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

Study Overview
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Brief Summary
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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-0325901 by MRI To characterize the pharmacokinetic profile of PD-0325901 when administered to this patient population To evaluate quality of life and pain during treatment with PD-0325901

Detailed Description
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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. Subjects will have retinal screening performed before starting PD-0325901 and regularly while on study drug. Patients with glaucoma, intraocular pressure >21 mmHg, or any other significant abnormality (excluding chronic, stable ophthalmological findings secondary to Optic Pathway Glioma) on ophthalmic examination (performed by an ophthalmologist) will not be eligible. Patients who have received radiation or cytotoxic therapy within 4 weeks of study entry and patients who have received radiation to the orbit at any time previously, will not be eligible for the study. Patients with other concurrent severe and/or uncontrolled medical disease will also be excluded. In addition, pregnant women will not be eligible for enrollment and subjects of reproductive age will be required to practice birth control while on treatment. Subjects entered on the trial will be carefully monitored for the development of PD-0325901 associated toxicities. In all consenting subjects entered on this trial, a complete pharmacokinetic profile of PD-0325901 after administration will be evaluated during course 1. Involvement with this part of the study will be required. Consenting subjects with dermal neurofibromas will have punch biopsies of dermal neurofibromas at two time points to determine if the PD-0325901 is affecting the biologic target. Involvement with this part of the study will be optional. Since plexiform neurofibromas may significantly impact the lives of patients with NF1, this study will evaluate the effects of the disease and treatment with PD-0325901 on the quality of life (QOL) of adolescents and adults. Involvement in this part of the study will be required. The Pediatric Quality of Life Inventory (PedsQL) Neurofibromatosis Type 1 Module will be used to assess the QOL of subjects. The PedsQL NF1 Module is a self-reported disease-specific QOL scale developed for adolescents and adults with NF1. It assesses 16 domains of functioning including physical functioning, emotional functioning, social functioning, cognitive functioning, physical appearance, worry, pain and hurt, fatigue, and daily activities. Preliminary data collected on this scale indicates good reliability and validity in adults. The preliminary data in a small sample of adolescents also looks promising. Data collected from this trial may be used toward validating this instrument since no disease specific QOL measure for NF1 currently exists, but such a tool is critically needed. Pain will be assessed using the Numeric Rating Scale-11 (NRS-11), which is an 11-point self-report scale of pain intensity. In addition, the Brief Pain Inventory Pain Interference Scale is a 7-item self-report questionnaire that measures the extent to which pain interferes with daily functioning. Both of these brief measures have been recommended to assess different aspects of pain in clinical trials. For subjects who respond to PD-0325901 (≥20% tumor volume reduction of target lesion by 12 courses), an MRI scan of the target lesion is requested (but not required) at 4 and 12 months after stopping drug (as long as the subject is still on protocol) in order to determine whether response is maintained post-therapy. These studies will not be requested from subjects who experience disease progression while on study drug. Before the subject can be enrolled, the responsible institutional investigator must sign and date the completed eligibility checklist. The completed eligibility checklist should be faxed to the NF Operations Center to confirm eligibility prior to subject enrollment.

Official Title
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A Phase 2 Trial of the MEK Inhibitor PD-0325901 in Adolescents and Adults With NF1-Associated Morbid Plexiform Neurofibromas

Conditions
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Neurofibromatosis Type 1 and Growing or Symptomatic, Inoperable PN

Intervention / Treatment
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* Drug: PD-0325901


