Busulfan, Melphalan, Topotecan Hydrochloride, and a Stem Cell Transplant in Treating Patients With Newly Diagnosed or Relapsed Solid Tumor

Pilot Study of High-Dose Chemotherapy With Busulfan, Melphalan, and Topotecan Followed by Autologous Hematopoietic Stem Cell Transplant in Advanced Stage and Recurrent Tumors

RATIONALE: Giving high-dose chemotherapy before an autologous stem cell transplant stops the growth of tumor cells by stopping them from dividing or killing them. Giving colony-stimulating factors, such as G-CSF, helps stem cells move from the bone marrow to the blood so they can be collected and stored. Chemotherapy is then given to prepare the bone marrow for the stem cell transplant. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy.

PURPOSE: This clinical trial is studying how well giving busulfan, melphalan, and topotecan hydrochloride together with a stem cell transplant works in treating patients with newly diagnosed or relapsed solid tumor.

Study Overview

• Status: Active, not recruiting
• Conditions: Unspecified Childhood Solid Tumor, Protocol Specific; Solid Tumor; Ewing Sarcoma; Unspecified Adult Solid Tumor, Protocol Specific; Recurrent Childhood Medulloblastoma; Recurrent Childhood Ependymoma; Recurrent Neuroblastoma; Recurrent Adult Soft Tissue Sarcoma; Recurrent Adult Brain Tumor; Recurrent Ovarian Germ Cell Tumor; Recurrent Wilms Tumor and Other Childhood Kidney Tumors; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Childhood Malignant Germ Cell Tumor; Adult Rhabdomyosarcoma; Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Malignant Testicular Germ Cell Tumor; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Pineoblastoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma; Recurrent Childhood Visual Pathway Glioma; Childhood Central Nervous System Germ Cell Tumor; Childhood Soft Tissue Sarcoma; Previously Untreated Childhood Rhabdomyosarcoma; Ovarian Mixed Germ Cell Tumor; Adult Central Nervous System Germ Cell Tumor; Recurrent Extragonadal Germ Cell Tumor; Recurrent Extragonadal Non-seminomatous Germ Cell Tumor
• Intervention / Treatment: Other: laboratory biomarker analysis; Drug: topotecan hydrochloride; Other: pharmacological study; Drug: melphalan; Drug: busulfan; Biological: filgrastim; Procedure: autologous hematopoietic stem cell transplantation; Procedure: autologous bone marrow transplantation

Detailed Description

OBJECTIVES:

I. To assess the feasibility of a novel combination conditioning therapy with busulfan/melphalan and topotecan followed by autologous hematopoietic stem cell transplantation (HSCT) in patients with relapsed, refractory and/or poor risk pediatric solid tumors.

II. To determine within the confines of this pilot study, myeloid and platelet engraftment, overall survival and disease-free survival in patients with relapsed, refractory pediatric solid tumors and in patients who have solid tumors with poor risk factors at the time of diagnosis.

III. To determine the pharmacokinetics of topotecan.

OUTLINE:

AUTOLOGOUS HEMATOPOIETIC STEM CELL OR AUTOLOGOUS BONE MARROW COLLECTION: Patients undergo stem cell mobilization per institutional guidelines with G-CSF IV or subcutaneously, continuing until the completion of leukapheresis. Patients undergo apheresis after mobilization and continue until a minimum of 2.0 x 10^6 CD34 cells/kg or more are collected. Cells are processed and cryopreserved following institutional guidelines. Patients who collect > 2.0 x 10^6 CD34+ cells/kg may proceed to high-dose chemotherapy.

HIGH-DOSE CHEMOTHERAPY: Patients receive topotecan hydrochloride IV continuously over 24 hours on days -8 to -4, busulfan IV every 6 hours on days -8 to -4, and melphalan IV over 30 minutes on days -3 and -2.

AUTOLOGOUS HEMATOPOIETIC STEM CELL OR AUTOLOGOUS BONE MARROW REINFUSION: Patients undergo autologous hematopoietic stem cell transplantation or autologous bone marrow transplantation on day 0. Patients also receive G-CSF IV daily beginning on day +5 and continuing until blood counts recover.

After completion of study treatment, patients are followed every 3 months for 1 year and then annually thereafter.

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 40 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion

