Trial Review

Technical difficulties have been reported by some users of the search function and is being investigated by technical staff. Thank you for your patience and apologies for any inconvenience caused.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT05233397


Additional trial details provided through ANZCTR are available at the end of this record.


Registration number
NCT05233397
Ethics application status
Date submitted
25/01/2022
Date registered
10/02/2022
Date last updated
11/01/2024

Titles & IDs
Public title
ACTEMRA® for the Treatment of Pediatric Adamantinomatous Craniopharyngioma
Scientific title
Phase 2 Study of Systemic IL-6 Receptor Antagonist ACTEMRA® (Tocilizumab) for the Treatment of Progressive/Recurrent Pediatric Adamantinomatous Craniopharyngioma
Secondary ID [1] 0 0
CONNECT1905
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Adamantinomatous Craniopharyngioma 0 0
Recurrent Adamantinomatous Craniopharyngioma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Brain
Cancer 0 0 0 0
Bone

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Tocilizumab

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


Treatment: Drugs: Tocilizumab
For < 30 kg: 12 mg/kg IV every 2 weeks; For =30 kg: 8 mg/kg IV every 2 weeks
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Sustained objective response rate of patients with recurrent/progressive previously irradiated ACP to treatment with systemic tocilizumab
Timepoint [1] 0 0
From Day 1 of treatment through 30 days following end of protocol treatment
Primary outcome [2] 0 0
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
Timepoint [2] 0 0
From Day 1 of treatment through 30 days following end of protocol treatment
Secondary outcome [1] 0 0
Biological effects of tocilizumab on ACP tumor tissue and cyst fluid.
Timepoint [1] 0 0
From Day 1 of treatment through 30 days following end of protocol treatment
Secondary outcome [2] 0 0
Toxicities associated with tocilizumab in children with ACP
Timepoint [2] 0 0
From Day 1 of treatment through 30 days following end of protocol treatment
Secondary outcome [3] 0 0
PFS of ACP patients treated with tocilizumab after radiation
Timepoint [3] 0 0
12 months
Secondary outcome [4] 0 0
PFS of ACP patients treated with tocilizumab who have not received radiation
Timepoint [4] 0 0
12 months

Eligibility
Key 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.
Minimum age
1 Year
Maximum age
25 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
N/A
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
16/12/2022
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/12/2026
Actual
Sample size
Target
38
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,WA
Recruitment hospital [1] 0 0
Sydney Children's Hospital - Randwick
Recruitment hospital [2] 0 0
Queensland Children's Hospital - South Brisbane
Recruitment hospital [3] 0 0
Perth Children's Hospital - Perth
Recruitment postcode(s) [1] 0 0
2031 - Randwick
Recruitment postcode(s) [2] 0 0
4101 - South Brisbane
Recruitment postcode(s) [3] 0 0
6000 - Perth
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Colorado
Country [2] 0 0
United States of America
State/province [2] 0 0
District of Columbia
Country [3] 0 0
United States of America
State/province [3] 0 0
Illinois
Country [4] 0 0
United States of America
State/province [4] 0 0
Massachusetts
Country [5] 0 0
United States of America
State/province [5] 0 0
North Carolina
Country [6] 0 0
United States of America
State/province [6] 0 0
Ohio
Country [7] 0 0
United States of America
State/province [7] 0 0
Texas
Country [8] 0 0
United States of America
State/province [8] 0 0
Washington
Country [9] 0 0
Canada
State/province [9] 0 0
Ontario
Country [10] 0 0
Canada
State/province [10] 0 0
Quebec
Country [11] 0 0
Germany
State/province [11] 0 0
Baden-Württemberg
Country [12] 0 0
Netherlands
State/province [12] 0 0
Utrecht
Country [13] 0 0
United Kingdom
State/province [13] 0 0
London

