ACTEMRA® for the Treatment of Pediatric Adamantinomatous Craniopharyngioma

Adamantinomatous Craniopharyngioma Clinical Trial

Official title:

Phase 2 Study of Systemic IL-6 Receptor Antagonist ACTEMRA® (Tocilizumab) for the Treatment of Progressive/Recurrent Pediatric Adamantinomatous Craniopharyngioma

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05233397
• Other study ID #: CONNECT1905
• Status: Recruiting
• Phase: Phase 2
• Start date: December 16, 2022
• Est. completion date: December 2026

Study information

• Verified date: January 2024
• Source: Nationwide Children's Hospital
• Contact: Leonie Mikael, PhD
• Phone: 16147223284
• Email: leonie.mikael[@]nationwidechildrens.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 38
• Est. completion date: December 2026
• Est. primary completion date: December 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Year to 25 Years

Eligibility

Inclusion Criteria:

1. Age: Patients must be = 12 months and = 25 years of age at the time of study enrollment.

2. 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.

3. 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.

4. 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.

5. Prior Therapy: Patients must have recovered or stabilized from the acute toxic effects of prior treatments

• Biologic (anti-neoplastic agent): At least 7 days must have elapsed after the last (systemic or intracystic) dose of a biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair

• Immunotherapy: At least 42 days after the completion of any type of systemic immunotherapy, e.g. tumor vaccines.

• Monoclonal antibodies: At least 21 days after the last dose of a monoclonal antibody.

• Radiation therapy: Patients must have had their last (conventional or hypofractionated) fraction of: a) Focal irradiation > 6 months prior to enrollment and b) No prior craniospinal irradiation is permitted.

• Corticosteroids: Patients receiving dexamethasone must be on a stable or decreasing dose for at least 1 week prior to enrollment

• Myelosuppressive systemic therapy: At least 21 days must have elapsed after the last systemic myelosuppressive therapy.

• Surgery: At least 6 weeks must have elapsed since surgery.

6. 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 for males and females. 6 to < 10 years: maximum serum creatinine 1.0 mg/dL for males and females. 10 to < 13 years: maximum serum creatinine 1.2 mg/dL for males and females. 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.

7. 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:

1. 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. For females of childbearing potential, agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods (bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices; hormonal contraceptive methods must be supplemented by a barrier method) and agreement to refrain from donating eggs are required. For males of reproductive potential, agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm.

2. Gastrointestinal Disease: Patients with a history of serious gastrointestinal disease, including inflammatory bowel disease or gastrointestinal perforation

3. Concomitant Medications

• Corticosteroids: 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.

4. 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.

Related Conditions & MeSH terms

• Adamantinomatous Craniopharyngioma
• Craniopharyngioma

Intervention

Drug:
• Tocilizumab
For < 30 kg: 12 mg/kg IV every 2 weeks; For =30 kg: 8 mg/kg IV every 2 weeks

Locations

Country	Name	City	State
Australia	Perth Children's Hospital	Perth	Western Australia
Australia	Sydney Children's Hospital	Randwick	New South Wales
Australia	Queensland Children's Hospital	South Brisbane	Queensland
Canada	Montreal Children's Hospital	Montréal	Quebec
Canada	The Hospital for Sick Children (SickKids)	Toronto	Ontario
Germany	Hopp Children's Cancer Center at NCT Heidelberg (KiTZ)	Heidelberg	Baden-Württemberg
Netherlands	Jasper van der Lugt	Utrecht
United Kingdom	Great Ormond Street Hospital	London
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Ann & Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	Duke University Health System	Durham	North Carolina
United States	Texas Children's Hospital	Houston	Texas
United States	Seattle Children's Hospital	Seattle	Washington
United States	Children's National Medical Center	Washington	District of Columbia

Sponsors (2)

Lead Sponsor	Collaborator
Nationwide Children's Hospital	Children's Hospital Colorado

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Germany,  Netherlands,  United Kingdom, 

References & Publications (16)

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De Benedetti F, Brunner HI, Ruperto N, Kenwright A, Wright S, Calvo I, Cuttica R, Ravelli A, Schneider R, Woo P, Wouters C, Xavier R, Zemel L, Baildam E, Burgos-Vargas R, Dolezalova P, Garay SM, Merino R, Joos R, Grom A, Wulffraat N, Zuber Z, Zulian F, Lovell D, Martini A; PRINTO; PRCSG. Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. N Engl J Med. 2012 Dec 20;367(25):2385-95. doi: 10.1056/NEJMoa1112802. Erratum In: N Engl J Med. 2015 Feb 26;372(9):887. — View Citation

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Gump JM, Donson AM, Birks DK, Amani VM, Rao KK, Griesinger AM, Kleinschmidt-DeMasters BK, Johnston JM, Anderson RC, Rosenfeld A, Handler M, Gore L, Foreman N, Hankinson TC. Identification of targets for rational pharmacological therapy in childhood craniopharyngioma. Acta Neuropathol Commun. 2015 May 21;3:30. doi: 10.1186/s40478-015-0211-5. — View Citation

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* Note: There are 16 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Sustained objective response rate of patients with recurrent/progressive previously irradiated ACP to treatment with systemic tocilizumab	To 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
Primary	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 tocilizumab	To 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	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
Secondary	Toxicities associated with tocilizumab in children with ACP	To 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
Secondary	PFS of ACP patients treated with tocilizumab after radiation	To 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
Secondary	PFS of ACP patients treated with tocilizumab who have not received radiation	To 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