Carmustine, Etoposide, Cyclophosphamide, and Stem Cell Transplant in Treating Patients With HIV-Associated Lymphoma

Sponsor

City of Hope Medical Center (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT00641381

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Location

Arm

271.7

Anticipated Duration (Months)

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

RATIONALE: Giving high-dose chemotherapy drugs, such as carmustine, etoposide, and cyclophosphamide, before a peripheral blood stem cell transplant stops the growth of cancer cells by stopping them from dividing or killing them. After treatment, stem cells that were collected from the patient's blood are returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy.

PURPOSE: This clinical trial is studying the side effects of giving high-dose carmustine, etoposide, and cyclophosphamide together with a stem cell transplant and to see how well it works in treating patients with HIV-associated lymphoma.

Condition or Disease	Intervention/Treatment	Phase
Lymphoma	Drug: carmustine Drug: cyclophosphamide Drug: etoposide Other: pharmacological study Procedure: autologous hematopoietic stem cell transplantation Procedure: peripheral blood stem cell transplantation	Phase 1

Detailed Description

OBJECTIVES:

Primary

To evaluate the feasibility and toxicity of high-dose chemotherapy comprising carmustine, etoposide, and cyclophosphamide followed by autologous stem cell infusion in patients with HIV-associated lymphoma receiving combination anti-HIV therapy and to determine the efficiency of stem cell collection from these patients.
To estimate the disease-free and overall survival of patients treated with this regimen.
To evaluate HIV viral load, CD+4/CD+8 counts, and immune recovery after high-dose anti- lymphoma chemotherapy.
To determine the pharmacokinetics of high-dose etoposide in patients receiving highly active anti-retroviral therapy (HAART).

OUTLINE: Patients undergo leukapheresis to obtain peripheral blood stem cells (PBSCs) for transplantation. At least 5 days later, patients with an adequate number of collected cells proceed to high-dose chemotherapy.

High-dose chemotherapy: Patients receive carmustine IV over 4 hours on days -7 to -5, etoposide IV over 4 hours on day -4, and cyclophosphamide IV on day -2.
Autologous PBSC transplantation: Patients receive PBSC infusion on day 0. Patients undergo blood sample collection periodically for pharmacokinetic studies of etoposide.

After completion of study treatment, patients are followed at approximately 30 days and 100 days, every 3 months for 1 year, every 6 months for 1 year, and then annually thereafter.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

25 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

High Dose Chemotherapy and Combination Anti-HIV Therapy for HIV-Associated Hodgkin's and Non-Hodgkin's Lymphoma

Actual Study Start Date :

May 10, 2000

Anticipated Primary Completion Date :

Dec 30, 2022

Anticipated Study Completion Date :

Dec 30, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (high-dose chemotherapy, anti-HIV therapy) Patients undergo leukapheresis to obtain PBSCs for transplantation. At least 5 days later, patients with an adequate number of collected cells proceed to high-dose chemotherapy. Patients receive carmustine IV over 4 hours on days -7 to -5, etoposide IV over 4 hours on day -4, and cyclophosphamide IV on day -2. Patients receive an autologous PBSC infusion on day 0.	Drug: carmustine 150 mg/m2 day -7, -6,and -5 prior to stem cell reinfusion Drug: cyclophosphamide 100 mg/kg on day -2 prior to stem cell reinfusion Drug: etoposide 60 mg/kg on day -4 prior to stem cell reinfusion Other: pharmacological study Prior to start of etoposide infusion, 2 hours after start of infusion, just prior to the end of infusion, then at 0.5, 1, 2, 4, 24 and 48 hours after the end of infusion Procedure: autologous hematopoietic stem cell transplantation Reinfusion of autologous stem cells Procedure: peripheral blood stem cell transplantation Reinfusion of autologous stem cells

Arm

Intervention/Treatment

Experimental: Treatment (high-dose chemotherapy, anti-HIV therapy)

Patients undergo leukapheresis to obtain PBSCs for transplantation. At least 5 days later, patients with an adequate number of collected cells proceed to high-dose chemotherapy. Patients receive carmustine IV over 4 hours on days -7 to -5, etoposide IV over 4 hours on day -4, and cyclophosphamide IV on day -2. Patients receive an autologous PBSC infusion on day 0.

Drug: carmustine

150 mg/m2 day -7, -6,and -5 prior to stem cell reinfusion

Drug: cyclophosphamide

100 mg/kg on day -2 prior to stem cell reinfusion

Drug: etoposide

60 mg/kg on day -4 prior to stem cell reinfusion

Other: pharmacological study

Prior to start of etoposide infusion, 2 hours after start of infusion, just prior to the end of infusion, then at 0.5, 1, 2, 4, 24 and 48 hours after the end of infusion

Procedure: autologous hematopoietic stem cell transplantation

Reinfusion of autologous stem cells

Procedure: peripheral blood stem cell transplantation

Reinfusion of autologous stem cells

Outcome Measures

Primary Outcome Measures

Number of days to engraftment as defined by the standard operating procedures of the department of biostatistics at the City of Hope [Day 100 post stem cell reinfusion]
Feasibility and treatment-associated toxicity of this regimen [1 year post stem cell reinfusion]

Secondary Outcome Measures

Ability to mobilize adequate numbers of peripheral blood stem cells (2.5 x 10e6 CD34+cells) [At the completion of stem cell collection]
Disease-free and overall survival [2 years post stem cell reinfusion]
HIV viral load, CD4+/CD8+ counts, and immune recovery [2 years post stem cell reinfusion]

