Simvastatin With Topotecan and Cyclophosphamide in Relapsed and/or Refractory Pediatric Solid and CNS Tumors

NCT02390843 | Completed Phase 1 DMC

• 1 other identifier: IRB00078790
• Study Type: interventional
• Target: 13
• Locations: 1 country
• Sites: 1

Brief Summary

This is a Phase I trial with new experimental drugs such as simvastatin in combination with topotecan and cyclophosphamide in the hopes of finding a drug that may work against tumors that have come back or that have not responded to standard therapy. This study will define toxicity of high dose simvastatin in combination with topotecan and cyclophosphamide and evaluate for cholesterol levels and IL6/STAT3 pathway changes as biomarkers of patient response.

Conditions

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

Outcome Measures

Primary Outcomes (2)

• Maximum Tolerated Dose (MTD) of Simvastatin

  MTD will be the maximum dose at which fewer than one-third of subjects experience dose-limiting toxicities (DLTs) during Cycle 1 of therapy.

  First treatment to toxicity (up to 24 months)

• Number of Dose-Limiting Toxicities (DLTs)

  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.

  Up to 24 months

Secondary Outcomes (6)

• Percentage of Participants With Overall Tumor Response (Response Rate)

  24 months

• Change in Total Cholesterol Level

  Baseline, 24 months

• Change in serum interleukin-6 (IL-6) level

  Baseline, 24 months

• Change in soluble interleukin 6 receptor (sIL-6R)

  Baseline, 24 months

• Change in signal transducer and activator of transcription 3 (STAT-3) expression

  Baseline, 24 months

Study Arms (1)

simvastatin + topotecan/cyclophosphamide

EXPERIMENTAL

During dose escalation (phase I), standard 3+3 design will be followed.

Drug: Simvastatin; Drug: Cyclophosphamide; Drug: Topotecan; Drug: Myeloid growth factor

Interventions

Simvastatin DRUG

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.

Also known as: zocor

simvastatin + topotecan/cyclophosphamide

Cyclophosphamide DRUG

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.

Also known as: Cytoxan, Neosar

simvastatin + topotecan/cyclophosphamide

Topotecan DRUG

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.

Also known as: Hycamtin

simvastatin + topotecan/cyclophosphamide

Myeloid growth factor DRUG

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

Also known as: Granulocyte colony-stimulating factor (G-CSF), pegylated granulocyte colony-stimulating factor

simvastatin + topotecan/cyclophosphamide

Eligibility Criteria

• Age: 1 Year - 29 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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 (the presence of at least one lesion that can be accurately measured in at least one dimension with the longest diameter at least 20 mm. With spiral CT scan, lesions must be at least 10 mm.) or evaluable disease (the presence of at least one lesion that cannot be accurately measured in at least one dimension. Such lesions may be evaluable by nuclear medicine techniques, immunocytochemistry techniques, tumor markers or other reliable measures.)
• 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
• 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.
• Monoclonal antibodies: At least 3 half-lives of the antibody after the last dose of a monoclonal antibody.
• 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 I131-meta-iodobenzylguanidine (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.
• Adequate Bone Marrow Function Defined as:
• For subjects with solid tumors without known bone marrow involvement: Peripheral absolute neutrophil count (ANC) ≥ 750/mm3, Platelet count ≥ 75,000/mm3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)

You may not qualify if:

• Pregnancy or breast-feeding
• Concomitant medication dependency including corticosteroids, investigational drugs, anti-cancer agents, anti-graft-versus-host disease (GVHD) agents post-transplant
• subjects who are unable to swallow a tablet or liquid must have a nasogastric (NG) or gastric (G) tube through which the medicine can be administered
• subjects receiving known cytochrome P450 3A4 (CYP3A4) Inhibitors or Inducers
• subjects with uncontrolled infection
• subjects who received prior solid organ transplantation
• subjects with current or previous treatment with 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase inhibitor (any statin)

Sponsors & Collaborators

• Emory University: lead
• Children's Healthcare of Atlanta: collaborator

Study Sites (1)

Children's Healthcare of Atlanta/Emory University

Atlanta, Georgia, 30322, United States

Location

Related Publications (1)

• Hattinger CM, Patrizio MP, Magagnoli F, Luppi S, Serra M. An update on emerging drugs in osteosarcoma: towards tailored therapies? Expert Opin Emerg Drugs. 2019 Sep;24(3):153-171. doi: 10.1080/14728214.2019.1654455. Epub 2019 Aug 14.

  PMID: 31401903 DERIVED

MeSH Terms

Conditions

Retinoblastoma; Sarcoma, Clear Cell; Carcinoma, Renal Cell; Rhabdoid Tumor; Wilms Tumor; Hepatoblastoma; Neuroblastoma; Neoplasms, Germ Cell and Embryonal; Sarcoma, Ewing; Sarcoma; Osteosarcoma; Rhabdomyosarcoma

Interventions

Simvastatin; Cyclophosphamide; Topotecan; Granulocyte Colony-Stimulating Factor; pegylated granulocyte colony-stimulating factor

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Retinal Neoplasms; Eye Neoplasms; Neoplasms by Site; Eye Diseases, Hereditary; Eye Diseases; Retinal Diseases; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Adenocarcinoma; Carcinoma; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases; Neoplasms, Complex and Mixed; Neoplastic Syndromes, Hereditary; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Neuroectodermal Tumors, Primitive, Peripheral; Neuroectodermal Tumors, Primitive; Neoplasms, Bone Tissue; Myosarcoma; Neoplasms, Muscle Tissue

Intervention Hierarchy (Ancestors)

Lovastatin; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Camptothecin; Alkaloids; Heterocyclic Compounds; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Study Officials

• Kelly Goldsmith, MD

  Emory University/Children's Healthcare of Atlanta

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: February 24, 2015
• First Posted: March 18, 2015
• Study Start: February 1, 2015
• Primary Completion: September 22, 2019
• Study Completion: September 22, 2019
• Last Updated: April 3, 2020

Record last verified: 2020-04

Locations

US (1)