Tocilizumab in Children With ACP

Study Overview
=================
Brief Summary
-----------------
This study will be conducted in two phases. The first phase (phase 0) will be looking at patients with new or recurrent/ progressed craniopharyngioma tumors. These patients will be given one dose of tocilizumab before they have SOC surgery of their tumor. The objective of this phase is to see if drug reaches the tumor. If phase 0 is favorable and shows that drug is penetrating the tumor, the second phase of the study (feasibility phase) will open. Both phases will remain open concurrently and patients will be able to enroll on the Phase 0 then roll over and enroll on the feasibility phase. During the feasibility phase patients will be administered tocilizumab every two weeks for up to 13 cycles (approximately 1 year). Patients will be followed for up to 5 years in the feasibility phase.

Official Title
-----------------
A Phase 0/Feasibility Trial of Tocilizumab in Children and Adolescents With Newly- Diagnosed or Recurrent/Progressive Adamantinomatous Craniopharyngioma

Conditions
-----------------
Adamantinomatous Craniopharyngioma

Intervention / Treatment
-----------------
* Drug: Tocilizumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria Phase 0 Eligibility: Tumor biopsy/resection and/or cyst aspiration planned for the clinical care of the patient independent of study participation by the treating pediatric neurosurgeon and neuro-oncologist Must meet one of the following criteria: Presumed craniopharyngioma based on imaging features and best judgement of treating medical team (if newly diagnosed) Previous histologically confirmed ACP that has progressed or recurred at the time of enrollment Feasibility Eligibility: Must meet one of the following criteria: Recurrent or progressive* ACP treated with surgery alone without radiation Recurrent or progressive* ACP treated with surgery and radiation * Progressive disease for eligibility purposes will be defined as follows: Solid disease: any growth deemed progression based on discretion of the investigator regardless of timing from RT Cystic disease: must be at least 6 months from last day of RT. Patients demonstrating isolated cyst growth >6 months after RT must show a continued increase in the cystic component on two serial MRI scans performed at least 4 weeks apart OR at least partial reaccumulation of the cyst following one or more cyst aspirations. Newly diagnosed, by histology or imaging ACP with unresectable residual cystic and/or solid disease that is measurable in 2 dimensions Subjects who participated in the Phase 0 portion and meet eligibility, may enroll in the Feasibility Phase of the study once open. Overall Study Inclusion Criteria: Age: ≥ 2 years and < 21 years Subjects may have received prior tocilizumab or other IL6 or IL6R inhibitor Organ Function Requirements Adequate bone marrow function defined as: Platelet count ≥100,000/μl (transfusion independent) Absolute neutrophil count (ANC) ≥1500/μl Adequate renal function defined as: Creatinine clearance or radioisotope GFR ≥70 ml/min/1.73 m2 or A serum creatinine based on age/gender as follows: (Age, Male, Female) 3 to < 6 years, 0.8, 0.8; 6 to < 10 years, 1, 1; 10 to < 13 years, 1.2, 1.2; 13 to < 16 years, 1.5, 1.4; 16 years to < 18 years, 1.7, 1.4 Adequate liver function defined as: SGOT (AST) and SGPT (ALT) <1.5x ULN for age Subjects must meet one of the following performance scores: ECOG performance status scores of 0, 1, or 2; Karnofsky score of ≥60 for patients > 16 years of age; or Lansky score of ≥60 for patients ≤16 years of age Subjects of childbearing or child fathering potential must be willing to use a medically acceptable form of birth control, which includes abstinence, while being treated on this study. Informed consent and assent obtained as appropriate. Exclusion Criteria Pregnant or breastfeeding Uncontrolled intercurrent illness including, but not limited to: ongoing or active infection (including active tuberculosis) symptomatic congestive heart failure unstable angina pectoris cardiac arrhythmia psychiatric illness/social situations that would limit compliance with study requirements are not eligible. Known hypersensitivity or history of anaphylaxis to tocilizumab Received any live vaccinations within 3 months prior to start of therapy Evidence of metastatic disease or other cancer Inability to return for follow up visits or obtain required follow-up studies to assess toxicity of therapy