Funding & Sponsors
Primary sponsor type
Other
Name
Nationwide Children's Hospital
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
Children's Hospital Colorado
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief 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.
Trial website
https://clinicaltrials.gov/ct2/show/NCT05233397
Trial related presentations / publications
Brunner HI, Ruperto N, Zuber Z, Keane C, Harari O, Kenwright A, Lu P, Cuttica R, Keltsev V, Xavier RM, Calvo I, Nikishina I, Rubio-Perez N, Alexeeva E, Chasnyk V, Horneff G, Opoka-Winiarska V, Quartier P, Silva CA, Silverman E, Spindler A, Baildam E, Gamir ML, Martin A, Rietschel C, Siri D, Smolewska E, Lovell D, Martini A, De Benedetti F; Paediatric Rheumatology International Trials Organisation PRINTO; Pediatric Rheumatology Collaborative Study Group (PRCSG). Efficacy and safety of tocilizumab in patients with polyarticular-course juvenile idiopathic arthritis: results from a phase 3, randomised, double-blind withdrawal trial. Ann Rheum Dis. 2015 Jun;74(6):1110-7. doi: 10.1136/annrheumdis-2014-205351. Epub 2014 May 16.
Roszkiewicz J, Orczyk K, Smolewska E. Tocilizumab in the treatment of systemic-onset juvenile idiopathic arthritis - single-centre experience. Reumatologia. 2018;56(5):279-284. doi: 10.5114/reum.2018.79497. Epub 2018 Oct 31.
Choy EH, Isenberg DA, Garrood T, Farrow S, Ioannou Y, Bird H, Cheung N, Williams B, Hazleman B, Price R, Yoshizaki K, Nishimoto N, Kishimoto T, Panayi GS. Therapeutic benefit of blocking interleukin-6 activity with an anti-interleukin-6 receptor monoclonal antibody in rheumatoid arthritis: a randomized, double-blind, placebo-controlled, dose-escalation trial. Arthritis Rheum. 2002 Dec;46(12):3143-50. doi: 10.1002/art.10623.
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.
Donson AM, Apps J, Griesinger AM, Amani V, Witt DA, Anderson RCE, Niazi TN, Grant G, Souweidane M, Johnston JM, Jackson EM, Kleinschmidt-DeMasters BK, Handler MH, Tan AC, Gore L, Virasami A, Gonzalez-Meljem JM, Jacques TS, Martinez-Barbera JP, Foreman NK, Hankinson TC; Advancing Treatment for Pediatric Craniopharyngioma Consortium. Molecular Analyses Reveal Inflammatory Mediators in the Solid Component and Cyst Fluid of Human Adamantinomatous Craniopharyngioma. J Neuropathol Exp Neurol. 2017 Sep 1;76(9):779-788. doi: 10.1093/jnen/nlx061.
Grob S, Mirsky DM, Donson AM, Dahl N, Foreman NK, Hoffman LM, Hankinson TC, Mulcahy Levy JM. Targeting IL-6 Is a Potential Treatment for Primary Cystic Craniopharyngioma. Front Oncol. 2019 Aug 21;9:791. doi: 10.3389/fonc.2019.00791. eCollection 2019.
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.
Gust J, Hay KA, Hanafi LA, Li D, Myerson D, Gonzalez-Cuyar LF, Yeung C, Liles WC, Wurfel M, Lopez JA, Chen J, Chung D, Harju-Baker S, Ozpolat T, Fink KR, Riddell SR, Maloney DG, Turtle CJ. Endothelial Activation and Blood-Brain Barrier Disruption in Neurotoxicity after Adoptive Immunotherapy with CD19 CAR-T Cells. Cancer Discov. 2017 Dec;7(12):1404-1419. doi: 10.1158/2159-8290.CD-17-0698. Epub 2017 Oct 12.
Mihara M, Kasutani K, Okazaki M, Nakamura A, Kawai S, Sugimoto M, Matsumoto Y, Ohsugi Y. Tocilizumab inhibits signal transduction mediated by both mIL-6R and sIL-6R, but not by the receptors of other members of IL-6 cytokine family. Int Immunopharmacol. 2005 Nov;5(12):1731-40. doi: 10.1016/j.intimp.2005.05.010.
Nellan A, McCully CML, Cruz Garcia R, Jayaprakash N, Widemann BC, Lee DW, Warren KE. Improved CNS exposure to tocilizumab after cerebrospinal fluid compared to intravenous administration in rhesus macaques. Blood. 2018 Aug 9;132(6):662-666. doi: 10.1182/blood-2018-05-846428. Epub 2018 Jun 28. No abstract available.
Nishimoto N, Kishimoto T. Inhibition of IL-6 for the treatment of inflammatory diseases. Curr Opin Pharmacol. 2004 Aug;4(4):386-91. doi: 10.1016/j.coph.2004.03.005.
Nishimoto N, Kishimoto T. Humanized antihuman IL-6 receptor antibody, tocilizumab. Handb Exp Pharmacol. 2008;(181):151-60. doi: 10.1007/978-3-540-73259-4_7.
Nishimoto N, Yoshizaki K, Maeda K, Kuritani T, Deguchi H, Sato B, Imai N, Suemura M, Kakehi T, Takagi N, Kishimoto T. Toxicity, pharmacokinetics, and dose-finding study of repetitive treatment with the humanized anti-interleukin 6 receptor antibody MRA in rheumatoid arthritis. Phase I/II clinical study. J Rheumatol. 2003 Jul;30(7):1426-35.
Nishimoto N, Yoshizaki K, Miyasaka N, Yamamoto K, Kawai S, Takeuchi T, Hashimoto J, Azuma J, Kishimoto T. Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial. Arthritis Rheum. 2004 Jun;50(6):1761-9. doi: 10.1002/art.20303.
Sato K, Tsuchiya M, Saldanha J, Koishihara Y, Ohsugi Y, Kishimoto T, Bendig MM. Reshaping a human antibody to inhibit the interleukin 6-dependent tumor cell growth. Cancer Res. 1993 Feb 15;53(4):851-6.
Yokota S, Miyamae T, Imagawa T, Iwata N, Katakura S, Mori M, Woo P, Nishimoto N, Yoshizaki K, Kishimoto T. Therapeutic efficacy of humanized recombinant anti-interleukin-6 receptor antibody in children with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 2005 Mar;52(3):818-25. doi: 10.1002/art.20944.
Public notes

