Therapy to Treat Ewing's Sarcoma, Rhabdomyosarcoma or Neuroblastoma

NCT00923351 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: 07020607-C-0206
• Study Type: interventional
• Target: 44
• Locations: 1 country
• Sites: 1

Brief Summary

Background:

• Pediatric solid tumors (Ewing's sarcoma, rhabdomyosarcoma, and neuroblastoma) are often difficult to cure with standard treatment.
• Immune therapy using an experimental vaccine made from proteins from the patient's tumor cells may boost the body's immune response against the tumor.
• The effects of chemotherapy on the immune system can potentially make immunotherapy more effective if administered soon after completion of chemotherapy. The addition of recombinant human IL-7 (interleukin 7) (rhIL-7 (recombinant human interleukin 7)) may make the immunotherapy more effective. Objectives:
• To determine whether immune therapy given after immune suppression can help the body fight the tumor and to determine the safety of the treatment. Eligibility:
• Patients with solid tumors, i.e., Ewing's sarcoma, rhabdomyosarcoma or neuroblastoma whose disease has recurred after treatment or spread beyond the original site Design:
• Patients undergo tumor biopsy (removal of a piece of tumor tissue) to collect tumor cells for making a vaccine from proteins in the patient's tumor and apheresis (removal of a quantity of white blood cells) to collect white cells for re-building the immune system after immune therapy. Apheresis is repeated three times during immunotherapy (weeks 8, 14 and 20).
• After receiving standard chemotherapy for their tumor (and an additional course of fludarabine and cyclophosphamide to further suppress immunity if needed) patients receive immune therapy in Cohorts A and B. rhIL-7 is given 48 hours before the vaccine, as an injection under the skin in an extremity that will not be used for the vaccine in patients in Cohort B only. You will be watched closely for 6 hours after the rhIL-7 for any signs of reaction. rhIL-7 will be given before vaccine doses #1, #2, #3, and #4. The vaccine is given at study weeks 2, 4, 6, 8, 10 and 12. Each vaccine is given as a total of six separate rhIL-7 followed by injections: three intradermal (like a (tuberculosis) TB test) on one arm or leg and three subcutaneous (like those for insulin injections for diabetes). on the other arm or leg. An anesthetic cream may be used to minimize the discomfort of injections.
• Patients' white cells are returned to them by infusion through a vein on the first day of immune therapy.
• Imaging studies and immune studies are done at weeks 1, 8 and 20 to determine the response to treatment on the tumor and on the immune system.

Conditions

Neuroblastoma; Sarcoma; Rhabdomyosarcoma-Embryonal; Rhabdomyosarcoma- Alveolar; Neuroectodermal Tumors, Primitive, Peripheral

Keywords

Vaccine; Immunotherapy; Cancer; Chemotherapy; Tumor Lysate/KLH Pulsed Dendritic Cell Vaccine; Neuroblastoma; Autologous Lymphocyte Infusion; Ewing's Sarcoma; Rhabdomyosarcoma

Outcome Measures

Primary Outcomes (3)

• Number of Participants With a Positive Immune Response as Evidenced by the Delayed Type of Hypersensitivity (DTH) Reaction Assay

  A positive response to the tumor vaccine requires a positive reaction in at least one of the two assays below (immune responses to tumor lysates using ex vivo and delayed type of hypersensitivity (DTH). The presence of a positive delayed type of hypersensitivity (DTH) reaction to the tumor lysate in a patient who did not show a positive DTH reaction prior to immunotherapy. A positive reaction is induration of at least 0.5 cm. Immunotherapy administered to patients with recurrent or metastatic pediatric solid tumors such as Ewing's sarcoma, rhabdomyosarcoma, or neuroblastoma. Each vaccine is given as 6 separate injections. Three intradermal on one arm or leg and three subcutaneous on the other arm or leg.

  Week 8, 14, 20 (Arm A) and on Days 42, 84 and 126 (± 7 days) (Arm B)

• Toxicity

  Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.

  Date treatment consent signed to date off study, approximately 49.5 months

• Overall Survival

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

  Time between the first day of treatment to the day of death or at the conclusion of 5 years of follow-up, whichever comes first, assessed up to approximately 11 years.

