A Phase 2b Trial of the MEK 1/2 Inhibitor (MEK) PD-0325901 in Adult and Pediatric Patients with Neurofibromatosis Type 1 (NF1)-Associated Inoperable Plexiform Neurofibromas (PNs) that are Causing Significant Morbidity

Study Description

MEK-NF-201 is a multi-center, open-label, longitudinal, uncontrolled, Phase 2b study to evaluate the efficacy, safety, and tolerability of PD-0325901 in participants ≥ 2 years of age with an inoperable NF1-associated PN that is progressing and/or causing significant morbidity. All participants will have their primary efficacy measure analysis conducted by a blinded central review.

Inclusion Criteria

Participants are eligible to be included in the study only if all of the following criteria apply:

Age

1. Participant must be ≥2 years of age inclusive, at the time of signing the informed consent/assent;

Type of Participant and Disease Characteristics

2. Participants must have EITHER the clinical diagnosis of NF1 using the NIH Consensus Conference criteria of at least 1 other diagnostic criterion (Inclusion 2.1 – 2.6) in addition to the presence of a PN, OR have a constitutional NF1 mutation documented in a Clinical Laboratory Improvement Amendments (CLIA) / College of American Pathologists (CAP) certified lab; additional criteria are as  follows: 2.1. Six or more café-au-lait macules with a diameter >5 mm in prepubertal and >15 mm in postpubertal individuals, respectively; 

Freckling in axilla or inguinal regions; 

• Optic glioma; 
• Two or more Lisch nodules; 
• A distinctive bony lesion (dysplasia of the sphenoid bone or dysplasia of thinning of long bone cortex); 
• A first degree relative with NF1;

3. Participants must have PN that is progressive (Inclusion 3) OR causing significant morbidity, such as (but not limited to) head and neck lesions that are compromising the airway or great vessels, brachial or lumbar plexus lesions that are causing nerve compression and loss of function, lesions causing major deformity or are significantly disfiguring (Inclusion 3.2), lesions of the extremity that cause limb hypertrophy or loss of function, and painful lesions. Participants with paraspinal plexiform neurofibromas will be eligible for this study. Histologic confirmation of tumor is not necessary in the presence of consistent clinical and radiographic findings but should be considered if malignant degeneration of a PN is clinically suspected;

4. Participant has a PN that is deemed inoperable, defined as a PN that cannot be completely surgically removed without risk for substantial morbidity due to: encasement of or close proximity to vital structures, invasiveness, or high vascularity of the PN, or the participant refuses surgery. Participants who previously underwent surgery for a PN will be eligible to enter the study after the surgery, provided the PN was incompletely resected and is evaluable by volumetric analysis;

5. Participants must have a target PN, defined as the clinically most relevant PN, least 1 measurable PN amenable to volumetric MRI analysis. For the purpose of this study, the target lesion must be seen on at least 3 consecutive MRI slices and the field of view must contain the entire tumor of interest. A target PN must be at least 5 mL in volume; 

6. For participants > 18 years of age, participants must have a PN amenable to a percutaneous biopsy and must be willing to undergo pre-, and on treatment tumor biopsies; there should be no contraindication for serial biopsy;

7. Participant has adequate organ and bone marrow function;

8. Participant has the ability to swallow capsules whole with no gastrointestinal conditions affecting absorption;

9. Participant is willing and able to comply with all aspects of the protocol;

10. Participant must have a body surface area (BSA) of at least 0.4m2 (inclusive) calculated using the Du Bois formula (BSA = 0.007184 × W0.425 × H0.725);

11. Male or Female

Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

a. Male participants:

Male participants are eligible to participate if they agree to the following during the intervention 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

OR

• Must agree to use a male condom when having sexual intercourse with a woman of child bearing potential (WOCBP). Refer to Section X for definition of a WOCPB.

b. Female participants:

Female participants are eligible to participate if they are not pregnant or breastfeeding, and at least one of the following conditions applies: 

• Is not a woman of childbearing potential (WOCBP)

OR

Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), preferably with low user dependency, as described in Section X during the treatment period and for at least 30 days after the last dose of study treatment and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during the study and for a period of 90 days. The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention. 

A 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.