Mirdametinib treatment for adults with Neurofibromatosis 1 and skin tumors

A Phase 1/2a Open-label, Multicenter Dose Finding Study to Evaluate the Safety and Anti-tumor Activity of Mirdametinib Monotherapy in Adults With Neurofibromatosis 1 (NF1) and Cutaneous Neurofibromas (cNF).

This study is testing a new treatment called mirdametinib to see if it can help adults with Neurofibromatosis 1 and skin tumors feel better and manage their condition.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 24 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Johns Hopkins University (Academic / other)
• Drugs / interventions: mirdametinib, chemotherapy, radiation
• Locations: 1 site (Baltimore, Maryland)
• Trial ID: NCT06159166 on ClinicalTrials.gov

What this trial studies

This is a Phase 1/2a, open-label, non-randomized study evaluating the safety and efficacy of mirdametinib monotherapy in adults diagnosed with Neurofibromatosis 1 (NF1) and cutaneous neurofibromas (cNF). The study consists of two phases: Phase 1 focuses on determining the safety and identifying the recommended phase 2 dose(s) through multiple dose regimens, while Phase 2a assesses the efficacy and safety of these doses. Participants will undergo screening, treatment, and post-study safety follow-up at the Johns Hopkins University NF1 and cNF specialty center.

Who should consider this trial

Good fit: Ideal candidates for this study are adults aged 18 and older who have a confirmed diagnosis of NF1 and at least 24 measurable cutaneous neurofibromas.

Not a fit: Patients with fewer than 24 measurable cutaneous neurofibromas or those who do not meet the diagnostic criteria for NF1 may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new therapeutic option for adults suffering from NF1 and associated cutaneous neurofibromas.

How similar studies have performed: While this approach is novel in the context of NF1 and cNF, similar studies targeting other conditions with mirdametinib have shown promising results.

Eligibility criteria

Inclusion Criteria:

1. Meet the diagnostic criteria for NF12
2. ≥ 18 years of age
3. Have a minimum of 24 measurable cNF (2 target areas of ≥6 measurable cNF)

   a. Measurable is defined as: i. non-pedunculated (no stalk) ii. surrounded by uninvolved skin and not adjacent to another cNF lesion iii. measuring ≥ 0.5 cm in the longest diameter and ≥ 0.5 cm in height iv. the 24 cNF must be located in two Target Areas. One target area must be located on the back and must have at least 6 measurable cNF. The second target area can be in any of the following body regions with at least 6 cNF: head and neck; upper extremities; anterior chest wall, anterior abdominal wall; pelvic region/gluteal region; lower extremities.
4. Participants must have cNF that meet eligibility criteria located within the two study designated target areas or outside of the target areas amenable to biopsy. If biopsy is taken within the target area there must be a minimum of 6 cNF remaining for long term surveillance after biopsy. Participants must be willing to undergo pre-, and on-treatment tumor biopsies providing fresh tumor tissue; there should be no contraindication for serial biopsy
5. Karnofsky performance level of ≥ 80%.
6. Adequate organ and bone marrow function as defined by the following Screening laboratory values:

   1. Absolute neutrophil count ≥ 1500 cells/µL;
   2. Platelets ≥ 100 x 103/µL;
   3. Hemoglobin ≥ 9.5 g/dL;
   4. Serum albumin ≥ 2.8 g/dL;
   5. Calculated creatinine clearance at Screening ≥ 60 mL/min (by Cockcroft-Gault formula) OR a normal serum creatinine.
7. Participant is willing and able to comply with all aspects of the protocol
8. Ability to understand and the willingness to sign written informed consent document(s).
9. Women of childbearing potential (WOCBP) must not be pregnant or breastfeeding during any portion of the study and must use an adequate method to avoid pregnancy during the study period and for 6 months after treatment conclusion and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during the study and for a period of 6 months after last dose of study treatment. The Investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study treatment (see the Approved Methods of birth control listed below).

   * In order for a woman to be determined not of childbearing potential, she must have ≥ 12 months of non-therapy-induced amenorrhea or be surgically or medically sterile.
   * WOCBP must have a negative serum pregnancy test result at Screening and a negative urine pregnancy test result at the Baseline visit prior to the first dose of study treatment.

     * The Investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
10. Male participants are eligible to participate if they agree to the following during the treatment period and for at least 90 days after the last dose of study treatment:

    * Refrain from donating sperm

PLUS either:

* Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent until 90 days after the last study drug treatment; OR
* Must agree to use a male condom when having sexual intercourse with a WOCBP and their female partner must utilize one the approved methods of birth control below:

Approved Methods of birth control for this study are:

* Total abstinence
* Male or female sterilization (vasectomy in males or surgical removal of ovaries or uterus in females)
* Unsterilized male study participants must use a male condom and their female partner must use one of the methods below:
* Unsterilized female study participants must use one of the following highly effective methods listed below:

Acceptable birth control methods which are considered highly effective if they result in a failure rate of less than 1% per year when used consistently and correctly:

