Study to Evaluate the Safety, Tolerability, PK Characteristics and Anti-tumor Activity of FCN-159 in Adult and Pediatric Participants With Neurofibromatosis Type 1

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Brief Title

Study to Evaluate the Safety, Tolerability, PK Characteristics and Anti-tumor Activity of FCN-159 in Adult and Pediatric Participants With Neurofibromatosis Type 1

Official Title

A Multi-center, Open-label, Single-arm Phase I Dose-escalation and Phase II Dose-expansion Study to Evaluate the Safety, Tolerability, PK Characteristics and Anti-tumor Activity of FCN-159 in Adult and Pediatric Participants With Neurofibromatosis Type 1

Brief Summary

      FCN-159 is a highly active MEK1/2 inhibitor that was designed, synthesized and screened on
      the basis of the structure of trametinib. FCN-159 is an orally available and highly potent
      selective inhibitor of MEK1/2, which is expected to be a targeted therapy for the treatment
      of advanced solid tumors and neurofibromatosis type 1.
    


Study Phase

Phase 1/Phase 2

Study Type

Interventional


Primary Outcome

Primary objectives of Phase I


Condition

Neurofibromatosis 1

Intervention

FCN-159

Study Arms / Comparison Groups

 Single Arm
Description:  

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

160

Start Date

August 2021

Completion Date

April 30, 2025

Primary Completion Date

November 30, 2024

Eligibility Criteria

        Inclusion Criteria:

        General inclusion criteria for Phase I and II:

        1.Cohort 1: 16-70 years of age (inclusive) with a body weight of ≥ 94 lbs or 42.5 kg.

        Cohort 2: 2-15 years of age (inclusive) and able to swallow whole tablet. 2.Participants
        must be diagnosed with NF1-related plexiform neurofibromas (PN) and symptomatic with
        requirement of systematic therapy per investigator's judgment. 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. Diagnosis of neurofibromatosis type 1 (NF1) is based
        on meeting at least 1 of the following 2 diagnostic criteria:

          1. Genetic testing confirmation: i.e., positive for NF1 germline mutation per
             CLIA-certified laboratory (or equivalent) testing. Note: NF1 germline mutation
             positive must either be confirmed by the FCN-159-002 central laboratory or have
             documentation of NF1 mutation issued by a CLIA-certified laboratory (or equivalent) -
             OR -

          2. Clinical and imaging confirmation: Meets at least 2 of the following 7 NF1 diagnostic
             criteria according to the clinical NIH consensus criteria:

               1. ≥ 6 cafe-au-lait macules (>0.5 cm in prepubertal participants and > 1.5 cm in
                  post-pubertal participants);

               2. Axillary freckling or freckling in inguinal regions;

               3. ≥2 neurofibromas of any type, or ≥ 1 plexiform neurofibroma;

               4. An optic pathway glioma;

               5. ≥2 Lisch nodules (iris hamartomas);

               6. A distinctive bony lesion such as dysplasia of the sphenoid bone or dysplasia or
                  thinning of long bone cortex);

               7. First-degree relative with NF1. 3. Participants should meet one of the following
                  criteria

               1. Must be judged by the investigator to be inoperable for complete resection
                  without causing substantial damage, or unsuitable for surgery with high surgical
                  risks or patient refuses surgery, e.g. due to encasement of or close proximity to
                  vital structures, invasiveness, or high vascularity. NF1 has to cause or has the
                  potential to cause significant morbidity, 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) or are significantly disfiguring, lesions of
                  the extremity that cause limb hypertrophy or loss of function, and painful
                  lesions.

               2. The participants who have previously received surgical treatment, if the PN
                  resection is incomplete, the postoperative residual exceeds 15% of the primary
                  lesion, or relapse after surgery, and the lesions of at least 3 cm are measured
                  in one dimension, are eligible for enrollment. At least a 28-day interval is
                  required between surgery and the first dose of FCN-159.

                  4. Participants must have a measurable lesion, defined as at least 3 cm in length
                  in at least one dimension, amenable to MRI for efficacy assessment.

                  5. Adult participants: Karnofsky performance level of ≥70%; Pediatric
                  participants: Lansky performance score ≥ 70%, see Appendix 18.

                  Note: Participants who are wheelchair bound because of paralysis secondary to a
                  plexiform neurofibroma should be considered ambulatory when they are in the
                  wheelchair. Similarly, participants with limited mobility secondary to the need
                  for mechanical support (such as an airway PN requiring tracheostomy or CPAP) will
                  also be considered ambulatory for the purposes of this study.

                  6. Coagulation function: International normalized ratio (INR) and activated
                  partial thromboplastin time (APTT) ≤ 1.5 ULN.

                  7. Participants or their legal guardians (if the participant is <18 years old)
                  are able to understand and voluntarily sign a written informed consent form.

                  8. For participants of childbearing potential: participants must agree to take
                  effective contraception, and receive double barrier contraception, condom, oral
                  or injectable contraceptives, intrauterine device and other contraceptive methods
                  during treatment and for at least 90 days after the last dose. Male participants
                  must agree to avoid sperm donation for at least 90 days after the last dose.

