Neoplasms

Heart and Blood Diseases

Blood and Lymph Conditions

Immune System Diseases

All Conditions

Rare Diseases

Multiple Myeloma

Neoplasms, Plasma Cell

Plasmacytoma

Neoplasms by Histologic Type

Hemostatic Disorders

Blood Coagulation Disorders

Vascular Diseases

Paraproteinemias

Blood Protein Disorders

Hematologic Diseases

Hemorrhagic Disorders

Lymphoproliferative Disorders

Immunoproliferative Disorders

Anti-Infective Agents

Antineoplastic Agents

All Drugs and Chemicals

Antirheumatic Agents

Bone Density Conservation Agents

Thalidomide

Cyclophosphamide

Melphalan

Lenograstim

Busulfan

Interferons

Interferon-alpha

Interferon alpha-2

Pamidronate

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Antiviral Agents

Adjuvants, Immunologic

Anti-Bacterial Agents

Angiogenesis Inhibitors

Growth Inhibitors

Patients receive high-dose (HD) melphalan intra-venously (IV) on day -1. Peripheral blood progenitor cells (PBPCs) are reinfused on day 0. Filgrastim (G-CSF) is administered IV or SC daily beginning on day 1 and continuing until blood counts recover. Between 8 and 14 weeks later, patients receive IV high-dose busulfan every 6 hours on days -7 to -4 and cyclophosphamide IV over 2 hours on days -3 and -2. PBPCs are reinfused on day 0 and G-CSF is administered IV or subcutaneously (SC) daily until blood counts recover.

filgrastim

recombinant interferon alfa

busulfan

cyclophosphamide

melphalan

pamidronate disodium

thalidomide

peripheral blood stem cell transplantation

George Somlo, MD

RATIONALE: Drugs used in chemotherapy work in different ways to stop cancer cells from dividing so they stop growing or die. Peripheral stem cell transplantation may allow doctors to give higher doses of chemotherapy drugs and kill more cancer cells. Biological therapies, such as interferon alfa, use different ways to stimulate the immune system and stop cancer cells from growing. Thalidomide may stop the growth of cancer cells by stopping blood flow to the tumor. Pamidronate may help to reduce the side effects of treatment for multiple myeloma.

PURPOSE: This phase II trial is studying combination chemotherapy, peripheral stem cell transplantation, biological therapy, pamidronate, and thalidomide to see how well they work in treating patients with stage I, stage II, or stage III multiple myeloma.

OBJECTIVES:

* Determine the feasibility and toxic effects of high-dose melphalan, busulfan, and cyclophosphamide followed by autologous peripheral blood stem cell rescue, interferon alfa, and pamidronate in patients with responsive or stable, low-bulk multiple myeloma.
* Determine the response rate and progression-free and overall survival of patients treated with this regimen.
* Determine the feasibility of adding thalidomide to interferon alfa and pamidronate in patients who are not in complete remission (CR) 6 months after the second course of high-dose chemotherapy.
* Determine whether administration of thalidomide can increase the CR rate in patients who are not in CR 6 months after the second course of high-dose chemotherapy and determine its effect on progression-free and overall survival of these patients.
* Determine the pharmacokinetics of busulfan and cyclophosphamide and correlate the pharmacokinetics with the toxic effects of these drugs and outcome in these patients.
* Determine the effect of thalidomide on microvascular density of bone marrow and correlate these possible effects with outcome in these patients.
* Determine the cytogenetics, gene rearrangement, and fluorescence in situ hybridization in baseline and post treatment bone marrow and blood specimens and correlate the presence/persistence of these features with treatment outcome in these patients.

OUTLINE: Patients receive cyclophosphamide IV over 2 hours on day 1 and filgrastim (G-CSF) subcutaneously (SC) or IV twice a day beginning on day 2 and continuing until peripheral blood stem cells (PBSCs) are collected. PBSCs are collected beginning on day 10.

Patients receive high-dose melphalan IV on day -1. PBSCs are reinfused on day 0. G-CSF is administered IV or SC daily beginning on day 1 and continuing until blood counts recover. Between 8 and 14 weeks later, patients receive high-dose busulfan IV every 6 hours on days -7 to -4 and cyclophosphamide IV over 2 hours on days -3 and -2. PBSCs are reinfused on day 0 and G-CSF is administered IV or SC daily until blood counts recover.

Patients with responding or stable disease after chemotherapy receive maintenance therapy with interferon alfa beginning 14-20 weeks after day 0 of the second course of chemotherapy. Interferon alfa is administered SC 3 times a week for 3 years. Patients also receive pamidronate IV every 4 weeks until disease progression. Patients who are not in complete remission (CR) 6 months after completing the second course of chemotherapy receive oral thalidomide daily for a maximum of 1 year or for 3 months after achieving CR.

Patients are followed monthly for 1 year, every 3 months for 1 year, and then periodically thereafter.

PROJECTED ACCRUAL: A total of 70 patients will be accrued for this study within approximately 2.5 years.

Combination Chemo, Peripheral Stem Cell Transplant, Biological Therapy, Pamidronate and Thalidomide for Multiple Myeloma

Sequential High-Dose Melphalan and Busulfan/Cyclophosphamide Followed by Peripheral Blood Progenitor Cell Rescue, Interferon/Thalidomide and Pamidronate for Patients With Multiple Myeloma

Response gradations are specified in the "Blade criteria", Br J Haematol 1998; 102: 1115-1123. Serum myeloma protein is measured 2x at least six weeks apart, and urine M-component is measured 2x at least 3 weeks apart. Complete response (CR): less than 3% plasma cells in bone marrow or blood. Very good partial response (VGPR): Greater than 90% decrease in myeloma protein, and urine M-component less than 0.1 gm/day. Partial response (PR) Greater than 50% decrease in myeloma protein; urine M-component less than 0.2 gm/day. Lytic skeletal lesions must not increase, and serum calcium level must remain normal. Stable disease (SD): 25-49% decrease in protein and 25% decrease in urine M-component. Progressive disease (PD): Greater than 25% increase in myeloma protein, or hypercalcemia. Relapse: 1) increase greater than 100% of myeloma protein; 2) More than 25% increase of myeloma protein; 3) reappearance of the myeloma peaks; 4) increase in lytic bone lesions on radiographs.

Kaplan-Meier estimate at three years post-first transplant of survival. Outcome is death or alive at follow-up (censored). 95 percent confidence interval of the point estimate is calculated using Greenwood's variance.

Kaplan-Meier estimate at three years post-first transplant of survival. Event of interest is the first of Death or Progression. Censoring is Alive in Continuous Complete Remission at date of last follow-up.

95 percent confidence interval of the point estimate is calculated using Greenwood's variance.

National Cancer Institute (NCI)

City of Hope Medical Center

When evaluating a toxicity, a modified National Cancer Institute (NCI) autologous bone marrow toxicity scale will be used.

Patients receive high-dose melphalan IV on day -1. PBSCs are reinfused on day 0. G-CSF is administered IV or SC daily beginning on day 1 and continuing until blood counts recover. Between 8 and 14 weeks later, patients receive high-dose busulfan IV every 6 hours on days -7 to -4 and cyclophosphamide IV over 2 hours on days -3 and -2. PBSCs are reinfused on day 0 and G-CSF is administered IV or SC daily until blood counts recover.

filgrastim

recombinant interferon alfa

busulfan

cyclophosphamide

melphalan

pamidronate disodium

thalidomide

peripheral blood stem cell transplantation

HD Chemo Followed by PBPC Rescue

HD Melphalan/Cyclophosphamide followed by PBPC Rescue, alpha-interferon, \& pamidronate

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Definitions are in section 4.0 "Staging Criteria" of the protocol: "Sequential High-Dose Melphalan and Busulfan/Cyclophosphamide Followed by Peripheral Blood Progenitor Cell Rescue, Interferon, Pamidronate, With or Without Thalidomide, for Patients with Multiple Myeloma"

Stage I is Low Tumor Mass -- Indolent Myeloma Stage II is Intermediate Tumor Mass -- Smoldering Myeloma Stage III is High Tumor Mass

Stage of Multiple Myeloma

M protein type

Prior Anthracycline Chemotherapy

Brenda Williams, Senior Director, Clinical Trials Office

Best Response Prior to Tandem Autologous Stem Cell Transplant

Response After Tandem Autologous Stem Cell Transplant

Three-year Overall Survival

Progression-free Survival

Best Response at 6 Months Post Tandem Autologous Stem Cell Transplant

Best Response After Tandem Autologous Stem Cell Transplant and Maintenance

Priming and Apheresis: Cyclophosphamide (CTX) 1.5 g/m2 and Filgrastim, 5 microgram/kg, t2x/day, until enough PBPC have been collected. This is day -10 to the first transplant.

