Phase I Study To Evaluate The Use Of Autologous T- Antigen-Presenting Cells (T-APC) To Enhance The Persistence Of Adoptively Transferred CD8+ Antigen-Specific T Cells (CTL) Following Cyclophosphamide Conditioning For Patients With Metastatic Melanoma
Overview
- Phase
- Phase 1
- Intervention
- cyclophosphamide
- Conditions
- Recurrent Melanoma
- Sponsor
- Fred Hutchinson Cancer Center
- Enrollment
- 12
- Locations
- 1
- Primary Endpoint
- Treatment-related dose limiting toxicity (DLT) as defined by Grade 3 or greater unexpected toxicity by the NCI Common Toxicity Criteria (CTC) v4.0
- Status
- Completed
- Last Updated
- 12 years ago
Overview
Brief Summary
This phase I trial studies the side effects and best dose of autologous T-antigen-presenting cells (T-APC) vaccine following therapeutic autologous lymphocytes (CTL) and cyclophosphamide in treating patients with metastatic melanoma. Aldesleukin may stimulate lymphocytes, such as CTL, to kill melanoma cells. Treating lymphocytes with aldesleukin in the laboratory may help the lymphocytes kill more tumor cells when they are put back in the body. Vaccines made from melanoma antigen may help the body build an effective immune response to kill tumor cells and may boost the effect of the CTL. Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving T-APC vaccine after CTL and cyclophosphamide may be an effective treatment for melanoma
Detailed Description
PRIMARY OBJECTIVES: I. Assess the safety and toxicity of T-APC vaccination following adoptive T cell therapy. II. Evaluate the functional and numeric in vivo persistence of adoptively transferred cytotoxic t lymphocytes (CTL) followed by T-APC vaccination. SECONDARY OBJECTIVES: I. Evaluate the antitumor effect of adoptive T cell therapy followed by T-APC vaccination. OUTLINE : This is a dose-escalation study of T-APC vaccine. INFUSION I: Patients receive high-dose cyclophosphamide intravenously (IV) on days -4 and -3 and low-dose aldesleukin (IL-2) subcutaneously (SC) twice daily (BID) on days 0-14. Patients also receive CTL IV on day 0. INFUSION II: Beginning 6-48 hours later, patients receive high-dose cyclophosphamide, low-dose IL-2, and CTL as in Infusion I. Patients also receive T-APC vaccine IV within 18-36 hours following CTL infusion and in week 4, and IL-2 SC BID on days 0-14 following second T-APC vaccination. After completion of study treatment, patients are followed up for 8 weeks.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Histopathological documentation of melanoma concurrent with the diagnosis of metastatic disease
- •Tumor expression of melanocyte differentiation antigen (MDA: MART-1 = 2+ staining or \> 25%) by immunohistochemistry (IHC)
- •Expression of human leukocyte antigen (HLA)-A201
- •Zubrod performance status of '0-1' at the time of treatment
- •Bi-dimensionally measurable disease by palpation on clinical exam, or radiographic imaging (X-ray, computed tomography \[CT\] scan)
- •Normal cardiac stress test will be required for all patients with any history of cardiac disease
Exclusion Criteria
- •Pregnant women, nursing mothers, men or women of reproductive ability who are unwilling to use effective contraception or abstinence; women of childbearing potential must have a negative pregnancy test within two weeks prior to entry
- •Serum creatinine \> 1.6 mg/dL or Creatinine clearance \< 75 ml/min
- •Serum glutamic oxaloacetic transaminase (SGOT) \> 150 IU or \> 3x upper limit of normal
- •Bilirubin \> 1.6 mg/dL
- •Prothrombin time \> 1.5 x control
- •Clinically significant pulmonary dysfunction, as determined by medical history and physical exam; patients so identified will undergo pulmonary functions testing and those with forced expiratory volume in one second (FEV1) \< 2.0 L or carbon monoxide diffusing capacity (DLco) (corr for hemoglobin \[Hgb\]) \< 75% will be excluded
- •Congestive heart failure
- •Clinically significant hypotension
- •Symptoms of coronary artery disease
- •Presence of cardiac arrhythmias on electrocardiograph (EKG) requiring drug therapy
Arms & Interventions
Treatment (dose-escalation, T-APC boost, CTL)
INFUSION I: Patients receive high-dose cyclophosphamide IV on day days -4 and -3 and low-dose IL-2 SC BID on days 0-14. Patients also receive CTL IV on day 0. INFUSION II: Beginning 6-48 hours later, patients receive high-dose cyclophosphamide, low-dose IL-2, and CTL as in Infusion I. Patients also receive T-APC vaccine IV within 18-36 hours following CTL infusion and in week 4, and IL-2 SC BID on days 0-14 following second T-APC vaccination.