Study Arms (2)

Arm A - Participants who did not receive rhIL-7

EXPERIMENTAL

Six patients with Ewings sarcoma family or tumors (ESFT) participants will receive cytotoxic/lympholytic therapy with cyclophosphamide and fludarabine (if cluster of differentiation 4 (CD4) count \> 200 cells/mcl). Participant will receive Tumor lysate/keyhole limpet hemocyanin (KLH) pulsed dendritic cell vaccine followed by Infusion of 8H9/CD25 depleted autologous lymphocyte infusion on Day 1, followed by Tumor lysate/KLH pulsed dendritic cell vaccine on week 4, 6, 8, 10, and 12.

Drug: Tumor Purged/CD25 Depleted Lymphocytes

Arm B - Participants who received rhIL-7

EXPERIMENTAL

Eight patients with rhabdomyosarcoma, fifteen patients with Ewings sarcoma family or tumors (ESFT), two patients with desmoplastic small round cell tumor, and one patient with synovial cell sarcoma participants will receive CYT107 20 mcg/kg/dose subcutaneous (SQ) (approx. 48h prior to vaccine\[Day 0\]), Tumor lysate/KLH pulsed dendritic cell vaccine followed by Infuse 8H9/CD25 depleted autologous lymphocyte infusion on Day 2, followed by CYT107 20 mcg/kg/dose SQ on days 14, 28 and 42 (± 7 days), and Tumor lysate/KLH pulsed dendritic cell vaccine on Days 16, 30, 44, 56, and 70 (± 7 days). Apheresis/flow cytometry/delayed type of hypersensitivity (DTH) responses for immune endpoint monitoring (skin tests) will be performed on Week 8, 14, 20 (Arm A) and on Days 42, 84 and 126 (+/- 7 days) (Arm B); and radiographic studies for clinical restaging will be performed on Week 8 and 20 (Arm A) and Days 42 and 126 (+/- 7 days) (Arm B).

Biological: Tumor Purged/CD25 Depleted Lymphocytes with Tumor Lysate/KLH Pulsed Dendritic Cell Vaccine; Drug: rhIL-7; Biological: Tumor Lysate/KLH Pulsed Dendritic Cell Vaccine

Interventions

Tumor Purged/CD25 Depleted Lymphocytes DRUG

Arm A - Participants who did not receive rhIL-7

Tumor Purged/CD25 Depleted Lymphocytes with Tumor Lysate/KLH Pulsed Dendritic Cell Vaccine BIOLOGICAL

Tumor lysate/KLH pulsed dendritic cells (minimum of 1 X 10e6 cells/kg) on Day2.

Arm B - Participants who received rhIL-7

rhIL-7 DRUG

rhIL-7 (20 mcg/kg/dose SQ) approx. 48 hours prior to vaccine) Day 0, Day 14, Day 28 and Day 42

Arm B - Participants who received rhIL-7

Tumor Lysate/KLH Pulsed Dendritic Cell Vaccine BIOLOGICAL

Tumor lysate/KLH Pulsed dendritic cell vaccine (1-5 X 10e7 cells/injection site, given in 3 sites intradermal) on Day 2, Day 16, Day 30, Day 44, Day 56, Day 70.

Arm B - Participants who received rhIL-7

Eligibility Criteria

• Age: 19 Months - 35 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• A. Diagnosis
• rhabdomyosarcoma: embryonal or alveolar.
• Ewing's sarcoma family of tumors (ESFT), which include: classical, atypical and extraosseous ESFT, peripheral primitive neuroectodermal tumors, peripheral neuroepithelioma, primitive sarcoma of bone, and ectomesenchymoma.
• neuroblastoma: may be diagnosed via histology or the standard clinical evidence for increased catecholamines in the urine plus tumor cells in the bone marrow.
• undifferentiated or embryonal sarcoma.
• desmoplastic small round cell tumor.
• synovial cell sarcoma.
• B. Extent of Disease/Previous Therapy
• Initial presentation: Stage IV or metastatic disease, enrolled prior to any cytoreductive therapy.
• Recurrent Disease:
• Patient \> 5yo must have recovered CD4 count to \> 350 cells/mm\^3 OR have disease free interval \> one year from completion of cytotoxic therapy
• Patients \< 5yo must have recovered CD4 count to \> 350 cells/mm\^3 OR have disease free interval \> six months from completion of cytotoxic therapy
• Multiple recurrences are allowable as long as CD4 count or disease-free intervals have been met.
• C. Age/Weight
• greater than 18 mos. and less than or equal to 35 years at the time of initial diagnosis.

