Tocilizumab in Children With ACP

• ClinicalTrials.gov Identifier: NCT03970226
• Recruitment Status: Recruiting
• First Posted: May 31, 2019
• Last Update Posted: May 17, 2022
• Sponsor: University of Colorado, Denver
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): University of Colorado, Denver

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Adamantinomatous Craniopharyngioma	Drug: Tocilizumab	Early Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 27 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Intervention 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)
• Primary Purpose: Treatment
• Official Title: A Phase 0/Feasibility Trial of Tocilizumab in Children and Adolescents With Newly- Diagnosed or Recurrent/Progressive Adamantinomatous Craniopharyngioma
• Actual Study Start Date: June 27, 2019
• Estimated Primary Completion Date: December 2024
• Estimated Study Completion Date: December 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Tocilizumab Administration: Phase 0; In Phase 0, patients will receive one dose of tocilizumab prior to surgery.	Drug: Tocilizumab; Phase 0: One dose of tocilizumab prior to surgery Feasibility phase: Tocilizumab administered every 2 weeks for up to 13 cycles (approximately 1 year).
Experimental: Tocilizumab Administration: Feasibility Phase; 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; Phase 0: One dose of tocilizumab prior to surgery Feasibility phase: Tocilizumab administered every 2 weeks for up to 13 cycles (approximately 1 year).

Outcome Measures

Primary Outcome Measures :

1. Phase 0: Presence of Tocilizumab and Metabolites [ Time Frame: Within 4 to 8 hours of administration of tocilizumab ]
   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.
2. Feasibility Phase: Toxicity Profile [ Time Frame: Start of study to end of study, up to 5 years ]
   To define toxicities of tocilizumab therapy using CTCAE version 5.

Secondary Outcome Measures :

1. Phase 0: IL6 and Inflammatory Cytokines [ Time Frame: Within 4 to 8 hours of administration of tocilizumab ]
   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
2. Feasibility Phase: Progression Free Survival (PFS) [ Time Frame: 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 ]
   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.
3. Feasibility Phase: Pathway Activation [ Time Frame: Start of study to end of study, up to 5 years ]
   To demonstrate evidence of WNT (Wingless-related integration site) in tumor tissue using immunohistochemistry and transcription array
4. Feasibility Phase: Pathway Activation [ Time Frame: Start of study to end of study, up to 5 years ]
   To demonstrate evidence of MAPK (mitogen activated protein kinases) in tumor tissue using immunohistochemistry and transcription arr
5. Feasibility Phase: Immunity [ Time Frame: Start of study to end of study, up to 5 years ]
   To demonstrate immune cell infiltration in tumor tissue using immunohistochemistry and flow cytometry
6. Feasibility Phase: Cytokines [ Time Frame: Start of study to end of study, up to 5 years ]
   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)
7. Feasibility Phase: Overall Response Rate (ORR) [ Time Frame: Start of study to end of study, or up to 5 years ]
   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.
8. Feasibility Phase: 1-Year Disease Stabilization [ Time Frame: Start of study to 1 year post treatment ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 2 Years to 21 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria

Phase 0 Eligibility:

1. 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

2. Must meet one of the following criteria:

   1. Presumed craniopharyngioma based on imaging features and best judgement of treating medical team (if newly diagnosed)
   2. Previous histologically confirmed ACP that has progressed or recurred at the time of enrollment

Feasibility Eligibility:

1. Must meet one of the following criteria:

   1. Recurrent or progressive* ACP treated with surgery alone without radiation

   2. 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.

   3. Newly diagnosed, by histology or imaging ACP with unresectable residual cystic and/or solid disease that is measurable in 2 dimensions
2. 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:

1. Age: ≥ 2 years and < 21 years
2. Subjects may have received prior tocilizumab or other IL6 or IL6R inhibitor

3. Organ Function Requirements

   1. Adequate bone marrow function defined as:

      • Platelet count ≥100,000/μl (transfusion independent)
      • Absolute neutrophil count (ANC) ≥1500/μl

   2. 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

   3. Adequate liver function defined as:

      • SGOT (AST) and SGPT (ALT) <1.5x ULN for age

4. Subjects must meet one of the following performance scores:

   1. ECOG performance status scores of 0, 1, or 2;
   2. Karnofsky score of ≥60 for patients > 16 years of age; or
   3. Lansky score of ≥60 for patients ≤16 years of age
5. 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.
6. Informed consent and assent obtained as appropriate.

Exclusion Criteria

1. Pregnant or breastfeeding

2. Uncontrolled intercurrent illness including, but not limited to:

   1. ongoing or active infection (including active tuberculosis)
   2. symptomatic congestive heart failure
   3. unstable angina pectoris
   4. cardiac arrhythmia
   5. psychiatric illness/social situations that would limit compliance with study requirements are not eligible.
3. Known hypersensitivity or history of anaphylaxis to tocilizumab
4. Received any live vaccinations within 3 months prior to start of therapy
5. Evidence of metastatic disease or other cancer
6. Inability to return for follow up visits or obtain required follow-up studies to assess toxicity of therapy

Contacts and Locations

Contacts

Contact: Ashley Mettetal; 720-777-5305; Ashley.Mettetal@childrenscolorado.org

Contact: Katie Dorris; 720-777-8314; kathleen.dorris@childrenscolorado.org

Locations

United States, Colorado

Children's Hospital Colorado; Recruiting

Aurora, Colorado, United States, 80045

Contact: Kathleen Dorris, MD kathleen.dorris@childrenscolorado.org

Sponsors and Collaborators

University of Colorado, Denver

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Kathleen Dorris, MD; University of Colorado, Denver

More Information

• Responsible Party: University of Colorado, Denver
• ClinicalTrials.gov Identifier: NCT03970226
• Other Study ID Numbers: 18-2143.cc; 1R03CA235200-01 ( U.S. NIH Grant/Contract ); P30CA046934 ( U.S. NIH Grant/Contract )
• First Posted: May 31, 2019
• Last Update Posted: May 17, 2022
• Last Verified: May 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University of Colorado, Denver:

Phase 0; Feasibility; Tocilizumab

Additional relevant MeSH terms:

Craniopharyngioma; Adamantinoma; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Bone Neoplasms; Neoplasms by Site; Bone Diseases; Musculoskeletal Diseases