Eligibility Criteria

Criteria

Ages Eligible for Study:

10 Years to 60 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

HIV seropositive at or before the time of lymphoma diagnosis
Subjects must be on a multi-drug regimen (excluding azidothymidine) to maintain HIV viral load less than 50,000 Gc/mL; if the CD4 count at enrollment is less than 100 then the viral load should be less than 10,000 by reverse transcriptase polymerase chain reaction (Rt-PCR); if the CD4 count is greater than 100/mm^{3 prior to the start
of any lymphoma chemotherapy and is greater than 100/mm}3 for at least 3 months then the viral load must be less than 150,000 gc/ml and clinically stable; if no pre-chemotherapy CD4 counts are available, then viral load alone will be used from enrollment
The known hematopoietic toxicity of AZT (zidovudine) prohibits its use pre-transplant during stem cell collection and during the immediate period of engraftment post-transplant; resumptions of AZT should not begin until there is evidence of stable engraftment; therefore, AZT should not be resumed until at least 2 months after last blood product support is used; since platelet support continues until approximately day +14 days in our experience with acquired immune deficiency syndrome (AIDS) patients transplanted date, AZT will be prohibited until at least 2 months after transplant; therefore, if the anti-HIV drug combination needs to be modified then AZT can be part of the new regimen
Karnofsky performance status >= 70%
Biopsy proven intermediate grade or high-grade Non-Hodgkin's lymphoma, (working formulation groups D-H and J, and Plasmablastic lymphoma of any disease state, including first remission given the poor risk nature of this histology) or Hodgkin's lymphoma of any subtype except nodular lymphocytic and histiocytic (L&H) lymphocyte predominant; tissue histology will be reviewed at the City of Hope
Patients with prior marrow involvement must demonstrate < 10% involvement (by morphology) pre stem cell collection
Pretreatment serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvate transaminase (SGPT) < 1.5 x institutional upper limit of normal
Serum bilirubin < 1.5 x institutional upper limit of normal
Patients who are Hepatitis C antibody positive or Hepatitis B surface antigen positive without clinical evidence of cirrhosis will be eligible after further evaluation; specifically, if patient hepatitis C or B positive viral loads will be measured; patients with hepatitis B and ongoing evidence of viral replication may require therapy prior to receiving high dose chemotherapy; this decision will be at the discretion of the treating physician
Serum creatinine < 2 x institutional upper limit of normal and a 24 hour urine creatinine clearance > 60 cc/min
Prothrombin time (PT)/partial thromboplastin time (PTT) < 2 x normal
Forced expiratory volume in one second (FEV1) or diffusing capacity of the lung for carbon monoxide (DLCO) >= 50% predicted
Left ventricular ejection fraction (LVEF) >= 50% (by 2 dimensional [2 D] echocardiogram or multi gated acquisition scan [MUGA] scan); absence of cardiomyopathy, congestive heart failure or dysrhythmia
If female of child bearing potential, must have negative serum pregnancy test
Subjects must be on a prophylactic regimen for pneumocystis pneumonia if the CD4 counts are < 200
Subjects who are not in complete remission must have measurable disease; measurable disease means that there are bidimensionally measurable lesions with clearly defined margins using either a medical photograph, computerized axial tomography (CAT) scan or magnetic resonance imaging (MRI) scan, or palpation of lesions with both diameters >= 2 cm; evaluable disease means that the lesions are only unidimensionally measurable, or have indistinct margins or have both diameters < 0.5 cm, or that the palpable lesions have a diameter < 2.0 cm, or are lesions in bone; pleural effusions and ascites are considered nonevaluable disease; scans must be within 28 days from enrollment
A minimum of 2.5 x 10^6 CD34 cells/kg must have been collected
Hodgkin's Lymphoma:
Partial response after standard chemotherapy OR
First relapse after initial complete remission with standard chemotherapy
Non-Hodgkin's Lymphoma:
First complete remission after standard chemotherapy with high risk features as specified by the International Prognostic Index;
Partial response after standard chemotherapy; OR
Relapse after initial complete remission with standard chemotherapy

Exclusion Criteria:

Active bacterial or fungal infection
AIDS related opportunistic infection within past year, excluding treatment-responsive Mycobacterium Avium Intracellular infection, and treatment-responsive oral thrush, herpes simplex or herpes zoster
Active cytomegalovirus (CMV) retinitis or other CMV-related organ dysfunction; patients with a history of treated CMV infection are not excluded
Relapse of pneumocystis carinii pneumonia within the past year
AIDS related syndromes or symptoms that pose a perceived excessive risk for transplantation-related morbidity as determined by the principle investigator
Intractable and severe diarrhea as defined as > 1500 cc diarrheal fluid per day of diarrhea causing persistent severed electrolyte abnormalities or hypoalbuminemia
History of grade III hemorrhagic cystitis due to prior chemotherapy
Pregnant or nursing women
Any prior malignancy except treated basal cell carcinoma of the skin; females with cervical dysplasia may be included at the discretion of the treating physician and the principle investigator
Patients with a history of positive cerebrospinal fluid (CSF) cytology that has become negative with intrathecal chemotherapy are eligible; patients should have a negative spinal fluid cytology within thirty days prior to enrollment
Abnormal cytogenetics on screening bone marrow biopsy
Psychosocial conditions that hinder compliance