Vaccine Therapy in Treating Patients With Stage III or Stage IV Melanoma

Condition(s) targeted: Melanoma (Skin)

Intervention: PADRE 965.10 (Drug); alpha-type-1 polarized dendritic cells (Drug); keyhole limpet hemocyanin (Drug); immunoenzyme technique (Procedure); therapeutic autologous dendritic cells (Procedure)

Phase: Phase 1

Status: Recruiting

Sponsored by: UPMC Cancer Centers

Official(s) and/or principal investigator(s):
John M. Kirkwood, MD, Study Chair, Affiliation: UPMC Cancer Centers

RATIONALE: Vaccines made from a person's dendritic cells mixed with tumor peptides and proteins may help the body build an effective immune response to kill tumor cells. Infusing the vaccine directly into the lymphatic system may cause a stronger immune response and kill more tumor cells.

PURPOSE: This randomized phase I trial is studying the side effects and best dose of two dendritic cell vaccines in treating patients with stage III or stage IV melanoma.

Official title: Phase I Evaluation of Alpha-Type-1 DC-Based and cDC-Based Intralymphatic Vaccines in Patients With Metastatic Melanoma

Study design: Treatment, Randomized, Open Label

Primary outcome:

Safety of intralymphatic autologous type-1-polarized dendritic cell vaccine and autologous mature dendritic cell vaccine

Cumulative increase in the sum of specific interferon gamma ELISPOTs against melanoma-specific A2-restricted peptides

Secondary outcome:

Peripheral blood CD8+ and CD4+ T-cell response to HLA-presented melanoma epitopes and autologous tumor cells by interferon gamma and interleukin-5 ELISPOT assay

Delayed-type hypersensitivity (DTH) response to treatment

DTH response to autologous tumor lysates

DTH response to keyhole limpet hemocyanin and pan-DR epitope (PADRE)

Correlation of treatment-associated changes in immune response with clinical outcome

Detailed description: OBJECTIVES:

Primary

- Compare the safety of intralymphatic autologous type-1-polarized dendritic cell vaccine

vs autologous mature dendritic cell vaccine loaded with antigenic peptides and proteins in patients with stage III or IV melanoma.

Secondary

- Determine peripheral blood CD8+ and CD4+ T-cell responses to HLA-presented melanoma

epitopes and autologous tumor cells using interferon gamma and interleukin-5 ELISPOT assay.

- Compare the delayed-type hypersensitivity (DTH) responses to these regimens and DTH to

autologous tumor lysates in these patients.

- Compare the DTH response to keyhole limpet hemocyanin and pan-DR epitope (PADRE) in

these patients.

- Correlate treatment-associated changes in immune response with clinical outcome.

OUTLINE: This is a randomized, open-label, dose-escalation study. Patients are randomized to 1 of 2 formulations of dendritic cell (DC) vaccines.

- Arm I: Patients receive intralymphatic autologous type-1-polarized (by

interleukin-1-beta, tumor necrosis factor [TNF] alfa, interferon alfa, poly-I: C, and interferon gamma) DC vaccine that has been loaded with tumor-related peptide antigens (gp100: 209-217[210M] peptide, tyrosinase peptide, MART-1: 27-35 peptide, MAGE-3/6, and EphA2) and proteins (keyhole limpet hemocyanin [KLH; first course] or pan-DR epitope [PADRE] [second course]) every 6 hours on days 1-4 of weeks 1 and 6.

- Arm II: Patients receive intralymphatic autologous mature (by interleukin-1-beta, TNF

alfa, interleukin-6, and prostaglandin E_2) DC vaccine that has been loaded with tumor-related peptide antigens and proteins as in arm I every 6 hours on days 1-4 of weeks 1 and 6.

Patients achieving complete response receive 2 more courses of treatment (3 months apart). Patients achieving partial response receive up to 8 more courses of treatment (1 month apart) in the absence of disease progression or unacceptable toxicity.

In each arm, cohorts of 4-7 patients receive escalating doses of DC vaccine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which no more than 1 of 7 patients experience dose-limiting toxicity.

Blood samples are obtained at baseline and periodically during and after treatment. Samples are examined by immunoenzyme techniques for immunologic measurements.

After completion of study therapy, patients are followed periodically for 10½ years and then annually thereafter.

PROJECTED ACCRUAL: A total of 40 patients will be accrued for this study.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

DISEASE CHARACTERISTICS:

- Pathologically confirmed stage III or IVA (M1a) melanoma

- Recurrent and inoperable disease

- Any tumor thickness and any number of lymph nodes involved

- Asymptomatic cutaneous and nodal disease allowed

- Asymptomatic pulmonary metastatic disease (stage IVB, M1b) allowed

- No advanced visceral disease, including any symptomatic visceral organ involvement, or

disease associated with increased serum lactic dehydrogenase (stage IVC, M1c)

- Standard curative or palliative measures do not exist or are no longer effective

- Sufficient numbers of monocytes (≥ 20 x 10^6) must be obtained for the preparation of

the vaccine

- If an insufficient number of cells is obtained on first venipuncture, a second

venipuncture may be performed (not exceeding 550 mL of blood within 8 weeks)

- No brain metastases by contrast-enhanced CT scan or MRI

- Prior brain metastases allowed provided they were successfully treated and

patient has been asymptomatic for ≥ 3 months

- HLA-A2 positive

PATIENT CHARACTERISTICS:

- ECOG performance status 0-1

- Life expectancy ≥ 6 months

- Granulocyte count ≥ 2,500/mm³

- Lymphocyte count ≥ 1,000/mm³

- Platelet count > 100,000/mm³

- Creatinine ≤ 1. 5 times upper limit of normal (ULN)

- AST and ALT ≤ 2. 5 times ULN

- Gamma-glutamyl transferase ≤ 2. 5 times ULN

- Lactic dehydrogenase ≤ 2. 5 times ULN

- Alkaline phosphatase ≤ 2. 5 times ULN

- Bilirubin ≤ 1. 5 times ULN

- No active infection

- No sensitivity to drugs that provide local anesthesia

- No pain uncontrolled by oral analgesics, including opiates and opiate analogs

- No active autoimmune disease

- No HIV, hepatitis B, or hepatitis C positivity

- Not pregnant or nursing

- Fertile patients must use effective contraception

- Negative pregnancy test

- No other malignancy except for nonmelanoma skin cancers or carcinoma in situ of the

cervix

PRIOR CONCURRENT THERAPY:

- Recovered from prior surgery

- No radiotherapy, chemotherapy, or immunotherapy within the past 4 weeks (6 weeks for

nitrosoureas or mitomycin C)

- No antibiotics within the past 7 days

- No systemic immunosuppressive agents, including steroids, within the past 4 weeks

- Concurrent maintenance steroids for adrenal insufficiency allowed

- No other concurrent anticancer investigational or commercial agents or therapies

UPMC Cancer Centers, Pittsburgh, Pennsylvania 15232, United States; Recruiting
John M. Kirkwood, MD, Phone: 412-623-7707

UPMC Cancer Center at Magee-Womens Hospital, Pittsburgh, Pennsylvania 15213, United States; Recruiting
Clinical Trials Office - UPMC Cancer Center at Magee-Womens Ho, Phone: 412-647-2811

Clinical trial summary from the National Cancer Institute's PDQ® database

Starting date: October 2006
Last updated: July 23, 2008