Clinical trial NCT00638898: Busulfan, Melphalan, Topotecan Hydrochloride, and a Stem Cell Transplant in Treating Patients With Newly Diagnosed or Relapsed Solid Tumor
Official title: Pilot Study of High-Dose Chemotherapy With Busulfan, Melphalan, and Topotecan Followed by Autologous Hematopoietic Stem Cell Transplant in Advanced Stage and Recurrent Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Solid Tumor
Adult Central Nervous System Germ Cell Tumor
Adult Rhabdomyosarcoma
Childhood Central Nervous System Germ Cell Tumor
Childhood Soft Tissue Sarcoma
Ewing Sarcoma
Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor
Ovarian Mixed Germ Cell Tumor
Previously Untreated Childhood Rhabdomyosarcoma
Recurrent Adult Brain Tumor
Recurrent Adult Soft Tissue Sarcoma
Recurrent Childhood Brain Stem Glioma
Recurrent Childhood Cerebellar Astrocytoma
Recurrent Childhood Cerebral Astrocytoma
Recurrent Childhood Ependymoma
Recurrent Childhood Malignant Germ Cell Tumor
Recurrent Childhood Medulloblastoma
Recurrent Childhood Pineoblastoma
Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor
Recurrent Childhood Visual Pathway and Hypothalamic Glioma
Recurrent Childhood Visual Pathway Glioma
Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor
Recurrent Extragonadal Germ Cell Tumor
Recurrent Extragonadal Non-seminomatous Germ Cell Tumor
Recurrent Malignant Testicular Germ Cell Tumor
Recurrent Neuroblastoma
Recurrent Ovarian Germ Cell Tumor
Recurrent Wilms Tumor and Other Childhood Kidney Tumors
Unspecified Adult Solid Tumor, Protocol Specific
Unspecified Childhood Solid Tumor, Protocol Specific
Lead sponsor: City of Hope Medical Center
Sponsor class: OTHER
First posted: 2008-03-19
Enrollment: 25
Sex: ALL
Minimum age (years): 6
Maximum age (years): 40
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Treatment feasibility in terms of investigational agent-related adverse events of a novel treatment combination followed by peripheral blood stem cell rescue
timeFrame: Day 100 post stem cell rescue
Secondary outcomes:
measure: Overall survival
timeFrame: 1 year post stem cell rescue
measure: Disease-free survival
timeFrame: 1 year post stem cell rescue
measure: Incidence of myeloid and platelet engraftment
timeFrame: Day 100 post stem cell rescue
measure: Pharmacokinetics and pharmacodynamics of topotecan hydrochloride and busulfan
timeFrame: Baseline through day 4 of investigational agent treatment
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope
state: California
Study officials:
affiliation: City of Hope Medical Center
name: Anna Pawlowska, MD
role: PRINCIPAL_INVESTIGATOR
References: