Selumetinib in Chinese Paediatric With Post-operative NF1-PNs, PhaseⅡ, Double-Blinded, Placebo-Controlled Study

NCT05825365 | Withdrawn Phase 2

• 1 other identifier: D1346C00018
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

This is a phase II, multicenter, randomised, parallel, double-blind, placebo-controlled study assessing the efficacy and safety of the MEKi selumetinib compared with placebo in Chinese paediatric participants with post-operative NF1-associated PNs.

Conditions

Neurofibromatosis Type 1; Plexiform Neurofibromas; Post-operative

Outcome Measures

Primary Outcomes (1)

• 2-year progression-free survival (PFS) Rate

  The time from randomisation to MRI assessment of objective disease progression (PD) or death (by any cause in the absence of progression) per REiNS criteria. PD is defined as an increase in target PN volume by 20% or more compared to baseline or compared to the time of best response after documenting a partial response (PR). The appearance of new PN (with the exception of new discrete subcutaneous neurofibromas) or unequivocal progression of existing clinically relevant non-target PN is also considered PD.

  2 years

Secondary Outcomes (13)

• Confirmed Partial Response(cPR) Rate in all participants who are randomised in the study.

  From begin to the end of treatment, around 2-3 years.

• Durable Partial Response (dPR) rate in all participants who are randomised in the study.

  From begin to the end of treatment, around 2-3 years.

• Complete Response (CR) rate in all participants who are randomised in the study.

  From begin to the end of treatment, around 2-3 years.

• Time to Initial Response in all participants who are randomised in the study.

  From begin to the end of treatment, around 2-3 years.

• Time to Best Response in all participants who are randomised in the study.

  From begin to the end of treatment, around 2-3 years.

Study Arms (2)

Selumetinib

ACTIVE COMPARATOR

Participants will orally receive selumetinib twice daily (BID) (approximately every 12 hours) at a dose of 25 mg per square meter of body surface area (BSA) on a continuous dosing schedule (28-day per cycle with no rest periods between cycles) for a maximum of 36 cycles.

Drug: Selumetinib

Placebo

PLACEBO COMPARATOR

Participants will orally receive placebo twice daily (BID) (approximately every12 hours) at a dose of 25 mg per square meter of body surface area (BSA) on a continuous dosing schedule (28-day per cycle with no rest periods between cycles) for a maximum of 36 cycles. Transfer to selumetinib on REiNS-defined PD.

Drug: Placebo

Interventions

Selumetinib DRUG

Selumetinib

Selumetinib

Placebo DRUG

Placebo (Transfer to selumetinib on REiNS-defined PD)

Placebo

Eligibility Criteria

• Age: 3 Years - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Paediatric subjects: Subjects ≥3 years and \<18 years of age with a BSA ≥0.55 m2 at the time of study enrolment.
• All study participants must have either positive genetic testing for NF1 or have at least one other diagnostic criterion for NF1 listed below Six or more macules (≥0.5cm in greatest diameter in pre-pubertal participants or ≥1.5 cm in greatest diameter in post-pubertal participants)； Freckling in the axillary or inguinal regions； Optic pathway glioma; Two or more iris Lisch nodules identified by slit lamp examination or 2 or more choroidal abnormalities-defined as bright, patchy nodules imaged by optical coherence tomography/near-infrared reflectance imaging; A distinctive bony lesion (such as: sphenoid dysplasia, anterolateral bowing of the tibia, or pseudoarthrosis of a long bone); A NF1 heterozygous pathogenic variant with a variant allele fraction of 50% in apparently normal tissue such as white blood cells; A parent with NF1 by the above criteria.
• Symptomatic PNs:The PN has to cause or have the potential to cause significant clinical complications, as judged by the investigator, such as (but not limited to) head and neck lesions that could compromise the airway or great vessels, paraspinal lesions that can cause myelopathy brachial or lumbar plexus lesions that could cause nerve compression and loss of function, lesions that could result in major deformity (e.g., orbital lesions) orare significantly disfiguring, lesions of the extremity that cause limb hypertrophy or loss of function, and painful lesions.
• A PN is defined as a neurofibroma that has grown along the length of a nerve and may involve multiple fascicles and branches. A spinal PN involves two or more levels with connection between the levels or extending laterally along the nerve.
• All study participants have received sub-total or partial resection of the targeted PN lesion (residue should be \> 20% of pre-operation volume, and measurable, defined as a lesion of ≥3 cm measured in one dimension on ≥3 imaging slices and have a reasonably well-defined contour), at least 4 weeks and up to 3 months after surgery.
• Performance status: Subjects \>16 years of age must have a Karnofsky performance level of ≥70, and children ≤16 years old must have a Lansky performance of ≥70 (Appendix G). Participants who are wheelchair bound or have limited mobility secondary to a need for mechanical breathing support (such as an airway PN requiring tracheostomy or continuous positive airway pressure) who must have a Lansky performance of ≥40 (Appendix G).
• All participants must be able to swallow whole capsules.
• Adequate organ and marrow function as follows with no blood transfusions (of red blood cells/ other blood products) within 28 days prior to screening assessment and no growth factors within 7 days prior to screening assessment:
• Haemoglobin ≥9.0 g/dL; Absolute neutrophil count ≥1.5×109/L; Platelet count ≥100×109/L; Total bilirubin (TBL) ≤1.5×the upper limit of normal (ULN) or ≤3×ULN in the presence of documented Gilbert's syndrome (unconjugated hyperbilirubinemia); Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) - choose from below options: ALT and AST ≤2×ULN; Serum creatinine or calculated creatinine clearance - choose from below options: Serum creatinine \>0.8 mg/dL for participants aged ≥1 to \<4 years or \>1.0 mg/dL for participants aged ≥4 years.
• Reproduction:
• Negative pregnancy test (serum) for women of childbearing potential. Female participants must be 1 year post-menopausal, surgically sterile, or using one highly effective form of birth control (a highly effective method of contraception is defined as one that can achieve a failure rate of less than 1% per year when used consistently and correctly) Women of childbearing potential must agree to use one highly effective method of birth control. They should have been stable on their chosen method of birth control for a minimum of 3 months before entering the study and continue to use it throughout the study and until at least 7 days after the last dose.
• Non sterilised male partners of a woman of childbearing potential must use a male condom plus spermicide (condom alone in countries where spermicides are not approved) throughout this period and until at least one week after the female participant's last dose of study intervention. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. Total sexual abstinence is an acceptable method provided it is the usual lifestyle of the participant.
• Non-sterilised male participants (including males sterilised by a method other than bilateral orchidectomy e.g., vasectomy) who intend to be sexually active with a female partner of childbearing potential must be using an acceptable method of contraception such as male condom plus spermicide (condom alone in countries where spermicides are not approved) from the time of screening throughout the total duration of the study and the drug washout period (at least 7 days after the last dose of study intervention) to prevent pregnancy in a partner. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. Vasectomised (i.e., sterile) males are considered fertile and should still use a male condom plus spermicide as indicated above during the clinical study. Even if the female partner is pregnant, male participants should still use a condom plus spermicide (where approved), as indicated above during the clinical study. Male participants must not donate or bank sperm during this same time period. Female partners (of childbearing potential) of male participants must also use a highly effective method of contraception throughout this period.
• Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial must only be done after obtaining written informed consent. Parent/legal guardian consent is required in the assent process with appropriate documentation. Mandatory provision of signed and dated parent/legal guardian consent for the study along with the paediatric assent form, when applicable. For participants who reach the age of legal consent during the clinical study, notification may be required and a new consent form may need to be signed by the participant.

