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ACTEMRA® for the Treatment of Pediatric Adamantinomatous Craniopharyngioma

PHASE2RECRUITING

ACTEMRA (tocilizumab) is an IL-6 receptor antagonist used for the treatment of adult Rheumatoid Arthritis as well as Polyarticular (PJIA) and Systemic (SJIA) Juvenile Idiopathic Arthritis. In this Phase II, the drug will be used to treat pediatric patients diagnosed with recurrent Adamantinomatous Craniopharyngioma including patients who have undergone surgery and/or radiation therapy.

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Study details:

Adamantinomatous Craniopharyngioma (ACP) is a highly debilitating pediatric brain tumor that lacks medical anti-tumor therapies. Current therapy, which depends largely on surgery and radiation, is associated with poor quality of life and becomes more challenging and risky in the setting of recurrent disease. Recent discoveries regarding the biological characteristics of ACP indicate that available agents, including IL-6 pathway blockers may have efficacy in the control of ACP.

We hypothesize that the IL6- receptor antagonist ACTEMRA (tocilizumab) will be safe and effective at inducing tumor response in children with residual ACP. In this study, up to 38 patients will receive tocilizumab at the dose approved for pediatric Systemic Juvenile Idiopathic Arthritis (\< 30 kg: 12 mg/kg IV every 2 weeks; ≥30 kg: 8 mg/kg IV every 2 weeks). Therapy may continue for up to two years (26 cycles).

It will be a multi-center Phase 2 trial with two strata for patients aged \>1 year and \<25 years with unresectable ACP who may have been previously treated with radiation (Stratum 1, 18 patients) or without radiation (Stratum 2, 18 patients).

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

Inclusion criteria

  • Age: Patients must be ≥ 12 months and ≤ 25 years of age at the time of study enrollment.
  • Diagnosis: Patients with histologically-confirmed adamantinomatous craniopharyngioma (ACP) Histologic confirmation of ACP may be made on solid tumor or, if no solid tumor can be safely obtained, cyst fluid with classic ACP characteristics of thick, cholesterol-rich, greenish-brown liquid in the context of imaging features consistent with craniopharyngioma, including lobulated, cystic/solid mass with calcifications that originates in the sellar/suprasellar region.
  • Disease Status: Patients must have measurable disease.
  • Stratum 1: Patients with progressive or recurrent ACP who demonstrate cystic and/or solid recurrence or progression at least 6 months post completion of radiation therapy
  • Stratum 2: Patients with measurable ACP who have undergone surgery but have NOT previously undergone irradiation (but may have received prior systemic or intracystic therapy). Progressive disease is allowed but not required.
  • Performance Level: Karnofsky ≥ 50% for patients > 16 years of age and Lansky ≥ 50 for patients ≤ 16 years of age (See Appendix I). Note: Neurologic deficits in patients with CNS tumors must have been stable for at least 7 days prior to study enrollment. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
  • Prior Therapy: Patients must have recovered or stabilized from the acute toxic effects of prior treatments
  • Organ Function Requirements: Adequate Bone Marrow Function Defined as: Peripheral absolute neutrophil count (ANC) ≥1000/mm3, Platelet count ≥100,000/mm3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment), Hemoglobin >8 g/dL (may be transfused).
  • Adequate Renal Function Defined as: Creatinine clearance or radioisotope GFR > 70ml/min/1.73 m2 or a serum creatinine based on (Schwartz et al. J. Peds, 106:522, 1985) age/gender as follows: 1 to < 2 years: maximum serum creatinine 0.6 mg/dL for males and females. 2 to < 6 years: maximum serum creatinine 0.8 mg/dL; 6 to < 10 years: maximum serum creatinine 1.0 mg/dL; 10 to < 13 years: maximum serum creatinine 1.2 mg/dL; 13 to < 16 years: maximum serum creatinine 1.5 mg/dL for males and 1.4 mg/dL for females; ≥ 16 years: maximum serum creatinine 1.7 mg/dL for males and 1.4 mg/dL for females.
  • Adequate Liver Function Defined as: Total bilirubin within normal institutional limits, AST (SGOT) ≤ 2.5 × institutional upper limit of normal, ALT (SGPT) ≤ 2.5 × institutional upper limit of normal.
  • Adequate Neurologic Function Defined as: Patients with neurological deficits should have deficits that are stable for a minimum of 1 week prior to enrollment. Patients with current seizure disorders may be enrolled if seizures are well-controlled on antiepileptic therapies.
  • Informed Consent: All patients and/or their parents or legally authorized representatives must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines.
  • Exclusion criteria