Contacts
Principal investigator
Name 0 0
Kathleen H Dorris, MD
Address 0 0
Children's Hospital Colorado
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Leonie Mikael, PhD
Address 0 0
Country 0 0
Phone 0 0
16147223284
Fax 0 0
Email 0 0
leonie.mikael@nationwidechildrens.org
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT05233397

Additional trial details provided through ANZCTR
Accrual to date
1
Recruiting in Australia
Recruitment state(s)
NSW,QLD,WA
Recruitment hospital [1] 127
Sydney Children's Hospital
Recruitment hospital [2] 128
Queensland Children's Hospital
Recruitment hospital [3] 129
Perth Children's Hospital
Recruitment postcode(s) [1] 129
2031
Recruitment postcode(s) [2] 130
4101
Recruitment postcode(s) [3] 131
6009
Funding & Sponsors
Primary sponsor
Other Collaborative groups
Primary sponsor name
Australia and New Zealand Children’s Haematology/Oncology Group (ANZCHOG
Primary sponsor address
27-31 Wright Street
Clayton, VIC, 3168
Primary sponsor country
Australia
Ethics approval
Ethics application status
Approved
Ethics committee name [1] 57
Child and Adolescent Health Service Human Research Ethics Committee
Address [1] 57
15 Hospital Avenue Nedlands, WA, 6009
Country [1] 57
Date submitted for ethics approval [1] 57
20/09/2022
Approval date [1] 57
26/10/2022
Ethics approval number [1] 57
RGS0000005636
 
Public notes

Contacts
Principal investigator
Title 369 0
Dr
Name 369 0
Neevkia Manoharan
Address 369 0
Sydney Children’s Hospital Kids Cancer Centre Level 1 South Wing, High Street Randwick 2031, NSW Australia
Country 369 0
Australia
Phone 369 0
+61 2 9382 1730
Fax 369 0
Email 369 0
 Neevika.Manoharan@health.nsw.gov.au
Contact person for public queries
Title 370 0
Ms
Name 370 0
Robyn Strong
Address 370 0
27-31 Wright Street Clayton, VIC, 3168
Country 370 0
Australia
Phone 370 0
+613 8572 2684
Fax 370 0
Email 370 0
anzchog_connect1905@anzchog.org
Contact person for scientific queries
Title 371 0
Dr
Name 371 0
Neevkia Manoharan
Address 371 0
Sydney Children’s Hospital Kids Cancer Centre Level 1 South Wing, High Street Randwick 2031, NSW Australia
Country 371 0
Australia
Phone 371 0
+61 2 9382 1730
Fax 371 0
Email 371 0
 Neevika.Manoharan@health.nsw.gov.au