A Phase 2 interventional study of therapeutic autologous dendritic cells and indinavir sulfate in Ewing's Sarcoma and Rhabdomyosarcoma, sponsored by National Cancer Institute (NCI). Completed at 1 site in United States. Open to participants aged 5 Years to 35 Years. Per ClinicalTrials.gov, last updated 2012-06-15.
Sponsored by National Cancer Institute (NCI) · Phase 2, Interventional, and Treatment
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.
1,667 studies on the registry are indexed under Sarcoma; 393 are open to participants now.
This study's enrollment of 42 is close to the median of 40 across 1,283 interventional studies indexed under Sarcoma.
Browse Sarcoma studies →National Cancer Institute (NCI) is the lead sponsor of 3,506 studies on the registry; 334 are open to participants now.
Of its 402 completed or terminated interventional studies of FDA-regulated products, 365 (91%) have results posted.
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Patients with fusion protein bearing, metastatic malignancies of the following histologic subtypes are eligible for evaluation for treatment on this protocol: alveolar rhabdomyosarcoma (AR), and Ewing's sarcoma family of tumors (ESFT) which includes classical, atypical and extraosseous Ewing's sarcoma, peripheral primitive neuroectodermal tumors, peripheral neuroepithelioma, primitive sarcoma of bone, and ectomesenchymoma. Eligibility will not be confirmed until the presence of a tumor-specific fusion protein is documented by reverse transcription polymerase chain reaction (RT-PCR) which corresponds to one of the tumor-specific peptides available for vaccination.
Patients with Stage IV or metastatic disease are eligible to be enrolled on study at the time of initial presentation with tumor, prior to any cytoreductive therapy.
Alternatively, patients who have recurrent disease, but who have been remotely treated (completed all antineoplastic therapy greater than or equal to one year prior to enrollment for patients who are greater than 5 years of age, or completed all antineoplastic therapy greater than 6 months prior to enrollment for patients who are less than or equal to 5 years of age), are also eligible for enrollment prior to any subsequent cytoreductive therapy.
Patients who have received cytoreductive therapy for Stage IV or metastatic disease may be enrolled at the time of completion of cytoreductive therapy if an apheresis specimen is available which was collected and processed prior to cytotoxic therapy according to the guidelines described in the protocol Section 3.2.2.
Such products will have been obtained by apheresis at the Clinical Center, National Institutes of Health (NIH), with informed consent administered as per protocol 98-C-37, 97-C-0050 or as described on standard government request form 2626 for invasive procedures.
Patients must be less than or equal to 35 years at the time of initial diagnosis of alveolar rhabdomyosarcoma or ESFT, weight greater than 10 kg at the time of apheresis. Patients between 10-15 kg must be approved by the apheresis unit in the Department of Transfusion Medicine (DTM) prior to enrollment on the protocol.
All patients or their legal guardians must give written informed consent indicating their understanding of the investigational nature and risks of the study.
Patients must have adequate renal function (serum creatinine (Cr) less than 1.5 mg/dl or creatinine clearance (Cr Cl), greater than 60 ml/min./1.73 m\^2 and liver function (transaminases less than 3 times normal, bilirubin less than 2.0 mg/dl). Patients will not be excluded based upon abnormal hepatic function which is related to hepatic involvement by tumor.
For remotely treated patients, a CD4 count of greater than or equal to 400 cells/mm\^3 is required.
EXCLUSION CRITERIA:
Women who are pregnant or lactating.
Patients with human immunodeficiency virus infection due to confounding effects on immune function.
Patients with hepatitis B or hepatitis C infection will be excluded due to the untoward risks to personnel working with blood specimens.
Patients who require daily oral corticosteroid therapy for any underlying disease will be excluded.
Topical or inhaled corticosteroids are permitted.
Patients who are allergic to eggs, egg products, or thimerosal, or have a history of Guillain-Barre syndrome may be enrolled on study but are ineligible to receive the influenza vaccine.
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.
Biological: therapeutic autologous dendritic cells · Drug: indinavir sulfate · Procedure: peripheral blood stem cell transplantation
3 syringes containing 1 x 10\^6peptide pulsed dendritic cells
Oral dose, 350 mg/m\^2 administered every 8 hours. Maximum dose is 800 mg every 8 hours.
Also known as: Crixivan
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.
Number of Participants With an Immune Response to Tumor-specific and Non-tumor Specific Peptides During a Period of Immune Reconstitution
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.
Time frame: 20 weeks post vaccination
The Percent of Patients Who Recover CD4 Counts Within 6 Months of Completion of Chemotherapy
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.
Time frame: 2 to 6 months
Number of Participants With an Immune Response to the Translocation Breakpoint Peptide
Immune responses were measured following 3 sequential influenza vaccines during the same period as the peptide-pulsed dendritic cell vaccines.
Time frame: 5 years
Number of Participants With an Immune Response to Non-Tumor-specific Peptide E7
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.
Time frame: 5 years
Number of Participants With an Immune Response to Tumor-Specific Peptides at the Time of Presentation
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.
Time frame: Once per enrollment
Percentage of Participants Overall Survival
Overall survival is defined as the time between the first day of treatment to the day of death.
Time frame: 5 years
Percent of Participants: Event Free Survival
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.
Time frame: 5 years
Number of Participants With Adverse Events
Here are the number of participants with adverse events. For the detailed list of adverse events see the adverse event module.
Time frame: 5 years
Median Overall Survival
Overall survival is defined as the time between the first day of treatment to the day of death.
