Bryostatin 1 Plus Vincristine in Treating Patients With Recurrent or Refractory HIV-Related Lymphoma

Study Overview
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Brief Summary
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Phase I trial to study the effectiveness of bryostatin 1 plus vincristine in treating patients who have recurrent or refractory lymphoma. Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Bryostatin 1 may help vincristine kill more cancer cells by making them more sensitive to the drug

Detailed Description
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OBJECTIVES: I. Determine the maximum tolerated dose of bryostatin 1 when administered with vincristine in patients with recurrent or refractory HIV-related B-cell lymphoma. II. Determine the toxicity profile of this regimen in these patients. III. Determine the objective response and survival of these patients treated with this regimen. IV. Determine the immunomodulatory effects of this regimen on interleukin-2 (IL-2), IL-2 receptor, and IL-6 cytokine levels in these patients. V. Determine the effect of this regimen on CD4+ lymphocyte count and HIV load in these patients. VI. Determine the effect of this regimen on the human herpes virus-8 load in these patients with body cavity-based lymphoma. OUTLINE: This is a multicenter, dose-escalation study of bryostatin 1. Patients receive bryostatin 1 IV continuously on days 1 and 15 and vincristine IV over 5 minutes on days 2 and 16. Treatment continues every 4 weeks for a minimum of 2 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of bryostatin 1 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.

Official Title
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A Phase I Trial of Combination Bryostatin-1 and Vincristine in HIV-Related B-cell Neoplasms

Conditions
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AIDS-related Diffuse Large Cell Lymphoma, AIDS-related Diffuse Mixed Cell Lymphoma, AIDS-related Peripheral/Systemic Lymphoma, AIDS-related Small Noncleaved Cell Lymphoma

Intervention / Treatment
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* Drug: bryostatin 1
* Drug: vincristine sulfate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed B-cell lymphoma Eligible subtypes: Intermediate or high-grade non-Hodgkin's lymphoma (NHL), defined as follicular large cell, mantle cell, diffuse mixed cell, diffuse large cell and variants, Burkitt or Burkitt-like, or unclassifiable aggressive histologies Body cavity-based lymphoma or primary effusion lymphoma Evidence of HIV infection Received at least 1 prior systemic chemotherapy regimen with failure to respond or relapse after completion of first-line therapy, including one of the following doxorubicin-based combinations: Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) Infusional cyclophosphamide, doxorubicin, and etoposide (CDE) Etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOCH) Evaluable disease outside of prior radiation port No CNS parenchymal or leptomeningeal involvement No primary CNS NHL No HTLV-1-associated leukemia or lymphoma Performance status - Karnofsky 70-100% At least 12 weeks Absolute granulocyte count at least 1,000/mm3 Platelet count at least 75,000/mm3 Hemoglobin at least 8.0 g/dL Bilirubin no greater than 1.5 mg/dL (unless concurrently on indinavir) SGOT and SGPT less than 3 times upper limit of normal Creatinine no greater than 1.5 mg/dL Creatinine clearance at least 50 mL/min No history of cardiac disease LVEF at least 45% by radionuclide ventriculography No symptomatic congestive heart failure No active angina pectoris No uncontrolled hypertension No history of symptomatic pulmonary disease Corrected DLCO more than 50% predicted No severe chronic obstructive lung disease No symptomatic restrictive lung disease Recurrent controllable infection (e.g., thrush) on chronic suppressive therapy allowed No active uncontrolled infection No active significant opportunistic infection (e.g., acute Pneumocystis pneumonia, cytomegalovirus retinitis on induction or maintenance therapy, acute toxoplasmosis) No grade 2 or greater peripheral neuropathy Not pregnant or nursing Negative pregnancy test Fertile patients must use effective barrier contraception At least 24 hours since prior transfusion At least 24 hours since prior colony-stimulating factor therapy No concurrent prophylactic filgrastim (G-CSF) See Disease Characteristics No concurrent hydroxyurea See Disease Characteristics At least 4 weeks since prior large-field radiotherapy At least 3 weeks since prior anticancer therapy and recovered Must be receiving stable antiretroviral regimen of at least 4 weeks duration

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (bryostatin 1, vincristine sulfate)<br>Patients receive bryostatin 1 IV continuously on days 1 and 15 and vincristine IV over 5 minutes on days 2 and 16. Treatment continues every 4 weeks for a minimum of 2 courses in the absence of disease progression or unacceptable toxicity. | Drug: bryostatin 1<br>* Given IV<br>* Other names: Bryostatin;Drug: vincristine sulfate<br>* Given IV<br>* Other names: Vincasar PFS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MTD of bryostatin-1 defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity |  | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicities | Defined as any >= grade 2 neuropathy, other grade 3 non-hematologic toxicity (excluding alopecia and grade 3 nausea and vomiting that is responsive to standard pharmacologic intervention) or grade 4 hematologic toxicity in 2 or more patients. The incidence of toxicity related dose reduction and treatment discontinuation will be summarized for each dose group. | 4 weeks | 
| Immunomodulatory effects of this combination | Measured by a solid phase Enzyme Amplified Sensitivity Immunoassay. | Up to 2 years |