Trametinib in neurofibromatosis type 1 related symptomatic plexiform neurofibromas

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04], Diseases [C] - Nervous System Diseases [C10]

Decision date (initial)

2024-09-06

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

External identifiers

EU CT number

2024-516593-30-00

EudraCT number

2019-001317-16

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Efficacy, Therapy

To determine whether trametinib can induce shrinkage in plexiform neurofibromas. Response to treatment is defined as a tumor volume decrease from baseline of at least 20%, monitored by using volumetric MRI analysis.

Secondary objectives 4

1. Effect on patient reported outcome measures
2. Effect of trametinib on disfigurement
3. Determine safety and tolerability of trametinib
4. Determine time to progression and incidence of surgical interventions under treatment with trametinib

Conditions and MedDRA coding

Neurofibromatosis type 1

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Patient with (mosaic) NF1
2. 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.
3. Signed, written informed consent
4. Age: 18 or higher
5. Karnofsky performance level of ≥70%
6. 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.
7. At least one measurable PNF, defined as a well-demarcated lesion of at least 3 cm measured in one dimension.
8. Able to swallow and retain orally administered medication.
9. Female Subjects of Childbearing Potential must have negative pregnancy test within 7 days prior study treatment and agrees to use highly effective contraception
10. Normal hematological function: Hemoglobin (Hb)≥6 mmol/l, absolute neutrophil count (ANC)≥1.5x109/l, and platelets≥100x109/l
11. Normal hepatic function: bilirubin <1.5x the upper limit of normal (UNL), unless gilbert then: bilirubin <3xUNL and AST/ALT <5xUNL
12. Normal renal function: creatinine <1.5xUNL

Exclusion criteria 15

1. Prior treatment with MEK inhibitor(s)
2. Inability to undergo MRI and/or contraindication for MRI examinations
3. History of a malignancy within 5 years of inclusion, except squamous cell carcinoma of the skin, cervical premalignant lesions and other curatively treated malignancy
4. Prior radiotherapy less than 6 weeks prior to enrollment
5. Prior major surgery less than 4 weeks prior to enrollment
6. An investigational agent within the past 30 days
7. Enzyme-inducing anticonvulsants, anti-coagulants (including platelet aggregation inhibitors) or other prohibited medication(s) or requirement for prohibited medications
8. 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.
9. 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
10. 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
11. 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.
12. Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g., inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption.
13. Any serious and/or unstable pre-existing medical disorder, psychiatric disorder, or other conditions that could interfere with subject’s safety
14. 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
15. Pregnant, lactating or actively breastfeeding female subjects

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Tumor volume on volumetric MRI analysis

Secondary endpoints 7

1. Numeric pain rating scale (NRS-11)
2. Pain interference (PROMIS)
3. QLQ-SF36
4. Medical photography
5. Adverse events according to CTCAEv5.0
6. Time to first significant progression defined as >20% volumetric growth of the index lesion(s)
7. Incidence of surgical interventions

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)

Sponsor organisation

Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)

Address

Dr. Molewaterplein 40

City

Rotterdam

Postcode

3015 GD

Country

Netherlands

Scientific contact point

Organisation

Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)

Contact name

Christine Noordhoek

Public contact point

Organisation

Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)

Contact name

Christine Noordhoek

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 4 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications