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indinavir sulfate

nelfinavir mesylate

paclitaxel

ritonavir

saquinavir mesylate

Jamie Hayden Von Roenn, MD

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die.

PURPOSE: Phase II trial to study the effectiveness of paclitaxel in treating patients with AIDS-related Kaposi's sarcoma.

OBJECTIVES:

* Determine whether the body distribution and plasma clearance of paclitaxel is affected by protease inhibitors (e.g., indinavir, ritonavir, saquinavir mesylate, or nelfinavir mesylate).

OUTLINE: Patients are stratified according to protease inhibitor treatment (yes vs no), prior paclitaxel (yes vs no), and prior doxorubicin or daunorubicin (yes vs no).

Patients receive paclitaxel IV over 3 hours on day 1. Treatment continues every 2 weeks for at least 1 course in the absence of disease progression or unacceptable toxicity. Patients who previously received paclitaxel receive no more than 1 course during this study.

PROJECTED ACCRUAL: A total of 33 patients will be accrued for this study.

Paclitaxel in Treating Patients With AIDS-Related Kaposi's Sarcoma

Pilot Study to Evaluate the Potential Interactions Between Paclitaxel and Protease Inhibitors in Patients With AIDS-Related Kaposi's Sarcoma

National Cancer Institute (NCI)

AIDS Associated Malignancies Clinical Trials Consortium

Eastern Cooperative Oncology Group

Group Chair

Skin and Connective Tissue Diseases

Sarcoma, Ewing

Rhabdomyosarcoma

Myosarcoma

Osteosarcoma

Neoplasms, Bone Tissue

Neoplasms, Connective Tissue

Ewing Sarcoma

Analgesics

Vaccines

Immunomodulating Agents

Interleukin-2

Patients receive oral indinavir sulfate 350 mg/m\^2 administered every 8 hours; maximum dose i.e. 800 mg every 8 hours; peptide pulsed dendritic cells 1 x 10\^6 injection; harvested autologous T cells (minimum dose 1 x 10\^6/kg will be thawed rapidly in 37 degree water bath and infused sequentially over 5-15 minutes.

3 syringes containing 1 x 10\^6peptide pulsed dendritic cells

therapeutic autologous dendritic cells

Oral dose, 350 mg/m\^2 administered every 8 hours. Maximum dose is 800 mg every 8 hours.

Harvested autologous T cells, minimum dose 1 x 10\^6/kg will be thawed rapidly in 37 degree water bath and infused sequentially over 5-15 minutes.

peripheral blood stem cell transplantation

Crystal Mackall, M.D.

This is a single arm study.

The tumor specimen is analyzed for the presence of a fusion protein which corresponds to available peptides. Patients undergo T cell harvest 10 days after an initial priming peptide-pulsed antigen presenting cell (APC) vaccine is performed.

Fresh APCs are utilized for initial priming vaccination. All subsequent vaccinations will use cryopreserved APCs. Minimum number of APCs administered per vaccination is 100,000/kg and maximum is 100,000,000/kg.

Patients undergo cytoreductive therapy for the treatment of their particular malignancy. This therapy usually consists of multiagent chemotherapy in the context of a separate protocol.

Following chemotherapy, infusion of harvested T cells followed by infusion of peptide-pulsed APC vaccinations occurs every 6 weeks for a total of 3 post-priming vaccinations. Influenza vaccine is administered by intramuscular injection concurrent to peptide-pulsed APC vaccines.

Interleukin -2 (IL-2) is administered as a continuous intravenous (IV) infusion for 4 days/week for 3 successive weeks starting on the same day as T cell /peptide-pulsed infusions.

Eradication of low tumor burdens can occur in vivo when T-cell mediated responses are generated against specific tumor antigens. The Ewing's sarcoma family of tumors (ESFT) and alveolar rhabdomyosarcoma (AR) display several features which make them candidate diseases for trials of such immunotherapy. First, intensive cytotoxic chemotherapy is generally able to eradicate bulk disease in patients with metastatic disease, but tumor relapse eventually occurs in nearly all patients. Second, tumor-specific chromosomal translocations resulting in the production of novel fusion proteins have been identified in the great majority of these tumors. Peptides derived from these fusion proteins have been shown to function as tumor antigens for cytolytic T cells in animal studies. Third, studies of immune reconstitution after intensive cytotoxic therapy have provided evidence that antigen-specific T cells can be generated in vivo when the adoptive transfer of peripheral T cells and antigen are provided during the period of T cell regeneration. This process can be augmented in murine models by the use of human immunodeficiency virus (HIV) active protease inhibitor, indinavir, potentially through inhibition of programmed cell death in expanding T cells. Merging these concepts, this protocol will attempt to eradicate minimal residual disease in pediatric patients with metastatic ESFT and AR via vaccination with tumor-specific peptides undertaken concomitant with autologous T cell transplantation and indinavir.