                  9. Willing to avoid excessive sun exposure and use adequate amounts of sunscreen
                  if sun exposure is anticipated.

                  Exclusion Criteria:

                  Participants who meet any of the following conditions shall not be included in
                  this clinical study:

                  Exclusion criteria for Phase I and II:

                    1. Participants who have previously received one of the following:

                         1. Chemotherapy for NF1 within 3 months of enrollment. Ongoing side
                            effects of that treatment > Grade 1 (except alopecia).

                         2. Treatment with any drug or biologic therapy within 14 days of starting
                            FCN-159, such as: tipifarnib, pirfenidone, Peg-Interferon, sorafenib or
                            other VEGFR inhibitors

                         3. Strong CYP3A4, CYP2C8 and CYP2C9 inhibitors or inducers (moderate
                            inducers for CYP2C8 and CYP2C9) within 14 days before treatment of the
                            study drug, except for topical skin use.

                         4. Use of growth factors to increase the number or function of platelets
                            or white blood cells within 7 days before administration of FCN-159.

                         5. Radiotherapy, surgery or immunotherapy within 4 weeks before
                            administration of FCN-159.

                         6. Participation in other interventional clinical trials within 4 weeks
                            before administration of FCN-159.

                         7. Prior treatment with selumetinib or any other MEK 1/2 inhibitors
                            (specific for phase 2 part).

                    2. Participants with malignant tumors associated with NF1 requiring
                       chemotherapy, radiotherapy, or surgery, such as intermediate- to high-grade
                       optic gliomas or malignant peripheral nerve sheath tumors.

                    3. Patients have other malignant tumor history or with other malignant tumors
                       simultaneously (excluding cured non-melanoma skin basal cell carcinoma,
                       breast carcinoma in situ or cervix cancer in situ, and other malignant
                       tumors without disease evidence for the past 5 years);

                    4. Participants who are unable to undergo MRI examination and/or for whom MRI
                       examination is contraindicated (e.g., due to prostheses, orthotics or dental
                       appliances or due to interference with volumetric analysis of target PN on
                       MRI).

                    5. Uncontrolled hypertension (despite medical therapy)

                         -  Adult participants: defined as systolic or diastolic blood pressures >
                            140/90 mmHg on repeat examination with existing anti-hypertension
                            therapy.

                         -  Pediatric participants: Blood pressure (BP) greater than or equal to
                            the 95th percentile for age, height, and gender measured as described
                            in (Appendix 19).

                    6. Participants with dysphagia, active digestive diseases, malabsorption
                       syndrome, or other conditions that might affect the absorption of the study
                       drug.

                    7. Previous or current retinal vein occlusion (RVO), retinal pigment epithelial
                       detachments (RPED), glaucoma and other significant abnormality in ophthalmic
                       examination.

                    8. Interstitial pneumonia, including existing clinically significant radiation
                       pneumonitis.

                    9. Cardiac dysfunction or concomitant diseases meeting any one of the following
                       conditions will be excluded:

                         1. Three 12-lead electrocardiogram (ECG) measurements performed at the
                            study site during the screening period for which the mean value of
                            three measurements was calculated according to the QTcF formula using
                            the instrument, with QTcF > 470 milliseconds; Participants with risk
                            factors for QTcF prolongation, such as uncorrectable hypokalemia,
                            hereditary long QT syndrome; or receiving drugs that prolong QTcF
                            interval (mainly class Ia, Ic, III antiarrhythmic drugs). Drugs with
                            potential to prolong QTcF interval, See Appendix 20.

                         2. New York Heart Association (NYHA) Class ≥ 3 congestive heart failure;

                         3. Clinically significant arrhythmia, including but not limited to
                            complete left bundle branch block, second degree atrioventricular
                            block;

                         4. Known concurrent clinically significant coronary artery disease,
                            cardiomyopathy, severe valvular disease.

                         5. Ultrasound Cardiogram performed during the screening showing. Left
                            ventricular ejection fraction LVEF < 50%.

                   10. Participants with active bacterial, fungal or viral infections, including
                       active hepatitis B (hepatitis B virus surface antigen positive and hepatitis
                       B virus DNA > 1000 IU/ml or meeting the study site's diagnostic criteria for
                       active hepatitis B infection), hepatitis C (hepatitis C virus RNA positive),
                       or human immunodeficiency virus infection (HIV positive).

                   11. Pregnant or lactating women.

                   12. Known hypersensitivity to the study drug, other MEK 1/2 inhibitor or its
                       excipients.

                   13. Clinically significant condition that, in the opinion of the investigator,
                       would preclude study participation or compliance with safety requirements.

                   14. Inability to attend in-person appointments per current clinical site COVID
                       19 guidelines and restrictions.
      

Gender

All

Ages

2 Years - 70 Years

Accepts Healthy Volunteers

No

Contacts

, +48608209264, [email protected]



Administrative Informations


NCT ID

NCT04954001

Organization ID

FCN-159-002


Responsible Party

Sponsor

Study Sponsor

Shanghai Fosun Pharmaceutical Development Co, Ltd.


Study Sponsor

, , 


Verification Date

June 2021