Trametinib for Neurofibromatosis type 1|Plexiform neurofibroma

Inclusion criteria

• {"criterion_text":"- Patient with (mosaic) NF1\n- Normal hematological function: Hemoglobin (Hb)≥6 mmol/l, absolute neutrophil count (ANC)≥1.5x109/l, and platelets≥100x109/l\n- Normal hepatic function: bilirubin <1.5x the upper limit of normal (UNL), unless gilbert then: bilirubin <3xUNL and AST/ALT <5xUNL\n- Normal renal function: creatinine <1.5xUNL\n- Patients with a clinically significant symptomatic plexiform neurofibroma (PNF), such as (but not limited to) head and neck lesions that could compromise the airway or great vessels, 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) or are significantly disfiguring, lesions of the extremity that cause limb hypertrophy or loss of function, and painful lesions. This will be determined by the treating physician.\n- Signed, written informed consent\n- Age: 18 or higher\n- Karnofsky performance level of ≥70%\n- No standard treatment options = inoperable PNF PNF that cannot be surgically completely removed without risk for substantial morbidity due to invasiveness, high vascularity or encasement of, or close proximity to, vital structures of the PNF.\n- At least one measurable PNF, defined as a well-demarcated lesion of at least 3 cm measured in one dimension.\n- Able to swallow and retain orally administered medication.\n- Female Subjects of Childbearing Potential must have negative pregnancy test within 7 days prior study treatment and agrees to use highly effective contraception"}

Exclusion criteria

• {"criterion_text":"- Prior treatment with MEK inhibitor(s)\n- Risk factors for gastrointestinal perforation, including history of diverticulitis, metastases to the gastrointestinal tract and concomitant use of medications with a recognized risk of gastrointestinal perforation\n- Any evidence of severe or uncontrolled systemic disease, active infection, active bleeding diatheses, or renal transplant, including any patient known to have hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) will be excluded.\n- Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g., inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption.\n- Any serious and/or unstable pre-existing medical disorder, psychiatric disorder, or other conditions that could interfere with subject’s safety\n- Known severe hypersensitivity to trametinib or any excipient of trametinib or history of allergic reactions attributed to compounds of similar chemical or biologic composition to trametinib\n- Pregnant, lactating or actively breastfeeding female subjects\n- Inability to undergo MRI and/or contraindication for MRI examinations\n- History of a malignancy within 5 years of inclusion, except squamous cell carcinoma of the skin, cervical premalignant lesions and other curatively treated malignancy\n- Prior radiotherapy less than 6 weeks prior to enrollment\n- Prior major surgery less than 4 weeks prior to enrollment\n- An investigational agent within the past 30 days\n- Enzyme-inducing anticonvulsants, anti-coagulants (including platelet aggregation inhibitors) or other prohibited medication(s) or requirement for prohibited medications\n- Left ventricular dysfunction, New York Heart Association Class II, III, or IV heart failure, acute coronary syndrome within the past 6 months, clinically significant uncontrolled arrhythmias, and uncontrolled hypertension.\n- A history of retinal vein occlusion (RVO) or predisposing factors for RVO, including uncontrolled glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled diabetes mellitus, or a history of hyperviscosity or hypercoagulability syndromes"}

Primary endpoints

• {"endpoint_text":"- Tumor volume on volumetric MRI analysis","definition_or_measurement_approach":"Measured by volumetric MRI analysis; response defined as a tumor volume decrease from baseline of at least 20% (\"Response to treatment is defined as a tumor volume decrease from baseline of at least 20%, monitored by using volumetric MRI analysis.\")."}

Secondary endpoints

• {"endpoint_text":"- Numeric pain rating scale (NRS-11)","definition_or_measurement_approach":"Patient-reported numeric rating scale (NRS-11)."}
• {"endpoint_text":"- Pain interference (PROMIS)","definition_or_measurement_approach":"Measured using PROMIS pain interference instrument."}
• {"endpoint_text":"- QLQ-SF36","definition_or_measurement_approach":"Health-related quality of life assessed by QLQ-SF36."}
• {"endpoint_text":"- Medical photography","definition_or_measurement_approach":"Standardised medical photography to document disfigurement/lesion appearance."}
• {"endpoint_text":"- Adverse events according to CTCAEv5.0","definition_or_measurement_approach":"Safety assessed by adverse events graded using CTCAE v5.0."}
• {"endpoint_text":"- Time to first significant progression defined as >20% volumetric growth of the index lesion(s)","definition_or_measurement_approach":"Time-to-event measure; progression defined as >20% volumetric growth of index lesion(s) measured by volumetric MRI."}
• {"endpoint_text":"- Incidence of surgical interventions","definition_or_measurement_approach":"Count/incidence of any surgical interventions performed during study treatment period."}

Netherlands

Earliest CTIS Part Ii Submission Date

02-09-2024

Latest Decision Or Authorization Date

06-09-2024

Processing Time Days

4

Number Of Sites

1

Number Of Participants

30

Primary sponsor

Full Name

Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

Netherlands