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Agent PD-0325901<br>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<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Participants With a 20% or More Change in Target Tumor Volume | Response is assessed by the NCI-POB at the time that follow-up 3D-MRI scans are performed (after course 4, 8, 12, and then after completion of every 6 courses thereafter). For the purpose of determining the level of response (complete, partial, etc.) measurements from the follow-up scans are compared to the target lesion size in the pretreatment MRI scan using 3D data analysis.Complete Response (CR): A complete resolution of the target plexiform neurofibroma for ≥ 4 weeks Partial Response (PR): A ≥20% reduction in the volume of the target plexiform neurofibroma lesion for ≥4 weeks. Stable Disease (SD): A <20% increase, and < 20% decrease in the volume of the target plexiform neurofibroma lesion for ≥4 weeks. Progressive Disease (PD): A ≥ 20% increase in the volume (by 3D-MRI) of the target plexiform neurofibroma compared to the pretreatment volume.. | baseline to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluable Participants Treated With PD-0325901 | Number of Evaluable Patients at 24 Months: Any subject with ≥ one dose of PD-0325901 and had a ≥ Grade 3 associated toxicity is evaluable for toxicity. In the absence of a ≥ Grade 3 toxicity, any subject who completed one full course of therapy is evaluable for toxicity. Evaluable For Response - Subjects who have completed at least two courses of therapy and have had their first follow-up MRI evaluation. Subjects who did not respond and are later found to have a target tumor other than a plexiform neurofibroma (e.g. malignant peripheral nerve sheath tumor) are not evaluable for response. Evaluable for Pharmacokinetics - Any subject who has at least 4 samples drawn for pharmacokinetics is evaluable for pharmacokinetics. Evaluable for Pharmacodynamics - Any subject who has a dermal neurofibroma biopsy for pharmacodynamics prior to starting therapy plus at least one other dermal neurofibroma biopsy is evaluable for | baseline to 24 months | 
| Toxicity of PD-0325901 | Number and Percent of Participants with AEs and SAEs | Baseline to 24 Months | 
| The Objective Response Rate of up to 2 Non-Target Plexiform Neurofibromas to PD-0325901 | radiographic response based on volumetric MRI measurements of up to 2 Non Target Plexiform Neurofibromas classified as complete, partial, stable or progressive | Baseline to 24 Months | 
| Area Under the Curve for the Parent Compound | Mean and Standard Deviation AUC Estimates of the levels of PD-0325901 over 12-Hours for both the Parent and Metabolite Compound, based on samples at Pre-dose, .5 Hr. Post dose, 1.0 Hr.Post dose, 2.0 Hr.Post dose, 3.0 Hr. Post dose, 4.0 Hr.Post dose, 6.0 Hr. Post dose, 8.0 Hr. Post dose, 10.0-12.0 Hr. Post dose. | Day 1; Course 1 | 
| Quality of Life Using the Pain Subscale of the NRS-11 and PedsQL™ NF1 for Subjects Receiving PD-0325901 Using Age-based Assessments | The PedsQL™ NF1 Module asks how much of a problem each item has been during the past one month. A 5-point response scale: 0= never a problem...4= almost always a problem). Items are reverse scored and linearly transformed to a scale of 0-100 Higher scores = better HRQOL. The total scale score is the sum of items divided by the number answered. Subscale scores are computed similarly. If more than 50% of the items in the scale are missing, the scale score is not computed. The Numerical Rating Scale-11 (NRS-11) is a self-report segmented 11-point numeric scale that assesses pain intensity with 0 representing no pain at the right end of the line and 10 representing worst pain you can imagine. The Brief Pain Inventory (BPI)-Pain Interference Scale is a 7-item self-report questionnaire asking (general activity, mood, walking, normal work, relations with other people, sleep, and enjoyment of life) in the past week with 0 = no interference and 10 = completely interferes. | Baseline to 12 Months | 
| Area Under the Curve for the Metabolite Compound | Mean 12-Hour AUC Estimates of the Parent and Metabolite Compound, based on samples at Pre-dose, .5 Hr. Post dose, 1.0 Hr.Post dose, 2.0 Hr.Post dose, 3.0 Hr. Post dose, 4.0 Hr.Post dose, 6.0 Hr. Post dose, 8.0 Hr. Post dose, 10.0-12.0 Hr. Post dose. | Day 1; Course 1 | 
| Mean Half-Life for the PD-0325901 Concentrations | Half life Estimates of PD-0325901 of the Parent and Metabolite Compound, based on samples at Pre-dose, .5 Hr. Post dose, 1.0 Hr.Post dose, 2.0 Hr.Post dose, 3.0 Hr. Post dose, 4.0 Hr.Post dose, 6.0 Hr. Post dose, 8.0 Hr. Post dose, 10.0-12.0 Hr. Post dose. | Day 1; Course 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neurofibromatosis Type 1 (Neurofibromas), PD-0325901, Radiographic Response, Inoperable Plexiform Neurofibromas