Clinical Trials

PRIMARY OBJECTIVES:

     I. Determine if monoclonal antibody Chl4.18 + cytokines + isotretinoin (13-cis-retinoic acid, or RA) improves event free survival after myeloablative therapy and stem cell rescue as compared to RA alone, in high risk neuroblastoma patients who have achieved a pre-ASCT response of CR, VGPR, or PR.

     SECONDARY OBJECTIVES:

     I. Determine if monoclonal antibody Chl4.18 + cytokines + isotretinoin (13-cis-retinoic acid, or RA) improves overall survival after myeloablative therapy and stem cell rescue as compared to RA alone, in high risk neuroblastoma patients who have achieved a pre-ASCT response of CR, VGPR, or PR.

     II. Determine if immunotherapy + RA improves event free survival and overall survival as compared to RA alone, in the subgroup of high risk INSS Stage 4 neuroblastoma patients who have achieved a pre-ASCT response of CR, VGPR, or PR.

     III. In the subgroup of neuroblastoma patients who have achieved a pre-ASCT response of CR, VGPR, or PR, determine if there is a difference between the two randomized regimens in reducing the minimal residual disease (MRD) burden as detected by the following parameters: meta-iodobenylguanidine (MIBG) scan, immunocytology (IC) of blood and bone marrow samples, RT-PCR for tyrosine hydroxylase, PGP 9.5, and MAGE-1 in blood and bone marrow.

     IV. Determine if change from baseline of MRD as measured by above parameters is associated with event free and overall survival V. Determine whether tumor biology at diagnosis correlates with event-free and overall survival, for either of the randomized regimens.

     VI. Determine the toxicities of the combination of monoclonal antibody Ch14.18 with cytokines.

     VII. To explore the relationship between antibody-dependent cellular cytoxicity (ADCC) and EFS.

     VIII. To determine a descriptive profile of human anti-chimeric antibody (HACA) during immunotherapy.

     IX. To compare the outcome data of the patients with persistent disease documented by biopsy (Stratum 07) to the historical data for the analogous patients from CCG-3981.

     X. To determine the variability of 13-cis-retinoic-acid pharmacokinetics and relationship to pharmacogenomic parameters and determine if these levels and/or genetic variations correlate with EFS or systemic toxicity.

     XI. To further describe and refine the EFS and OS estimates and baseline characteristics for subjects receiving Chl4.18 + cytokines + RA, following cessation of the randomized portion of the study.

     XII. To further describe the safety and toxicity of Chl4.18 + cytokines + RA under the new administration guidelines implemented following cessation of the randomized portion of the study with focus on: a) number of courses delivered per subject; b) number of dose reductions or stoppage (ch14.18 and/or IL-2); and c) number of toxic deaths.

     XIII. To determine the potential effect of ch14.18 on cardiac repolarization and to evaluate ch14.18 plasma levels.

     XIV. To determine if the presence of naturally occurring anti-glycan antibodies correlates with allergic reactions and blood levels of ch14.18.

     XV. To determine if the genotype of FcR and Kir/Kir-Ligand correlate with EFS.

     OUTLINE: This is a randomized, multicenter study. Patients are stratified according to pre-autologous stem cell transplantation (ASCT) response (complete vs very good partial vs partial), stem cells received (purged vs unpurged), and frontline chemotherapy (COG-A3973 vs POG 9341/9342 vs COG-ANGL02P1 vs other therapy). A further stratum consists of patients with biopsy-confirmed post-ASCT persistent disease who are also enrolled on COG-A3973 or COG-ANBL0532. These patients are not randomized but assigned to treatment arm II. Patients in the first set of strata are randomized to 1 of 2 treatment arms.

     ARM I: Beginning on day 67 post-ASCT, patients receive oral isotretinoin twice daily for 14 days. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients may cross over to Arm II provided they have not experienced disease progression and have not received any further anti-neuroblastoma therapy following completion of isotretinoin therapy.

     ARM II: Beginning on day 56 post-ASCT, patients receive immunotherapy comprising sargramostim (GM-CSF) subcutaneously (SC) or IV over 2 hours on days 0-13 during courses 1, 3, and 5 and monoclonal antibody Ch14.18 IV over 10-20 hours on days 3-6 of courses 1-5. Patients also receive interleukin-2 IV continuously on days 0-3 and 7-10 during courses 2 and 4. Immunotherapy repeats every 28 days for 5 courses in the absence of disease progression or unacceptable toxicity. Patients also receive oral isotretinoin as in arm I beginning on and day 11 of immunotherapy.

     Patients are followed periodically for 10 years.

The purpose of the study is to assess the safety and efficacy of targeted intramyocardial delivery of Auto-CD34+ cells for increasing exercise time and amelioration of anginal symptoms in subjects with refractory angina and chronic myocardial ischemia.

The study tests the hypothesis that related hematopoietic stem cell donors are at a higher risk for acute medical and psychological toxicity associated with the donation process compared to adult unrelated hematopoietic stem cell donors. The study will also assess the hypothesis that young (<18 years) and older (>60 years) related donors are at increased risk for toxicity associated with donation compared to younger adult donors by describing the adverse events reported in these populations. An ancillary study of the psychological impact of donation on health-related quality of life (HRQoL) will enroll related donors and compare them to an age-matched normative cohort.

OBJECTIVES:

     Primary

       -  To determine if topically administered supersaturated calcium phosphate (Caphosol), rinsed orally four times daily at the initiation of conditioning for hematopoietic stem cell transplantation (HSCT), reduces oral mucositis as demonstrated by a decrease in duration of severe oral mucositis (World Health Organization [WHO] Grade 3 or 4), compared to placebo.