  • Pregnancy or Breast-Feeding: Pregnant or breast-feeding women will not be entered on this study due to unknown risks of fetal and teratogenic adverse events as seen in animal/human studies. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method for at least 90 days after discontinuation of drug for females and at least 60 days for males.
  • Gastrointestinal Disease: Patients with a history of serious gastrointestinal disease, including inflammatory bowel disease or gastrointestinal perforation.
  • Concomitant Medications: Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible.
  • Investigational Drugs: Patients who are currently receiving another investigational drug are not eligible.
  • Anti-cancer Agents: Patients who are currently receiving other anti-cancer agents are not eligible.
  • Study Specific: Patients who have an uncontrolled infection are not eligible.
  • Patients who have received any live or attenuated vaccinations within three months prior to start of therapy are not eligible.
  • Any significant concurrent medical or surgical condition that would jeopardize the patient's safety or ability to complete the study, including, but not limited to, disease of the nervous, renal, hepatic, cardiac (such as symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia), pulmonary, or endocrine system.
  • Patients who have a history of Human Immunodeficiency Virus, Hepatitis B Virus, Hepatitis C Virus or Tuberculosis infection are not eligible.
  • Patients who have received a prior solid organ transplantation are not eligible.
  • Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible.
  • Patients who have a history of alcohol, drug, or chemical abuse within 6 months of screening.
  • Patients who have had surgery within the last 6 weeks or who have concerns for poor postsurgical wound healing.
  • Patients who have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to tocilizumab and its excipients are not eligible.
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    Eligibility

    Age eligible for study : 1 and older

    Healthy volunteers accepted : No

    Gender eligible for study: All

    Things to know

    Study dates

    Study start: 2022-12-16

    Primary completion: 2025-12-01

    Study completion finish: 2027-12-01

    study type

    Study type

    TREATMENT

    phase

    Phase

      PHASE2

    trial

    Trial ID

    NCT05233397

    Intervention or treatment

    DRUG: Tocilizumab

    Conditions

    • Recurrent Adamantinomatous Craniopharyngioma
    • Adamantinomatous Craniopharyngioma
    Image related to Recurrent Adamantinomatous Craniopharyngioma
    • Condition: Recurrent Adamantinomatous Craniopharyngioma, Adamantinomatous Craniopharyngioma

    • DRUG: Tocilizumab

    • Randwick, New South Wales, Australia and more

    • Sponsor: Nationwide Children's Hospital

    Find a site

    Closest Location:

    Sydney Children's Hospital

    Research sites nearby

    Select from list below to view details:

    • Sydney Children's Hospital

      Randwick, New South Wales, Australia

    • Queensland Children's Hospital

      South Brisbane, Queensland, Australia

    • Perth Children's Hospital

      Perth, Western Australia, Australia

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    Study Plan

    This section provides details of the study plan, including how the study is designed and what the study is measuring.

    How is the study designed?

    Participant Group/ArmIntervention/Treatment
    EXPERIMENTAL: Stratum 1 and Stratum 2
    • Stratum 1: Patients with progressive or recurrent adamantinomatous craniopharyngiomas following radiation therapy.
    • Stratum 2: Patients with measurable adamantinomatous craniopharyngioma who have undergone surgery but have not previously received radiation therapy. Progressive disease is allowed but not required
    DRUG: Tocilizumab
    • For \< 30 kg: 12 mg/kg IV every 2 weeks; For ≥30 kg: 8 mg/kg IV every 2 weeks

    What is the study measuring?

    Primary outcome

    Primary Outcome MeasurePrimary Outcome DescriptionPrimary Outcome Time Frame
    Sustained objective response rate of patients with recurrent/progressive previously irradiated ACP to treatment with systemic tocilizumabTo calculate the number of patients who experience sustained objective response rate \[minor response (MR) + partial response (PR) + complete response (CR)\] of patients with recurrent/progressive previously irradiated Adamantinomatous Craniopharyngioma to treatment with systemic tocilizumab (Stratum 1).From Day 1 of treatment through 30 days following end of protocol treatment
    Sustained objective response rate of patients with measurable ACP who have undergone surgery but have not been previously treated with radiation to treatment with systemic tocilizumabTo calculate the number of patients who experience sustained objective response rate (MR + PR + CR) of patients with measurable Adamantinomatous Craniopharyngioma who have undergone surgery but have not been previously treated with radiation to treatment with systemic tocilizumab (Stratum 2).From Day 1 of treatment through 30 days following end of protocol treatment

    Secondary outcome

    Secondary Outcome MeasureSecondary Outcome DescriptionSecondary Outcome Time Frame
    Biological effects of tocilizumab on ACP tumor tissue and cyst fluid.To measure the concentrations of IL-6, IL-8, IL-10, CXCL1, CXCR2, IDO-1 and IL-6R using a combination of ELISA, RNAseq, immunohistochemistry and immunofluorescence in cyst fluid or tumor tissue or blood. Comparisons will be made with known levels in the literature and among patient samples from within the study.From Day 1 of treatment through 30 days following end of protocol treatment
    Toxicities associated with tocilizumab in children with ACPTo calculate the number of participants with, as well as frequency and severity of, tocilizumab-related Adverse Events as assessed by CTCAE v5.0 in children with recurrent or refractory ACP.From Day 1 of treatment through 30 days following end of protocol treatment
    PFS of ACP patients treated with tocilizumab after radiationTo assess one-year progression-free survival (PFS) rates for patients with ACP who are treated with tocilizumab following progression after radiation (Stratum 1).12 months
    PFS of ACP patients treated with tocilizumab who have not received radiationTo assess one-year progression-free survival (PFS) rates for patients with ACP who are treated with tocilizumab who have not previously received radiation (Stratum 2).12 months

    Frequently Asked Questions

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    References

    Clinical Trials Gov: ACTEMRA® for the Treatment of Pediatric Adamantinomatous Craniopharyngioma

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