* Combined (estrogen and progestogen containing) hormonal contraceptive that stops the release of eggs from the ovary (oral, intravaginal, or transdermal)
* Progestogen-only hormonal contraception that stops the release of eggs from the ovary (oral, injectable, implantable)
* Intrauterine device (IUD)
* Intrauterine hormone-releasing system (IUS)
* Bilateral tubal occlusion or bilateral tubal ligation

Exclusion Criteria:

1. Participant has a altered screening values:

   1. alanine transaminase (ALT) value of \> 2.0 x upper limit of normal (ULN);
   2. total bilirubin value of \> 1.5 x ULN (isolated bilirubin \> 1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin \< 35%);
2. Participant has a history of malignancy associated hypercalcemia;
3. Participant has an active parathyroid disorder, hyperphosphatemia at Screening (serum phosphorus \> 1 x ULN), or serum calcium (mg/dL) x serum phosphorus (mg/dL) product \> 70 at Screening;
4. Any clinically significant active or known history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones);
5. Hepatitis serology will be tested at Screening. Participants who are hepatitis B surface antigen (HBsAg) positive or hepatitis C virus (HCV) antibody positive at Screening must not be enrolled until further definite testing with hepatitis B virus (HBV) deoxyribonucleic acid (DNA) titers is \< 500 IU/mL or HCV ribonucleic acid (RNA) polymerase chain reaction test is negative;
6. Lymphoma, leukemia, or any malignancy (including malignant glioma or MPNST) within the past 5 years except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 years;
7. Breast cancer within the past 3 years;
8. Active optic glioma or other low-grade glioma requiring treatment with chemotherapy or radiation therapy.

   a. Participants not requiring treatment are eligible. Ophthalmological findings secondary to long-standing optic pathway glioma (such as visual loss, optic nerve pallor or strabismus) or long-standing orbito-temporal PN (such as visual loss, strabismus) will NOT be considered a significant abnormality for the purposes of the study;
9. Abnormal QT interval corrected by Fridericia's formula (\> 450 msec for male participants, \> 470 msec for female participants, or \> 480 msec for participants with known bundle branch block), calculated from triplicate ECG readings taken approximately 2 to 3 minutes apart and averaged at Screening;
10. Participant has experienced any of the following within 6 months (24 weeks) of signing informed consent/assent: clinically significant cardiac disease, myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, cerebrovascular accident, transient ischemic attack, or symptomatic pulmonary embolism;
11. A recorded LVEF \< 55% at screening or within 3 years of signing informed consent/assent, OR has a history of congestive heart failure;
12. Participants with a history of, or evidence of, retinal pathology on ophthalmologic examination that is considered a risk factor for central serous retinopathy, retinal vein occlusion (RVO), or neovascular macular degeneration. Participants will be excluded from study participation if they have any of the following risk factors for RVO at Screening:

    * Intraocular pressure \> 21 mmHg;
    * Serum cholesterol \> 300 mg/dL;
    * Serum triglycerides \> 300 mg/dL;
    * Hyperglycemia (fasting blood glucose \> 125 mg/dL or random blood glucose \> 200 mg/dL);
    * Hypertension (BP ≥ 140/90 mm Hg)
13. History of glaucoma;
14. Known history of a positive human immunodeficiency virus (HIV) antibody test;
15. Known malabsorption syndrome or preexisting gastrointestinal conditions that may impair absorption of mirdametinib (e.g., gastric bypass, lap band, or other gastric procedures). Delivery of mirdametinib via nasogastric tube or gastrostomy tube is not allowed.
16. Previously treated with MEK inhibitor including mirdametinib (PD-0325901) and had to stop treatment due to adverse event.
17. Currently receiving therapy with a MEK inhibitor including mirdametinib (PD-0325901) or treated with a MEK inhibitor in the 12 months prior to prior to first dose of study treatment.
18. Received radiation therapy within the 6 months prior to prior to first dose of study treatment. Participants who have received radiation to the orbit at any time are excluded.
19. Pregnant or breastfeeding women may not take study drug.
20. Current enrollment or past participation in any other clinical study (excluding observational studies) within 28 days of first dose of study treatment.
21. Known sensitivity to the study treatment, or components thereof, or drug or other allergy that, could compromise safety of the subject
22. Participant is receiving systemic (oral, inhaled, of IV/SC) or ocular glucocorticoid therapy (with the exception of participants with endocrine deficiencies who are allowed to receive physiologic or stress doses of steroids, if necessary) within 14 days prior to first dose of study treatment;
23. Participants are excluded if they have severe and/or uncontrolled medical disease or social situation, which could compromise participation in the study (e.g. uncontrolled diabetes, uncontrolled hypertension, severe infection, severe malnutrition, chronic liver or renal disease, active upper GI tract ulceration, congestive heart failure, drug or alcohol dependence, etc.).
24. Participants is receiving systemic treatment of a pan-cytochrom 450 (CYP) inducers such as rifampin or ritonavir within 14-days prior to first dose of study treatment Drug Development and Drug Interactions

Where this trial is running

Baltimore, Maryland

• Johns Hopkins Hospital — Baltimore, Maryland, United States (Recruiting)

Study contacts

• Principal investigator: Carlos Romo, MD — Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Study coordinator: Carlos Romo, MD

Conditions NF1; Cutaneous Neurofibroma; Monotherapy; Mirdametinib