Intervention: cyclophosphamide
Treatment (dose-escalation, T-APC boost, CTL)
INFUSION I: Patients receive high-dose cyclophosphamide IV on day days -4 and -3 and low-dose IL-2 SC BID on days 0-14. Patients also receive CTL IV on day 0. INFUSION II: Beginning 6-48 hours later, patients receive high-dose cyclophosphamide, low-dose IL-2, and CTL as in Infusion I. Patients also receive T-APC vaccine IV within 18-36 hours following CTL infusion and in week 4, and IL-2 SC BID on days 0-14 following second T-APC vaccination.
Intervention: aldesleukin
Treatment (dose-escalation, T-APC boost, CTL)
INFUSION I: Patients receive high-dose cyclophosphamide IV on day days -4 and -3 and low-dose IL-2 SC BID on days 0-14. Patients also receive CTL IV on day 0. INFUSION II: Beginning 6-48 hours later, patients receive high-dose cyclophosphamide, low-dose IL-2, and CTL as in Infusion I. Patients also receive T-APC vaccine IV within 18-36 hours following CTL infusion and in week 4, and IL-2 SC BID on days 0-14 following second T-APC vaccination.
Intervention: autologous tumor cell vaccine
Treatment (dose-escalation, T-APC boost, CTL)
INFUSION I: Patients receive high-dose cyclophosphamide IV on day days -4 and -3 and low-dose IL-2 SC BID on days 0-14. Patients also receive CTL IV on day 0. INFUSION II: Beginning 6-48 hours later, patients receive high-dose cyclophosphamide, low-dose IL-2, and CTL as in Infusion I. Patients also receive T-APC vaccine IV within 18-36 hours following CTL infusion and in week 4, and IL-2 SC BID on days 0-14 following second T-APC vaccination.
Intervention: laboratory biomarker analysis
Treatment (dose-escalation, T-APC boost, CTL)
INFUSION I: Patients receive high-dose cyclophosphamide IV on day days -4 and -3 and low-dose IL-2 SC BID on days 0-14. Patients also receive CTL IV on day 0. INFUSION II: Beginning 6-48 hours later, patients receive high-dose cyclophosphamide, low-dose IL-2, and CTL as in Infusion I. Patients also receive T-APC vaccine IV within 18-36 hours following CTL infusion and in week 4, and IL-2 SC BID on days 0-14 following second T-APC vaccination.
Intervention: immunologic technique
Treatment (dose-escalation, T-APC boost, CTL)
INFUSION I: Patients receive high-dose cyclophosphamide IV on day days -4 and -3 and low-dose IL-2 SC BID on days 0-14. Patients also receive CTL IV on day 0. INFUSION II: Beginning 6-48 hours later, patients receive high-dose cyclophosphamide, low-dose IL-2, and CTL as in Infusion I. Patients also receive T-APC vaccine IV within 18-36 hours following CTL infusion and in week 4, and IL-2 SC BID on days 0-14 following second T-APC vaccination.
Intervention: immunohistochemistry staining method
Treatment (dose-escalation, T-APC boost, CTL)
INFUSION I: Patients receive high-dose cyclophosphamide IV on day days -4 and -3 and low-dose IL-2 SC BID on days 0-14. Patients also receive CTL IV on day 0. INFUSION II: Beginning 6-48 hours later, patients receive high-dose cyclophosphamide, low-dose IL-2, and CTL as in Infusion I. Patients also receive T-APC vaccine IV within 18-36 hours following CTL infusion and in week 4, and IL-2 SC BID on days 0-14 following second T-APC vaccination.
Intervention: polymerase chain reaction
Treatment (dose-escalation, T-APC boost, CTL)
INFUSION I: Patients receive high-dose cyclophosphamide IV on day days -4 and -3 and low-dose IL-2 SC BID on days 0-14. Patients also receive CTL IV on day 0. INFUSION II: Beginning 6-48 hours later, patients receive high-dose cyclophosphamide, low-dose IL-2, and CTL as in Infusion I. Patients also receive T-APC vaccine IV within 18-36 hours following CTL infusion and in week 4, and IL-2 SC BID on days 0-14 following second T-APC vaccination.
Intervention: therapeutic autologous lymphocytes
Outcomes
Primary Outcomes
Treatment-related dose limiting toxicity (DLT) as defined by Grade 3 or greater unexpected toxicity by the NCI Common Toxicity Criteria (CTC) v4.0
Time Frame: Up to 8 weeks after the T cell infusion
Assessed at the maximum tolerated dose (MTD) or dose level immediately below the dose level for which the incidence of DLT was less than 35%.
In vivo persistence of adoptively transferred T cells
Time Frame: At 4 weeks
Assessed by intrapatient comparison between the first (without T-APC) and second (with T-APC) CTL infusion. Descriptive statistics will be applied and t-tests of intrapatient in vivo T cell persistence between the two Infusions will be determined.
Secondary Outcomes
- Clinical response(Up to 8 weeks after second dose)