You may not qualify if:

• Participants with confirmed or suspected malignant glioma or MPNST. Participants with low-grade gliomas (LGG) (including optic glioma) not requiring systemic therapy or radiation therapy are permitted.
• History of malignancy except for malignancy treatment with curative intent with no known active disease ≥2 years before the first dose of study intervention and of low potential risk of recurrence.
• Subjects with clinically significant cardiovascular disease as defined by the following:
• Known inherited coronary disease; Blood Pressure (BP): Uncontrolled hypertension (at screening: BP ≥140/90 mmHg despite optimal therapy); Acute coronary syndrome within 6 months prior to starting treatment; Uncontrolled angina - Canadian Cardiovascular Society grade II to IV despite medical therapy (Appendix F); Symptomatic heart failure New York Heart Association Class II to IV, prior or current cardiomyopathy, or severe valvular heart disease (Appendix F); Prior or current cardiomyopathy; Baseline left ventricular ejection fraction (LVEF) below the lower limit of normal (LLN) or \<55% measured by echocardiogram or institution's LLN for multigated acquisition (MUGA); Severe valvular heart disease; Symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Participants with atrial fibrillation controlled by medication may be permitted upon discussion with the AstraZeneca Medical Monitor; QT interval corrected by Fridericia's method (QTcF) \>470 ms or other factors that increase the risk of QT prolongation.
• Subjects with the following ophthalmological findings/conditions:
• Current or past history of retinal pigment epithelial detachment/central serous retinopathy or retinal vein occlusion; Intraocular pressure \>21 mmHg (or ULN adjusted by age) or uncontrolled glaucoma (irrespective of IOP). Subjects with known glaucoma and increased IOP who do not have meaningful vision (light perception only or no light perception) and are not experiencing pain related to the glaucoma, may be eligible after discussion with the Medical Monitor; Participants with any other significant abnormality on ophthalmic examination should be discussed with the Sponsor for potential eligibility.
• Have received or are receiving an IMP or other systemic PN target treatment (including chemotherapy, immunotherapy, targeted therapy, biologic therapy or monoclonal antibodies) within 4 weeks prior to the first dose of study treatment, or within a period during which the IMP or systemic PN target treatment has not been cleared from the body (e.g. a period of 5 'half-lives'), whichever is longer.
• Has received radiotherapy in the 6 weeks prior to the start of study intervention or any prior radiotherapy directed at the target or non-target PN.
• Inability to undergo MRI and/or contraindication for MRI examinations. Prosthesis or orthopaedic or dental braces in close proximity to the area of interest that would interfere with volumetric analysis of target PN on MRI.
• Refractory nausea and vomiting, chronic gastrointestinal disease, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption, distribution, metabolism, or excretion of selumetinib.
• Have had prior treatment with a MEK inhibitor.
• Has received Vitamin E in the 7 days prior to initiation of IMP (does not apply to Granule formulation).
• Receiving herbal supplements or medications known to be strong or moderate inhibitors or inducers of the cytochrome P450 (CYP)2C19 and CYP3A4 enzymes or fluconazole unless such products can be safely discontinued at least 14 days or 5 half-lives (whichever is longer) before the first dose of study medication.
• Persistent toxicities (CTCAE Grade ≥2) caused by previous therapy for NF1-PN, excluding hair changes such as alopecia or hair lightening. If considered appropriate for a study then include: Participants with irreversible toxicity that is not reasonably expected to be exacerbated by study intervention may be included (e.g., hearing loss) after consultation with the AstraZeneca Medical Monitor.
• Currently pregnant (confirmed with positive pregnancy test) or breastfeeding (lactation must be discontinued throughout the period of the study and until at least one week after the last dose of study intervention).

Sponsors & Collaborators

• AstraZeneca: lead

MeSH Terms

Conditions

Neurofibromatosis 1; Neurofibroma, Plexiform

Interventions

AZD 6244

Condition Hierarchy (Ancestors)

Neurofibromatoses; Neurofibroma; Nerve Sheath Neoplasms; Neoplasms, Nerve Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplastic Syndromes, Hereditary; Neurocutaneous Syndromes; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Peripheral Nervous System Diseases; Neuromuscular Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Peripheral Nervous System Neoplasms; Nervous System Neoplasms

Study Officials

• Xin Ni

  Beijing Children's Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 11, 2023
• First Posted: April 24, 2023
• Study Start: August 31, 2023
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): June 30, 2026
• Last Updated: August 14, 2023

Record last verified: 2023-08