Now Available: Final Rule for FDAAA 801 and NIH Policy on Clinical Trial Reporting

MEK Inhibitor PD-0325901 Trial in Adolescents and Adults With NF1 (MEK Inhibitor)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
University of Alabama at Birmingham
ClinicalTrials.gov Identifier:
NCT02096471
First received: March 12, 2014
Last updated: November 16, 2016
Last verified: March 2016
  Purpose

This phase II open label study will evaluate adolescents (≥ 16 years of age) and adults with neurofibromatosis type-1 (NF1) and plexiform neurofibromas treated with the MEK inhibitor PD-0325901. The primary aim of the study will be to assess quantitative radiographic response in a target lesion. Subjects will receive PD-0325901 by mouth on a bid dosing schedule of 2 mg/m2/dose with a maximum dose of 4 mg bid. Each course is 4 weeks duration, and subjects will receive drug on a 3 week on/1 week off schedule. Subjects may receive additional courses beyond course 8 only if there is at least 15% reduction in volume of the target tumor. Subjects who have a 20% or greater reduction in target tumor volume at the end of 12 courses can continue on therapy for up to an additional year (maximum of 24 total courses). However, subjects who do not achieve at least 15% reduction in volume of the target tumor after 8 courses (~8 months) will be considered treatment failures and taken off study.

The Primary purpose of this protocol is to determine whether PD-0325901 results in objective radiographic responses based on volumetric MRI measurements in adolescents and adults with NF1 and growing or symptomatic inoperable PN.

There are several secondary aims of this protocol:

To evaluate the feasibility and toxicity of chronic PD-0325901 administration in this patient population

To estimate the objective response rate of up to 2 non-target plexiform neurofibromas to PD-0325901by MRI

To characterize the pharmacokinetic profile of PD-0325901 when administered to this patient population

To characterize the pharmacodynamic profile of PD-0325901 when administered to this patient population using dermal neurofibromas as a surrogate for plexiform neurofibroma cells

To characterize the activity of PD-0325901 on neurofibroma cell gene expression

To characterize the activity of PD-0325901 on plasma cytokines and growth factors

To correlate pERK levels to pharmacokinetic data and response

To evaluate quality of life and pain during treatment with PD-0325901

To validate the PedsQL NF1 QOL Module, a disease specific QOL scale, for use in this patient population, and

To determine whether subjects who respond (≥20% objective radiographic response of target lesion by 12 courses) to PD-0325901 will maintain that response for 1 year one they come off therapy


Condition Intervention Phase
Neurofibromatosis Type 1 and Growing or Symptomatic, Inoperable PN
Drug: PD-0325901
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 2 Trial of the MEK Inhibitor PD-0325901 in Adolescents and Adults With NF1-Associated Morbid Plexiform Neurofibromas

Resource links provided by NLM:


Further study details as provided by University of Alabama at Birmingham:

Primary Outcome Measures:
  • The change in tumor size based on radiographic assessment [ Time Frame: baseline to 24 months ] [ Designated as safety issue: No ]
    The Primary purpose of this protocol is to determine whether PD-0325901 results in objective radiographic responses based on volumetric MRI measurements in adolescents and adults with NF1 and growing or symptomatic inoperable PN.


Secondary Outcome Measures:
  • The ability of subjects to adhere to use of protracted PD-0325901 regimen [ Time Frame: baseline to 24 months ] [ Designated as safety issue: Yes ]
    We will evaluate the feasibility of protracted PD-0325901 administration in this patient population by assessing the number of AEs and SAEs experienced by subjects

  • The change in non-target tumor size based on radiographic assessment [ Time Frame: baseline to 24 months ] [ Designated as safety issue: No ]
    We will estimate the objective response rate of up to 2 non-target plexiform neurofibromas to PD-0325901 by MRI.

  • The calculated exposure of drug in subjects receiving PD-0325901 [ Time Frame: at 1 month past baseline ] [ Designated as safety issue: No ]
    We will characterize the pharmacokinetic profile of PD-0325901 when administered to this patient population

  • The change in target proteins using Dermal fibromas as a marker of drug effect. [ Time Frame: 1 month after baseline ] [ Designated as safety issue: No ]
    We will characterize the pharmacodynamics profile of PD-0325901 when administered to this patient population by assaying host tissues (dermal neurofibromas) as a surrogate for plexiform neurofibroma cells before and after drug administration.

