obtained according to institutional guidelines

Exclusion Criteria

  • Pregnant or breast-feeding women will not be entered on this study; pregnancy tests must be obtained in girls who are post-menarchal; males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method during treatment and for 3 months after stopping treatment
  • Concomitant medications * Corticosteroids: subjects receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible * Investigational drugs: subjects who are currently receiving another investigational drug are not eligible * Anti-cancer agents: subjects who are currently receiving other anti-cancer agents are not eligible * Anti-graft-versus-host disease (GVHD) agents post-transplant: subjects who are receiving cyclosporine, tacrolimus, or other agents to prevent graft-versus-host disease post bone marrow transplant are not eligible for this trial * Study specific: subjects who are unable to swallow a tablet or swallow liquid are still eligible provided they have a nasogastric (NG) or gastric (G) tube through which the medicine can be administered * Cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inhibitors: subjects chronically receiving drugs that are known potent CYP3A4 inhibitors within 7 days prior to study enrollment, including but not limited to ketoconazole, itraconazole, miconazole, clarithromycin, erythromycin, ritonavir, indinavir, nelfinavir, saquinavir, amprenavir, delavirdine, nefazodone, diltiazem, verapamil, and grapefruit juice are not eligible; the topical use of these medications (if applicable), e.g. 2% ketoconazole cream, is allowed * CYP3A4 inducers: subjects chronically receiving drugs that are known potent CYP3A4 inducers within 12 days prior to study enrollment, including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, tipranavir, ritonavir, and St. John’s wort are not eligible
  • Subjects who have an uncontrolled infection are not eligible
  • Subjects who have received prior solid organ transplantation are not eligible
  • Subjects who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible
  • Current or previous treatment with an 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG CoA) reductase inhibitor (any statin)

Georgia

Atlanta
Children's Healthcare of Atlanta - Egleston
Status: ACTIVE
Contact: Kelly C. Goldsmith
Phone: 404-727-2655

PRIMARY OBJECTIVES:

I. To estimate the recommended phase 2 dose (RP2D) or maximum tolerated dose

(MTD) of simvastatin administered orally twice daily in combination with topotecan (topotecan hydrochloride) and cyclophosphamide in children with refractory/relapsed solid and CNS tumors.

II. To define and describe the toxicities of simvastatin in combination with topotecan and cyclophosphamide administered on this schedule.

SECONDARY OBJECTIVES:

I. To preliminarily define the antitumor activity of simvastatin in combination with topotecan and cyclophosphamide within the confines of a Phase 1 study.

II. To examine the relationship between serum cholesterol levels and response to simvastatin in combination with topotecan and cyclophosphamide.

III. To examine the relationship between serum and bone marrow levels of interleukin (IL)-6, soluble interleukin 6 receptor (sIL-6R), signal transducer and activator of transcription 3 (acute-phase response factor) (STAT-3), and phosphorylated (phospho)-STAT3 and clinical response to simvastatin in combination with topotecan and cyclophosphamide.

OUTLINE: This is a dose-escalation study of simvastatin.

Patients receive simvastatin orally (PO) twice daily (BID) on days 1-21, cyclophosphamide intravenously (IV) over 30 minutes, and topotecan hydrochloride IV over 30 minutes on days 1-5. Treatment repeats every 21 days for 35 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
Children's Healthcare of Atlanta - Egleston

Principal Investigator
Kelly C. Goldsmith

  • Primary ID AFLACST1402
  • Secondary IDs NCI-2015-00420, IRB00078790
  • Clinicaltrials.gov ID NCT02390843