Oblimersen and Gemcitabine in Treating Patients With Advanced Solid Tumor or Lymphoma

Study Overview
=================
Brief Summary
-----------------
Drugs used in chemotherapy such as gemcitabine use different ways to stop cancer cells from dividing so they stop growing or die. Oblimersen may increase the effectiveness of gemcitabine by making cancer cells more sensitive to the drug. This phase I trial is studying the side effects and best dose of oblimersen and gemcitabine in treating patients with metastatic or unresectable solid tumors or lymphoma

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. Determine the maximum tolerated dose and dose-limiting toxicity of oblimersen and gemcitabine in patients with advanced solid tumor or lymphoma. II. Determine the effect of oblimersen on the pharmacokinetics and pharmacodynamics of gemcitabine in these patients. III. Determine the toxic effects of this regimen in these patients. OUTLINE: This is a dose-escalation study. Patients receive oblimersen IV continuously on days 1-5 and gemcitabine IV over 2-3 hours on day 5. Courses repeat every 2 weeks in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of oblimersen and gemcitabine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Up to 10 additional patients receive treatment at the MTD. PROJECTED ACCRUAL: Approximately 15 patients will be accrued for this study within 6-8 months.

Official Title
-----------------
A Phase I Study of Oblimersen (Genasense™, G3139) in Combination With Gemcitabine in Advanced Malignancies

Conditions
-----------------
Stage IV Adult Hodgkin Lymphoma, Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue, Nodal Marginal Zone B-cell Lymphoma, Recurrent Adult Burkitt Lymphoma, Recurrent Adult Diffuse Large Cell Lymphoma, Recurrent Adult Diffuse Mixed Cell Lymphoma, Recurrent Adult Diffuse Small Cleaved Cell Lymphoma, Recurrent Adult Hodgkin Lymphoma, Recurrent Adult Immunoblastic Large Cell Lymphoma, Recurrent Adult Lymphoblastic Lymphoma, Recurrent Adult T-cell Leukemia/Lymphoma, Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma, Recurrent Grade 1 Follicular Lymphoma, Recurrent Grade 2 Follicular Lymphoma, Recurrent Grade 3 Follicular Lymphoma, Recurrent Mantle Cell Lymphoma, Recurrent Marginal Zone Lymphoma, Recurrent Small Lymphocytic Lymphoma, Splenic Marginal Zone Lymphoma, Stage IV Adult Burkitt Lymphoma, Stage IV Adult Diffuse Large Cell Lymphoma, Stage IV Adult Diffuse Mixed Cell Lymphoma, Stage IV Adult Diffuse Small Cleaved Cell Lymphoma, Stage IV Adult Immunoblastic Large Cell Lymphoma, Stage IV Adult Lymphoblastic Lymphoma, Stage IV Adult T-cell Leukemia/Lymphoma, Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma, Stage IV Grade 1 Follicular Lymphoma, Stage IV Grade 2 Follicular Lymphoma, Stage IV Grade 3 Follicular Lymphoma, Stage IV Mantle Cell Lymphoma, Stage IV Marginal Zone Lymphoma, Stage IV Small Lymphocytic Lymphoma, Unspecified Adult Solid Tumor, Protocol Specific

Intervention / Treatment
-----------------
* Biological: oblimersen sodium
* Drug: gemcitabine hydrochloride
* Other: pharmacological study
* Other: laboratory biomarker analysis


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed malignancy for which there is no standard or effective curative or palliative therapy Solid tumors and lymphoma allowed Metastatic or unresectable disease Measurable or evaluable nonmeasurable disease Evaluable nonmeasurable disease includes ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal masses not followed by CT scan or MRI, or cystic lesions Disease characterized by elevated serum tumor marker alone is allowed No known brain metastases Performance status - ECOG 0-2 Performance status - Karnofsky 60-100% More than 3 months Absolute neutrophil count at least 1,500/mm^3 Platelet count at least 100,000/mm^3 Bilirubin no greater than 1.5 mg/dL AST and ALT no greater than 2.5 times upper limit of normal No history of portal hypertension No history of cirrhosis or hepatitis No radiographic evidence of cirrhosis and/or varices Creatinine normal Creatinine clearance at least 60 mL/min No symptomatic congestive heart failure No unstable angina pectoris No cardiac arrhythmia Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No prior allergic reaction attributed to compounds of similar chemical or biological composition to oblimersen or other study agents No other concurrent uncontrolled illness that would preclude study participation No ongoing or active infection No psychiatric illness or social situation that would preclude study compliance No concurrent prophylactic colony-stimulating factors such as filgrastim (G-CSF) or sargramostim (GM-CSF) Concurrent interventional growth factors allowed No growth factor administration within 24 hours before study chemotherapy Concurrent epoetin alfa allowed No more than 3 prior chemotherapy regimens More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) More than 2 weeks since prior hormonal therapy Concurrent megestrol for anorexia/cachexia allowed No prior pelvic or whole abdominal radiotherapy More than 4 weeks since prior radiotherapy More than 4 weeks since prior major surgery Recovered from prior therapy More than 4 weeks since prior investigational therapy No prior oblimersen No other concurrent investigational agents No other concurrent anticancer therapy No concurrent combination antiretroviral therapy for HIV-positive patients

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (oblimersen sodium and gemcitabine hydrochloride)<br>Patients receive oblimersen IV continuously on days 1-5 and gemcitabine IV over 2-3 hours on day 5. Courses repeat every 2 weeks in the absence of disease progression or unacceptable toxicity. | Biological: oblimersen sodium<br>* Given IV<br>* Other names: Genasense;Drug: gemcitabine hydrochloride<br>* Given IV<br>* Other names: Gemzar;Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MTD defined as the dose level at which less than 2 out of 6 patients experience DLT assessed using NCI CTC version 2.0 | Descriptive statistics will be employed in the analysis of all safety and laboratory observations. | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics | Peak concentration and area under the concentration time curves of gemcitabine triphosphate will be will be utilized to assess the pharmacodynamic relationship of gemcitabine triphosphate concentration to bivariate toxicity and tumor responses using logistic regression analysis. | Pre-dose, 4, 8, 12, 24, 48, 72, 96, 120, 121.67, 126, and 129 hours |