     Secondary

       -  To determine whether Caphosol administration, when compared to placebo, reduces oral mucositis as demonstrated by a decrease in incidence of severe oral mucositis (WHO Grade 3 or 4); severity of mucositis according to mouth pain categorical rating scale and Oral Mucositis Daily Questionnaire (OMDQ); incidence, total dose, and duration of parenteral opioid analgesic use (morphine equivalents); and incidence and duration of total parenteral nutrition (TPN) administration.

       -  To determine whether Caphosol administration, when compared to placebo, reduces the incidence of febrile neutropenia and invasive bacterial infections.

       -  To validate a new pediatric measure of oral mucositis termed the Children's International Mucositis Evaluation Scale (ChIMES).

     OUTLINE: This is a multicenter study. Patients are stratified according to conditioning regimen (total-body irradiation [TBI] or melphalan vs neither TBI nor melphalan) and hematopoietic stem cell transplantation (HSCT) (autologous vs allogeneic). Patients are randomized to 1 of 2 treatment arms.

       -  Arm I: Patients rinse and gargle with supersaturated calcium phosphate rinse over 1 minute four* times daily beginning on the first day (about day -7) of the conditioning regimen.

       -  Arm II: Patients rinse and gargle with placebo over 1 minute four* times daily beginning the first day (about day -7) of the conditioning regimen.

       -  NOTE: * Patients who reach WHO grade 3 or 4 mucositis have the option to request a total of 6 rinses daily.

     In both arms, treatment continues until day 20 post-transplantation OR until mucositis resolves to WHO Grade ≤ 2 for two consecutive days OR on day 12 in patients who do not experience oral mucositis of at least WHO Grade ≥ 1.

     Patients are assessed daily by trained healthcare professionals using the Oral Mucositis Daily Questionnaire (OMDQ), the Pain Rating Scale, the WHO Mucositis Scale, and the Children's International Mucositis Evaluation Scale (ChIMES) from day -1 and continuing until day 20. Patients are also observed for the incidence of total dose and duration of parenteral opioid analgesic use, duration of total parenteral nutrition (TPN) administration, febrile neutropenia, and invasive bacterial infections.

     After completion of study therapy, patients are followed up for 30 days.

OBJECTIVES:

     Primary

       -  Compare the event-free and overall survival of patients with tumor of the Ewing's family treated with standard induction chemotherapy comprising vincristine, dactinomycin, ifosfamide and etoposide (VIDE) followed by consolidation chemotherapy comprising vincristine, dactinomycin, and ifosfamide versus high-dose busulfan and melphalan (Bu-Mel) followed by autologous peripheral blood stem cell (PBSC) transplantation with or without radiotherapy and/or surgery.

     Secondary

       -  Determine the prognostic significance of EWS-Flil transcript in these patients.

       -  Determine the frequency and prognostic value of minimal disease in bone marrow and PBSC, as determined by the presence or absence of EWS-Flil transcript, in these patients.

       -  Determine the feasibility and toxicity of VIDE induction chemotherapy in these patients.

       -  Determine the response of these patients to VIDE induction chemotherapy.

       -  Determine the feasibility and toxicity of VAI consolodation chemotherapy in these patients.

       -  Determine the feasibility and toxicity of Bu-Mel consolodation chemotherapy in these patients.

       -  Determine event-free survival and overall survival of patients treated with these regimens by prognostic group analysis.

     OUTLINE: This is a randomized, multicenter study. Patients are stratified according to age and local treatment of the primary tumor (yes vs no).

     Patients receive induction chemotherapy comprising vincristine IV on day 1 and ifosfamide IV over 3 hours, doxorubicin IV over 4 hours, and etoposide IV over 1 hour on days 1-3 (VIDE). Treatment repeats every 21 days for 4 courses in the absence of unacceptable toxicity. Peripheral blood stem cells (PBSC) are collected after course 3 and/or 4. Patients are evaluated after course 4. Patients in need of early radiotherapy due to an axial tumor or patients who require radiotherapy to the brain and/or spinal cord (at any time during study) are assigned to group 1. Patients not needing early radiotherapy are assigned to group 2.

       -  Group 1: Patients receive 2 additional courses of VIDE induction chemotherapy (courses 5 and 6). Patients requiring radiotherapy to the axial tumor also undergo concurrent radiotherapy 5 days a week. Some patients may then undergo surgical resection of the tumor. All patients will then receive vincristine IV on day 1 and dactinomycin IV and ifosfamide IV over 3 hours on days 1 and 2 (VAI). Treatment repeats every 21 days for 8 courses (courses 7-14). Patients requiring radiotherapy to the brain and/or spinal cord also undergo concurrent radiotherapy.

       -  Group 2: Patients undergo 2 additional courses of VIDE induction chemotherapy (courses 5 and 6). Some patients may then undergo surgical resection of the tumor. All patients receive VAI chemotherapy as in group 1 for 1 course. Patients are randomized to 1 of 2 consolidation therapy arms.

            -  Arm I: Patients receive 7 additional courses of VAI chemotherapy (courses 8-14). Patients with unresectable, partially resected, or inadequately resected disease undergo concurrent whole-lung radiotherapy for 6-12 days.

            -  Arm II: Patients receive high-dose chemotherapy comprising oral busulfan every 6 hours on days -6 to -3 and melphalan IV over 30 minutes on day -2. Patients receive autologous PBSC IV on day 0. Patients with unresectable, partially resected, or inadequately resected disease undergo concurrent radiotherapy 5 days a week for at least 5 weeks.

     Patients are followed every 3 months for 4 years, every 6 months for 1 year, and then periodically thereafter.

     Peer Reviewed and Funded or Endorsed by Cancer Research UK

     PROJECTED ACCRUAL: Approximately 1,200 patients will be accrued for this study within approximately 7 years.