  • The activity of PD-0325901 on gene expression [ Time Frame: at 4 months after baseline ] [ Designated as safety issue: No ]
    We will characterize the activity of PD-0325901 on specific neurofibroma cell gene expression

  • The activity of PD-325901 on plasma cytokines and growth factors [ Time Frame: at 4 months after baseline ] [ Designated as safety issue: No ]
    To characterize the activity of PD-0325901 on plasma cytokines and growth factors

  • Relate pERK levels with blood levels of PD-0325901 [ Time Frame: 24 months after baseline ] [ Designated as safety issue: No ]
    We will correlate pERK levels with pharmacokinetic data

  • Quality of Life of subjects receiving PD-0325901 using age-based measurement tools [ Time Frame: up to 24 months post baseline ] [ Designated as safety issue: No ]
    We will assess quality of life and pain in patients on PD-0325901

  • Confirm that the PedsQL NF1 QOL Module is valid in this patient population. [ Time Frame: 36 months after baseline ] [ Designated as safety issue: No ]
    We will validate the PedsQL NF1 QOL Module, a disease specific QOL scale, for use in this patient population

  • The change in tumor size based on radiographic assessment 12 months after going off PD-0325901 for those subjects who respond to drug [ Time Frame: up to 36 months from baseline ] [ Designated as safety issue: No ]
    To determine whether subjects who respond (≥20% objective radiographic response of target lesion by 12 courses) to PD-0325901 will maintain that response for 1 year off therapy

  • The number of Subjects experiencing an SAE after receiving PD-0325901 [ Time Frame: baseline to 24 months ] [ Designated as safety issue: Yes ]
    To evaluate the toxicity of protracted PD-0325901 administration in this patient population by assessing the number of AEs and SAEs experienced by subjects


Enrollment: 19
Study Start Date: June 2014
Estimated Study Completion Date: December 2018
Estimated Primary Completion Date: September 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Agent PD-0325901
The primary aim of the study will be to assess quantitative radiographic response in a target lesion. Subjects will receive PD-0325901 by mouth on a bid dosing schedule of 2 mg/m2/dose with a maximum dose of 4 mg bid. Each course is 4 weeks duration, and subjects will receive drug on a 3 week on/1 week off schedule. Subjects may receive additional courses beyond course 8 only if there is at least 15% reduction in volume of the target tumor. Subjects who have a 20% or greater reduction in target tumor volume at the end of 12 courses can continue on therapy for up to an additional year (maximum of 24 total courses). However, subjects who do not achieve at least 15% reduction in volume of the target tumor after 8 courses (~8 months) will be considered treatment failures and taken off study.
Drug: PD-0325901

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   16 Years and older   (Child, Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • All studies to determine eligibility must be performed within 2 weeks prior to enrollment unless otherwise indicated below. All clinical and laboratory data required for eligibility of a subject must be available in the subject's medical or research record.
  • All subjects must have EITHER the clinical diagnosis of NF1 using the NIH Consensus Conference criteria OR have a constitutional NF1 mutation documented in a CLIA/CAP certified lab.
  • Subjects must have plexiform neurofibroma(s) that are progressive OR are 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 (e.g., orbital lesions) or are significantly disfiguring lesions of the extremity that cause limb hypertrophy or loss of function, and painful lesions. Subjects with paraspinal plexiform neurofibromas will be eligible for this trial. Histologic confirmation of tumor is not necessary in the presence of consistent clinical and radiographic findings
  • For subjects enrolled for tumor progression, progression is defined as:

    • Presence of new plexiform neurofibroma on MRI or CT (documented by comparison with prior MRI or CT), OR
    • A measurable increase in plexiform neurofibroma size (≥ 20% increase in the volume, or a ≥ 13% increase in the product of the two longest perpendicular diameters, or a ≥ 6% increase in the longest diameter) documented by comparison of two scans (MRI or CT) approximately one year or less prior to evaluation for this study.
  • For subjects enrolled for a "major deformity" or "significantly disfiguring" tumor, eligible tumors will be limited to tumors of the head & neck or those on other areas of the body that are unable to be concealed by standard garments. In order to enroll a plexiform neurofibroma for these indications, the Study Chair or Co-Chair must be contacted to review subject eligibility prior to enrollment.
  • Measurable disease: Subjects must have measurable plexiform neurofibroma(s) amenable to volumetric MRI analysis. 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. Tumors must be at least 3 mL in volume (most PNs 3 cm in longest diameter will meet this criteria). If the tumor is <3 cm in longest diameter, the subject may still be eligible. Central review of the MRI of the target plexiform is required prior to enrollment to ensure that the tumor is measurable and amenable to volumetric analysis. After consenting, images will be sent for Central review
  • Age: Subjects must be ≥ 16 years of age at the time of study entry.
  • Durable Power of Attorney: Adults who are unable to provide informed consent will NOT be enrolled on this study.
  • Performance Level: Karnofsky greater than or equal to 50% Note: Subjects who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
  • Prior Therapy: Subjects are only eligible if complete resection of a plexiform neurofibroma with acceptable morbidity is not feasible, or if a subject with surgical option refuses surgery.
  • Subjects who underwent surgery for a progressive plexiform neurofibroma will be eligible to enter the study after the surgery, provided the plexiform neurofibroma was incompletely resected and is evaluable by volumetric analysis.
  • Subjects may have been previously treated for a plexiform neurofibroma or other tumor/malignancy, but must have fully recovered from the acute toxic effects of all prior chemotherapy or radiotherapy prior to entering this study.
  • Myelosuppressive chemotherapy: Must not have received within 4 weeks of entry onto this study.
  • Hematopoietic growth factors: At least 7 days since the completion of therapy with a growth factor that supports platelet, red or white cell number or function.
  • Biologic (anti-neoplastic agent): At least 14 days since the completion of therapy with a biologic agent. These subjects must be discussed with the Study Chair on a case-by-case basis.
  • Investigational Drugs: Subjects must not have received an investigational drug within 4 weeks.
  • Steroids: Subjects with endocrine deficiencies are allowed to receive physiologic or stress doses of steroids if necessary.
  • 6 months from involved field radiation to index plexiform neurofibroma(s); 6 weeks must have elapsed if subject has received radiation to areas outside index plexiform neurofibroma(s). Subjects who have received radiation to the orbit at any time are excluded.
  • Surgery: At least 2 weeks since undergoing any major surgery and must be recovered from effects of surgery.
  • Organ Function Requirements

