Phase I Study of Ipilimumab (Anti-CTLA-4) in Children and Adolescents With Treatment-Resistant Cancer
Condition: Sarcoma; Wilm's Tumor; Lymphoma; Neuroblastoma
MeSH terms: Sarcoma; Neuroblastoma; Wilms Tumor
Study type: Interventional
Phase: Phase 1

Summary: 
      This study will examine the safety and efficacy of ipilimumab-an experimental cancer
      treatment drug used to boost immune response-in children, adolescents, and young adults.
      Ipilimumab may allow immune cells to react to and destroy abnormal cells in the body, and has
      been tested in adults for a variety of cancers and has shown responses in some research
      studies. Because ipilimumab has not been tested in children, adolescents, or young adults, it
      is considered an experimental drug. The purposes of this research study are to determine the
      highest safe dose of ipilimumab for children, adolescents, and young adults with solid tumor
      cancers; examine its effectiveness and possible side effects; and better understand how the
      body and the immune system process it over time.

      Candidates must be between 2 and 21 years of age and must have solid malignant tumors that
      have been resistant to standard therapy. Volunteers will be screened with a medical history,
      a clinical examination, and computerized scans such as magnetic resonance imaging (MRI).
      Participants must have completed their last dose of chemotherapy, radiation, chemotherapy, or
      antibody or investigational therapy at least four weeks prior to enrollment.

      During the study, participants will receive an intravenous dose of ipilimumab once every
      three weeks. The infusion of ipilimumab will last 90 minutes, and the participant s vital
      signs will be monitored while the medicine is infusing and several times in the first 24
      hours after the first dose (requiring a hospital stay during that time). If the participant
      is able to tolerate the first dose of ipilimumab, further doses (called cycles ) may be
      received on an outpatient basis. Blood and urine tests will be given on a regular basis
      during these cycles. After four cycles, participants whose tumors do not grow and who do not
      have unacceptable side effects will continue to receive ipilimumab every three months to
      maintain the current condition, until researchers conclude the study.
    

Detailed description: 
      Background:

      Solid tumors represent approximately one fourth of cancer diagnoses in children. Despite
      intensive regimens, patients with metastatic or recurrent solid tumors have unsatisfactory
      survival rates. Therefore new therapies are needed to improve outcomes.

      Accumulating preclinical and clinical evidence supports the use of biologic approaches to
      heighten antitumor immunity in order to improve the effectiveness of immune based therapy.
      Both directly activating immune based therapies such as cytokines and tumor vaccines as well
      as therapies which disrupt negative counterregulatory signals such as those mediated by
      CTLA-4:B7 may enhance existent antitumor immune responses.

      Antibodies directed against CTLA-4 potently augment immune responses in animal models and
      anti-CTLA-4 antibodies have demonstrated antitumor effects in a variety of preclinical tumor
      models.

      Phase I and phase II studies using ipilimumab have been performed in adults with a variety of
      tumor types. Clinical responses have been observed in renal cell carcinoma, melanoma, and
      prostate cancer. No trials have yet been performed to evaluate ipilimumab in children with
      malignancy.

      Objectives:

      To determine the tolerance and toxicity profile of ipilimumab at a range of doses up to, but
      not exceeding, the highest dose tolerated in adults, in patients less than or equal to 21
      years of age with refractory solid tumors.

      To assess the pharmacokinetics of ipilimumab administered intravenously in patients less than
      or equal to 21 years of age with advanced and/or refractory solid tumors.

      Eligibility:

      Patients must be 1-21 years of age at the time of enrollment with solid malignant tumors
      refractory to standard therapy.

      Design:

      A Phase I dose finding study with 4 planned dose levels.

      Three patients will be enrolled at each dose level with an expanded cohort of 12 at the
      highest or maximum torlerated dose with intent to include 6 patients < 12 years.

      Re-induction with 4 infusions of ipilimumab at the assigned dose followed by another
      maintenance phase is possible for subjects who have progressed during maintenance therapy.
    

Intervention name(s): Ipilimumab
Intervention type(s): Drug
Intervention description(s): Dose Level Escalation: 1mg/kg, 3mg/kg, 5mg/kg, 10mg/kg
Intervention MeSH terms: Ipilimumab
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Solid Tumor; Monoclonal Antibody; Pediatrics; Pharmacokinetics; Immunotherapy; Sarcoma; Lymphoma; Neuroblastoma