Cycle (transplant) 1: day -1: Melphalan 150 mg/m2 IV; day 0: reinfusion of half of the collected stem cells; day +1: Filgrastim 5 micrograms/kg/day IV until ANC\>1000 per microliter.

Day 0 of cycle 2 (C2) is at least 12 weeks and not past 18 weeks from day 1 of cycle 1. Day -8 C2: Start Dilantin 1000 mg IV. Days -7 through -4 of C2: Busulfan 0.8 mg/kg every 6 hours, 4 x per day. Dilantin 300 micrograms/day. Day -3 C2: CTX 60 mg/kg; start IV Mesna. Day -2 C2: CTX 60 mg/kg; continue Mesna IV. Day 0 C2: Reinfuse PBPC. Start Filgrastim 5 microgram/kg daily.

12-18 weeks from day 0 of C2: alpha interferon 3 x 10 E 6 units/m2 3x per week (TIW) for 3 years.

At 6 months following day 0 of C2, Thalidomide 400 mg/m2 will be administered orally to patients not in Complete Remission.

High-dose Chemotherapy Followed by PBPC Rescue

Overall Study

Skin and Connective Tissue Diseases

Symptoms and General Pathology

Breast Neoplasms

Recurrence

Breast Diseases

Skin Diseases

Carboplatin

Etoposide

Doxorubicin

Liposomal doxorubicin

Docetaxel

Cisplatin

Etoposide phosphate

Thiotepa

Anastrozole

Tubulin Modulators

Antimitotic Agents

Antibiotics, Antitubercular

Enzyme Inhibitors

Antineoplastic Agents, Hormonal

Aromatase Inhibitors

Estrogens

Estrogen Antagonists

Estrogen Receptor Antagonists

Hormones

Hormone Antagonists

anastrozole

carboplatin

cisplatin

docetaxel

doxorubicin hydrochloride

etoposide

thiotepa

Andrew L. Pecora, MD, FACP

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining chemotherapy with peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells.

PURPOSE: Phase II trial to study the effectiveness of combination chemotherapy plus peripheral stem cell transplantation in treating women who have metastatic breast cancer.

OBJECTIVES: I. Assess the toxicity and response rates to induction therapy with docetaxel and doxorubicin in women with chemotherapy naive metastatic breast cancer. II. Assess the toxicity and response rates to sequential high dose chemotherapy following induction chemotherapy in women with metastatic breast cancer. III. Determine the hematopoietic recovery rate following CD34+ selected peripheral blood stem cell support in this patient population. IV. Assess the toxicity of noncytotoxic maintenance therapy following high dose chemotherapy in this patient population.

OUTLINE: This is a multicenter study. Patients with no prior chemotherapy for metastatic disease receive induction chemotherapy consisting of doxorubicin IV immediately followed by docetaxel IV over 1 hour on day 1. Patients receive filgrastim (G-CSF) subcutaneously (SQ) beginning on day 2 and continuing until day 11-15. Induction therapy repeats every 3 weeks for 4 courses. Within 4 weeks of the last course of induction chemotherapy, patients receive mobilization chemotherapy consisting of cyclophosphamide IV for 2 days, and etoposide IV and cisplatin IV for 3 days. At 24 hours following completion of chemotherapy, patients receive G-CSF SQ twice daily until the target number of peripheral blood stem cells (PBSC) are reached. Within 5 weeks following completion of mobilization chemotherapy, patients receive cyclophosphamide IV, thiotepa IV, and carboplatin IV continuously on days -7 through -4. Patients receive CD34+ selected PBSC on day 0 followed 4 hours later by G-CSF SQ daily and continuing until blood counts recover. Within 30 days of blood count recovery or immediately following completion of post transplantation radiotherapy, patients receive maintenance therapy consisting of oral anastrozole daily until disease progression. Patients with bone involvement also receive pamidronate IV over 2 hours monthly for 1 year. Patients are followed monthly for 6 months, every 3 months for 1 year, every 4-6 months for 5 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 50 patients will be accrued for this study over 12 months.

