ACTEMRA® for the Treatment of Pediatric Adamantinomatous Craniopharyngioma

Официальное название

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

Обзор

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.

Подробное описание

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-CLOSED to enrollment).

Вмешательства

• Препарат Tocilizumab
  For \< 30 kg: 12 mg/kg IV every 2 weeks; For ≥30 kg: 8 mg/kg IV every 2 weeks

Первичные конечные точки

• Sustained objective response rate of patients with recurrent/progressive previously irradiated ACP to treatment with systemic tocilizumab [Срок оценки: 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 tocilizumab [Срок оценки: From Day 1 of treatment through 30 days following end of protocol treatment]

Вторичные конечные точки (4)

• Biological effects of tocilizumab on ACP tumor tissue and cyst fluid. [Срок оценки: From Day 1 of treatment through 30 days following end of protocol treatment]
• Toxicities associated with tocilizumab in children with ACP [Срок оценки: From Day 1 of treatment through 30 days following end of protocol treatment]
• PFS of ACP patients treated with tocilizumab after radiation [Срок оценки: 12 months]
• PFS of ACP patients treated with tocilizumab who have not received radiation [Срок оценки: 12 months]

Критерии участия

Критерии включения

• Age: Patients must be ≥ 12 months and ≤ 39 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 (CLOSED): 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

• 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 major or intermediate surgery. Major surgery includes major craniotomy for tumor resection or cyst fenestration, organ resection, exploratory laparotomy. Intermediate procedures include ventriculoperitoneal shunt placement, stereotactic brain biopsy and intraventricular catheter placement. Minor procedures that are not excluded include skin biopsy/incision and drainage, bone marrow aspirate, and central venous catheter placement. Ommaya aspirations and Lumbar Punctures are considered minor procedures..
• 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.
• 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.

Критерии исключения

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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 8 центров

• Children's Hospital Colorado — Aurora
• Children's National Medical Center — Washington D.C.
• Nicklaus Children's Hospital — Miami
• Duke Children's Hospital — Durham
• Cincinnati Children's Hospital Medical Center — Cincinnati
• Nationwide Children's Hospital — Columbus
• Texas Children's Hospital — Houston
• Seattle Children's Hospital — Seattle

Австралия · 3 центра

• Sydney Children's Hospital — Randwick
• Queensland Children's Hospital — South Brisbane
• Perth Children's Hospital — Perth

Канада · 3 центра

• Stollery Children's Hospital — Edmonton
• The Hospital for Sick Children (SickKids) — Toronto
• McGill University Health Center — Montreal

Публикации

• 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 PMID 24834925
• 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. PMID 30505008
• 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- PMID 12483717
• 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):23 PMID 23252525
• 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 Comp PMID 28859336
• 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. PMID 31497533
• 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. PMID 25990246
• 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 201 PMID 29025771

Идентификаторы

NCT: NCT05233397 · CONNECT1905

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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