You may not qualify if:

• A. Other conditions
• Clinically significant unrelated systemic illness, such as serious infections, autoimmunity or organ dysfunction, which in the judgment of the Principal or Associate Investigators would compromise the patient's ability to tolerate the investigational agents or are likely to interfere with the study procedures or results.
• Previous allogeneic stem cell or allogeneic bone marrow transplantation.
• Conditions related to tumor, which require emergency treatment (airway compression, spinal cord compression) since enrollment would delay initiation of such therapy.
• Women who are pregnant or lactating.
• Corticosteroids initiated at the time of tumor diagnosis or recurrence for treatment of nerve compression or other symptoms is permitted during this phase of the trial, but will not be permitted during the immunotherapy phase, with the exception of a self limited course of steroids as described in Section 2.1.4.A.
• Patients with a history of central nervous system (CNS) metastases from cancer are not excluded provided that the metastatic CNS disease has been effectively treated and there is no evidence of active CNS disease as evidenced by stable clinical findings and stable radiographic findings for a period of 6 weeks.
• Patients with human immunodeficiency virus infection, hepatitis B, or hepatitis C due to confounding effects on immune system.
• A. Informed Consent
• Because significant time will have elapsed between apheresis/tumor biopsy and the initiation of immunotherapy, all patients or their legal guardians (if the patient is less than 18 years old) must sign a second informed consent to document their understanding of the investigational nature and the risks of this study before any protocol related studies are performed (other than the studies which were performed to determine patient eligibility).
• B. Time and Recovery from Cytotoxic Therapy
• At least 3 weeks should have elapsed since the last cycle of cytotoxic therapy or since the last dose of radiation therapy, at least 4 weeks must have elapsed since the patient has received any investigational therapy, and patients should have recovered from toxic side effects of previous therapy to a grade 1 or less, with the exception of the following:
• Hematological toxicity: recovery to levels required in Section 2.1.1.E.
• Low electrolyte levels (Such individuals should receive appropriate supplementation).
• For patients on anticoagulant therapy or with pre-existing coagulation abnormalities, prothrombin time (PT), partial thromboplastin time (PTT) must return to baseline.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• Arndt CA, Crist WM. Common musculoskeletal tumors of childhood and adolescence. N Engl J Med. 1999 Jul 29;341(5):342-52. doi: 10.1056/NEJM199907293410507. No abstract available.

  PMID: 10423470 BACKGROUND

• La TH, Meyers PA, Wexler LH, Alektiar KM, Healey JH, Laquaglia MP, Boland PJ, Wolden SL. Radiation therapy for Ewing's sarcoma: results from Memorial Sloan-Kettering in the modern era. Int J Radiat Oncol Biol Phys. 2006 Feb 1;64(2):544-50. doi: 10.1016/j.ijrobp.2005.07.299. Epub 2005 Sep 28.

  PMID: 16198063 BACKGROUND

• Barker LM, Pendergrass TW, Sanders JE, Hawkins DS. Survival after recurrence of Ewing's sarcoma family of tumors. J Clin Oncol. 2005 Jul 1;23(19):4354-62. doi: 10.1200/JCO.2005.05.105. Epub 2005 Mar 21.

  PMID: 15781881 BACKGROUND

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Neuroblastoma; Sarcoma; Rhabdomyosarcoma, Embryonal; Rhabdomyosarcoma, Alveolar; Neuroectodermal Tumors, Primitive, Peripheral; Neoplasms; Sarcoma, Ewing; Rhabdomyosarcoma

Interventions

efineptakin alfa

Condition Hierarchy (Ancestors)

Neuroectodermal Tumors, Primitive; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Neoplasms, Connective and Soft Tissue; Myosarcoma; Neoplasms, Muscle Tissue; Osteosarcoma; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue

Limitations and Caveats

Re: Reason stopped: Of 30 pts who have received immunotherapy,12 remain on F/U, are stable or without evidence of disease,11 died of PD, 7 are currently receiving additional therapy (NOT ON THIS PROTOCOL) for PD.

Results Point of Contact

• Title: Dr. John Glod
• Organization: National Cancer Institute, National Institutes of Health

john.glod@nih.gov

301-451-0391

Study Officials

• John Glod, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Staff Clinician

Study Record Dates

• First Submitted: June 17, 2009
• First Posted: June 18, 2009
• Study Start: June 2, 2007
• Primary Completion: August 30, 2012
• Study Completion: May 15, 2018
• Last Updated: June 15, 2018
• Results First Posted: September 20, 2013

Record last verified: 2018-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)