Combination Chemotherapy and Peripheral Stem Cell Transplantation in Treating Women With Metastatic Breast Cancer

A Phase II Multi-Institution Study of Docetaxel and Doxorubicin as Induction Therapy Followed by Sequential High Dose Chemotherapy and CD 34+ Selected Stem Cell Support for Women With Metastatic Breast Cancer

Hackensack Meridian Health

Arsenic Trioxide

Patients receive pamidronate IV and over 2 hours on days 1 and 15 and arsenic trioxide IV over 2 hours on days 1-5 and 15-19. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

arsenic trioxide

laboratory biomarker analysis

pharmacological study

Przemyslaw Twardowski

Drugs used in chemotherapy, such as arsenic trioxide and pamidronate, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Arsenic trioxide and pamidronate may also stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Pamidronate may also stop the growth of cancer cells by blocking blood flow to the cancer. Giving arsenic trioxide together with pamidronate may kill more cancer cells. This phase I trial is studying the side effects and best dose of arsenic trioxide and pamidronate in treating patients with advanced solid tumors or multiple myeloma

PRIMARY OBJECTIVES:

I. To describe the toxicities of the combination of arsenic trioxide in combination with pamidronate disodium at four dose levels.

II. To assess the pharmacokinetics of pamidronate disodium when given in combination with arsenic trioxide.

III. Utilizing 2-color immunofluorescence (IF) to determine if the treatment with combination of arsenic trioxide and pamidronate disodium affects the phosphorylation of epidermal growth factor receptor (EGFR) IV. In patients with multiple myeloma utilizing western blot to evaluate the pre- and post-treatment levels of protein tyrosine phosphatase 1B in lysates of multiple myeloma cells.

V. To obtain preliminary data for response to this regimen in this patient population.

OUTLINE: This is a dose-escalation, multicenter study.

Patients receive pamidronate IV and over 2 hours on days 1 and 15 and arsenic trioxide IV over 2 hours on days 1-5 and 15-19. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of pamidronate and arsenic trioxide until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose limiting toxicity.

After completion of study treatment, patients are followed periodically.

PROJECTED ACCRUAL: Approximately 12-24 patients will be accrued for this study.

Arsenic Trioxide and Pamidronate in Treating Patients With Advanced Solid Tumors or Multiple Myeloma

Phase I Trial of Arsenic Trioxide in Combination With Pamidronate Disodium

The toxicities observed at each dose level will be summarized in terms of type, severity, time of onset, duration, and reversibility or outcome. Tables will be created to summarize these toxicities and side effects by dose and by course. Tabular and graphical summaries will be used to explore the relationship of type and grade of toxicity to dose, course, and pharmacokinetics.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Combination Chemo, Peripheral Stem Cell Transplant, Biological Therapy, Pamidronate and Thalidomide for Multiple Myeloma	NCT00004088	Multiple Myelom...	filgrastim recombinant int... busulfan cyclophosphamid... melphalan pamidronate dis... thalidomide peripheral bloo...	- 65 Years	City of Hope Medical Center
Combination Chemotherapy and Peripheral Stem Cell Transplantation in Treating Women With Metastatic Breast Cancer	NCT00004906	Breast Cancer	filgrastim anastrozole carboplatin cisplatin cyclophosphamid... docetaxel doxorubicin hyd... etoposide pamidronate dis... thiotepa peripheral bloo...	18 Years - 65 Years	National Cancer Institute (NCI)
Combination Chemotherapy and Peripheral Stem Cell Transplantation in Treating Women With Metastatic Breast Cancer	NCT00004906	Breast Cancer	filgrastim anastrozole carboplatin cisplatin cyclophosphamid... docetaxel doxorubicin hyd... etoposide pamidronate dis... thiotepa peripheral bloo...	18 Years - 65 Years	National Cancer Institute (NCI)
Arsenic Trioxide and Pamidronate in Treating Patients With Advanced Solid Tumors or Multiple Myeloma	NCT00124605	Refractory Mult... Unspecified Adu...	pamidronate dis... arsenic trioxid... laboratory biom... pharmacological...	18 Years -	National Cancer Institute (NCI)

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