    • Adequate Bone Marrow Function
    • Adequate Renal Function
    • Adequate Liver Function

Exclusion Criteria:

  • Chronic treatment with systemic steroids or another immunosuppressive agent. Subjects with endocrine deficiencies are allowed to receive physiologic or stress doses of steroids if necessary.
  • Evidence of an active optic glioma or other low-grade glioma, requiring treatment with chemotherapy or radiation therapy. Subjects not requiring treatment are eligible for this protocol.
  • Patients with malignant glioma, malignant peripheral nerve sheath tumor, or other malignancy requiring treatment in the last 12 months.
  • Subjects who have received radiation to the orbit at any time previously
  • Subjects with glaucoma, intraocular pressure >21 mmHg, or any other significant abnormality on ophthalmic examination (performed by an ophthalmologist).
  • Ophthalmological findings secondary to long-standing Optic Pathway Glioma such as optic nerve pallor or strabismus will NOT be considered significant for the purposes of the study.
  • Tumor not able to be reliably evaluated by volumetric analysis.
  • Other concurrent severe and/or uncontrolled medical disease, 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, etc.)
  • Subjects who have an uncontrolled infection.
  • Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of PD-0325901 (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection). A nasogastric tube (NG tube) or gastric tube (G tube) is allowed.
  • Women who are pregnant or breast feeding.
  • Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method during the period they are receiving the study drug and for 3 months thereafter. Abstinence is an acceptable method of birth control. Women of childbearing potential will be given a pregnancy test within 7 days prior to administration of PD-0325901 and must have a negative urine or serum pregnancy test.
  • History of noncompliance to medical regimens.
  • Subjects unwilling to or unable to comply with the protocol, or who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study.
  • Prior treatment with a MEK inhibitor of any kind
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02096471

Locations
United States, California
Children's Hospital Los Angeles
Los Angeles, California, United States, 90027
United States, District of Columbia
Children's National Medical Center
District of Columbia, District of Columbia, United States, 20010
United States, Illinois
University of Chicago
Chicago, Illinois, United States, 60637
United States, Indiana
Indiana Unversity
Indianapolis, Indiana, United States, 46202
United States, Maryland
National Cancer Institute (NCI)
Bethesda, Maryland, United States, 20892
United States, Massachusetts
Children's Hospital Boston
Boston, Massachusetts, United States, 02115
United States, Missouri
Washington University - St. Louis
St. Louis, Missouri, United States, 63110
United States, New York
New York University Medical Center
New York, New York, United States, 10016
United States, Ohio
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States, 45229
United States, Pennsylvania
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19096
United States, Utah
University of Utah
Salt Lake City, Utah, United States, 84132
Sponsors and Collaborators
University of Alabama at Birmingham
  More Information

Responsible Party: University of Alabama at Birmingham
ClinicalTrials.gov Identifier: NCT02096471     History of Changes
Other Study ID Numbers: WI176190 
Study First Received: March 12, 2014
Last Updated: November 16, 2016
Health Authority: United States: Food and Drug Administration
United States: CDMRP US Army Department of Defense
United States: Pfizer, Inc.
United States: Data Safety Monitoring Board (DSMB)
United States: Medical Monitor
United States: UAB IRB of Record

Keywords provided by University of Alabama at Birmingham:
Neurofibromatosis Type 1 (Neurofibromas)
PD-0325901
Radiographic Response
Inoperable Plexiform Neurofibromas

Additional relevant MeSH terms:
Neurofibromatoses
Neurofibroma
Neurofibromatosis 1
Neurofibroma, Plexiform
Nerve Sheath Neoplasms
Neoplasms, Nerve Tissue
Neoplasms by Histologic Type
Neoplasms
Neoplastic Syndromes, Hereditary
Neurocutaneous Syndromes
Nervous System Diseases
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Genetic Diseases, Inborn
Peripheral Nervous System Neoplasms
Nervous System Neoplasms
Peripheral Nervous System Diseases
Neuromuscular Diseases

ClinicalTrials.gov processed this record on December 07, 2016