Ages Eligible for Study
-----------------
Minimum Age: 2 Years
Maximum Age: 21 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Phase 0 to open first and if outcomes are favorable showing drug penetration then the Feasibility Phase will open. Both arms will be open concurrently.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tocilizumab Administration: Phase 0<br>In Phase 0, patients will receive one dose of tocilizumab prior to surgery. | Drug: Tocilizumab<br>* Phase 0: One dose of tocilizumab prior to surgery Feasibility phase: Tocilizumab administered every 2 weeks for up to 13 cycles (approximately 1 year).<br>* Other names: Actemra;|
| Experimental: Tocilizumab Administration: Feasibility Phase<br>During the Feasibility Phase, patients will receive tocilizumab every 2 weeks for up to 13 cycles (approximately 1 year). Patients will be followed for up to 5 years. | Drug: Tocilizumab<br>* Phase 0: One dose of tocilizumab prior to surgery Feasibility phase: Tocilizumab administered every 2 weeks for up to 13 cycles (approximately 1 year).<br>* Other names: Actemra;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 0: Presence of Tocilizumab and Metabolites | Utilize biopsy and/or drainage to identify the presence of tocilizumab and its metabolites in adamantinomatous craniopharyngioma (ACP) tumor tissue and/or cyst fluid and/or CSF following one dose of systemically administered tocilizumab. | Within 4 to 8 hours of administration of tocilizumab | 
| Feasibility Phase: Toxicity Profile | To define toxicities of tocilizumab therapy using CTCAE version 5. | Start of study to end of study, up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 0: IL6 and Inflammatory Cytokines | To define levels of IL6 and other inflammatory cytokines in biopsied tissue and/or cyst fluid as measured by enzyme-linked immunosorbent assay (ELISA) following 1 dose of systemically administered tocilizumab | Within 4 to 8 hours of administration of tocilizumab | 
| Feasibility Phase: Progression Free Survival (PFS) | Utilize radiography to estimate PFS of subjects with newly diagnosed, unresectable or recurrent/progressive ACP (with or without prior radiation therapy) treated with systemic tocilizumab. | From date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months | 
| Feasibility Phase: Pathway Activation | To demonstrate evidence of WNT (Wingless-related integration site) in tumor tissue using immunohistochemistry and transcription array | Start of study to end of study, up to 5 years | 
| Feasibility Phase: Pathway Activation | To demonstrate evidence of MAPK (mitogen activated protein kinases) in tumor tissue using immunohistochemistry and transcription arr | Start of study to end of study, up to 5 years | 
| Feasibility Phase: Immunity | To demonstrate immune cell infiltration in tumor tissue using immunohistochemistry and flow cytometry | Start of study to end of study, up to 5 years | 
| Feasibility Phase: Cytokines | To characterize cytokine signaling in tumor tissue and/or cyst fluid using enzyme-linked immunosorbent assay (ELISA)To characterize cytokine signaling in tumor tissue and/or cyst fluid using enzyme-linked immunosorbent assay (ELISA) | Start of study to end of study, up to 5 years | 
| Feasibility Phase: Overall Response Rate (ORR) | Utilize radiography to estimate the overall response rate of subjects with newly diagnosed, unresectable or recurrent/progressive ACP (with or without prior radiation therapy) treated with systemic tocilizumab. | Start of study to end of study, or up to 5 years | 
| Feasibility Phase: 1-Year Disease Stabilization | Utilize radiography to estimate the 1-year disease stabilization rate of subjects with newly diagnosed, unresectable or recurrent/progressive ACP (with or without prior radiation therapy) treated with systemic tocilizumab. | Start of study to 1 year post treatment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Phase 0, Feasibility, Tocilizumab