Neurofibromatosis Type 1 and Growing or Symptomatic, Inoperable PNPhase 2MEK InhibitorNCT02096471
MEK Inhibitor PD-0325901 Trial in Adolescents and Adults With NF1
A Phase 2 study testing PD-0325901 in people with Neurofibromatosis Type 1 and Growing or Symptomatic, Inoperable PN, run by University of Alabama at Birmingham at 11 sites in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 16 years and older
- Conditions the study is for
- Neurofibromatosis Type 1 and Growing or Symptomatic, Inoperable PN
- What is being tested?
- PD-0325901
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 19 participants
- Where
- 11 sitesUnited States
- Study dates
- Jun 2014to 1 Aug 2018
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 16 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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.
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- 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
Who cannot join
- 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.
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- 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
Trial locations and contacts
11 sites in 1 country.
11 sites in 1 country
United States11 sites
National Cancer Institute (NCI)
Bethesda, Maryland, 20892
Children's Hospital Boston
Boston, Massachusetts, 02115
University of Chicago
Chicago, Illinois, 60637
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, 45229
Indiana Unversity
Indianapolis, Indiana, 46202
Children's Hospital Los Angeles
Los Angeles, California, 90027
New York University Medical Center
New York, New York, 10016
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, 19096
University of Utah
Salt Lake City, Utah, 84132
Washington University - St. Louis
St Louis, Missouri, 63110
Children's National Medical Center
Washington D.C., District of Columbia, 20010
About this study
Official title: A Phase 2 Trial of the MEK Inhibitor PD-0325901 in Adolescents and Adults With NF1-Associated Morbid Plexiform Neurofibromas
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.
Read more
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
Read the detailed description
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.
- Being tested
- PD-0325901
- Keywords
- Neurofibromatosis Type 1 (Neurofibromas), PD-0325901, Radiographic Response, Inoperable Plexiform Neurofibromas
- Medical subject headings
- Neurofibromatosis 1, Neurofibroma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PD-0325901Drug
| Study group | Role | What they receive |
|---|---|---|
| Agent PD-0325901 | Experimental | 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. Receives: Drug: PD-0325901 |
What is being measured
The primary outcome is the main question the study is designed to answer.
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..
Measured: baseline to 24 months
Secondary outcomes (7)
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
Measured: baseline to 24 months
Toxicity of PD-0325901
Number and Percent of Participants with AEs and SAEs
Measured: 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
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Day 1; Course 1
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Mar 2014 (estimated)
- Study startJun 2014
- Primary completion9 Aug 2017
- Study completion1 Aug 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Neurofibromatosis Type 1 and Growing or Symptomatic, Inoperable PNStudies of the same condition, open and under way.
- More trials run by University of Alabama at BirminghamThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 19 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Alabama at Birmingham
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Bruce Korf, MD, University of Alabama at Birmingham
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02096471
- Sponsor's protocol ID
- WI176190
- Acronym
- MEK Inhibitor
- Status last verified
- Dec 2018
- First submitted
- 12 Mar 2014
- Last updated
- 10 Jan 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Weiss BD, Wolters PL, Plotkin SR, Widemann BC, Tonsgard JH, Blakeley J, Allen JC, Schorry E, Korf B, Robison NJ, Goldman S, Vinks AA, Emoto C, Fukuda T, Robinson CT, Cutter G, Edwards L, Dombi E, Ratner N, Packer R, Fisher MJ. NF106: A Neurofibromatosis Clinical Trials Consortium Phase II Trial of the MEK Inhibitor Mirdametinib (PD-0325901) in Adolescents and Adults With NF1-Related Plexiform Neurofibromas. J Clin Oncol. 2021 Mar 1;39(7):797-806. doi: 10.1200/JCO.20.02220. Epub 2021 Jan 28.
PubMed 33507822
Study at a glance
From the registry record, last updated by the sponsor on 10 Jan 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 2 Trial of the MEK Inhibitor PD-0325901 in Adolescents and Adults With NF1-Associated Morbid Plexiform Neurofibromas
- ClinicalTrials.gov ID
- NCT02096471
- Acronym / sponsor ID
- MEK Inhibitor / WI176190
- Keywords
- Neurofibromatosis Type 1 (Neurofibromas), PD-0325901, Radiographic Response, Inoperable Plexiform Neurofibromas
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 19 participants (actual)
- Lead sponsor
- University of Alabama at BirminghamUniversity, hospital or other
- Study start
- Jun 2014
- Primary completion
- 9 Aug 2017 (actual)
- Study completion
- 1 Aug 2018 (actual)
- First posted
- 26 Mar 2014 (estimated)
- Results
- Posted 10 Jan 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Agent PD-0325901 | Experimental | Drug: PD-0325901The 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. |
Who may qualify
- Ages
- 16 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (25 listed)
- 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:
- 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.
Key exclusion criteria (15 listed)
- 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).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PD-0325901 | Drug | Agent PD-0325901 |
Primary outcome
Percent of Participants With a 20% or More Change in Target Tumor Volume
Time frame: baseline to 24 months
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..
7 secondary outcomes
Evaluable Participants Treated With PD-0325901
Time frame: baseline to 24 months
Toxicity of PD-0325901
Time frame: Baseline to 24 Months
The Objective Response Rate of up to 2 Non-Target Plexiform Neurofibromas to PD-0325901
Time frame: Baseline to 24 Months
Area Under the Curve for the Parent Compound
Time frame: 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
Time frame: Baseline to 12 Months
Area Under the Curve for the Metabolite Compound
Time frame: Day 1; Course 1
Mean Half-Life for the PD-0325901 Concentrations
Time frame: Day 1; Course 1
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Jan 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 33507822Weiss BD, Wolters PL, Plotkin SR, Widemann BC, Tonsgard JH, Blakeley J, Allen JC, Schorry E, Korf B, Robison NJ, Goldman S, Vinks AA, Emoto C, Fukuda T, Robinson CT, Cutter G, Edwards L, Dombi E, Ratner N, Packer R, Fisher MJ. NF106: A Neurofibromatosis Clinical Trials Consortium Phase II Trial of the MEK Inhibitor Mirdametinib (PD-0325901) in Adolescents and Adults With NF1-Related Plexiform Neurofibromas. J Clin Oncol. 2021 Mar 1;39(7):797-806. doi: 10.1200/JCO.20.02220. Epub 2021 Jan 28.
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
11 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing PD-0325901 in people with Neurofibromatosis Type 1 and Growing or Symptomatic, Inoperable PN, run by University of Alabama at Birmingham at 11 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 25 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 10 Jan 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 11 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 10 Jan 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percent of Participants With a 20% or More Change in Target Tumor Volume (time frame: baseline to 24 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02096471, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Jan 2019.