Time frame: 5.4 years
42 patients were enrolled in this study.
| Milestone | Peptide Vaccine/Autologous T Cell Transplant/Indinavir Therapy |
|---|---|
| Started | 42 |
| Completed immunotherapy | 23 |
| Completed | 23 |
| Not completed | 19 |
| Withdrew: Patients' choice to discontinue protocol | 3 |
| Withdrew: Stopped after c3 due to symptomatic pd | 1 |
| Withdrew: Death | 13 |
| Withdrew: Lost to follow-up | 1 |
| Withdrew: Unable to complete initial apheresis | 1 |
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.
| Participants | Peptide Vaccine/Autologous T Cell Transplant/Indinavir Therapy |
|---|---|
| Immune response to tumor specific peptides | 9 |
| Immune response to non-tumor specific peptides | 23 |
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.
| Percentage of participants | Peptide Vaccine/Autologous T Cell Transplant/Indinavir Therapy |
|---|---|
| The Percent of Patients Who Recover CD4 Counts Within 6 Months of Completion of Chemotherapy | 12.5 |
Immune responses were measured following 3 sequential influenza vaccines during the same period as the peptide-pulsed dendritic cell vaccines.
| Participants | Peptide Vaccine/Autologous T Cell Transplant/Indinavir Therapy |
|---|---|
| Number of Participants With an Immune Response to the Translocation Breakpoint Peptide | 9 |
Overall survival is defined as the time between the first day of treatment to the day of death.
| Percentage of participants | Peptide Vaccine/Autologous T Cell Transplant/Indinavir Therapy |
|---|---|
| Percentage of Participants Overall Survival | 43 |
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.
| Percentage of participants | Peptide Vaccine/Autologous T Cell Transplant/Indinavir Therapy |
|---|---|
| Percent of Participants: Event Free Survival | 31 |
Here are the number of participants with adverse events. For the detailed list of adverse events see the adverse event module.
| Participants | Peptide Vaccine/Autologous T Cell Transplant/Indinavir Therapy |
|---|---|
| Number of Participants With Adverse Events | 27 |
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.
| Participants | Peptide Vaccine/Autologous T Cell Transplant/Indinavir Therapy |
|---|---|
| Number of Participants With an Immune Response to Non-Tumor-specific Peptide E7 | 3 |
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.
| Participants | Peptide Vaccine/Autologous T Cell Transplant/Indinavir Therapy |
|---|---|
| Number of Participants With an Immune Response to Tumor-Specific Peptides at the Time of Presentation | 5 |
Overall survival is defined as the time between the first day of treatment to the day of death.
| Years | Peptide Vaccine/Autologous T Cell Transplant/Indinavir Therapy |
|---|---|
| Median Overall Survival | 4.1 (3.4 to 5.4) |
Collected over 5 years. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Peptide Vaccine/Autologous T Cell Transplant/Indinavir Therapy | — | 15/42 (35.7%) | 27/42 (64.3%) |
| Event | Peptide Vaccine/Autologous T Cell Transplant/Indinavir Therapy |
|---|---|
| NeutropeniaInvestigations | 3/42 |
| DiarrheaGastrointestinal disorders | 2/42 |
| ThrombocytopeniaBlood and lymphatic system disorders | 2/42 |
| Abdominal pain or crampingGastrointestinal disorders | 1/42 |
| AnorexiaGastrointestinal disorders | 1/42 |
| CPK (Creatine phosphokinase)Investigations | 1/42 |
| DVT (deep vein thrombosis)Vascular disorders | 1/42 |
| Elevated total bilirubinInvestigations | 1/42 |
| HeadacheNervous system disorders | 1/42 |
| HemorrhageBlood and lymphatic system disorders | 1/42 |
| Event | Peptide Vaccine/Autologous T Cell Transplant/Indinavir Therapy |
|---|---|
| FatigueGeneral disorders | 16/42 |
| EosinophiliaInvestigations | 13/42 |
| FeverGeneral disorders | 12/42 |
| NauseaGastrointestinal disorders | 12/42 |
| HeadacheNervous system disorders | 11/42 |
| Nasal congestionRespiratory, thoracic and mediastinal disorders | 11/42 |
| Elevated SGPT (serum glutamic pyruvic transaminase)Investigations | 10/42 |
| VomitingGastrointestinal disorders | 10/42 |
| DiarrheaGastrointestinal disorders | 8/42 |
| Elevated SGOT(serum glutamic oxaloacetic transaminase)Investigations | 8/42 |
| Age, Categorical(Participants) | Peptide Vaccine/Autologous T Cell Transplant/Indinavir Therapy |
|---|---|
| <=18 years | 26 |
| Between 18 and 65 years | 16 |
| >=65 years | 0 |
| Age Continuous(years) | Peptide Vaccine/Autologous T Cell Transplant/Indinavir Therapy |
|---|---|
| Mean | 18.67 ± 8.59 |
| Sex: Female, Male(Participants) | Peptide Vaccine/Autologous T Cell Transplant/Indinavir Therapy |
|---|---|
| Female | 17 |
| Male | 25 |
| Ethnicity (NIH/OMB)(Participants) | Peptide Vaccine/Autologous T Cell Transplant/Indinavir Therapy |
|---|---|
| Hispanic or Latino | 2 |
| Not Hispanic or Latino | 40 |
| Unknown or Not Reported | 0 |
| Region of Enrollment(participants) | Peptide Vaccine/Autologous T Cell Transplant/Indinavir Therapy |
|---|---|
| United States | 42 |
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