• Patients with relapsed neuroblastoma, rhabdomyosarcoma, Ewing's sarcoma, PNET, brain tumors, soft tissue sarcomas, Wilm's tumors, germ cell tumors or other solid tumors who achieved at least partial response (PR) to chemotherapy, surgery, or radiotherapy
• Newly diagnosed patients for poor-risk pediatric solid tumors: metastatic Ewing's, metastatic PNET, rhabdomyosarcoma, soft tissue sarcomas, octeomesenchymoma, and others that are at a high risk of relapse and who have achieved at least partial response (PR) to chemotherapy, surgery, or radiotherapy
• For any of the above categories, an attempt to achieve a complete response (CR) or PR should be made; pre-transplant modalities may include surgery, chemotherapy, or radiation therapy; radiation must not include lung fields; only patients in CR or PR at the primary site will be eligible
• HIGH-DOSE CHEMOTHERAPY: Histologically confirmed diagnosis by Anatomic Pathology Department; if recurrent or metastatic disease, histologic confirmation should be obtained, with the exception of brain stem tumors; in neuroblastoma, demonstration of marrow metastases with elevated urinary catecholamines is adequate for diagnosis
• HIGH-DOSE CHEMOTHERAPY: No contraindications to the stem cell collection by apheresis or by bone marrow harvesting
• HIGH-DOSE CHEMOTHERAPY: All patients, or their legal guardians must have signed a voluntary informed consent in accordance with the institutional and federal guidelines
• HIGH-DOSE CHEMOTHERAPY: Adequate renal function as demonstrated by creatinine clearance (12 or 24 hour urine collection) or glomerular filtration rate (GFR) > 60 ml/min/1.73m^2
• HIGH-DOSE CHEMOTHERAPY: Adequate cardiac function as demonstrated by ejection fraction > 55% by echocardiogram or MUGA
• HIGH-DOSE CHEMOTHERAPY: Adequate hepatic function as demonstrated by bilirubin < 2 mg/dL, SGOT and SGPT < 5 x upper limits of normal
• HIGH-DOSE CHEMOTHERAPY: Adequate bone marrow function as evidenced by platelet count > 50,000/ul and absolute granulocyte count >= 750 ul
• HIGH-DOSE CHEMOTHERAPY: Adequate pulmonary function adults (older than 16 years): FEV1 > 2 liters, room air PaO2 > 70 mm Hg, room air PaCO2 < 42 mm Hg, and DLCO > 50% predicted; children (younger than 16 years): DLCO > 50% predicted
• HIGH-DOSE CHEMOTHERAPY: Pretreatment tests and clinical and laboratory tests must have been performed within 4 weeks prior to initiation of high-dose chemotherapy
• HIGH-DOSE CHEMOTHERAPY: No other medical and/or psychosocial problems which in the opinion of the primary physician or principal investigator would place the patient at unacceptable risk from this regimen
• HIGH-DOSE CHEMOTHERAPY: Greater than 2-week period of recovery from prior modality used to control primary or recurrent site

Exclusion

• Histologically confirmed bone marrow metastases within 30 days prior to transplant; prior bone marrow metastases with clearing of bone marrow (< 5% contamination as measured by bilateral bone marrow biopsies) at the time for evaluation for this protocol is acceptable
• Karnofsky performance status < 60% or Lansky performance status < 50% for patients younger than 16 years old
• Females of reproductive age who are not using adequate birth control measures or who are pregnant
• HIV disease
• Patients with prior treatment with myeloablative therapy are excluded

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Arm I; See Detailed Description

Other: laboratory biomarker analysis; Correlative studies; Drug: topotecan hydrochloride; Given IV; Other Names: Hycamtin; SKF S-104864-A; hycamptamine; TOPO; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies; Drug: melphalan; Given IV; Other Names: Alkeran; CB-3025; L-PAM; L-phenylalanine mustard; L-Sarcolysin; Melfalan; Drug: busulfan; Given IV; Other Names: BSF; BU; Misulfan; Mitosan; Myeloleukon; Myelosan; Biological: filgrastim; Given IV or subcutaneously; Other Names: G-CSF; r-metHuG-CSF; Neupogen; Recombinant Methionyl Human Granulocyte Colony Stimulating Factor; granulocyte colony-stimulating factor; Procedure: autologous hematopoietic stem cell transplantation; Undergo transplantation; Procedure: autologous bone marrow transplantation; Undergo transplantation; Other Names: ABMT; bone marrow transplantation, autologous; transplantation, autologous bone marrow

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Treatment feasibility in terms of investigational agent-related adverse events of a novel treatment combination followed by peripheral blood stem cell rescue	Day 100 post stem cell rescue

Secondary Outcome Measures

Outcome Measure	Time Frame
Overall survival	1 year post stem cell rescue
Disease-free survival	1 year post stem cell rescue
Incidence of myeloid and platelet engraftment	Day 100 post stem cell rescue
Pharmacokinetics and pharmacodynamics of topotecan hydrochloride and busulfan	Baseline through day 4 of investigational agent treatment

Collaborators and Investigators

• Sponsor: City of Hope Medical Center
• Investigators: Principal Investigator: Anna Pawlowska, MD, City of Hope Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): February 26, 2007
• Primary Completion (Actual): January 19, 2013
• Study Completion (Estimated): December 30, 2024

Study Registration Dates

• First Submitted: March 18, 2008
• First Submitted That Met QC Criteria: March 18, 2008
• First Posted (Estimated): March 19, 2008

Study Record Updates

• Last Update Posted (Actual): March 19, 2024
• Last Update Submitted That Met QC Criteria: March 18, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Neoplasms, Glandular and Epithelial; Endocrine System Diseases; Disease Attributes; Gonadal Disorders; Endocrine Gland Neoplasms; Genital Neoplasms, Male; Testicular Diseases; Genetic Diseases, Inborn; Neoplasms, Neuroepithelial; Neoplasms, Nerve Tissue; Kidney Neoplasms; Brain Neoplasms; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplastic Syndromes, Hereditary; Neoplasms, Complex and Mixed; Osteosarcoma; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Neoplasms, Muscle Tissue; Myosarcoma; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Genital Diseases, Male; Genital Diseases; Neoplasms; Sarcoma; Neoplasms, Germ Cell and Embryonal; Testicular Neoplasms; Recurrence; Glioma; Sarcoma, Ewing; Ependymoma; Medulloblastoma; Astrocytoma; Neuroblastoma; Rhabdomyosarcoma; Neuroectodermal Tumors; Neuroectodermal Tumors, Primitive; Wilms Tumor; Neuroectodermal Tumors, Primitive, Peripheral; Pinealoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Topoisomerase Inhibitors; Adjuvants, Immunologic; Topoisomerase I Inhibitors; Lenograstim; Melphalan; Topotecan; Busulfan
• Other Study ID Numbers: 03112; NCI-2009-01600 (Registry Identifier: CDR0000589296)