A Pilot Study of Autologous T-Cell Transplantation With Vaccine Driven Expansion of Anti-Tumor Effectors After Cytoreductive Therapy in Metastatic Pediatric Sarcomas

Immune response was defined as a percent specific lysis of \>10% following challenge with peptide pulsed targets, or interferon gamma production following challenge with peptide pulsed targets \>2-fold that found with no-peptide controls or a proliferation index \>3.0. Tumor specific peptides: Ewings sarcoma Type 1: EF-1 (EWS/FLI-1)\*SSSYGQQN/PSYDSVRRGA,Ewing's Sarcoma Type 2: EF-2 (EWS/FLI-2)\* SSSYGQ/QSSLLAYNT, Alveolar rhabdomyosarcoma: PXFK (PAX3/FKHR)† TIGNGLSPQ/NSIRHNLSL. Non-tumor specific peptide:HPV16E7 MLDLQPETT-MET-9-THR. See protocol link module for additional information re: peptides.

CD4 counts were measured from peripheral blood using standard flow cytometric techniques at the following timepoints: 2 months post-chemotherapy, 4 months post-chemotherapy and 6 months post-chemotherapy. To be eligible for evaluation for this endpoint, patient much have been \<10 years of age and sustained a CD4 count of \<300 cells/mcl upon completion of standard therapy. Recovery was defined as a CD4 count \> 500 cells/mcl at any timepoint within 6 months of completing chemotherapy.

Immune responses were measured following 3 sequential influenza vaccines during the same period as the peptide-pulsed dendritic cell vaccines.

Immune response was defined as a percent specific lysis of \>10% following challenge with peptide pulsed targets, or interferon gamma production following challenge with peptide pulsed targets \>2-fold that found with no-peptide controls or a proliferation index \>3.0.

Immune response was defined as a percent specific lysis of \>10% following challenge with tumor peptide pulsed targets, or interferon gamma production following challenge with tumor peptide pulsed targets \>2-fold that found with no-peptide controls or a proliferation index \>3.0 to tumor peptide targets.Tumor specific peptides: Ewings sarcoma Type 1: EF-1 (EWS/FLI-1)\*SSSYGQQN/PSYDSVRRGA,Ewing's Sarcoma Type 2: EF-2 (EWS/FLI-2)\* SSSYGQ/QSSLLAYNT, Alveolar rhabdomyosarcoma: PXFK (PAX3/FKHR)† TIGNGLSPQ/NSIRHNLSL. See protocol link module for additional information re: peptides.

Overall survival is defined as the time between the first day of treatment to the day of death.

Event free survival is calculated from the date of diagnosis for patients enrolled with newly diagnosed metastatic disease and from the date of the last recurrence detection before enrollment on this study for patients with recurrent disease.

Here are the number of participants with adverse events. For the detailed list of adverse events see the adverse event module.

Crystal L. Mackall, M.D./National Cancer Institute

Peptide Vaccine/Autologous T Cell Transplant/Indinavir Therapy

Age, Categorical

Age Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

United States

Region of Enrollment

Immune response to tumor specific peptides

Immune response to non-tumor specific peptides

Number of Participants With an Immune Response to Tumor-specific and Non-tumor Specific Peptides During a Period of Immune Reconstitution

The Percent of Patients Who Recover CD4 Counts Within 6 Months of Completion of Chemotherapy

Number of Participants With an Immune Response to the Translocation Breakpoint Peptide

Percentage of Participants Overall Survival

Percent of Participants: Event Free Survival

Number of Participants With Adverse Events

12 patients were human leukocyte antigen serotype within HLA-A A serotype group (HLA-A2+) and therefore evaluable for response to E7 peptides.

Number of Participants With an Immune Response to Non-Tumor-specific Peptide E7

Number of Participants With an Immune Response to Tumor-Specific Peptides at the Time of Presentation

Median Overall Survival

Overall Study

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Paclitaxel in Treating Patients With AIDS-Related Kaposi's Sarcoma	NCT00003008	Sarcoma	indinavir sulfa... nelfinavir mesy... paclitaxel ritonavir saquinavir mesy...	18 Years - 120 Years	Eastern Cooperative Oncology Group
A Pilot Study of Autologous T-Cell Transplantation With Vaccine Driven Expansion of Anti-Tumor Effectors After Cytoreductive Therapy in Metastatic Pediatric Sarcomas	NCT00001566	Ewing's Sarcoma Rhabdomyosarcom...	therapeutic aut... indinavir sulfa... peripheral bloo...	5 Years - 35 Years	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for indinavir sulfate